今日の臨床サポート

本態性高血圧症

著者: 苅尾七臣 自治医科大学内科学講座循環器内科学部門

監修: 今井靖 自治医科大学 薬理学講座臨床薬理学部門・内科学講座循環器内科学部門

著者校正/監修レビュー済:2020/12/03
参考ガイドライン:
  1. 日本高血圧学会:高血圧治療ガイドライン2019
  1. 米国心臓病学会(ACC)/米国心臓協会(AHA):2017ACC/AHA高血圧治療ガイドライン
  1. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:1269-1324.
  1. 欧州高血圧学会(ESH)/欧州心臓病学会(ESC):2018ESH/ESC高血圧治療ガイドライン
  1. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39:3021-3104.
患者向け説明資料

概要・推奨   

  1. 24時間自由行動下血圧測定(ABPM)や家庭血圧での診察室外血圧平均値は、診察室での血圧よりも脳梗塞の発生、心筋梗塞の発症とより強い相関があることが知られている。したがって、ABPM家庭血圧を参考に治療することが推奨される(推奨度2)
  1. 塩分制限指導で食事の塩分を1g/日減らすごとに血圧が約1mmHg減少し、心血管イベントも減らせることが報告されている。このことより、高血圧患者に塩分制限指導を行うことが推奨される(推奨度1)
  1. 降圧利尿薬を含む降圧薬3剤を用いても目標血圧に達しない状態を「治療抵抗性高血圧」と呼ぶ。治療抵抗性の高血圧患者では二次性高血圧、低アドヒアランスなどの原因を究明することが推奨される(推奨度2)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
苅尾七臣 : 未申告[2021年]
監修:今井靖 : 講演料(第一三共株式会社)[2021年]

改訂のポイント:
  1. 主に日本高血圧学会刊行の高血圧治療ガイドライン2019に基づき、改訂を行った。

病態・疫学・診察

疾患情報  
  1. 日本の高血圧患者は約4,300万人と推定されている。
  1. 高血圧の診断は、複数機会の測定で血圧が高いことを確認し、白衣高血圧を除外することでなされる。
  1. 本態性高血圧症の診断は、二次性高血圧を除外することが大事である。診断後、治療方針の決定のために心血管イベント危険因子と臓器障害を評価し、危険因子を層別化して降圧目標を設定する。
  1. 治療目標は、心血管イベントやそれによる機能障害の発症・進展、死亡を抑制することである。
  1. 病態に応じて降圧目標が設定されている。高リスク高血圧例ほど、厳格な降圧が治療目標の達成に重要である。
問診・診察のポイント  
  1. 血圧値に関する診断では、白衣高血圧を除外することと、仮面高血圧を見逃さないことに留意する。白衣高血圧や仮面高血圧の診断には家庭血圧または24時間自由行動下血圧測定(ABPM)が有効である。

今なら12か月分の料金で14ヶ月利用できます(個人契約、期間限定キャンペーン)

11月30日(火)までにお申込みいただくと、
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文献 

著者: Tine Willum Hansen, Jørgen Jeppesen, Susanne Rasmussen, Hans Ibsen, Christian Torp-Pedersen
雑誌名: Am J Hypertens. 2006 Mar;19(3):243-50. doi: 10.1016/j.amjhyper.2005.09.018.
Abstract/Text BACKGROUND: Information on the relationship between ambulatory blood pressure (BP) and cardiovascular disease in the general population is sparse.
METHODS: Prospective study of a random sample of 1700 Danish men and women, aged 41 to 72 years, without major cardiovascular diseases. At baseline, ambulatory BP, office BP, and other risk factors were recorded. The end point was a combined end point consisting of cardiovascular mortality, ischemic heart disease, and stroke.
RESULTS: After a mean follow-up of 9.5 years, 156 end points were recorded. In multivariate models, the relative risk (95% confidence interval) associated with increments of 10/5 mmHg of systolic/diastolic ambulatory BP were 1.35 (1.21-1.50) and 1.27 (1.16-1.39). The corresponding figures for office BP were 1.18 (1.09-1.29) and 1.11 (1.03-1.19). Compared with normotension (office BP <140/90 mm Hg; daytime BP <135/85 mm Hg) the relative risks associated with isolated office hypertension (office BP >/=140/90 mm Hg; daytime BP <135/85 mm Hg), isolated ambulatory hypertension (office BP <140/90 mm Hg; daytime BP >/=135/85 mm Hg), and sustained hypertension (office BP >/=140/90 mm Hg; daytime BP >/=135/85 mm Hg) were 0.66 (0.30-1.44), 1.52 (0.91-2.54), and 2.10 (1.45-3.06), respectively. A blunted BP decrease at night was a risk factor (P = .02) in subjects with daytime ambulatory hypertension, but not in subjects with daytime ambulatory normotension (P = .13).
CONCLUSIONS: Ambulatory BP provided prognostic information about cardiovascular disease better than office BP. Isolated office hypertension was not a risk factor and isolated ambulatory hypertension tended to be associated with increased risk. A blunted BP decrease at night was a risk factor in subjects with daytime ambulatory hypertension.

PMID 16500508  Am J Hypertens. 2006 Mar;19(3):243-50. doi: 10.1016/j.a・・・
著者: José R Banegas, Luis M Ruilope, Alejandro de la Sierra, Ernest Vinyoles, Manuel Gorostidi, Juan J de la Cruz, Gema Ruiz-Hurtado, Julián Segura, Fernando Rodríguez-Artalejo, Bryan Williams
雑誌名: N Engl J Med. 2018 Apr 19;378(16):1509-1520. doi: 10.1056/NEJMoa1712231.
Abstract/Text BACKGROUND: Evidence for the influence of ambulatory blood pressure on prognosis derives mainly from population-based studies and a few relatively small clinical investigations. This study examined the associations of blood pressure measured in the clinic (clinic blood pressure) and 24-hour ambulatory blood pressure with all-cause and cardiovascular mortality in a large cohort of patients in primary care.
METHODS: We analyzed data from a registry-based, multicenter, national cohort that included 63,910 adults recruited from 2004 through 2014 in Spain. Clinic and 24-hour ambulatory blood-pressure data were examined in the following categories: sustained hypertension (elevated clinic and elevated 24-hour ambulatory blood pressure), "white-coat" hypertension (elevated clinic and normal 24-hour ambulatory blood pressure), masked hypertension (normal clinic and elevated 24-hour ambulatory blood pressure), and normotension (normal clinic and normal 24-hour ambulatory blood pressure). Analyses were conducted with Cox regression models, adjusted for clinic and 24-hour ambulatory blood pressures and for confounders.
RESULTS: During a median follow-up of 4.7 years, 3808 patients died from any cause, and 1295 of these patients died from cardiovascular causes. In a model that included both 24-hour and clinic measurements, 24-hour systolic pressure was more strongly associated with all-cause mortality (hazard ratio, 1.58 per 1-SD increase in pressure; 95% confidence interval [CI], 1.56 to 1.60, after adjustment for clinic blood pressure) than the clinic systolic pressure (hazard ratio, 1.02; 95% CI, 1.00 to 1.04, after adjustment for 24-hour blood pressure). Corresponding hazard ratios per 1-SD increase in pressure were 1.55 (95% CI, 1.53 to 1.57, after adjustment for clinic and daytime blood pressures) for nighttime ambulatory systolic pressure and 1.54 (95% CI, 1.52 to 1.56, after adjustment for clinic and nighttime blood pressures) for daytime ambulatory systolic pressure. These relationships were consistent across subgroups of age, sex, and status with respect to obesity, diabetes, cardiovascular disease, and antihypertensive treatment. Masked hypertension was more strongly associated with all-cause mortality (hazard ratio, 2.83; 95% CI, 2.12 to 3.79) than sustained hypertension (hazard ratio, 1.80; 95% CI, 1.41 to 2.31) or white-coat hypertension (hazard ratio, 1.79; 95% CI, 1.38 to 2.32). Results for cardiovascular mortality were similar to those for all-cause mortality.
CONCLUSIONS: Ambulatory blood-pressure measurements were a stronger predictor of all-cause and cardiovascular mortality than clinic blood-pressure measurements. White-coat hypertension was not benign, and masked hypertension was associated with a greater risk of death than sustained hypertension. (Funded by the Spanish Society of Hypertension and others.).

PMID 29669232  N Engl J Med. 2018 Apr 19;378(16):1509-1520. doi: 10.10・・・
著者: Guillaume Bobrie, Gilles Chatellier, Nathalie Genes, Pierre Clerson, Laurent Vaur, Bernard Vaisse, Joël Menard, Jean-Michel Mallion
雑誌名: JAMA. 2004 Mar 17;291(11):1342-9. doi: 10.1001/jama.291.11.1342.
Abstract/Text CONTEXT: Blood pressure (BP) measurement in clinicians' offices with a mercury sphygmomanometer has numerous drawbacks. In contrast, the use of home BP measurement improves measurement precision and reproducibility. However, data about its prognostic value are lacking.
OBJECTIVE: To assess the prognostic value of home vs office BP measurement by general practitioners in a European population of elderly patients being treated for hypertension.
DESIGN, SETTING, AND PARTICIPANTS: Office and home BP and cardiac risk factors were measured at baseline in a cohort of 4939 treated hypertensive patients (mean age, 70 [SD, 6.5] years; 48.9% men) who were recruited and followed up by their usual general practitioners without specific recommendations about their management. The cohort was then followed up for a mean of 3.2 (SD, 0.5) years. The thresholds defining uncontrolled hypertension were at least 140/90 mm Hg for office BP and 135/85 mm Hg for home BP.
MAIN OUTCOME MEASURES: The primary end point was cardiovascular mortality. Secondary end points were total mortality and the combination of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, hospitalization for angina or heart failure, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft surgery.
RESULTS: At the end of follow-up, clinical status was known for 99.9% of patients. At least 1 cardiovascular event had occurred in 324 (incidence, 22.2/1000 patient-years). For BP self-measurement at home, each 10-mm Hg increase in systolic BP increased the risk of a cardiovascular event by 17.2% (95% confidence interval [CI], 11.0%-23.8%) and each 5-mm Hg increase in diastolic BP increased that risk by 11.7% (95% CI, 5.7%-18.1%). Conversely, for the same increase in BP observed using office measurement, there was no significant increase in the risk of a cardiovascular event. In a multivariable model with patients having controlled hypertension (normal home and office BP) as the referent, the hazard ratio of cardiovascular events was 1.96 (95% CI, 1.27-3.02) in patients with uncontrolled hypertension (high BP with both measurement methods), 2.06 (95% CI, 1.22-3.47) in patients with normal office BP and elevated home BP, and 1.18 (95% CI, 0.67-2.10) in patients with elevated office BP and normal home BP.
CONCLUSIONS: Our findings suggest that home BP measurement has a better prognostic accuracy than office BP measurement. Blood pressure should systematically be measured at home in patients receiving treatment for hypertension.

PMID 15026401  JAMA. 2004 Mar 17;291(11):1342-9. doi: 10.1001/jama.291・・・
著者: Kazuomi Kario, Ikuo Saito, Toshio Kushiro, Satoshi Teramukai, Yusuke Ishikawa, Yoshihiro Mori, Fumiaki Kobayashi, Kazuyuki Shimada
雑誌名: Hypertension. 2014 Nov;64(5):989-96. doi: 10.1161/HYPERTENSIONAHA.114.04262. Epub 2014 Aug 25.
Abstract/Text UNLABELLED: This study aimed to investigate the relationship between on-treatment morning home blood pressure (HBP) and incidence of cardiovascular events using data from the Home Blood Pressure Measurement With Olmesartan Naive Patients to Establish Standard Target Blood Pressure (HONEST) study, a prospective observational study of 21 591 outpatients with essential hypertension (mean age, 64.9 years; women, 50.6%) enrolled between 2009 and 2010 at clinics and hospitals in Japan. They received olmesartan-based treatment throughout. The primary end point was major cardiovascular events. After a mean follow-up period of 2.02 years, cardiovascular events occurred in 280 patients (incidence, 6.46/1000 patient-years). The risk for the primary end point was significantly higher in patients with on-treatment morning HBP ≥145 to <155 mm Hg (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.12-2.99) and ≥155 mm Hg (HR, 5.03; 95% CI, 3.05-8.31) than <125 mm Hg and with on-treatment clinic blood pressure ≥150 to <160 mm Hg (HR, 1.69; 95% CI, 1.10-2.60) and ≥160 mm Hg (HR, 4.38; 95% CI, 2.84-6.75) than <130 mm Hg. Morning HBP associated with minimum risk was 124 mm Hg by spline regression analysis. Cardiovascular risk was increased in patients with morning HBP ≥145 mm Hg and clinic blood pressure <130 mm Hg (HR, 2.47; 95% CI, 1.20-5.08) compared with morning HBP <125 mm Hg and clinic blood pressure <130 mm Hg. In conclusion, it is essential to control morning HBP to <145 mm Hg, even in patients with controlled clinic blood pressure.
CLINICAL TRIAL REGISTRATION URL: http://www.umin.ac.jp/ctr/index.htm. UMIN Clinical Trials Registry, trial No. UMIN000002567.

© 2014 American Heart Association, Inc.
PMID 25156169  Hypertension. 2014 Nov;64(5):989-96. doi: 10.1161/HYPER・・・
著者: Satoshi Hoshide, Yuichiro Yano, Hajime Haimoto, Kayo Yamagiwa, Kiyoshi Uchiba, Shoichiro Nagasaka, Yoshio Matsui, Akira Nakamura, Motoki Fukutomi, Kazuo Eguchi, Joji Ishikawa, Kazuomi Kario, J-HOP Study Group
雑誌名: Hypertension. 2016 Jul;68(1):54-61. doi: 10.1161/HYPERTENSIONAHA.116.07201. Epub 2016 May 9.
Abstract/Text UNLABELLED: Our aim is to determine the optimal time schedule for home blood pressure (BP) monitoring that best predicts stroke and coronary artery disease in general practice. The Japan Morning Surge-Home Blood Pressure (J-HOP) study is a nationwide practice-based study that included 4310 Japanese with a history of or risk factors for cardiovascular disease, or both (mean age, 65 years; 79% used antihypertensive medication). Home BP measures were taken twice daily (morning and evening) over 14 days at baseline. During a mean follow-up of 4 years (16 929 person-years), 74 stroke and 77 coronary artery disease events occurred. Morning systolic BP (SBP) improved the discrimination of incident stroke (C statistics, 0.802; 95% confidence interval, 0.692-0.911) beyond traditional risk factors including office SBP (0.756; 0.646-0.866), whereas the changes were smaller with evening SBP (0.764; 0.653-0.874). The addition of evening SBP to the model (including traditional risk factors plus morning SBP) significantly reduced the discrimination of incident stroke (C statistics difference, -0.008; 95% confidence interval: -0.015 to -0.008; P=0.03). The category-free net reclassification improvement (0.3606; 95% confidence interval, 0.1317-0.5896), absolute integrated discrimination improvement (0.015; SE, 0.005), and relative integrated discrimination improvement (58.3%; all P<0.01) with the addition of morning SBP to the model (including traditional risk factors) were greater than those with evening SBP and with combined morning and evening SBP. Neither morning nor evening SBP improved coronary artery disease risk prediction. Morning home SBP itself should be evaluated to ensure best stroke prediction in clinical practice, at least in Japan. This should be confirmed in the different ethnic groups.
CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN000000894.

© 2016 American Heart Association, Inc.
PMID 27160200  Hypertension. 2016 Jul;68(1):54-61. doi: 10.1161/HYPERT・・・
著者: Satoshi Hoshide, Yuichiro Yano, Hiroyuki Mizuno, Hiroshi Kanegae, Kazuomi Kario
雑誌名: Hypertension. 2018 Jan;71(1):177-184. doi: 10.1161/HYPERTENSIONAHA.117.10385. Epub 2017 Nov 13.
Abstract/Text We assessed the relationship between day-by-day home blood pressure (BP) variability and incident cardiovascular disease (CVD) in clinical practice. J-HOP study (Japan Morning Surge-Home Blood Pressure) participants underwent home BP monitoring in the morning and evening for a 14-day period, and their BP levels and BP variability independent of the mean (VIM) were assessed. Incident CVD events included coronary heart disease and stroke. Cox models were fitted to assess the home BP variability-CVD risk association. Among 4231 participants (mean±SD age, 64.9±10.9 years; 53.3% women; 79.1% taking antihypertensive medication), mean (SD) home systolic BP (SBP) levels over time and VIMSBP were 134.2 (14.3) and 6.8 (2.5) mm Hg, respectively. During a 4-year follow-up period (16 750.3 person-years), 148 CVD events occurred. VIMSBP was associated with CVD risk (hazard ratio per 1-SD increase, 1.32; 95% confidence interval [CI], 1.15-1.52), independently of mean home SBP levels over time and circulating B-type natriuretic peptide levels or urine albumin-to-creatinine ratio. Adding VIMSBP to the CVD prediction model improved the discrimination (C statistic, 0.785 versus 0.770; C statistic difference, 0.015; 95% CI, 0.003-0.028). Changes in continuous net reclassification improvement (0.259; 95% CI, 0.052-0.537), absolute integrated discrimination improvement (0.010; 95% CI, 0.003-0.016), and relative integrated discrimination improvement (0.104; 95% CI, 0.037-0.166) were also observed with the addition of VIMSBP to the CVD prediction models. In addition to the assessments of mean home SBP levels and cardiovascular end-organ damage, home BP variability measurements may provide a clinically useful distinction between high- and low-risk groups among Japanese outpatients.

© 2017 American Heart Association, Inc.
PMID 29133364  Hypertension. 2018 Jan;71(1):177-184. doi: 10.1161/HYPE・・・
著者: Grace Ma, Norman Sabin, Martin Dawes
雑誌名: CMAJ. 2008 Feb 26;178(5):585-9. doi: 10.1503/cmaj.070975.
Abstract/Text BACKGROUND: The measurement of blood pressure is a common clinical exam with important health consequences. We sought to determine whether the measurement of blood pressure over a sleeved arm varies from that taken on a bare arm.
METHODS: We recruited 376 patients between 18 and 85 years of age from a family medicine clinic between September 2004 and November 2006. They all had their blood pressure recorded using the same automatic oscillometric device, with the cuff placed over their bare arms for the first reading. Each patient was then randomly assigned to either the bare-arm group, for which the second blood pressure reading was also taken on a bare arm, or the sleeved-arm group, for which the second reading was taken with the cuff placed over the patient's sleeve.
RESULTS: The mean age of the 376 participants was 61.6 years (standard deviation 15.0), 61% of the participants were male, 41% had hypertension and 11.7% had diabetes. We found no clinically important differences between the bare-arm group (n = 180) and the sleeved-arm group (n = 196) in age, sex or body mass index. The mean differences between the first and second readings for patients in the bare-arm group were 4.1 mm Hg (95% confidence interval [CI] 2.8 to 5.5) for systolic blood pressure and 0.1 mm Hg (95% CI -0.7 to 0.9) for diastolic blood pressure. The mean differences between the first and second readings for patients in the sleeved-arm group were 3.4 mm Hg (95% CI 2.1 to 4.7) for systolic blood pressure and 0.4 mm Hg (95% CI -0.4 to 1.3) for diastolic blood pressure. The between-group differences in these values was 0.76 mm Hg (95% CI -1.13 to 2.65) for systolic and -0.31 mm Hg (95% CI -1.48 to 0.86) for diastolic blood pressure; neither of these differences was clinically important or statistically significant.
INTERPRETATION: We found that there was no significant difference in blood pressure recorded over a sleeve or on a bare arm. For practical purposes, the decision to measure blood pressure on a bare arm or over a sleeved arm should be left to the judgment of the health care professional taking the blood pressure.

PMID 18299548  CMAJ. 2008 Feb 26;178(5):585-9. doi: 10.1503/cmaj.07097・・・
著者: Thomas G Pickering, Daichi Shimbo, Donald Haas
雑誌名: N Engl J Med. 2006 Jun 1;354(22):2368-74. doi: 10.1056/NEJMra060433.
Abstract/Text
PMID 16738273  N Engl J Med. 2006 Jun 1;354(22):2368-74. doi: 10.1056/・・・
著者: Thomas G Pickering, Kazuo Eguchi, Kazuomi Kario
雑誌名: Hypertens Res. 2007 Jun;30(6):479-88. doi: 10.1291/hypres.30.479.
Abstract/Text Masked hypertension is defined as a normal blood pressure (BP) in the clinic or office (<140/90 mmHg), but an elevated BP out of the clinic (ambulatory daytime BP or home BP>135/85 mmHg). It may occur in as many as 10% of the general population, and is important because it is not diagnosed by routine medical examinations, but carries an adverse prognosis, both in terms of increased target organ damage and cardiovascular events. Possible characteristics of individuals with masked hypertension are: relatively young age, male sex, stress or increased physical activity during the daytime, and smoking or drinking habits. Masked hypertension has also been described in treated hypertensive patients (in whom the prognosis is worse than predicted from the clinic pressure) and in children, in whom it may be a precursor of sustained hypertension. It may be suspected in individuals who have a history of occasional high BP readings, but who are apparently normotensive when checked in the office. One practical point is that we should continue to follow such people rather than dismissing them, and encourage out-of-clinic monitoring of BP. This would apply particularly to smokers and those with BP in the prehypertensive range. The potential implications of masked hypertension are huge, but the optimal strategy for detecting the condition in the general population is not yet clear.

PMID 17664850  Hypertens Res. 2007 Jun;30(6):479-88. doi: 10.1291/hypr・・・
著者: T G Pickering, G D James, C Boddie, G A Harshfield, S Blank, J H Laragh
雑誌名: JAMA. 1988 Jan 8;259(2):225-8.
Abstract/Text Twenty-one percent of 292 patients with untreated borderline hypertension (clinic diastolic blood pressures persistently between 90 and 104 mm Hg) were found to have normal daytime ambulatory pressures (defined from a population of normotensive subjects). These patients were defined as having "white coat" hypertension, and they were more likely to be female and younger, to weigh less, and to be more recently diagnosed than patients whose pressure was elevated both in the clinic and during ambulatory monitoring. Patients with white coat hypertension did not show a generalized increase of blood pressure lability, nor an exaggerated pressor response while at work. The phenomenon is more pronounced when blood pressure is measured by a physician than by a technician. In such patients, the pressor response may be relatively specific to the physician's office and lead to significant misclassification of hypertension.

PMID 3336140  JAMA. 1988 Jan 8;259(2):225-8.
著者: A M Sinclair, C G Isles, I Brown, H Cameron, G D Murray, J W Robertson
雑誌名: Arch Intern Med. 1987 Jul;147(7):1289-93.
Abstract/Text The prevalence, reversibility, and mortality of secondary hypertension among 3783 patients with moderately severe nonmalignant hypertension attending the Glasgow (Scotland) Blood Pressure Clinic were assessed. Underlying causes of hypertension were found in 297 patients (7.9%). Eighty-seven patients (2.3%) were considered to have a potentially reversible cause for their hypertension, including the oral contraceptive pill (38 patients), renovascular disease (27 patients), and primary hyperaldosteronism (ten patients), but of these only 33 patients (0.9% of total clinic population) were cured by specific intervention. Two hundred ten patients (5.6%) had irreversible renal parenchymal disease and significantly higher mortality than men and women with other causes of hypertension. Excess deaths in the renal group were attributed to renal failure (International Classification of Diseases [ICD] 580 to 589) and vascular causes (ICD 390 to 458) but not to cancer (ICD 140 to 208; 235 to 239) or other nonvascular disease. These results suggest that investigation of hypertension for an underlying cause will reveal a small number of patients with treatable disorders, of whom only a few will be cured by specific intervention, and a moderate number with irreversible disease who are at high risk of myocardial infarction and stroke.

PMID 3606286  Arch Intern Med. 1987 Jul;147(7):1289-93.
著者: J S Williams, G H Williams, A Raji, X Jeunemaitre, N J Brown, P N Hopkins, P R Conlin
雑誌名: J Hum Hypertens. 2006 Feb;20(2):129-36. doi: 10.1038/sj.jhh.1001948.
Abstract/Text Screening for primary hyperaldosteronism (PHA) is often indicated in individuals with resistant hypertension or hypokalaemia. However, in the far larger subset of the hypertensive population who do not fit into these criteria, the evidence for screening is conflicting and dependent on the disease prevalence. The purpose of this study was to examine the prevalence of PHA in a large population with mild to moderate hypertension and without hypokalaemia using a carefully controlled study protocol including a normotensive control population. Hypertensive subjects underwent medication washout and both hypertensive and normotensive subjects placed on a high-sodium diet prior to biochemical and haemodynamic testing. Study specific cutoff values were based on results from the normotensive population studied under identical conditions. A screening test (serum aldosterone/PRA ratio [ARR]>25 with a serum aldosterone level >8 ng/dl) was followed by a confirmatory test (urine aldosterone excretion rate [AER] >17 microg/24 h) to demonstrate evidence of PHA. An elevated ARR with a concomitant elevated serum aldosterone was present in 26 (7.5%) individuals. Of these, 11 (3.2%) had an elevated AER, consistent with evidence of PHA. Individuals with PHA had higher blood pressure and lower serum potassium levels while on a high-sodium diet. Sodium restriction neutralized these differences between PHA and essential hypertensives. The prevalence of PHA in this mild to moderate hypertensive population without hypokalaemia is at most 3.2%, a rate that might lead to excessive false positives with random screening in comparable populations. Hyperaldosteronism, when present, is responsive to sodium restriction.

PMID 16292348  J Hum Hypertens. 2006 Feb;20(2):129-36. doi: 10.1038/sj・・・
著者: T Nishikawa, M Omura
雑誌名: Biomed Pharmacother. 2000 Jun;54 Suppl 1:83s-85s.
Abstract/Text We studied 1,020 patients with hypertension visiting our outpatient clinic during a five-year period, from 1995 until 1999. Those subjects were screened by determining plasma renin activity (PRA) and plasma aldosterone concentration (PAC) after testing routine laboratory examinations in order to differentiate secondary hypertension from essential hypertension. All patients with low-reninemic hypertension were examined by furosemide plus the upright test. This led to an increase in diagnoses of primary aldosteronism (PA) (confirmed by captopril-loading test). Our studies demonstrated that the incidence of PA is 5.4%, and also that the plasma potassium level is not always beneficial for suspecting the presence of PA, because 28% of the patients with PA show only hypokalemia. We would like to emphasize that adrenal venous sampling plays a critical role in establishing the optimal management for patients with PA, because CT imaging is limited to detection of adrenal masses.

PMID 10914999  Biomed Pharmacother. 2000 Jun;54 Suppl 1:83s-85s.
著者: Michael Stowasser, Richard D Gordon
雑誌名: Mol Cell Endocrinol. 2004 Mar 31;217(1-2):33-9. doi: 10.1016/j.mce.2003.10.006.
Abstract/Text Once considered rare, primary aldosteronism (PAL) is now regarded as the commonest potentially curable and specifically treatable form of hypertension. At Greenslopes Hospital Hypertension Unit (GHHU), the decision in 1991 to screen all (and not just hypokalemic or resistant) hypertensives by aldosterone/renin ratio (ARR) testing led to a 10-fold increase in detection rate of PAL and four-fold increase in removal rate of aldosterone-producing adenomas (APAs). The GHHU/Princess Alexandra Hospital Hypertension Unit PAL series stands at 977 patients and 250 APAs removed with hypertension cured in 50-60% (remainder improved). Reliable detection requires that interfering medications are withdrawn (or their effects considered) before ARR measurement, and reliable methods (such as fludrocortisone suppression testing) to confirm PAL. Adrenal venous sampling is the only dependable way to differentiate APA from bilateral adrenal hyperplasia. Genetic testing has facilitated detection of glucocorticoid-remediable, familial PAL. Identification of mutations causing the more common familial variety described by GHHU in 1991 should further aid in detection of PAL.

PMID 15134798  Mol Cell Endocrinol. 2004 Mar 31;217(1-2):33-9. doi: 10・・・
著者: P O Lim, R T Jung, T M MacDonald
雑誌名: Br J Clin Pharmacol. 1999 Nov;48(5):756-60.
Abstract/Text AIMS: Aldosterone/renin ratio is an index for inappropriate aldosterone activity, and it is increasingly being used to screen for primary aldosteronism within the hypertensive population. It may also be a good index to help predict the response to spironolactone. To assess the blood pressure response to oral spironolactone in hypertensive patients with primary aldosteronism identified with raised aldosterone to renin ratio.
METHODS: We conducted a prospective cohort study of hypertensive patients with raised aldosterone/renin ratio, who failed to suppress plasma aldosterone with salt loading and fludrocortisone suppression test. These patients were treated with spironolactone and were followed-up for a period of up to 3 years.
RESULTS: We studied 28 (12 male) subjects with a mean age of 55 (s.d. 10) years who were followed up for a mean period of 12.9 (7) months. At baseline, the patients were taking a mean of 2.1 (1.2) antihypertensive drugs, but despite this 16/28 (57%) had diastolic BP >90 mmHg, 39% with systolic BP >160 mmHg. After commencing spironolactone, three patients complained of breast tenderness but continued treatment and one patient was intolerant of spironolactone and had to stop treatment. Of the remaining 27 patients, the mean number of antihypertensive drugs used dropped to spironolactone plus 0.7 (s.d. 0.9). All but one patient (96%) achieved a diastolic BPCONCLUSIONS: Spironolactone was a highly effective antihypertensive agent in hypertensive patients who had a raised aldosterone/renin ratio. As a raised ratio was highly predictive of nonsuppression of plasma aldosterone suggesting primary aldosteronism, it might be worthwhile using spironolactone in this subgroup of hypertensive patients with raised aldosterone/renin ratios, provided that adrenal adenomas are excluded with imaging techniques.

PMID 10594479  Br J Clin Pharmacol. 1999 Nov;48(5):756-60.
著者: Kazuomi Kario
雑誌名: Hypertens Res. 2009 Jun;32(6):428-32. doi: 10.1038/hr.2009.56.
Abstract/Text Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for hypertension and cardiovascular disease. OSAS is the frequent underlying disease of secondary hypertension and resistant hypertension. OSAS increases both daytime and night-time ambulatory blood pressures through the activation of various neurohumoral factors including the sympathetic nervous system and the renin-angiotensin-aldosterone system. In particular, OSAS predominantly increases ambulatory BP during sleep compared with the awake period, with the result that OSAS is likely to be associated with the non-dipping pattern (diminished nocturnal BP fall) or riser pattern (higher sleep BP than awake BP) of nocturnal BP. An additional characteristic of ABP in OSAS is increased BP variability. The newly developed non-invasive hypoxia-trigger BP-monitoring system detected marked midnight BP surges (ranging from around 10 to 100 mm Hg) during sleep in OSAS patients. The exaggerated BP surge may trigger OSAS-related cardiovascular events occurring during sleep. Clinically, as nocturnal hypoxia is the determinant of morning minus evening BP difference (ME difference), OSAS should be strongly suspected when morning BP cannot be controlled <135/85 mm Hg with increased ME difference even by the specific antihypertensive medications targeting morning hypertension such as bedtime dosing of antihypertensive drugs. Understanding the characteristics of OSAS-related hypertension is essentially important to achieve perfect BP control over a 24-h period, including the sleep period, for more effective prevention of cardiovascular disease.

PMID 19494815  Hypertens Res. 2009 Jun;32(6):428-32. doi: 10.1038/hr.2・・・
著者: SPRINT Research Group, Jackson T Wright, Jeff D Williamson, Paul K Whelton, Joni K Snyder, Kaycee M Sink, Michael V Rocco, David M Reboussin, Mahboob Rahman, Suzanne Oparil, Cora E Lewis, Paul L Kimmel, Karen C Johnson, David C Goff, Lawrence J Fine, Jeffrey A Cutler, William C Cushman, Alfred K Cheung, Walter T Ambrosius
雑誌名: N Engl J Med. 2015 Nov 26;373(22):2103-16. doi: 10.1056/NEJMoa1511939. Epub 2015 Nov 9.
Abstract/Text BACKGROUND: The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain.
METHODS: We randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.
RESULTS: At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). All-cause mortality was also significantly lower in the intensive-treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P=0.003). Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive-treatment group than in the standard-treatment group.
CONCLUSIONS: Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01206062.).

PMID 26551272  N Engl J Med. 2015 Nov 26;373(22):2103-16. doi: 10.1056・・・
著者: Akira Okayama, Takashi Kadowaki, Tomonori Okamura, Takehito Hayakawa, Hirotsugu Ueshima, NIPPON DATA80 Research Group
雑誌名: J Hypertens. 2006 Mar;24(3):459-62. doi: 10.1097/01.hjh.0000209981.43983.cf.
Abstract/Text OBJECTIVE: To clarify the relationship between mortality due to cardiovascular diseases (CVD) and systolic blood pressure (SBP) and diastolic blood pressure (DBP) in young and elderly Japanese men in the absence of antihypertensive treatments.
DESIGN: A 19-year cohort study using the 1980 National Survey of Cardiovascular Diseases and the identification of the underlying causes of death using national vital statistics data.
METHODS: In 1999, a 19-year follow-up study was conducted among participants randomly selected from the Japanese population for the 1980 National Survey of Cardiovascular Diseases. Among the male participants that were not receiving antihypertensive treatment, information was obtained for about 91.3% of the subjects (n = 3779). Age-adjusted mortality rates using the person-year method were calculated to compare the relationships of SBP and DBP levels with CVD mortality for different age groups (aged 30-64, 65-74, and 75 years or more).
RESULTS: The total number of observed person-years was 64 598 and the number of CVD-related deaths after 19 years was 253. Both SBP and DBP levels were significantly and linearly related to CVD mortality in the age groups 30-64 years (P < 0.001 and P = 0.01, respectively) and 65-74 years (P < 0.001 and P = 0.03, respectively). In the group of participants that were at least 75 years old, however, no significant increase in the relative risk of CVD was observed with increasing DBP levels (P = 0.156), whereas the relative risk of CVD increased significantly with increasing SBP levels (P = 0.038). Multivariate analysis adjusting for major risk factors confirmed these relationships. Standardized hazard ratios (95% confidence intervals) of SBP were 1.53 (1.19-1.96) for 30-64 year olds, 1.70 (1.31-2.20) for 64-74 year olds, and 1.23 (1.03-1.47) for participants 75 years old or more, whereas those of DBP were 1.52 (1.12-2.06), 1.60 (1.21-2.10), and 1.10 (0.94-1.28), respectively.
CONCLUSIONS: These data show that elevated SBP is an independent risk factor for CVD mortality for Japanese men of all ages, whereas elevated DBP is not an independent risk factor for CVD mortality for elderly men.

PMID 16467648  J Hypertens. 2006 Mar;24(3):459-62. doi: 10.1097/01.hjh・・・
著者: Michelle C Odden, Carmen A Peralta, Mary N Haan, Kenneth E Covinsky
雑誌名: Arch Intern Med. 2012 Aug 13;172(15):1162-8. doi: 10.1001/archinternmed.2012.2555.
Abstract/Text BACKGROUND: The association of hypertension and mortality is attenuated in elderly adults. Walking speed, as a measure of frailty, may identify which elderly adults are most at risk for the adverse effects of hypertension. We hypothesized that elevated blood pressure (BP) would be associated with a greater risk of mortality in faster-, but not slower-, walking older adults.
METHODS: Participants included 2340 persons 65 years and older in the National Health and Nutrition Examination Survey, 1999-2000 and 2001-2002. Mortality data were linked to death certificates in the National Death Index. Walking speed was measured over a 20-ft (6 m) walk and classified as faster (≥ 0.8 m/s [n = 1307]), slower (n = 790), or incomplete (n = 243). Potential confounders included age, sex, race, survey year, lifestyle and physiologic variables, health conditions, and antihypertensive medication use.
RESULTS: Among the participants, there were 589 deaths through December 31, 2006. The association between BP and mortality varied by walking speed. Among faster walkers, those with elevated systolic BP (≥ 140 mm Hg) had a greater adjusted risk of mortality compared with those without (hazard ratio [HR], 1.35; 95% CI, 1.03-1.77). Among slower walkers, neither elevated systolic nor diastolic BP (≥ 90 mm Hg) was associated with mortality. In participants who did not complete the walk test, elevated BP was strongly and independently associated with a lower risk of death: HR, 0.38; 95% CI, 0.23-0.62 (systolic); and HR, 0.10; 95% CI, 0.01-0.81 (diastolic).
CONCLUSIONS: Walking speed could be a simple measure to identify elderly adults who are most at risk for adverse outcomes related to high BP.

PMID 22801930  Arch Intern Med. 2012 Aug 13;172(15):1162-8. doi: 10.10・・・
著者: L Hansson, A Zanchetti, S G Carruthers, B Dahlöf, D Elmfeldt, S Julius, J Ménard, K H Rahn, H Wedel, S Westerling
雑誌名: Lancet. 1998 Jun 13;351(9118):1755-62.
Abstract/Text BACKGROUND: Despite treatment, there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension.
METHODS: 18790 patients, from 26 countries, aged 50-80 years (mean 61.5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure < or =90 mm Hg, 6264 to < or =85 mm Hg, and 6262 to < or =80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo.
FINDINGS: Diastolic blood pressure was reduced by 20.3 mm Hg, 22.3 mm Hg, and 24.3 mm Hg, in the < or =90 mm Hg, < or =85 mm Hg, and < or =80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group < or =80 mm Hg compared with target group < or =90 mm Hg (p for trend=0.005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0.03) and all myocardial infarction by 36% (p=0.002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0.001).
INTERPRETATION: Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events. The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg. Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction. There was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common.

PMID 9635947  Lancet. 1998 Jun 13;351(9118):1755-62.
著者:
雑誌名: BMJ. 1998 Sep 12;317(7160):713-20.
Abstract/Text OBJECTIVE: To determine whether tight control of blood pressure with either a beta blocker or an angiotensin converting enzyme inhibitor has a specific advantage or disadvantage in preventing the macrovascular and microvascular complications of type 2 diabetes.
DESIGN: Randomised controlled trial comparing an angiotensin converting enzyme inhibitor (captopril) with a beta blocker (atenolol) in patients with type 2 diabetes aiming at a blood pressure of <150/<85 mm Hg.
SETTING: 20 hospital based clinics in England, Scotland, and Northern Ireland.
SUBJECTS: 1148 hypertensive patients with type 2 diabetes (mean age 56 years, mean blood pressure 160/94 mm Hg). Of the 758 patients allocated to tight control of blood pressure, 400 were allocated to captopril and 358 to atenolol. 390 patients were allocated to less tight control of blood pressure.
MAIN OUTCOME MEASURES: Predefined clinical end points, fatal and non-fatal, related to diabetes, death related to diabetes, and all cause mortality. Surrogate measures of microvascular and macrovascular disease included urinary albumin excretion and retinopathy assessed by retinal photography.
RESULTS: Captopril and atenolol were equally effective in reducing blood pressure to a mean of 144/83 mm Hg and 143/81 mm Hg respectively, with a similar proportion of patients (27% and 31%) requiring three or more antihypertensive treatments. More patients in the captopril group than the atenolol group took the allocated treatment: at their last clinic visit, 78% of those allocated captopril and 65% of those allocated atenolol were taking the drug (P<0.0001). Captopril and atenolol were equally effective in reducing the risk of macrovascular end points. Similar proportions of patients in the two groups showed deterioration in retinopathy by two grades after nine years (31% in the captopril group and 37% in the atenolol group) and developed clinical grade albuminuria >=300 mg/l (5% and 9%). The proportion of patients with hypoglycaemic attacks was not different between groups, but mean weight gain in the atenolol group was greater (3.4 kg v 1.6 kg).
CONCLUSION: Blood pressure lowering with captopril or atenolol was similarly effective in reducing the incidence of diabetic complications. This study provided no evidence that either drug has any specific beneficial or deleterious effect, suggesting that blood pressure reduction in itself may be more important than the treatment used.

PMID 9732338  BMJ. 1998 Sep 12;317(7160):713-20.
著者: ACCORD Study Group, William C Cushman, Gregory W Evans, Robert P Byington, David C Goff, Richard H Grimm, Jeffrey A Cutler, Denise G Simons-Morton, Jan N Basile, Marshall A Corson, Jeffrey L Probstfield, Lois Katz, Kevin A Peterson, William T Friedewald, John B Buse, J Thomas Bigger, Hertzel C Gerstein, Faramarz Ismail-Beigi
雑誌名: N Engl J Med. 2010 Apr 29;362(17):1575-85. doi: 10.1056/NEJMoa1001286. Epub 2010 Mar 14.
Abstract/Text BACKGROUND: There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., <120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events.
METHODS: A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years.
RESULTS: After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001).
CONCLUSIONS: In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. (ClinicalTrials.gov number, NCT00000620.)

2010 Massachusetts Medical Society
PMID 20228401  N Engl J Med. 2010 Apr 29;362(17):1575-85. doi: 10.1056・・・
著者: Sripal Bangalore, Sunil Kumar, Iryna Lobach, Franz H Messerli
雑誌名: Circulation. 2011 Jun 21;123(24):2799-810, 9 p following 810. doi: 10.1161/CIRCULATIONAHA.110.016337. Epub 2011 May 31.
Abstract/Text BACKGROUND: Most guidelines for treatment of hypertension recommend a blood pressure (BP) goal of <140/90 mm Hg, and a more aggressive goal of <130/80 mm Hg for patients with diabetes mellitus. However, in the recent Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, a lower BP was not beneficial. The optimal BP target in subjects with diabetes mellitus or those with impaired fasting glucose/glucose tolerance is therefore not well defined.
METHODS AND RESULTS: We performed PUBMED, EMBASE, and CENTRAL searches for randomized clinical trials from 1965 through October 2010 of antihypertensive therapy in patients with type 2 diabetes mellitus or impaired fasting glucose/impaired glucose tolerance that enrolled at least 100 patients with achieved systolic BP of ≤ 135 mm Hg in the intensive BP control group and ≤ 140 mm Hg in the standard BP control group, had a follow-up of at least 1 year, and evaluated macrovascular or microvascular events. We identified 13 randomized clinical trials enrolling 37 736 participants. Intensive BP control was associated with a 10% reduction in all-cause mortality (odds ratio, 0.90; 95% confidence interval, 0.83 to 0.98), a 17% reduction in stroke, and a 20% increase in serious adverse effects, but with similar outcomes for other macrovascular and microvascular (cardiac, renal, and retinal) events compared with standard BP control. The results were similar in a sensitivity analysis using a bayesian random-effects model. More intensive BP control (≤ 130 mm Hg) was associated with a greater reduction in stroke, but did not reduce other events. Meta-regression analysis showed continued risk reduction for stroke to a systolic BP of <120 mm Hg. However, at levels <130 mm Hg, there was a 40% increase in serious adverse events with no benefit for other outcomes.
CONCLUSIONS: The present body of evidence suggests that in patients with type 2 diabetes mellitus/impaired fasting glucose/impaired glucose tolerance, a systolic BP treatment goal of 130 to 135 mm Hg is acceptable. However, with more aggressive goals (<130 mm Hg), we observed target organ heterogeneity in that the risk of stroke continued to fall, but there was no benefit regarding the risk of other macrovascular or microvascular (cardiac, renal and retinal) events, and the risk of serious adverse events even increased.

PMID 21632497  Circulation. 2011 Jun 21;123(24):2799-810, 9 p followin・・・
著者: SPS3 Study Group, O R Benavente, C S Coffey, R Conwit, R G Hart, L A McClure, L A Pearce, P E Pergola, J M Szychowski
雑誌名: Lancet. 2013 Aug 10;382(9891):507-15. doi: 10.1016/S0140-6736(13)60852-1. Epub 2013 May 29.
Abstract/Text BACKGROUND: Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown. We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke.
METHODS: In this randomised open-label trial, eligible patients lived in North America, Latin America, and Spain and had recent, MRI-defined symptomatic lacunar infarctions. Patients were recruited between March, 2003, and April, 2011, and randomly assigned, according to a two-by-two multifactorial design, to a systolic-blood-pressure target of 130-149 mm Hg or less than 130 mm Hg. The primary endpoint was reduction in all stroke (including ischaemic strokes and intracranial haemorrhages). Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00059306.
FINDINGS: 3020 enrolled patients, 1519 in the higher-target group and 1501 in the lower-target group, were followed up for a mean of 3·7 (SD 2·0) years. Mean age was 63 (SD 11) years. After 1 year, mean systolic blood pressure was 138 mm Hg (95% CI 137-139) in the higher-target group and 127 mm Hg (95% CI 126-128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0·81, 95% CI 0·64-1·03, p=0·08), disabling or fatal stroke (0·81, 0·53-1·23, p=0·32), and the composite outcome of myocardial infarction or vascular death (0·84, 0·68-1·04, p=0·32) with the lower target. The rate of intracerebral haemorrhage was reduced significantly (0·37, 0·15-0·95, p=0·03). Treatment-related serious adverse events were infrequent.
INTERPRETATION: Although the reduction in stroke was not significant, our results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial.
FUNDING: National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS).

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23726159  Lancet. 2013 Aug 10;382(9891):507-15. doi: 10.1016/S014・・・
著者: Kazunori Toyoda, Masahiro Yasaka, Shinichiro Uchiyama, Takehiko Nagao, Jun Gotoh, Ken Nagata, Yukihiro Koretsune, Tomohiro Sakamoto, Kazunori Iwade, Masahiro Yamamoto, Jun C Takahashi, Kazuo Minematsu, Bleeding with Antithrombotic Therapy (BAT) Study Group
雑誌名: Stroke. 2010 Jul;41(7):1440-4. doi: 10.1161/STROKEAHA.110.580506. Epub 2010 May 20.
Abstract/Text BACKGROUND AND PURPOSE: A prospective, multicenter, observational cohort study was conducted to clarify the association between major bleeding events and blood pressure (BP) levels during follow-up before development of bleeding events in antithrombotic users.
METHODS: A total of 4009 patients taking oral antithrombotic agents for cardiovascular or cerebrovascular diseases (2728 men, 69+/-10 years old) were followed. Changes in systolic and diastolic BPs between entry and the last clinic visit before intracranial hemorrhage (ICH) or extracranial hemorrhage were assessed.
RESULTS: Over a median follow-up of 19 months, ICH developed in 31 patients and extracranial hemorrhage developed in 77. Entry BP levels were similar among patients with ICH, those with extracranial hemorrhage, and those without hemorrhagic events. Both systolic BP and diastolic BP were relatively high during follow-up as compared with the levels at entry in patients with ICH, whereas they showed plateaus in patients with extracranial hemorrhage and patients without hemorrhagic events. Average systolic BP levels between 1 and 6 months (hazard ratio, 1.45; 95% CI, 1.08 to 1.92 per 10-mm Hg increase) and between 7 and 12 months (hazard ratio, 1.47; 95% CI, 1.05 to 2.01) as well as average diastolic BP levels between 7 and 12 months (hazard ratio, 2.05; 95% CI, 1.15 to 3.62) were independently associated with development of ICH after adjustment for established ICH predictors. The optimal cutoff BP level to predict impending risk of ICH was >or=130/81 mm Hg using receiver operating characteristic curve analysis.
CONCLUSIONS: An increase in BP levels during antithrombotic medication was positively associated with development of ICH, suggesting the importance of adequate BP control for avoiding ICH. BP levels did not appear to be associated with extracranial hemorrhage.

PMID 20489173  Stroke. 2010 Jul;41(7):1440-4. doi: 10.1161/STROKEAHA.1・・・
著者: P M Rothwell, S C Howard, J D Spence, Carotid Endarterectomy Trialists' Collaboration
雑誌名: Stroke. 2003 Nov;34(11):2583-90. doi: 10.1161/01.STR.0000094424.38761.56. Epub 2003 Oct 30.
Abstract/Text BACKGROUND AND PURPOSE: Blood pressure lowering in patients with a previous transient ischemic attack (TIA) or stroke reduces the risk of recurrent stroke and coronary vascular events. However, there is uncertainty about the risks and benefits in patients with severe carotid occlusive disease, particularly those with a carotid occlusion or bilateral > or =70% carotid stenosis in whom cerebral perfusion is often impaired and may depend directly on systemic blood pressure. Therefore, we studied the effect of carotid artery disease on the relationship between blood pressure and stroke risk in patients with recent TIA or stroke.
METHODS: We compared the relationship between blood pressure (systolic and diastolic blood pressures, pulse pressure) and stroke risk in TIA and stroke patients with documented stenosis of at least 1 carotid artery [European Carotid Surgery Trial (ECST) and North American Symptomatic Carotid Endarterectomy Trial (NASCET)] with that in TIA and stroke patients with a low prevalence of carotid disease [United Kingdom Transient Ischaemic Attack (UK-TIA) Aspirin Trial]. In ECST and NASCET, we also determined the relationship between blood pressure and stroke risk in patients with unilateral carotid occlusion and patients with bilateral > or =70% carotid stenosis.
RESULTS: Stroke risk on medical treatment increased with blood pressure in ECST and NASCET, but the relationships were less steep than in the UK-TIA trial. The relationship between blood pressure and stroke risk was not affected by the presence of a unilateral carotid occlusion but was significantly affected by the presence of bilateral carotid stenosis > or =70% (interaction: systolic blood pressure, P=0.002; diastolic blood pressure, P=0.03; pulse pressure, P=0.003). In this group, the relationship was inverted because of the high stroke risks at lower blood pressures. This interaction was not present after carotid endarterectomy and was not present for the risk of myocardial infarction.
CONCLUSIONS: The risk of stroke increases with blood pressure in the great majority of patients with symptomatic carotid artery disease, but the relationship is less steep than in other patients with TIA or stroke. The relationship is unaffected by unilateral carotid occlusion alone but is inverted in patients with bilateral > or =70% carotid stenosis, suggesting that aggressive blood pressure lowering may not be advisable in this group. These patients represent only a few percent of all patients with TIA or stroke but have a high risk of recurrent stroke.

PMID 14593126  Stroke. 2003 Nov;34(11):2583-90. doi: 10.1161/01.STR.00・・・
著者: Tanya N Turan, George Cotsonis, Michael J Lynn, Seemant Chaturvedi, Marc Chimowitz, Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) Trial Investigators
雑誌名: Circulation. 2007 Jun 12;115(23):2969-75. doi: 10.1161/CIRCULATIONAHA.106.622464. Epub 2007 May 21.
Abstract/Text BACKGROUND: Many clinicians allow blood pressure to run high in patients with intracranial stenosis to protect against hypoperfusion. We sought to determine whether higher blood pressure decreases the risk of stroke in these patients.
METHODS AND RESULTS: Data on 567 patients in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial were analyzed. Time to ischemic stroke and stroke in the same territory of the stenotic vessel was compared in patients grouped by mean systolic blood pressure (SBP) and mean diastolic blood pressure (DBP) during the study. Additional analyses were based on severity and location of stenosis. Ischemic stroke risk increased with increasing mean SBP and DBP on univariate analysis (P<0.0001, P<0.0001) and after adjustment for risk factors (P=0.0008, P<0.0001). Elevated mean SBP and DBP also resulted in increased risk of stroke in the territory in univariate (P=0.0065, P<0.0001) and adjusted (P=0.0002, P=0.0005) analyses. The increased risk of stroke with increasing SBP was driven largely by patients in the highest SBP group. Patients with moderate (< 70%) stenosis had increased risk of stroke (P<0.0001, P=0.003) and stroke in the territory (P=0.0002, P=0.010) with increased SBP and DBP. Patients with severe (> or = 70%) stenosis had increased risk of stroke and stroke in the territory with elevated DBP (P=0.004, P=0.004).
CONCLUSIONS: In patients with intracranial stenosis, higher blood pressure is associated with increased (not decreased) risk of ischemic stroke and stroke in the territory of the stenotic vessel. These findings argue strongly against the common clinical practice of maintaining high blood pressure in patients with intracranial stenosis.

PMID 17515467  Circulation. 2007 Jun 12;115(23):2969-75. doi: 10.1161/・・・
著者: Karen L Furie, Scott E Kasner, Robert J Adams, Gregory W Albers, Ruth L Bush, Susan C Fagan, Jonathan L Halperin, S Claiborne Johnston, Irene Katzan, Walter N Kernan, Pamela H Mitchell, Bruce Ovbiagele, Yuko Y Palesch, Ralph L Sacco, Lee H Schwamm, Sylvia Wassertheil-Smoller, Tanya N Turan, Deidre Wentworth, American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on Quality of Care and Outcomes Research
雑誌名: Stroke. 2011 Jan;42(1):227-76. doi: 10.1161/STR.0b013e3181f7d043. Epub 2010 Oct 21.
Abstract/Text The aim of this updated statement is to provide comprehensive and timely evidence-based recommendations on the prevention of ischemic stroke among survivors of ischemic stroke or transient ischemic attack. Evidence-based recommendations are included for the control of risk factors, interventional approaches for atherosclerotic disease, antithrombotic treatments for cardioembolism, and the use of antiplatelet agents for noncardioembolic stroke. Further recommendations are provided for the prevention of recurrent stroke in a variety of other specific circumstances, including arterial dissections; patent foramen ovale; hyperhomocysteinemia; hypercoagulable states; sickle cell disease; cerebral venous sinus thrombosis; stroke among women, particularly with regard to pregnancy and the use of postmenopausal hormones; the use of anticoagulation after cerebral hemorrhage; and special approaches to the implementation of guidelines and their use in high-risk populations.

PMID 20966421  Stroke. 2011 Jan;42(1):227-76. doi: 10.1161/STR.0b013e3・・・
著者: Parveen Rashid, Jo Leonardi-Bee, Philip Bath
雑誌名: Stroke. 2003 Nov;34(11):2741-8. doi: 10.1161/01.STR.0000092488.40085.15. Epub 2003 Oct 23.
Abstract/Text BACKGROUND: High blood pressure is a risk factor for stroke recurrence. We assessed the effectiveness of lowering blood pressure in preventing recurrent vascular events in patients with previous stroke or transient ischemic attack.
SUMMARY OF REVIEW: We performed a systematic review and meta-regression of completed randomized controlled trials that investigated the effect of lowering blood pressure on recurrent vascular events in patients with prior ischemic or hemorrhagic stroke or transient ischemic attack. Trials were identified from searches of 3 electronic databases (Cochrane Library, EMBASE, MEDLINE). Seven randomized controlled trials, with 8 comparison groups, were included. Lowering blood pressure or treating hypertension with a variety of antihypertensive agents reduced stroke (odds ratio [OR], 0.76; 95% CI, 0.63 to 0.92), nonfatal stroke (OR, 0.79; 95% CI, 0.65 to 0.95), myocardial infarction (OR, 0.79; 95% CI, 0.63 to 0.98), and total vascular events (OR, 0.79; 95% CI, 0.66 to 0.95). No effect was seen on vascular or all-cause mortality. Heterogeneity was present for several outcomes and was partly related to the class of antihypertensive drugs used; angiotensin-converting enzyme inhibitors and diuretics separately, and especially together, reduced vascular events, while beta-receptor antagonists had no discernable effect. The reduction in stroke was related to the difference in systolic blood pressure between treatment and control groups (P=0.002).
CONCLUSIONS: Evidence from randomized controlled trials supports the use of antihypertensive agents in lowering blood pressure for the prevention of vascular events in patients with previous stroke or transient ischemic attack. Vascular prevention is associated positively with the magnitude by which blood pressure is reduced.

PMID 14576382  Stroke. 2003 Nov;34(11):2741-8. doi: 10.1161/01.STR.000・・・
著者: PROGRESS Collaborative Group
雑誌名: Lancet. 2001 Sep 29;358(9287):1033-41. doi: 10.1016/S0140-6736(01)06178-5.
Abstract/Text BACKGROUND: Blood pressure is a determinant of the risk of stroke among both hypertensive and non-hypertensive individuals with cerebrovascular disease. However, there is uncertainty about the efficacy and safety of blood-pressure-lowering treatments for many such patients. The perindopril protection against recurrent stroke study (PROGRESS) was designed to determine the effects of a blood-pressure-lowering regimen in hypertensive and non-hypertensive patients with a history of stroke or transient ischaemic attack.
METHODS: 6105 individuals from 172 centres in Asia, Australasia, and Europe were randomly assigned active treatment (n=3051) or placebo (n=3054). Active treatment comprised a flexible regimen based on the angiotensin- converting-enzyme inhibitor perindopril (4 mg daily), with the addition of the diuretic indapamide at the discretion of treating physicians. The primary outcome was total stroke (fatal or non-fatal). Analysis was by intention to treat.
FINDINGS: Over 4 years of follow up, active treatment reduced blood pressure by 9/4 mm Hg. 307 (10%) individuals assigned active treatment suffered a stroke, compared with 420 (14%) assigned placebo (relative risk reduction 28% [95% CI 17-38], p<0.0001). Active treatment also reduced the risk of total major vascular events (26% [16-34]). There were similar reductions in the risk of stroke in hypertensive and non-hypertensive subgroups (all p<0.01). Combination therapy with perindopril plus indapamide reduced blood pressure by 12/5 mm Hg and stroke risk by 43% (30-54). Single-drug therapy reduced blood pressure by 5/3 mm Hg and produced no discernable reduction in the risk of stroke.
INTERPRETATION: This blood-pressure-lowering regimen reduced the risk of stroke among both hypertensive and non-hypertensive individuals with a history of stroke or transient ischaemic attack. Combination therapy with perindopril and indapamide produced larger blood pressure reductions and larger risk reductions than did single drug therapy with perindopril alone. Treatment with these two agents should now be considered routinely for patients with a history of stroke or transient ischaemic attack, irrespective of their blood pressure.

PMID 11589932  Lancet. 2001 Sep 29;358(9287):1033-41. doi: 10.1016/S01・・・
著者: Salim Yusuf, Hans-Christoph Diener, Ralph L Sacco, Daniel Cotton, Stephanie Ounpuu, William A Lawton, Yuko Palesch, Reneé H Martin, Gregory W Albers, Philip Bath, Natan Bornstein, Bernard P L Chan, Sien-Tsong Chen, Luis Cunha, Björn Dahlöf, Jacques De Keyser, Geoffrey A Donnan, Conrado Estol, Philip Gorelick, Vivian Gu, Karin Hermansson, Lutz Hilbrich, Markku Kaste, Chuanzhen Lu, Thomas Machnig, Prem Pais, Robin Roberts, Veronika Skvortsova, Philip Teal, Danilo Toni, Cam VanderMaelen, Thor Voigt, Michael Weber, Byung-Woo Yoon, PRoFESS Study Group
雑誌名: N Engl J Med. 2008 Sep 18;359(12):1225-37. doi: 10.1056/NEJMoa0804593. Epub 2008 Aug 27.
Abstract/Text BACKGROUND: Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood pressure with a renin-angiotensin system inhibitor soon after a stroke has not been clearly established. We evaluated the effects of therapy with an angiotensin-receptor blocker, telmisartan, initiated early after a stroke.
METHODS: In a multicenter trial involving 20,332 patients who recently had an ischemic stroke, we randomly assigned 10,146 to receive telmisartan (80 mg daily) and 10,186 to receive placebo. The primary outcome was recurrent stroke. Secondary outcomes were major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure) and new-onset diabetes.
RESULTS: The median interval from stroke to randomization was 15 days. During a mean follow-up of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval [CI], 0.86 to 1.04; P=0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P=0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P=0.10).
CONCLUSIONS: Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. (ClinicalTrials.gov number, NCT00153062.)

2008 Massachusetts Medical Society
PMID 18753639  N Engl J Med. 2008 Sep 18;359(12):1225-37. doi: 10.1056・・・
著者: Hisatomi Arima, John Chalmers, Mark Woodward, Craig Anderson, Anthony Rodgers, Stephen Davis, Stephen Macmahon, Bruce Neal, PROGRESS Collaborative Group
雑誌名: J Hypertens. 2006 Jun;24(6):1201-8. doi: 10.1097/01.hjh.0000226212.34055.86.
Abstract/Text OBJECTIVE: To explore the likely optimum blood pressure (BP) level for patients with a history of cerebrovascular disease.
METHODS: The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a randomized, placebo-controlled trial that established the beneficial effects of BP lowering in 6105 patients with cerebrovascular disease. The present study comprises two series of post hoc analyses. The first was designed to investigate the effects of randomized treatment on recurrent stroke by baseline BP levels, and the second was a corresponding observational analysis investigating the association between achieved follow-up BP levels and recurrent stroke risk.
RESULTS: Analyses of the randomized treatment comparisons showed that BP lowering with combination therapy produced similar risk reductions in each of four subgroups defined by baseline BP of less than 120, 120-139, 140-159, and 160 mmHg or greater (P homogeneity = 0.5). The effects of single-drug therapy were also comparable across these subgroups (P homogeneity = 0.2), but consistently greater benefits were observed with combination compared to single-drug therapy. The analyses of achieved follow-up BP showed that the lowest risk of recurrence was among the one-quarter of participants with the lowest follow-up BP levels (median 112/72 mmHg), and that risks rose progressively with higher follow-up BP levels. Minor side-effects were progressively more common at lower BP levels (P homogeneity = 0.04), but there was no excess of serious complications (all P homogeneity > 0.2).
CONCLUSION: These analyses provide no evidence of a J-curve relationship between BP level and stroke risk among patients with cerebrovascular disease, and identify no patient group among whom more intensive BP lowering would not be expected to produce greater risk reductions.

PMID 16685221  J Hypertens. 2006 Jun;24(6):1201-8. doi: 10.1097/01.hjh・・・
著者: K M Fox, EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators
雑誌名: Lancet. 2003 Sep 6;362(9386):782-8.
Abstract/Text BACKGROUND: Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces the rate of cardiovascular events among patients with left-ventricular dysfunction and those at high risk of such events. We assessed whether the ACE inhibitor perindopril reduced cardiovascular risk in a low-risk population with stable coronary heart disease and no apparent heart failure.
METHODS: We recruited patients from October, 1997, to June, 2000. 13655 patients were registered with previous myocardial infarction (64%), angiographic evidence of coronary artery disease (61%), coronary revascularisation (55%), or a positive stress test only (5%). After a run-in period of 4 weeks, in which all patients received perindopril, 12218 patients were randomly assigned perindopril 8 mg once daily (n=6110), or matching placebo (n=6108). The mean follow-up was 4.2 years, and the primary endpoint was cardiovascular death, myocardial infarction, or cardiac arrest. Analysis was by intention to treat.
FINDINGS: Mean age of patients was 60 years (SD 9), 85% were male, 92% were taking platelet inhibitors, 62% beta blockers, and 58% lipid-lowering therapy. 603 (10%) placebo and 488 (8%) perindopril patients experienced the primary endpoint, which yields a 20% relative risk reduction (95% CI 9-29, p=0.0003) with perindopril. These benefits were consistent in all predefined subgroups and secondary endpoints. Perindopril was well tolerated.
INTERPRETATION: Among patients with stable coronary heart disease without apparent heart failure, perindopril can significantly improve outcome. About 50 patients need to be treated for a period of 4 years to prevent one major cardiovascular event. Treatment with perindopril, on top of other preventive medications, should be considered in all patients with coronary heart disease.

PMID 13678872  Lancet. 2003 Sep 6;362(9386):782-8.
著者: Dena Ettehad, Connor A Emdin, Amit Kiran, Simon G Anderson, Thomas Callender, Jonathan Emberson, John Chalmers, Anthony Rodgers, Kazem Rahimi
雑誌名: Lancet. 2016 Mar 5;387(10022):957-67. doi: 10.1016/S0140-6736(15)01225-8. Epub 2015 Dec 24.
Abstract/Text BACKGROUND: The benefits of blood pressure lowering treatment for prevention of cardiovascular disease are well established. However, the extent to which these effects differ by baseline blood pressure, presence of comorbidities, or drug class is less clear. We therefore performed a systematic review and meta-analysis to clarify these differences.
METHOD: For this systematic review and meta-analysis, we searched MEDLINE for large-scale blood pressure lowering trials, published between Jan 1, 1966, and July 7, 2015, and we searched the medical literature to identify trials up to Nov 9, 2015. All randomised controlled trials of blood pressure lowering treatment were eligible for inclusion if they included a minimum of 1000 patient-years of follow-up in each study arm. No trials were excluded because of presence of baseline comorbidities, and trials of antihypertensive drugs for indications other than hypertension were eligible. We extracted summary-level data about study characteristics and the outcomes of major cardiovascular disease events, coronary heart disease, stroke, heart failure, renal failure, and all-cause mortality. We used inverse variance weighted fixed-effects meta-analyses to pool the estimates.
RESULTS: We identified 123 studies with 613,815 participants for the tabular meta-analysis. Meta-regression analyses showed relative risk reductions proportional to the magnitude of the blood pressure reductions achieved. Every 10 mm Hg reduction in systolic blood pressure significantly reduced the risk of major cardiovascular disease events (relative risk [RR] 0·80, 95% CI 0·77-0·83), coronary heart disease (0·83, 0·78-0·88), stroke (0·73, 0·68-0·77), and heart failure (0·72, 0·67-0·78), which, in the populations studied, led to a significant 13% reduction in all-cause mortality (0·87, 0·84-0·91). However, the effect on renal failure was not significant (0·95, 0·84-1·07). Similar proportional risk reductions (per 10 mm Hg lower systolic blood pressure) were noted in trials with higher mean baseline systolic blood pressure and trials with lower mean baseline systolic blood pressure (all ptrend>0·05). There was no clear evidence that proportional risk reductions in major cardiovascular disease differed by baseline disease history, except for diabetes and chronic kidney disease, for which smaller, but significant, risk reductions were detected. β blockers were inferior to other drugs for the prevention of major cardiovascular disease events, stroke, and renal failure. Calcium channel blockers were superior to other drugs for the prevention of stroke. For the prevention of heart failure, calcium channel blockers were inferior and diuretics were superior to other drug classes. Risk of bias was judged to be low for 113 trials and unclear for 10 trials. Heterogeneity for outcomes was low to moderate; the I(2) statistic for heterogeneity for major cardiovascular disease events was 41%, for coronary heart disease 25%, for stroke 26%, for heart failure 37%, for renal failure 28%, and for all-cause mortality 35%.
INTERPRETATION: Blood pressure lowering significantly reduces vascular risk across various baseline blood pressure levels and comorbidities. Our results provide strong support for lowering blood pressure to systolic blood pressures less than 130 mm Hg and providing blood pressure lowering treatment to individuals with a history of cardiovascular disease, coronary heart disease, stroke, diabetes, heart failure, and chronic kidney disease.
FUNDING: National Institute for Health Research and Oxford Martin School.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 26724178  Lancet. 2016 Mar 5;387(10022):957-67. doi: 10.1016/S014・・・
著者: F J He, G A MacGregor
雑誌名: J Hum Hypertens. 2002 Nov;16(11):761-70. doi: 10.1038/sj.jhh.1001459.
Abstract/Text Two recent meta-analyses of randomised salt reduction trials have concluded that there is little purpose in reducing salt intake in the general population. However, the authors, as with other previous meta-analyses, included trials of very short duration (eg 1 week or less) and trials of acute salt loading followed by abrupt reductions to very low salt intake (eg from 20 to less than 1 g of salt/day). These acute salt loading and salt depletion experiments are known to increase sympathetic tone, and with salt depletion cause a rise in renin release and, thereby, plasma angiotensin II. These trials are not appropriate, therefore, for helping to inform public health policy, which is for a more modest reduction in salt intake, ie, from a usual intake of approximately 10 to approximately 5 g of salt per day over a more prolonged period of time. We carried out a meta-analysis to assess the effect of a modest salt reduction on blood pressure. Our data sources were MEDLINE, EMBASE, Cochrane library, CINAHL, and the reference lists of original and review articles. We included randomised trials with a modest reduction in salt intake and a duration of 4 or more weeks. Meta-analysis, meta-regression, and funnel plots were performed. A total of 17 trials in hypertensives (n=734) and 11 trials in normotensives (n=2220) were included in our study. The median reduction in 24-h urinary sodium excretion was 78 mmol (equivalent to 4.6 g of salt/day) in hypertensives and 74 mmol in normotensives. The pooled estimates of blood pressure fall were 4.96/2.73+/-0.40/0.24 mmHg in hypertensives (P<0.001 for both systolic and diastolic) and 2.03/0.97+/-0.27/0.21 mmHg in normotensives (P<0.001 for both systolic and diastolic). Weighted linear regression analyses showed a dose response between the change in urinary sodium and blood pressure. A reduction of 100 mmol/day (6 g of salt) in salt intake predicted a fall in blood pressure of 7.11/3.88 mmHg (P<0.001 for both systolic and diastolic) in hypertensives and 3.57/1.66 mmHg in normotensive individuals (systolic: P<0.001; diastolic: P<0.05). Our results demonstrate that a modest reduction in salt intake for a duration of 4 or more weeks does have a significant and, from a population viewpoint, important effect on blood pressure in both hypertensive and normotensive individuals. This meta-analysis strongly supports other evidence for a modest and long-term reduction in population salt intake, and would be predicted to reduce stroke deaths immediately by approximately 14% and coronary deaths by approximately 9% in hypertensives, and reduce stroke and coronary deaths by approximately 6 and approximately 4%, in normotensives, respectively.

PMID 12444537  J Hum Hypertens. 2002 Nov;16(11):761-70. doi: 10.1038/s・・・
著者: Yuhei Kawano, Katsuyuki Ando, Hideo Matsuura, Takuya Tsuchihashi, Toshiro Fujita, Hirotsugu Ueshima, Working Group for Dietary Salt Reduction of the Japanese Society of Hypertension
雑誌名: Hypertens Res. 2007 Oct;30(10):879-86. doi: 10.1291/hypres.30.879.
Abstract/Text Salt excess is well known to be involved in the pathophysiology of hypertension, and thus restriction of salt intake is widely recommended for management of the disease. Excessive salt intake induces blood pressure (BP)-dependent as well as -independent progression of cardiovascular disease. Although the human body is considered to be adapted to very low salt intake (0.5-3 g/day), restriction to such a low level of salt intake is extremely difficult to accomplish in developed countries. Significant BP reduction has been reported in large-scale clinical studies in which salt intake was decreased to less than 6 g/day, and the results of a meta-analysis have shown that systolic BP was reduced about 1 mmHg with every decrease in salt intake of 1 g/day in hypertensive subjects. Current guidelines for the treatment of hypertension, including Japanese guidelines, recommend dietary salt reduction to 6 g/day or less in hypertensive patients. However, it appears to be fairly difficult to attain this target of salt intake, especially in Japan. There is thus a need for feasible and effective measures to attain this salt restriction target.

PMID 18049018  Hypertens Res. 2007 Oct;30(10):879-86. doi: 10.1291/hyp・・・
著者: Nancy R Cook, Jeffrey A Cutler, Eva Obarzanek, Julie E Buring, Kathryn M Rexrode, Shiriki K Kumanyika, Lawrence J Appel, Paul K Whelton
雑誌名: BMJ. 2007 Apr 28;334(7599):885-8. doi: 10.1136/bmj.39147.604896.55. Epub 2007 Apr 20.
Abstract/Text OBJECTIVE: To examine the effects of reduction in dietary sodium intake on cardiovascular events using data from two completed randomised trials, TOHP I and TOHP II.
DESIGN: Long term follow-up assessed 10-15 years after the original trial.
SETTING: 10 clinic sites in 1987-90 (TOHP I) and nine sites in 1990-5 (TOHP II). Central follow-up conducted by post and phone.
PARTICIPANTS: Adults aged 30-54 years with prehypertension.
INTERVENTION: Dietary sodium reduction, including comprehensive education and counselling on reducing intake, for 18 months (TOHP I) or 36-48 months (TOHP II).
MAIN OUTCOME MEASURE: Cardiovascular disease (myocardial infarction, stroke, coronary revascularisation, or cardiovascular death).
RESULTS: 744 participants in TOHP I and 2382 in TOHP II were randomised to a sodium reduction intervention or control. Net sodium reductions in the intervention groups were 44 mmol/24 h and 33 mmol/24 h, respectively. Vital status was obtained for all participants and follow-up information on morbidity was obtained from 2415 (77%), with 200 reporting a cardiovascular event. Risk of a cardiovascular event was 25% lower among those in the intervention group (relative risk 0.75, 95% confidence interval 0.57 to 0.99, P=0.04), adjusted for trial, clinic, age, race, and sex, and 30% lower after further adjustment for baseline sodium excretion and weight (0.70, 0.53 to 0.94), with similar results in each trial. In secondary analyses, 67 participants died (0.80, 0.51 to 1.26, P=0.34).
CONCLUSION: Sodium reduction, previously shown to lower blood pressure, may also reduce long term risk of cardiovascular events.

PMID 17449506  BMJ. 2007 Apr 28;334(7599):885-8. doi: 10.1136/bmj.3914・・・
著者: Francis Dumler
雑誌名: J Ren Nutr. 2009 Jan;19(1):57-60. doi: 10.1053/j.jrn.2008.10.006.
Abstract/Text We sought to summarize major recent studies in the field of dietary sodium intake and arterial blood pressure, and discuss the following trials. INTERSALT: Sodium intake correlates with the rise in blood pressure with age, but not with the prevalence of hypertension. The population study identified a minimal impact of sodium intake on blood pressure (0.9 mm Hg/10 mmol difference in salt intake). DASH: This diet induced significant reductions in blood pressure compared with the control diet. Further decreases were observed with DASH and a 50 mmol/day sodium intake. VANGUARD: Blood pressure was inversely related to urinary potassium, calcium and magnesium but not to sodium excretion. TONE: Cardiovascular events were highest in the usual care group (83%) and lowest in the sodium reduction-plus-weight loss group (56%). META-ANALYSIS: A systematic review of 11 long-term controlled randomized trials reported a small decrease (1.1 mm Hg) in median systolic but not diastolic blood pressure with a reduced dietary sodium intake. In conclusion, (1) sodium restriction in hypertensive patients reduces blood pressure, and (2) the long-term impact of reduced salt intake on blood pressure, mortality, and morbidity remains to be defined.

PMID 19121772  J Ren Nutr. 2009 Jan;19(1):57-60. doi: 10.1053/j.jrn.20・・・
著者: Martin J O'Donnell, Salim Yusuf, Andrew Mente, Peggy Gao, Johannes F Mann, Koon Teo, Matthew McQueen, Peter Sleight, Arya M Sharma, Antonio Dans, Jeffrey Probstfield, Roland E Schmieder
雑誌名: JAMA. 2011 Nov 23;306(20):2229-38. doi: 10.1001/jama.2011.1729.
Abstract/Text CONTEXT: The precise relationship between sodium and potassium intake and cardiovascular (CV) risk remains uncertain, especially in patients with CV disease.
OBJECTIVE: To determine the association between estimated urinary sodium and potassium excretion (surrogates for intake) and CV events in patients with established CV disease or diabetes mellitus.
DESIGN, SETTING, AND PATIENTS: Observational analyses of 2 cohorts (N = 28,880) included in the ONTARGET and TRANSCEND trials (November 2001-March 2008 from initial recruitment to final follow-up). We estimated 24-hour urinary sodium and potassium excretion from a morning fasting urine sample (Kawasaki formula). We used restricted cubic spline plots to describe the association between sodium and potassium excretion and CV events and mortality, and to identify reference categories for sodium and potassium excretion. We used Cox proportional hazards multivariable models to determine the association of urinary sodium and potassium with CV events and mortality.
MAIN OUTCOME MEASURES: CV death, myocardial infarction (MI), stroke, and hospitalization for congestive heart failure (CHF).
RESULTS: At baseline, the mean (SD) estimated 24-hour excretion for sodium was 4.77 g (1.61); and for potassium was 2.19 g (0.57). After a median follow-up of 56 months, the composite outcome occurred in 4729 (16.4%) participants, including 2057 CV deaths, 1412 with MI, 1282 with stroke, and 1213 with hospitalization for CHF. Compared with the reference group with estimated baseline sodium excretion of 4 to 5.99 g per day (n = 14,156; 6.3% participants with CV death, 4.6% with MI, 4.2% with stroke, and 3.8% admitted to hospital with CHF), higher baseline sodium excretion was associated with an increased risk of CV death (9.7% for 7-8 g/day; hazard ratio [HR], 1.53; 95% CI, 1.26-1.86; and 11.2% for >8 g/day; HR, 1.66; 95% CI, 1.31-2.10), MI (6.8%; HR, 1.48; 95% CI, 1.11-1.98 for >8 g/day), stroke (6.6%; HR, 1.48; 95% CI, 1.09-2.01 for >8 g/day), and hospitalization for CHF (6.5%; HR, 1.51; 1.12-2.05 for >8 g/day). Lower sodium excretion was associated with an increased risk of CV death (8.6%; HR, 1.19; 95% CI, 1.02-1.39 for 2-2.99 g/day; 10.6%; HR, 1.37; 95% CI, 1.09-1.73 for <2 g/day), and hospitalization for CHF (5.2%; HR, 1.23; 95% CI, 1.01-1.49 for 2-2.99 g/day) on multivariable analysis. Compared with an estimated potassium excretion of less than 1.5 g per day (n = 2194; 6.2% with stroke), higher potassium excretion was associated with a reduced risk of stroke (4.7% [HR, 0.77; 95% CI, 0.63-0.94] for 1.5-1.99 g/day; 4.3% [HR, 0.73; 95% CI, 0.59-0.90] for 2-2.49 g/day; 3.9% [HR, 0.71; 95% CI, 0.56-0.91] for 2.5-3 g/day; and 3.5% [HR, 0.68; 95% CI, 0.49-0.92] for >3 g/day) on multivariable analysis.
CONCLUSIONS: The association between estimated sodium excretion and CV events was J-shaped. Compared with baseline sodium excretion of 4 to 5.99 g per day, sodium excretion of greater than 7 g per day was associated with an increased risk of all CV events, and a sodium excretion of less than 3 g per day was associated with increased risk of CV mortality and hospitalization for CHF. Higher estimated potassium excretion was associated with a reduced risk of stroke.

PMID 22110105  JAMA. 2011 Nov 23;306(20):2229-38. doi: 10.1001/jama.20・・・
著者: Katarzyna Stolarz-Skrzypek, Tatiana Kuznetsova, Lutgarde Thijs, Valérie Tikhonoff, Jitka Seidlerová, Tom Richart, Yu Jin, Agnieszka Olszanecka, Sofia Malyutina, Edoardo Casiglia, Jan Filipovský, Kalina Kawecka-Jaszcz, Yuri Nikitin, Jan A Staessen, European Project on Genes in Hypertension (EPOGH) Investigators
雑誌名: JAMA. 2011 May 4;305(17):1777-85. doi: 10.1001/jama.2011.574.
Abstract/Text CONTEXT: Extrapolations from observational studies and short-term intervention trials suggest that population-wide moderation of salt intake might reduce cardiovascular events.
OBJECTIVE: To assess whether 24-hour urinary sodium excretion predicts blood pressure (BP) and health outcomes.
DESIGN, SETTING, AND PARTICIPANTS: Prospective population study, involving 3681 participants without cardiovascular disease (CVD) who are members of families that were randomly enrolled in the Flemish Study on Genes, Environment, and Health Outcomes (1985-2004) or in the European Project on Genes in Hypertension (1999-2001). Of 3681 participants without CVD, 2096 were normotensive at baseline and 1499 had BP and sodium excretion measured at baseline and last follow-up (2005-2008).
MAIN OUTCOME MEASURES: Incidence of mortality and morbidity and association between changes in BP and sodium excretion. Multivariable-adjusted hazard ratios (HRs) express the risk in tertiles of sodium excretion relative to average risk in the whole study population.
RESULTS: Among 3681 participants followed up for a median 7.9 years, CVD deaths decreased across increasing tertiles of 24-hour sodium excretion, from 50 deaths in the low (mean, 107 mmol), 24 in the medium (mean, 168 mmol), and 10 in the high excretion group (mean, 260 mmol; P < .001), resulting in respective death rates of 4.1% (95% confidence interval [CI], 3.5%-4.7%), 1.9% (95% CI, 1.5%-2.3%), and 0.8% (95% CI, 0.5%-1.1%). In multivariable-adjusted analyses, this inverse association retained significance (P = .02): the HR in the low tertile was 1.56 (95% CI, 1.02-2.36; P = .04). Baseline sodium excretion predicted neither total mortality (P = .10) nor fatal combined with nonfatal CVD events (P = .55). Among 2096 participants followed up for 6.5 years, the risk of hypertension did not increase across increasing tertiles (P = .93). Incident hypertension was 187 (27.0%; HR, 1.00; 95% CI, 0.87-1.16) in the low, 190 (26.6%; HR, 1.02; 95% CI, 0.89-1.16) in the medium, and 175 (25.4%; HR, 0.98; 95% CI, 0.86-1.12) in the high sodium excretion group. In 1499 participants followed up for 6.1 years, systolic blood pressure increased by 0.37 mm Hg per year (P < .001), whereas sodium excretion did not change (-0.45 mmol per year, P = .15). However, in multivariable-adjusted analyses, a 100-mmol increase in sodium excretion was associated with 1.71 mm Hg increase in systolic blood pressure (P.<001) but no change in diastolic BP.
CONCLUSIONS: In this population-based cohort, systolic blood pressure, but not diastolic pressure, changes over time aligned with change in sodium excretion, but this association did not translate into a higher risk of hypertension or CVD complications. Lower sodium excretion was associated with higher CVD mortality.

PMID 21540421  JAMA. 2011 May 4;305(17):1777-85. doi: 10.1001/jama.201・・・
著者: R M Hartley, R Velez, R W Morris, M F D'Souza, R F Heller
雑誌名: Br Med J (Clin Res Ed). 1983 Jan 22;286(6361):287-9.
Abstract/Text Patients with newly found raised blood pressure are known to have lower pressures at subsequent measurements even when not treated. A study was undertaken to determine the extent to which (a) the number of follow-up measurements and (b) the duration of the intervals between them contributed to this fall in pressure. In 42 general practices 110 patients were identified as having for the first time a diastolic pressure (phase V) greater than 90 and less than 110 mm Hg. Both diastolic and systolic pressures were appreciably lower when measured at return visits when compared with the first measurement. The systolic pressure dropped appreciably in the intervals between the first and the second visits and again between the second and third visits. The diastolic pressure fell appreciably only between the first and second visits. The duration of the interval between visits was not associated with a fall in either systolic or diastolic pressure, but the number of measurements was. This pattern of fall in pressure was not affected by the patient's age or sex. From these results we conclude that patients with newly identified blood pressures that are mildly raised should be seen at two further visits before a decision about treatment is made. The timing of these follow-up visits is not crucial.

PMID 6402075  Br Med J (Clin Res Ed). 1983 Jan 22;286(6361):287-9.
著者: R D Watson, R Lumb, M A Young, T J Stallard, P Davies, W A Littler
雑誌名: J Hypertens. 1987 Apr;5(2):207-11.
Abstract/Text Thirty-two patients with mildly elevated blood pressure (BP), but without target organ damage, attended a BP measuring clinic where duplicate BP measurements were made on 12 visits. During visits 1-3, BP showed a systematic decrease which varied from patient to patient. During visits 4-12, no further systematic changes in BP were observed. During the latter period, between-visit variation in BP was substantial, the standard deviation of the difference in BP from one visit to another being 10.4 mmHg for systolic, 6.8 mmHg for diastolic (phase IV) and 7.0 mmHg for diastolic (phase V). These values were used to determine the chance that the BP estimated after a number of visits differed from the average stable BP. After visit 4, the chance of a difference of 5 mmHg or more was 0.50 systolic blood pressure (SBP) and 0.32 diastolic blood pressure (DBP; phase V). Increasing the number of visits to six or more reduced the chance of error. Before initiating lifelong treatment in mild hypertensives free of target organ damage, BP should be recorded in duplicate on a minimum of six visits.

PMID 3611770  J Hypertens. 1987 Apr;5(2):207-11.
著者: C J Vaughan, N Delanty
雑誌名: Lancet. 2000 Jul 29;356(9227):411-7. doi: 10.1016/S0140-6736(00)02539-3.
Abstract/Text A hypertensive emergency is a situation in which uncontrolled hypertension is associated with acute end-organ damage. Most patients presenting with hypertensive emergency have chronic hypertension, although the disorder can present in previously normotensive individuals, particularly when associated with pre-eclampsia or acute glomerulonephritis. The pathophysiological mechanisms causing acute hypertensive endothelial failure are complex and incompletely understood but probably involve disturbances of the renin-angiotensin-aldosterone system, loss of endogenous vasodilator mechanisms, upregulation of proinflammatory mediators including vascular cell adhesion molecules, and release of local vasoconstrictors such as endothelin 1. Magnetic resonance imaging has demonstrated a characteristic hypertensive posterior leucoencephalopathy syndrome predominantly causing oedema of the white matter of the parietal and occipital lobes; this syndrome is potentially reversible with appropriate prompt treatment. Generally, the therapeutic approach is dictated by the particular presentation and end-organ complications. Parenteral therapy is generally preferred, and strategies include use of sodium nitroprusside, beta-blockers, labetelol, or calcium-channel antagonists, magnesium for pre-eclampsia and eclampsia; and short-term parenteral anticonvulsants for seizures associated with encephalopathy. Novel therapies include the peripheral dopamine-receptor agonist, fenoldapam, and may include endothelin-1 antagonists.

PMID 10972386  Lancet. 2000 Jul 29;356(9227):411-7. doi: 10.1016/S0140・・・
著者: Heather O Dickinson, James M Mason, Donald J Nicolson, Fiona Campbell, Fiona R Beyer, Julia V Cook, Bryan Williams, Gary A Ford
雑誌名: J Hypertens. 2006 Feb;24(2):215-33. doi: 10.1097/01.hjh.0000199800.72563.26.
Abstract/Text PURPOSE: To quantify effectiveness of lifestyle interventions for hypertension.
DATA SOURCES: Electronic bibliographic databases from 1998 onwards, existing guidelines, systematic reviews.
STUDY SELECTION AND DATA ABSTRACTION: We included randomized, controlled trials with at least 8 weeks' follow-up, comparing lifestyle with control interventions, enrolling adults with blood pressure at least 140/85 mmHg. Primary outcome measures were systolic and diastolic blood pressure. Two independent reviewers selected trials and abstracted data; differences were resolved by discussion.
RESULTS: We categorized trials by type of intervention and used random effects meta-analysis to combine mean differences between endpoint blood pressure in treatment and control groups in 105 trials randomizing 6805 participants. Robust statistically significant effects were found for improved diet, aerobic exercise, alcohol and sodium restriction, and fish oil supplements: mean reductions in systolic blood pressure of 5.0 mmHg [95% confidence interval (CI): 3.1-7.0], 4.6 mmHg (95% CI: 2.0-7.1), 3.8 mmHg (95% CI: 1.4-6.1), 3.6 mmHg (95% CI: 2.5-4.6) and 2.3 mmHg (95% CI: 0.2-4.3), respectively, with corresponding reductions in diastolic blood pressure. Relaxation significantly reduced blood pressure only when compared with non-intervention controls. We found no robust evidence of any important effect on blood pressure of potassium, magnesium or calcium supplements.
CONCLUSIONS: Patients with elevated blood pressure should follow a weight-reducing diet, take regular exercise, and restrict alcohol and salt intake. Available evidence does not support relaxation therapies, calcium, magnesium or potassium supplements to reduce blood pressure.

PMID 16508562  J Hypertens. 2006 Feb;24(2):215-33. doi: 10.1097/01.hjh・・・
著者: M L Tuck, J Sowers, L Dornfeld, G Kledzik, M Maxwell
雑誌名: N Engl J Med. 1981 Apr 16;304(16):930-3. doi: 10.1056/NEJM198104163041602.
Abstract/Text We investigated the relation between changes in the renin-aldosterone axis and reduction in blood pressure in 25 obese patients placed on a 12-week reducing diet; sodium intake was either medium (120 mmol) or low (40 mmol). Plasma renin activity (PRA) declined with weight loss, so that by 12 weeks there was a significant decrease in PRA (P less than 0.01) as well as plasma aldosterone (P less than 0.05), regardless of sodium intake. Weight loss with low sodium intake was equal to that with medium intake. The reduction in PRA but not in aldosterone correlated with weight loss in both sodium-intake groups (r = 0.58). Mean arterial pressure fell significantly and equally in both groups, correlating with weight loss throughout the study (r = 0.56) and with PRA from the fourth through 12th weeks (r = 0.48) These results demonstrate that weight loss is accompanied by reductions in PRA and aldosterone; PRA reductions, irrespective of sodium intake, may contribute to the decline in blood pressure.

PMID 7010165  N Engl J Med. 1981 Apr 16;304(16):930-3. doi: 10.1056/N・・・
著者: P K Whelton, L J Appel, M A Espeland, W B Applegate, W H Ettinger, J B Kostis, S Kumanyika, C R Lacy, K C Johnson, S Folmar, J A Cutler
雑誌名: JAMA. 1998 Mar 18;279(11):839-46.
Abstract/Text CONTEXT: Nonpharmacologic interventions are frequently recommended for treatment of hypertension in the elderly, but there is a paucity of evidence from randomized controlled trials in support of this recommendation.
OBJECTIVE: To determine whether weight loss or reduced sodium intake is effective in the treatment of older persons with hypertension.
DESIGN: Randomized controlled trial.
PARTICIPANTS: A total of 975 [corrected] men and women aged 60 to 80 years with systolic blood pressure lower than 145 mm Hg and diastolic blood pressure lower than 85 mm Hg while receiving treatment with a single antihypertensive medication.
SETTING: Four academic health centers.
INTERVENTION: The 585 obese participants were randomized to reduced sodium intake, weight loss, both, or usual care, and the 390 nonobese participants were randomized to reduced sodium intake or usual care. Withdrawal of antihypertensive medication was attempted after 3 months of intervention.
MAIN OUTCOME MEASURE: Diagnosis of high blood pressure at 1 or more follow-up visits, or treatment with antihypertensive medication, or a cardiovascular event during follow-up (range, 15-36 months; median, 29 months).
RESULTS: The combined outcome measure was less frequent among those assigned vs not assigned to reduced sodium intake (relative hazard ratio, 0.69; 95% confidence interval [CI], 0.59-0.81; P<.001) and, in obese participants, among those assigned vs not assigned to weight loss (relative hazard ratio, 0.70; 95% CI, 0.57-0.87; P<.001). Relative to usual care, hazard ratios among the obese participants were 0.60 (95% CI, 0.45-0.80; P<.001) for reduced sodium intake alone, 0.64 (95% CI, 0.49-0.85; P=.002) for weight loss alone, and 0.47 (95% CI, 0.35-0.64; P<.001) for reduced sodium intake and weight loss combined. The frequency of cardiovascular events during follow-up was similar in each of the 6 treatment groups.
CONCLUSION: Reduced sodium intake and weight loss constitute a feasible, effective, and safe nonpharmacologic therapy of hypertension in older persons.

PMID 9515998  JAMA. 1998 Mar 18;279(11):839-46.
著者: V J Stevens, S A Corrigan, E Obarzanek, E Bernauer, N R Cook, P Hebert, M Mattfeldt-Beman, A Oberman, C Sugars, A T Dalcin
雑誌名: Arch Intern Med. 1993 Apr 12;153(7):849-58.
Abstract/Text BACKGROUND: Phase 1 of the Trials of Hypertension Prevention was a collaborative, randomized controlled clinical trial designed to determine the feasibility and efficacy of selected nonpharmacologic interventions in reducing or preventing an increase in diastolic blood pressure.
METHODS: Participants aged 30 to 54 years who had a high-normal diastolic blood pressure (80 to 89 mm Hg), and were between 115% and 165% of their desirable body weight, were randomly assigned to either an 18-month weight loss intervention (n = 308) or a usual-care control condition (N = 256). Intervention consisted of 14 weekly group meetings followed by monthly maintenance sessions. Intervention participants received training in behavioral self-management technique and were asked to make life-style changes aimed at achieving a moderate reduction in energy intake and an increase in physical activity.
RESULTS: The average weight losses in the intervention group at 6, 12, and 18 months of follow-up were 6.5, 5.6, and 4.7 kg for men and 3.7, 2.7, and 1.6 kg for women. The mean (+/- SE) change in diastolic blood pressure for intervention participants compared with controls at termination was -2.8 +/- 0.6 mm Hg for men and -1.1 +/- 0.9 mm Hg for women. For systolic blood pressure, the corresponding change was -3.1 +/- 0.7 mm Hg for men and -2.0 +/- 1.3 mm Hg for women. Blood pressure reductions were greater for those who lost larger amounts of weight. Sex-related differences in blood pressure response were largely due to the smaller amount of weight lost by women, and sex differences in weight loss could be accounted for by differences in baseline body weight.
CONCLUSIONS: During an 18-month follow-up period, this weight reduction program was shown to be an effective nonpharmacologic intervention for reducing blood pressure in overweight adults with high-normal blood pressure.

PMID 8466377  Arch Intern Med. 1993 Apr 12;153(7):849-58.
著者: Lawrence J Appel, Catherine M Champagne, David W Harsha, Lawton S Cooper, Eva Obarzanek, Patricia J Elmer, Victor J Stevens, William M Vollmer, Pao-Hwa Lin, Laura P Svetkey, Sarah W Stedman, Deborah R Young, Writing Group of the PREMIER Collaborative Research Group
雑誌名: JAMA. 2003 Apr 23-30;289(16):2083-93. doi: 10.1001/jama.289.16.2083.
Abstract/Text CONTEXT: Weight loss, sodium reduction, increased physical activity, and limited alcohol intake are established recommendations that reduce blood pressure (BP). The Dietary Approaches to Stop Hypertension (DASH) diet also lowers BP. To date, no trial has evaluated the effects of simultaneously implementing these lifestyle recommendations.
OBJECTIVE: To determine the effect on BP of 2 multicomponent, behavioral interventions.
DESIGN, SETTING, AND PARTICIPANTS: Randomized trial with enrollment at 4 clinical centers (January 2000-June 2001) among 810 adults (mean [SD] age, 50 [8.9] years; 62% women; 34% African American) with above-optimal BP, including stage 1 hypertension (120-159 mm Hg systolic and 80-95 mm Hg diastolic), and who were not taking antihypertensive medications.
INTERVENTION: Participants were randomized to one of 3 intervention groups: (1) "established," a behavioral intervention that implemented established recommendations (n = 268); (2) "established plus DASH,"which also implemented the DASH diet (n = 269); and (3) an "advice only" comparison group (n = 273).
MAIN OUTCOME MEASURES: Blood pressure measurement and hypertension status at 6 months.
RESULTS: Both behavioral interventions significantly reduced weight, improved fitness, and lowered sodium intake. The established plus DASH intervention also increased fruit, vegetable, and dairy intake. Across the groups, gradients in BP and hypertensive status were evident. After subtracting change in advice only, the mean net reduction in systolic BP was 3.7 mm Hg (P<.001) in the established group and 4.3 mm Hg (P<.001) in the established plus DASH group; the systolic BP difference between the established and established plus DASH groups was 0.6 mm Hg (P =.43). Compared with the baseline hypertension prevalence of 38%, the prevalence at 6 months was 26% in the advice only group, 17% in the established group (P =.01 compared with the advice only group), and 12% in the established plus DASH group (P<.001 compared with the advice only group; P =.12 compared with the established group). The prevalence of optimal BP (<120 mm Hg systolic and <80 mm Hg diastolic) was 19% in the advice only group, 30% in the established group (P =.005 compared with the advice only group), and 35% in the established plus DASH group (P<.001 compared with the advice only group; P =.24 compared with the established group).
CONCLUSION: Individuals with above-optimal BP, including stage 1 hypertension, can make multiple lifestyle changes that lower BP and reduce their cardiovascular disease risk.

PMID 12709466  JAMA. 2003 Apr 23-30;289(16):2083-93. doi: 10.1001/jama・・・
著者: Patricia J Elmer, Eva Obarzanek, William M Vollmer, Denise Simons-Morton, Victor J Stevens, Deborah Rohm Young, Pao-Hwa Lin, Catherine Champagne, David W Harsha, Laura P Svetkey, Jamy Ard, Phillip J Brantley, Michael A Proschan, Thomas P Erlinger, Lawrence J Appel, PREMIER Collaborative Research Group
雑誌名: Ann Intern Med. 2006 Apr 4;144(7):485-95.
Abstract/Text BACKGROUND: The main 6-month results from the PREMIER trial showed that comprehensive behavioral intervention programs improve lifestyle behaviors and lower blood pressure.
OBJECTIVE: To compare the 18-month effects of 2 multicomponent behavioral interventions versus advice only on hypertension status, lifestyle changes, and blood pressure.
DESIGN: Multicenter, 3-arm, randomized trial conducted from January 2000 through November 2002.
SETTING: 4 clinical centers and a coordinating center.
PATIENTS: 810 adult volunteers with prehypertension or stage 1 hypertension (systolic blood pressure, 120 to 159 mm Hg; diastolic blood pressure, 80 to 95 mm Hg). Interventions: A multicomponent behavioral intervention that implemented long-established recommendations ("established"); a multicomponent behavioral intervention that implemented the established recommendations plus the Dietary Approaches to Stop Hypertension (DASH) diet ("established plus DASH"); and advice only.
MEASUREMENTS: Lifestyle variables and blood pressure status. Follow-up for blood pressure measurement at 18 months was 94%.
RESULTS: Compared with advice only, both behavioral interventions statistically significantly reduced weight, fat intake, and sodium intake. The established plus DASH intervention also statistically significantly increased fruit, vegetable, dairy, fiber, and mineral intakes. Relative to the advice only group, the odds ratios for hypertension at 18 months were 0.83 (95% CI, 0.67 to 1.04) for the established group and 0.77 (CI, 0.62 to 0.97) for the established plus DASH group. Although reductions in absolute blood pressure at 18 months were greater for participants in the established and the established plus DASH groups than for the advice only group, the differences were not statistically significant.
LIMITATIONS: The exclusion criteria and the volunteer nature of this cohort may limit generalizability. Although blood pressure is a well-accepted risk factor for cardiovascular disease, the authors were not able to assess intervention effects on clinical cardiovascular events in this limited time and with this sample size.
CONCLUSIONS: Over 18 months, persons with prehypertension and stage 1 hypertension can sustain multiple lifestyle modifications that improve control of blood pressure and could reduce the risk for chronic disease.

PMID 16585662  Ann Intern Med. 2006 Apr 4;144(7):485-95.
著者: Koshi Nakamura, Tomonori Okamura, Takehito Hayakawa, Atsushi Hozawa, Takashi Kadowaki, Yoshitaka Murakami, Yoshikuni Kita, Akira Okayama, Hirotsugu Ueshima, NIPPON DATA90 Research Group
雑誌名: Hypertens Res. 2007 Aug;30(8):663-8. doi: 10.1291/hypres.30.663.
Abstract/Text Japanese men consume more alcoholic beverages than men in many other developed countries. The high consumption rate of alcoholic beverages among Japanese men may contribute to the high prevalence of hypertension in Japan. In the present study, we calculated the odds ratio for hypertension in alcohol drinkers based on recent criteria using data from a nationwide survey conducted in Japan in 1990, and estimated, among total hypertensives in a general Japanese population, the percentage of hypertensives whose condition was due to alcohol consumption. Of 3,454 male participants, 64.8% were drinkers (1 gou/day, 28.9%; 2 gou/day, 20.1%; 3 gou/day or more, 8.7%; ex-drinkers, 7.0%) and 49.8% were hypertensive, whereas 7.6% of 4,808 female participants were drinkers (1 gou/day, 5.2%; 2 gou/day or more, 1.3%; ex-drinkers, 1.1%) and 43.1% were hypertensive (1 gou=23.0 g of alcohol). In both sexes, drinkers had a higher odds ratio for hypertension than never drinkers, and there was a significant dose-response relationship between the amount of alcohol consumed and the odds ratio for hypertension. Among all hypertensives, the percentage whose hypertension was due to alcohol consumption was 34.5% (95% confidence interval, 10.9%-51.9%) for men and 2.6% (0.8%-5.8%) for women. The corresponding proportion based on daily alcohol intake was 12.7% for 1 gou/day, 11.1% for 2 gou/day, 5.8% for 3 gou/day or more, and 4.8% for ex-drinkers in men, and 1.8% for 1 gou/day, 0.7% for 2 gou/day or more, and -0.1% for ex-drinkers in women. In conclusion, we found that a large percentage of the hypertensives in a general Japanese male population had alcohol-induced hypertension.

PMID 17917312  Hypertens Res. 2007 Aug;30(8):663-8. doi: 10.1291/hypre・・・
著者: X Xin, J He, M G Frontini, L G Ogden, O I Motsamai, P K Whelton
雑誌名: Hypertension. 2001 Nov;38(5):1112-7.
Abstract/Text Alcohol drinking has been associated with increased blood pressure in epidemiological studies. We conducted a meta-analysis of randomized controlled trials to assess the effects of alcohol reduction on blood pressure. We included 15 randomized control trials (total of 2234 participants) published before June 1999 in which alcohol reduction was the only intervention difference between active and control treatment groups. Using a standard protocol, information on sample size, participant characteristics, study design, intervention methods, duration, and treatment results was abstracted independently by 3 investigators. By means of a fixed-effects model, findings from individual trials were pooled after results for each trial were weighted by the inverse of its variance. Overall, alcohol reduction was associated with a significant reduction in mean (95% confidence interval) systolic and diastolic blood pressures of -3.31 mm Hg (-2.52 to -4.10 mm Hg) and -2.04 mm Hg (-1.49 to -2.58 mm Hg), respectively. A dose-response relationship was observed between mean percentage of alcohol reduction and mean blood pressure reduction. Effects of intervention were enhanced in those with higher baseline blood pressure. Our study suggests that alcohol reduction should be recommended as an important component of lifestyle modification for the prevention and treatment of hypertension among heavy drinkers.

PMID 11711507  Hypertension. 2001 Nov;38(5):1112-7.
著者: A L Klatsky, G D Friedman, A B Siegelaub, M J Gérard
雑誌名: N Engl J Med. 1977 May 26;296(21):1194-200. doi: 10.1056/NEJM197705262962103.
Abstract/Text We studied blood pressure in relation to known drinking habits of 83,947 men and women of three races (83.5 per cent white). Using health-check-up questionnaire responses, we classified persons as nondrinkers or according to usual daily number of drinks: two or fewer per day, three to five per day, or six or more per day. As compared to nondrinkers blood pressures of men taking two or fewer drinks per day were similar. Women who took two or fewer drinks per day had slightly lower pressures. Men and women who took three or more drinks per day had higher systolic pressures (P less than 10(-24) in white men, and less than 10(-12) in white women), higher diastolic pressures (P less than 10(-24) in white men, and less than 10(-6) in white women), and substantially higher prevalence of pressures greater than or equal to 160/95 mm Hg. The associations of blood pressure and drinking were independent of age, sex, race, smoking, coffee use, former "heavy" drinking, educational attainment and adiposity. The findings strongly suggest that regular use of three or more drinks of alcohol per day is a risk factor for hypertension.

PMID 854058  N Engl J Med. 1977 May 26;296(21):1194-200. doi: 10.105・・・
著者: Giuseppe Mancia, Guy De Backer, Anna Dominiczak, Renata Cifkova, Robert Fagard, Giuseppe Germano, Guido Grassi, Anthony M Heagerty, Sverre E Kjeldsen, Stephane Laurent, Krzysztof Narkiewicz, Luis Ruilope, Andrzej Rynkiewicz, Roland E Schmieder, Harry Aj Struijker Boudier, Alberto Zanchetti, ESH-ESC Task Force on the Management of Arterial Hypertension
雑誌名: J Hypertens. 2007 Sep;25(9):1751-62. doi: 10.1097/HJH.0b013e3282f0580f.
Abstract/Text
PMID 17762635  J Hypertens. 2007 Sep;25(9):1751-62. doi: 10.1097/HJH.0・・・
著者: A J Palmer, A E Fletcher, C J Bulpitt, D G Beevers, E C Coles, J G Ledingham, J C Petrie, J Webster, C T Dollery
雑誌名: J Hypertens. 1995 Sep;13(9):957-64.
Abstract/Text OBJECTIVE: To determine the benefits and risks of drinking alcohol in treated hypertensives.
DESIGN: A prospective study of 6,369 hypertensives (3,161 men) attending primarily hospital clinics in the UK.
METHODS: Relative risks both for drinkers compared with non-drinkers and for level of alcohol consumption were calculated for mortality from ischaemic heart disease, stroke, non-circulatory and all causes.
RESULTS: At presentation 76% of the men and 48% of the women reported recent alcohol consumption. Compared with drinkers, non-drinkers were older, less likely to smoke and had a higher untreated blood pressure. After adjustment for confounding factors, male drinkers had a reduced risk of stroke mortality and possibly of ischaemic heart disease mortality. Similar results were observed in women for stroke mortality but not for ischaemic heart disease mortality. The trend remained after adjustment for previous cardiovascular disease. In men the lowest risk of ischaemic heart disease mortality occurred at intakes of > 21 units per week and stroke mortality was lowest at 1-10 units per week. Men consuming > 21 units per week had a twofold higher non-circulatory mortality. Total mortality was lowest in men who drank 1-10 units per week. Similar effects of alcohol on cardiovascular mortality were observed in women.
CONCLUSIONS: Alcohol intake may reduce stroke mortality in treated hypertensives. Ischaemic heart disease mortality in men may also be reduced, especially at higher intakes ( > 21 units per week). The beneficial effects were offset by increasing incidence of non-circulatory causes of death. Alcohol consumption of 1-10 units per week was associated with the lowest mortality in men.

PMID 8586830  J Hypertens. 1995 Sep;13(9):957-64.
著者: Jacobus Lubsen, Gilbert Wagener, Bridget-Anne Kirwan, Sophie de Brouwer, Philip A Poole-Wilson, ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) investigators
雑誌名: J Hypertens. 2005 Mar;23(3):641-8.
Abstract/Text OBJECTIVE: To examine the effects of nifedipine GITS on clinical outcome in patients with concurrent stable angina and hypertension.
METHODS: Data from the double-blind placebo-controlled ACTION trial was stratified for hypertension (blood pressure > or = 140/90 mmHg), at baseline.
RESULTS: A total of 52% of 7665 ACTION patients were hypertensive. Some 80% were on a beta blocker; hypertensives were more often treated with other blood pressure-lowering drugs. Mean baseline blood pressure was 122/74 mmHg among normotensives and 151/85 mmHg among hypertensives. Follow-up blood pressures were reduced by nifedipine (P < 0.001) on the average by 3.9/2.4 and 6.6/3.5 mmHg among normotensives and hypertensives, respectively. Nifedipine GITS significantly (P < 0.05) reduced the combined incidence of all-cause mortality, myocardial infarction, refractory angina, heart failure, stroke and peripheral revascularization by 13% in hypertensives only. Nifedipine significantly reduced the incidence of any stroke or transient ischemic attack by almost 30% in both subgroups and the need for coronary angiography by 21% in normotensives and 16% in hypertensives. Among hypertensives, the incidence of new overt heart failure was significantly reduced by 38% and of debilitating stroke by 33%. Among normotensives, the need for coronary bypass grafting was significantly reduced by 32%. Nifedipine did not affect all-cause death, cardiovascular death and myocardial infarction in either normo- or hypertensives, but increased the need for peripheral revascularization.
CONCLUSION: The salutary effects of the addition of nifedipine GITS to the basic regimen of patients with concurrent stable symptomatic coronary artery disease and hypertension emphasize the need for blood pressure control.

PMID 15716708  J Hypertens. 2005 Mar;23(3):641-8.
著者: Steven E Nissen, E Murat Tuzcu, Peter Libby, Paul D Thompson, Magdi Ghali, Dahlia Garza, Lance Berman, Harry Shi, Ethel Buebendorf, Eric J Topol, CAMELOT Investigators
雑誌名: JAMA. 2004 Nov 10;292(18):2217-25. doi: 10.1001/jama.292.18.2217.
Abstract/Text CONTEXT: The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease (CAD) and normal blood pressure remains uncertain.
OBJECTIVE: To compare the effects of amlodipine or enalapril vs placebo on cardiovascular events in patients with CAD.
DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, multicenter, 24-month trial (enrollment April 1999-April 2002) comparing amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD (>20% stenosis by coronary angiography) and diastolic blood pressure <100 mm Hg. A substudy of 274 patients measured atherosclerosis progression by intravascular ultrasound (IVUS).
INTERVENTIONS: Patients were randomized to receive amlodipine, 10 mg; enalapril, 20 mg; or placebo. IVUS was performed at baseline and study completion.
MAIN OUTCOME MEASURES: The primary efficacy parameter was incidence of cardiovascular events for amlodipine vs placebo. Other outcomes included comparisons of amlodipine vs enalapril and enalapril vs placebo. Events included cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina pectoris, hospitalization for congestive heart failure, fatal or nonfatal stroke or transient ischemic attack, and new diagnosis of peripheral vascular disease. The IVUS end point was change in percent atheroma volume.
RESULTS: Baseline blood pressure averaged 129/78 mm Hg for all patients; it increased by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4 mm Hg in the amlodipine and enalapril groups, respectively (P<.001 for both vs placebo). Cardiovascular events occurred in 151 (23.1%) placebo-treated patients, in 110 (16.6%) amlodipine-treated patients (hazard ratio [HR], 0.69; 95% CI, 0.54-0.88 [P = .003]), and in 136 (20.2%) enalapril-treated patients (HR, 0.85; 95% CI, 0.67-1.07 [P = .16]. Primary end point comparison for enalapril vs amlodipine was not significant (HR, 0.81; 95% CI, 0.63-1.04 [P = .10]). The IVUS substudy showed a trend toward less progression of atherosclerosis in the amlodipine group vs placebo (P = .12), with significantly less progression in the subgroup with systolic blood pressures greater than the mean (P = .02). Compared with baseline, IVUS showed progression in the placebo group (P<.001), a trend toward progression in the enalapril group (P = .08), and no progression in the amlodipine group (P = .31). For the amlodipine group, correlation between blood pressure reduction and progression was r = 0.19, P = .07.
CONCLUSIONS: Administration of amlodipine to patients with CAD and normal blood pressure resulted in reduced adverse cardiovascular events. Directionally similar, but smaller and nonsignificant, treatment effects were observed with enalapril. For amlodipine, IVUS showed evidence of slowing of atherosclerosis progression.

PMID 15536108  JAMA. 2004 Nov 10;292(18):2217-25. doi: 10.1001/jama.29・・・
著者: Tazeen H Jafar, Paul C Stark, Christopher H Schmid, Marcia Landa, Giuseppe Maschio, Paul E de Jong, Dick de Zeeuw, Shahnaz Shahinfar, Robert Toto, Andrew S Levey, AIPRD Study Group
雑誌名: Ann Intern Med. 2003 Aug 19;139(4):244-52.
Abstract/Text BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce blood pressure and urine protein excretion and slow the progression of chronic kidney disease.
PURPOSE: To determine the levels of blood pressure and urine protein excretion associated with the lowest risk for progression of chronic kidney disease during antihypertensive therapy with and without ACE inhibitors.
DATA SOURCES: 11 randomized, controlled trials comparing the efficacy of antihypertensive regimens with or without ACE inhibitors for patients with predominantly nondiabetic kidney disease.
STUDY SELECTION: MEDLINE database search for English-language studies published between 1977 and 1999.
DATA EXTRACTION: Data on 1860 nondiabetic patients were pooled in a patient-level meta-analysis. Progression of kidney disease was defined as a doubling of baseline serum creatinine level or onset of kidney failure. Multivariable regression analysis was performed to assess the association of systolic and diastolic blood pressure and urine protein excretion with kidney disease progression at 22 610 patient visits.
DATA SYNTHESIS: Mean duration of follow-up was 2.2 years. Kidney disease progression was documented in 311 patients. Systolic blood pressure of 110 to 129 mm Hg and urine protein excretion less than 2.0 g/d were associated with the lowest risk for kidney disease progression. Angiotensin-converting enzyme inhibitors remained beneficial after adjustment for blood pressure and urine protein excretion (relative risk, 0.67 [95% CI, 0.53 to 0.84]). The increased risk for kidney progression at higher systolic blood pressure levels was greater in patients with urine protein excretion greater than 1.0 g/d (P < 0.006).
CONCLUSION: Although reverse causation cannot be excluded with certainty, a systolic blood pressure goal between 110 and 129 mm Hg may be beneficial in patients with urine protein excretion greater than 1.0 g/d. Systolic blood pressure less than 110 mm Hg may be associated with a higher risk for kidney disease progression.

PMID 12965979  Ann Intern Med. 2003 Aug 19;139(4):244-52.
著者: Hisashi Kai, Takafumi Ueno, Takeshi Kimura, Hisashi Adachi, Yutaka Furukawa, Toru Kita, Tsutomu Imaizumi, CREDO-Kyoto Investigators
雑誌名: J Hypertens. 2011 Oct;29(10):1889-96. doi: 10.1097/HJH.0b013e32834a5a67.
Abstract/Text OBJECTIVES: It remains controversial whether extremely low DBP is a risk for cardiovascular events in patients with coronary artery disease (CAD). Coronary revascularization therapy became prevalent in CAD patients. We sought to determine the impact of low DBP on cardiovascular events and to investigate the predicting factors in revascularized CAD patients.
METHODS: We subanalyzed 7180 stable, chronic CAD patients (median follow-up period 3.6 years) of 9877 patients undergoing first coronary artery bypass graft or percutaneous coronary intervention in the registry of the Coronary REvascularization Demonstrating Outcome study in Kyoto (CREDO-Kyoto).
RESULTS: Kaplan-Meier analysis revealed that unadjusted cumulative incidence of cardiovascular death was greater in patients with preprocedural DBP of less than 70 mmHg than in those with DBP of at least 70 mmHg, whereas the cumulative incidences of nonfatal myocardial infarction (MI) and of stroke were similar between the two groups. Stepwise logistic regression analysis showed that estimated glomerular filtration ratio (inversely), pulse pressure, left ventricular ejection fraction of less than 0.40, history of heart failure, prior cerebrovascular disease, and prior MI were independent risks for cardiovascular death in patients with DBP of less than 70 mmHg. After adjustments for the independent risks, the cumulative hazard ratio for cardiovascular death did not differ between patients with DBP of less than 70 mmHg and those with DBP of at least 70 mmHg.
CONCLUSION: Renal insufficiency, more advanced vascular damage, and left ventricular systolic dysfunction were significant factors accounting for increased cardiovascular death in revascularized CAD patients with DBP of less than 70 mmHg. It was suggested that after adjustments for these independent risks, low DBP may not be a significant risk for cardiovascular death in revascularized CAD patients.

PMID 21857536  J Hypertens. 2011 Oct;29(10):1889-96. doi: 10.1097/HJH.・・・
著者: G W Somes, M Pahor, R I Shorr, W C Cushman, W B Applegate
雑誌名: Arch Intern Med. 1999 Sep 27;159(17):2004-9.
Abstract/Text OBJECTIVE: To assess the role of treated diastolic blood pressure (DBP) level in stroke, coronary heart disease (CHD), and cardiovascular disease (CVD) in patients with isolated systolic hypertension (ISH).
DESIGN: An analysis of the 4736 participants in the Systolic Hypertension in the Elderly Program (SHEP) was undertaken. The SHEP was a randomized multicenter double-blind outpatient clinical trial of the impact of treating ISH in men and women aged 60 years and older.
MAIN OUTCOME MEASURES: Cox proportional hazards regression analysis, with DBP and systolic blood pressure (SBP) as time-dependent covariables.
RESULTS: After adjustment for the baseline risk factors of race (black vs other), sex, use of antihypertensive medication before the study, a composite variable (diabetes, previous heart attack, or stroke), age, and smoking history (ever vs never) and adjustment for the SBP as a time-dependent variable, we found, for the active treatment group only, that a decrease of 5 mm Hg in DBP increased the risk for stroke (relative risk, [RR], 1.14; 95% confidence interval [CI], 1.05-1.22), for CHD (RR, 1.08; 95% CI, 1.00-1.16), and for CVD (RR, 1.11; 95% CI, 1.05-1.16).
CONCLUSIONS: Some patients with ISH may be treated to a level that uncovers subclinical disease, and some may be overtreated. Further studies need to determine whether excessively low DBP can be prevented by more careful titration of antihypertensive therapy while maintaining SBP control. It is reassuring that patients receiving treatment for ISH never perform worse than patients receiving placebo in terms of CVD events.

PMID 10510985  Arch Intern Med. 1999 Sep 27;159(17):2004-9.
著者: Robert H Fagard, Jan A Staessen, Lutgarde Thijs, Hilde Celis, Christopher J Bulpitt, Peter W de Leeuw, Gastone Leonetti, Jaakko Tuomilehto, Yair Yodfat
雑誌名: Arch Intern Med. 2007 Sep 24;167(17):1884-91. doi: 10.1001/archinte.167.17.1884.
Abstract/Text BACKGROUND: It has been suggested that low diastolic blood pressure (BP) while receiving antihypertensive treatment (hereinafter called on-treatment BP) is harmful in older patients with systolic hypertension. We examined the association between on-treatment diastolic BP, mortality, and cardiovascular events in the prospective placebo-controlled Systolic Hypertension in Europe Trial.
METHODS: Elderly patients with systolic hypertension were randomized into the double-blind first phase of the trial, after which all patients received active study drugs (phase 2). We assessed the relationship between outcome and on-treatment diastolic BP by use of multivariate Cox regression analysis during receipt of placebo (phase 1) and during active treatment (phases 1 and 2).
RESULTS: Rates of noncardiovascular mortality, cardiovascular mortality, and cardiovascular events were 11.1, 12.0, and 29.4, respectively, per 1000 patient-years with active treatment (n = 2358) and 11.9, 12.6, and 39.0, respectively, with placebo (n = 2225). Noncardiovascular mortality, but not cardiovascular mortality, increased with low diastolic BP with active treatment (P < .005) and with placebo (P < .05); for example, hazard ratios for lower diastolic BP, that is, 65 to 60 mm Hg, were, respectively, 1.15 (95% confidence interval, 1.00-1.31) and 1.28 (95% confidence interval, 1.03-1.59). Low diastolic BP with active treatment was associated with increased risk of cardiovascular events, but only in patients with coronary heart disease at baseline (P < .02; hazard ratio for BP 65-60 mm Hg, 1.17; 95% confidence interval, 0.98-1.38).
CONCLUSIONS: These findings support the hypothesis that antihypertensive treatment can be intensified to prevent cardiovascular events when systolic BP is not under control in older patients with systolic hypertension, at least until diastolic BP reaches 55 mm Hg. However, a prudent approach is warranted in patients with concomitant coronary heart disease, in whom diastolic BP should probably not be lowered to less than 70 mm Hg.

PMID 17893310  Arch Intern Med. 2007 Sep 24;167(17):1884-91. doi: 10.1・・・
著者: James M Wright, Vijaya M Musini
雑誌名: Cochrane Database Syst Rev. 2009 Jul 8;(3):CD001841. doi: 10.1002/14651858.CD001841.pub2. Epub 2009 Jul 8.
Abstract/Text BACKGROUND: Sustained elevated blood pressure, unresponsive to lifestyle measures, leads to a critically important clinical question: What class of drug to use first-line? This review answers that question.
OBJECTIVES:
PRIMARY OBJECTIVE: To quantify the benefits and harms of the major first-line anti-hypertensive drug classes: thiazides, beta-blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, alpha-blockers, and angiotensin II receptor blockers (ARB).
SEARCH STRATEGY: Electronic search of MEDLINE (Jan. 1966-June 2008), EMBASE, CINAHL, the Cochrane clinical trial register, using standard search strategy of the hypertension review group with additional terms.
SELECTION CRITERIA: Randomized trials of at least one year duration comparing one of 6 major drug classes with a placebo or no treatment. More than 70% of people must have BP >140/90 mmHg at baseline.
DATA COLLECTION AND ANALYSIS: The outcomes assessed were mortality, stroke, coronary heart disease (CHD), cardiovascular events (CVS), decrease in systolic and diastolic blood pressure, and withdrawals due to adverse drug effects. Risk ratio (RR) and a fixed effects model were used to combine outcomes across trials.
MAIN RESULTS: Of 57 trials identified, 24 trials with 28 arms, including 58,040 patients met the inclusion criteria. Thiazides (19 RCTs) reduced mortality (RR 0.89, 95% CI 0.83, 0.96), stroke (RR 0.63, 95% CI 0.57, 0.71), CHD (RR 0.84, 95% CI 0.75, 0.95) and CVS (RR 0.70, 95% CI 0.66, 0.76). Low-dose thiazides (8 RCTs) reduced CHD (RR 0.72, 95% CI 0.61, 0.84), but high-dose thiazides (11 RCTs) did not (RR 1.01, 95% CI 0.85, 1.20). Beta-blockers (5 RCTs) reduced stroke (RR 0.83, 95% CI 0.72, 0.97) and CVS (RR 0.89, 95% CI 0.81, 0.98) but not CHD (RR 0.90, 95% CI 0.78, 1.03) or mortality (RR 0.96, 95% CI 0.86, 1.07). ACE inhibitors (3 RCTs) reduced mortality (RR 0.83, 95% CI 0.72-0.95), stroke (RR 0.65, 95% CI 0.52-0.82), CHD (RR 0.81, 95% CI 0.70-0.94) and CVS (RR 0.76, 95% CI 0.67-0.85). Calcium-channel blocker (1 RCT) reduced stroke (RR 0.58, 95% CI 0.41, 0.84) and CVS (RR 0.71, 95% CI 0.57, 0.87) but not CHD (RR 0.77 95% CI 0.55, 1.09) or mortality (RR 0.86 95% CI 0.68, 1.09). No RCTs were found for ARBs or alpha-blockers.
AUTHORS' CONCLUSIONS: First-line low-dose thiazides reduce all morbidity and mortality outcomes. First-line ACE inhibitors and calcium channel blockers may be similarly effective but the evidence is less robust. First-line high-dose thiazides and first-line beta-blockers are inferior to first-line low-dose thiazides.

PMID 19588327  Cochrane Database Syst Rev. 2009 Jul 8;(3):CD001841. do・・・
著者: F H Messerli, E Grossman, U Goldbourt
雑誌名: JAMA. 1998 Jun 17;279(23):1903-7.
Abstract/Text OBJECTIVE: To assess antihypertensive efficacy of beta-blockers and their effects on cardiovascular morbidity and mortality and all-cause morbidity compared with diuretics in elderly patients with hypertension.
DATA SOURCE: A MEDLINE search of English-language articles published between January 1966 and January 1998 using the terms hypertension (drug therapy) and elderly or aged or geriatric, and cerebrovascular or cardiovascular diseases, and morbidity or mortality. References from identified articles were also reviewed.
DATA SELECTION: Randomized trials lasting at least 1 year, which used as first-line agents diuretics and/or beta-blockers, and reported morbidity and mortality outcomes in elderly patients with hypertension. DATA SYNTHESIS AND RESULTS: Ten trials involving a total of 16164 elderly patients (> or =60 years) were included. Two thirds of the patients assigned to diuretics were well controlled on monotherapy, whereas less than a third of the patients assigned to beta-blockers were well controlled on monotherapy. Diuretic therapy was superior to beta-blockade with regard to all end points and was effective in preventing cerebrovascular events (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.51-0.72), fatal stroke (OR, 0.67; 95% CI, 0.49-0.90), coronary heart disease (OR, 0.74; 95% CI, 0.64-0.85), cardiovascular mortality (OR, 0.75; 95% CI, 0.64-0.87), and all-cause mortality (OR, 0.86; 95% CI, 0.77-0.96). In contrast, beta-blocker therapy only reduced the odds for cerebrovascular events (OR, 0.75; 95% CI, 0.57-0.98) but was ineffective in preventing coronary heart disease, cardiovascular mortality, and all-cause mortality (ORs, 1.01, 0.98, and 1.05, respectively).
CONCLUSIONS: In contrast to diuretics, which remain the standard first-line therapy, beta-blockers, until proven otherwise, should no longer be considered appropriate first-line therapy of uncomplicated hypertension in the elderly hypertensive patient.

PMID 9634263  JAMA. 1998 Jun 17;279(23):1903-7.
著者: Nadia Khan, Finlay A McAlister
雑誌名: CMAJ. 2006 Jun 6;174(12):1737-42. doi: 10.1503/cmaj.060110.
Abstract/Text BACKGROUND: In a recently published meta-analysis, investigators asserted that beta-blockers should not be used to treat hypertension. Because the pathophysiology of hypertension differs in older and younger patients, we designed this meta-analysis to clarify the efficacy of beta-blockers in different age groups. The primary outcome was a composite of stroke, myocardial infarction and death.
METHODS: We identified randomized controlled trials that evaluated the efficacy of beta-blockers as first-line therapy for hypertension in preventing major cardiovascular outcomes. Both authors independently evaluated the eligibility of all trials. Trials enrolling older (mean age at baseline > or = 60 years) patients were separated from those enrolling younger (mean age < 60 years) patients. Data were pooled using a random effects model.
RESULTS: Our analysis incorporated data from 145 811 participants in 21 hypertension trials. In placebo-controlled trials, beta-blockers reduced major cardiovascular outcomes in younger patients (risk ratio [RR] 0.86, 95% confidence interval [CI] 0.74-0.99, based on 794 events in 19 414 patients) but not in older patients (RR 0.89, 95% CI 0.75-1.05, based on 1115 events in 8019 patients). In active comparator trials, beta-blockers demonstrated similar efficacy to other antihypertensive agents in younger patients (1515 events in 30 412 patients, RR 0.97, 95% CI 0.88-1.07) but not in older patients (7405 events in 79 775 patients, RR 1.06, 95% CI 1.01-1.10), with the excess risk being particularly marked for strokes (RR 1.18, 95% CI 1.07-1.30).
INTERPRETATION: beta-blockers should not be considered first-line therapy for older hypertensive patients without another indication for these agents; however, in younger patients beta-blockers are associated with a significant reduction in cardiovascular morbidity and mortality.

PMID 16754904  CMAJ. 2006 Jun 6;174(12):1737-42. doi: 10.1503/cmaj.060・・・
著者: David S Wald, Malcolm Law, Joan K Morris, Jonathan P Bestwick, Nicholas J Wald
雑誌名: Am J Med. 2009 Mar;122(3):290-300. doi: 10.1016/j.amjmed.2008.09.038.
Abstract/Text OBJECTIVE: To quantify the incremental effect of combining blood pressure-lowering drugs from any 2 classes of thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers over 1 drug alone and to compare the effects of combining drugs with doubling dose.
METHODS: Meta-analysis of factorial trials in which participants were randomly allocated to 1 drug alone, another drug alone, both drugs together, or a placebo.
RESULTS: We identified 42 trials (10,968 participants). With a thiazide used alone, the mean placebo-subtracted reduction in systolic blood pressure was 7.3 mm Hg and 14.6 mm Hg combined with a drug from another class. The corresponding reductions were 9.3 mm Hg and 18.9 mm Hg with a beta-blocker, 6.8 mm Hg and 13.9 mm Hg with an angiotensin-converting enzyme, and 8.4 mm Hg and 14.3 mm Hg with a calcium channel blocker. The expected blood pressure reduction from 2 drugs together, assuming an additive effect, closely predicted the observed blood pressure reductions. The ratios of the observed to expected incremental blood pressure reductions from combining each class of drug with any other over that from 1 drug were, respectively, for thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers: 1.04 (95% confidence interval [CI], 0.88-1.20), 1.00 (95% CI, 0.76-1.24), 1.16 (95% CI, 0.93-1.39), and 0.89 (95% CI, 0.69-1.09); the overall average was 1.01 (95% CI, 0.90-1.12). Comparison of our results with those of a published meta-analysis of different doses of the same drug showed that doubling the dose of 1 drug had approximately one fifth of the equivalent incremental effect (0.22 [95% CI, 0.19-0.25]).
CONCLUSION: Blood pressure reduction from combining drugs from these 4 classes can be predicted on the basis of additive effects. The extra blood pressure reduction from combining drugs from 2 different classes is approximately 5 times greater than doubling the dose of 1 drug.

PMID 19272490  Am J Med. 2009 Mar;122(3):290-300. doi: 10.1016/j.amjme・・・
著者: R Ginsburg, I H Lamb, J S Schroeder, M Hu, D C Harrison
雑誌名: Am Heart J. 1982 Jan;103(1):44-9.
Abstract/Text Twelve patients were entered prospectively into a randomized double-blind study comparing the efficacy of nifedipine and isosorbide dinitrate (ISDN) in the treatment of variant angina pectoris due to coronary artery spasm. Using the diary technique, both anginal episodes and nitroglycerin tablets consumed were recorded during the pretrial, no drug period, and both active drug phases. During the baseline pretrial period, an average of 1.1 anginal episodes/day occurred with reduction to 0.28/day during nifedipine treatment and 0.39/day during ISDN treatment. Headache was the major side effect during ISDN treatment, occurring in 9 of 11 (81%) patients; and nonheart failure related pedal edema during nifedipine treatment, occurring in 4 of 12 (33%) patients. Intolerable side effects necessitating cessation of treatment occurred in two patients during nifedipine treatment and in three patients during ISDN treatment. Patients preferred nifedipine over ISDN because of increased efficacy and fewer uncomfortable side effects. We conclude that both nifedipine and ISDN are effective therapy for coronary spasm, but that nifedipine was more effective and was preferred by the majority of patients.

PMID 7034513  Am Heart J. 1982 Jan;103(1):44-9.
著者: R A Chahine, R L Feldman, T D Giles, P Nicod, A E Raizner, R J Weiss, S K Vanov
雑誌名: J Am Coll Cardiol. 1993 May;21(6):1365-70.
Abstract/Text OBJECTIVES: This study was designed to assess the efficacy and safety of amlodipine, a long-acting calcium channel blocker, in patients with vasospastic angina.
BACKGROUND: Previous studies have established the value of short-acting calcium channel blockers in the treatment of coronary spasm.
METHODS: Fifty-two patients with well documented vasospastic angina were entered into the present study. After a single-blind placebo run-in period, patients were randomized (in a double-blind protocol) to receive either amlodipine (10 mg) or placebo every morning for 4 weeks. Twenty-four patients received amlodipine and 28 received placebo. All patients were given diaries in which to record both the frequency, severity, duration and circumstances of anginal episodes and their intake of sublingual nitroglycerin tablets.
RESULTS: The rate of anginal episodes decreased significantly (p = 0.009) with amlodipine treatment compared with placebo and the intake of nitroglycerin tablets showed a similar trend. Peripheral edema was the only adverse event seen more frequently in amlodipine-treated patients. No patient was withdrawn from the double-blind phase of the study because of an adverse event. Patients who completed the double-blind phase as responders to amlodipine or as nonresponders to placebo were offered the option of receiving amlodipine in a long-term, open label extension phase. During the extension, the daily dose of amlodipine was adjusted to 5 or 15 mg if needed and the rate of both anginal episodes and nitroglycerin tablet consumption showed statistically significant decreases between baseline and final assessment.
CONCLUSION: This study suggests that amlodipine given once daily is efficacious and safe in the treatment of vasospastic angina.

PMID 8166777  J Am Coll Cardiol. 1993 May;21(6):1365-70.
著者: Kazuhiko Nishigaki, Yukiko Inoue, Yoshio Yamanouchi, Yoshihiro Fukumoto, Satoshi Yasuda, Shozo Sueda, Hidenori Urata, Hiroaki Shimokawa, Shinya Minatoguchi
雑誌名: Circ J. 2010 Sep;74(9):1943-50. Epub 2010 Jul 21.
Abstract/Text BACKGROUND: Although calcium channel blockers (CCB) are highly effective for suppression of vasospastic angina (VSA) attacks, their prognostic effects in VSA patients remain to be examined in a large number of patients.
METHODS AND RESULTS: Databases for related papers were searched and then a meta-analysis regarding the effects of CCB on major adverse cardiovascular events (MACE) in Japanese VSA patients with the 4 previous studies was performed. A total of 1,997 patients with positive coronary spasm provocation tests were evaluated. They were treated with either alone or combination of benidipine (n=320), amlodipine (n=308), nifedipine (n=182) or diltiazem (n=960). MACE were observed in 143 patients (cardiac death: 36, myocardial infarction: 51, heart failure: 26, stroke: 65, and aortic aneurysm: 11). The hazard ratio for the occurrence of MACE was significantly lower in patients treated with benidipine than in those with diltiazem. There was no significant difference in the clinical characteristics affecting the occurrence of MACE among the 4 CCB groups. Furthermore, the hazard ratio for the occurrence of MACE was significantly lower in those treated with benidipine, even after correction for patient characteristics that could have affected the occurrence of MACE (hazard ratio 0.41, P=0.016).
CONCLUSIONS: These results suggest that among the 4 major CCB that effectively suppress VSA attacks in general, benidipine showed significantly more beneficial prognostic effects than others.

PMID 20668353  Circ J. 2010 Sep;74(9):1943-50. Epub 2010 Jul 21.
著者: L L van de Ven, A Vermeulen, J G Tans, A C Tans, K L Liem, N C Lageweg, K I Lie
雑誌名: Int J Cardiol. 1995 Jan 6;47(3):217-23.
Abstract/Text The choice between beta-blockade or nitrates as first line treatment for stable angina pectoris is based upon the different mechanisms of action and patient characteristics. We performed a clinical trial comparing the efficacy of the longacting beta-blocker bisoprolol once daily and the short acting nitrate, isosorbide dinitrate, three times daily in the reduction of anginal complaints in daily life and under stress. Thirty patients were enrolled in a double-blind randomised cross-over study. Both bisoprolol and isosorbide dinitrate were effective in reducing anginal attacks and nitroglycerin consumption significantly, but bisoprolol was significantly more effective than isosorbide dinitrate. Bisoprolol improved the workload during bicycle exercise testing significantly, but the improvement with isosorbide dinitrate was not significant. Despite the reduction in maximal rate pressure product, bisoprolol was significantly (P < 0.05) more effective at improving total workload and reducing the time to onset of angina than isosorbide dinitrate. The rate pressure product did not change significantly with isosorbide dinitrate. In this study, bisoprolol 10 mg once daily was more effective and caused less side effects than isosorbide dinitrate 20 mg three times a day. It seems questionable if monotherapy of isosorbide dinitrate 20 mg t.i.d is an adequate drug regime for stable angina pectoris.

PMID 7721498  Int J Cardiol. 1995 Jan 6;47(3):217-23.
著者: P A Heidenreich, K M McDonald, T Hastie, B Fadel, V Hagan, B K Lee, M A Hlatky
雑誌名: JAMA. 1999 May 26;281(20):1927-36.
Abstract/Text CONTEXT: Which drug is most effective as a first-line treatment for stable angina is not known.
OBJECTIVE: To compare the relative efficacy and tolerability of treatment with beta-blockers, calcium antagonists, and long-acting nitrates for patients who have stable angina.
DATA SOURCES: We identified English-language studies published between 1966 and 1997 by searching the MEDLINE and EMBASE databases and reviewing the bibliographies of identified articles to locate additional relevant studies.
STUDY SELECTION: Randomized or crossover studies comparing antianginal drugs from 2 or 3 different classes (beta-blockers, calcium antagonists, and long-acting nitrates) lasting at least 1 week were reviewed. Studies were selected if they reported at least 1 of the following outcomes: cardiac death, myocardial infarction, study withdrawal due to adverse events, angina frequency, nitroglycerin use, or exercise duration. Ninety (63%) of 143 identified studies met the inclusion criteria.
DATA EXTRACTION: Two independent reviewers extracted data from selected articles, settling any differences by consensus. Outcome data were extracted a third time by 1 of the investigators. We combined results using odds ratios (ORs) for discrete data and mean differences for continuous data. Studies of calcium antagonists were grouped by duration and type of drug (nifedipine vs nonnifedipine).
DATA SYNTHESIS: Rates of cardiac death and myocardial infarction were not significantly different for treatment with beta-blockers vs calcium antagonists (OR, 0.97; 95% confidence interval [CI], 0.67-1.38; P = .79). There were 0.31 (95% CI, 0.00-0.62; P = .05) fewer episodes of angina per week with beta-blockers than with calcium antagonists. beta-Blockers were discontinued because of adverse events less often than were calcium antagonists (OR, 0.72; 95% CI, 0.60-0.86; P<.001). The differences between beta-blockers and calcium antagonists were most striking for nifedipine (OR for adverse events with beta-blockers vs nifedipine, 0.60; 95% CI, 0.47-0.77). Too few trials compared nitrates with calcium antagonists or beta-blockers to draw firm conclusions about relative efficacy.
CONCLUSIONS: beta-Blockers provide similar clinical outcomes and are associated with fewer adverse events than calcium antagonists in randomized trials of patients who have stable angina.

PMID 10349897  JAMA. 1999 May 26;281(20):1927-36.
著者: M A Pfeffer, E Braunwald, L A Moyé, L Basta, E J Brown, T E Cuddy, B R Davis, E M Geltman, S Goldman, G C Flaker
雑誌名: N Engl J Med. 1992 Sep 3;327(10):669-77. doi: 10.1056/NEJM199209033271001.
Abstract/Text BACKGROUND: Left ventricular dilatation and dysfunction after myocardial infarction are major predictors of death. In experimental and clinical studies, longterm therapy with the angiotensin-converting--enzyme inhibitor captopril attenuated ventricular dilatation and remodeling. We investigated whether captopril could reduce morbidity and mortality in patients with left ventricular dysfunction after a myocardial infarction.
METHODS: Within 3 to 16 days after myocardial infarction, 2231 patients with ejection fractions of 40 percent or less but without overt heart failure or symptoms of myocardial ischemia were randomly assigned to receive doubleblind treatment with either placebo (1116 patients) or captopril (1115 patients) and were followed for an average of 42 months.
RESULTS: Mortality from all causes was significantly reduced in the captopril group (228 deaths, or 20 percent) as compared with the placebo group (275 deaths, or 25 percent); the reduction in risk was 19 percent (95 percent confidence interval, 3 to 32 percent; P = 0.019). In addition, the incidence of both fatal and nonfatal major cardiovascular events was consistently reduced in the captopril group. The reduction in risk was 21 percent (95 percent confidence interval, 5 to 35 percent; P = 0.014) for death from cardiovascular causes, 37 percent (95 percent confidence interval, 20 to 50 percent; P less than 0.001) for the development of severe heart failure, 22 percent (95 percent confidence interval, 4 to 37 percent; P = 0.019) for congestive heart failure requiring hospitalization, and 25 percent (95 percent confidence interval, 5 to 40 percent; P = 0.015) for recurrent myocardial infarction.
CONCLUSIONS: In patients with asymptomatic left ventricular dysfunction after myocardial infarction, long-term administration of captopril was associated with an improvement in survival and reduced morbidity and mortality due to major cardiovascular events. These benefits were observed in patients who received thrombolytic therapy, aspirin, or beta-blockers, as well as those who did not, suggesting that treatment with captopril leads to additional improvement in outcome among selected survivors of myocardial infarction.

PMID 1386652  N Engl J Med. 1992 Sep 3;327(10):669-77. doi: 10.1056/N・・・
著者:
雑誌名: Lancet. 1993 Oct 2;342(8875):821-8.
Abstract/Text Survival after acute myocardial infarction has been enhanced by treatment with thrombolytic agents, aspirin, and beta-adrenoceptor blockade. However there remains a substantial subgroup of patients who manifest clinical evidence of heart failure despite the first two of these treatments, and for whom beta-adrenoceptor antagonists are relatively or absolutely contraindicated. These patients have a greatly increased risk of fatal and non-fatal ischaemic, arrhythmic, and haemodynamic events. In this selected high-risk subset of patients we investigated the effect of therapy with the angiotensin converting enzyme (ACE) inhibitor rampiril, postulating that it would lengthen survival. 2006 patients who had shown clinical evidence of heart failure at any time after an acute myocardial infarction (AMI) were recruited from 144 centres in 14 countries. Patients were randomly allocated to double-blind treatment with either placebo (992 patients) or ramipril (1014 patients) on day 3 to day 10 after AMI (day 1). Patients with severe heart failure resistant to conventional therapy, in whom the attending physician considered the use of an ACE inhibitor to be mandatory, were excluded. Follow-up was continued for a minimum of 6 months and an average of 15 months. On intention-to-treat analysis mortality from all causes was significantly lower for patients randomised to receive ramipril (170 deaths; 17%) than for those randomised to receive placebo (222 deaths; 23%). The observed risk reduction was 27% (95 % Cl 11% to 40%; p = 0.002). Analysis of prespecified secondary outcomes revealed a risk reduction of 19% for the first validated outcome (i.e., first event in an individual patient)--namely, death, severe/resistent heart failure, myocardial infarction, or stroke (95% Cl 5% to 31%; p = 0.008). Oral administration of rampiril to patients with clinical evidence of either transient or ongoing heart failure, initiated between the second and ninth day after myocardial infarction, resulted in a substantial reduction in premature death from all causes. This benefit was apparent as early as 30 days and was consistent across a range of subgroups.

PMID 8104270  Lancet. 1993 Oct 2;342(8875):821-8.
著者: L Køber, C Torp-Pedersen, J E Carlsen, H Bagger, P Eliasen, K Lyngborg, J Videbaek, D S Cole, L Auclert, N C Pauly
雑誌名: N Engl J Med. 1995 Dec 21;333(25):1670-6. doi: 10.1056/NEJM199512213332503.
Abstract/Text BACKGROUND: Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces mortality among survivors of acute myocardial infarction, but whether to use ACE inhibitors in all patients or only in selected patients is uncertain.
METHODS: We screened 6676 consecutive patients with 7001 myocardial infarctions confirmed by enzyme studies. A total of 2606 patients had echocardiographic evidence of left ventricular systolic dysfunction (ejection fraction, < or = 35 percent). On days 3 to 7 after infarction, 1749 patients were randomly assigned to receive oral trandolapril (876 patients) or placebo (873 patients). The duration of follow-up was 24 to 50 months.
RESULTS: During the study period, 304 patients (34.7 percent) in the trandolapril group died, as compared with 369 (42.3 percent) in the placebo group (P = 0.001). The relative risk of death in the trandolapril group, as compared with the placebo group, was 0.78 (95 percent confidence interval, 0.67 to 0.91). Trandolapril also reduced the risk of death from cardiovascular causes (relative risk, 0.75; 95 percent confidence interval, 0.63 to 0.89; P = 0.001) and sudden death (relative risk, 0.76; 95 percent confidence interval, 0.59 to 0.98; P = 0.03). Progression to severe heart failure was less frequent in the trandolapril group (relative risk, 0.71; 95 percent confidence interval, 0.56 to 0.89; P = 0.003). In contrast, the risk of recurrent myocardial infarction (fatal or nonfatal) was not significantly reduced (relative risk, 0.86; 95 percent confidence interval, 0.66 to 1.13; P = 0.29).
CONCLUSIONS: Long-term treatment with trandolapril in patients with reduced left ventricular function soon after myocardial infarction significantly reduced the risk of overall mortality, mortality from cardiovascular causes, sudden death, and the development of severe heart failure. That mortality was reduced in a randomized study enrolling 25 percent of consecutive patients screened should encourage the selective use of ACE inhibition after myocardial infarction.

PMID 7477219  N Engl J Med. 1995 Dec 21;333(25):1670-6. doi: 10.1056/・・・
著者: S A Hunt, D W Baker, M H Chin, M P Cinquegrani, A M Feldman, G S Francis, T G Ganiats, S Goldstein, G Gregoratos, M L Jessup, R J Noble, M Packer, M A Silver, L W Stevenson, R J Gibbons, E M Antman, J S Alpert, D P Faxon, V Fuster, G Gregoratos, A K Jacobs, L F Hiratzka, R O Russell, S C Smith, American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure), International Society for Heart and Lung Transplantation, Heart Failure Society of America
雑誌名: Circulation. 2001 Dec 11;104(24):2996-3007.
Abstract/Text
PMID 11739319  Circulation. 2001 Dec 11;104(24):2996-3007.
著者: Mariell Jessup, William T Abraham, Donald E Casey, Arthur M Feldman, Gary S Francis, Theodore G Ganiats, Marvin A Konstam, Donna M Mancini, Peter S Rahko, Marc A Silver, Lynne Warner Stevenson, Clyde W Yancy
雑誌名: Circulation. 2009 Apr 14;119(14):1977-2016. doi: 10.1161/CIRCULATIONAHA.109.192064. Epub 2009 Mar 26.
Abstract/Text
PMID 19324967  Circulation. 2009 Apr 14;119(14):1977-2016. doi: 10.116・・・
著者: John J V McMurray, Stamatis Adamopoulos, Stefan D Anker, Angelo Auricchio, Michael Böhm, Kenneth Dickstein, Volkmar Falk, Gerasimos Filippatos, Cândida Fonseca, Miguel Angel Gomez-Sanchez, Tiny Jaarsma, Lars Køber, Gregory Y H Lip, Aldo Pietro Maggioni, Alexander Parkhomenko, Burkert M Pieske, Bogdan A Popescu, Per K Rønnevik, Frans H Rutten, Juerg Schwitter, Petar Seferovic, Janina Stepinska, Pedro T Trindade, Adriaan A Voors, Faiez Zannad, Andreas Zeiher, ESC Committee for Practice Guidelines
雑誌名: Eur Heart J. 2012 Jul;33(14):1787-847. doi: 10.1093/eurheartj/ehs104. Epub 2012 May 19.
Abstract/Text
PMID 22611136  Eur Heart J. 2012 Jul;33(14):1787-847. doi: 10.1093/eur・・・
著者: ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
雑誌名: JAMA. 2002 Dec 18;288(23):2981-97.
Abstract/Text CONTEXT: Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality, but the optimal first-step therapy is unknown.
OBJECTIVE: To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease (CHD) or other cardiovascular disease (CVD) events vs treatment with a diuretic.
DESIGN: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, active-controlled clinical trial conducted from February 1994 through March 2002.
SETTING AND PARTICIPANTS: A total of 33 357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers.
INTERVENTIONS: Participants were randomly assigned to receive chlorthalidone, 12.5 to 25 mg/d (n = 15 255); amlodipine, 2.5 to 10 mg/d (n = 9048); or lisinopril, 10 to 40 mg/d (n = 9054) for planned follow-up of approximately 4 to 8 years.
MAIN OUTCOME MEASURES: The primary outcome was combined fatal CHD or nonfatal myocardial infarction, analyzed by intent-to-treat. Secondary outcomes were all-cause mortality, stroke, combined CHD (primary outcome, coronary revascularization, or angina with hospitalization), and combined CVD (combined CHD, stroke, treated angina without hospitalization, heart failure [HF], and peripheral arterial disease).
RESULTS: Mean follow-up was 4.9 years. The primary outcome occurred in 2956 participants, with no difference between treatments. Compared with chlorthalidone (6-year rate, 11.5%), the relative risks (RRs) were 0.98 (95% CI, 0.90-1.07) for amlodipine (6-year rate, 11.3%) and 0.99 (95% CI, 0.91-1.08) for lisinopril (6-year rate, 11.4%). Likewise, all-cause mortality did not differ between groups. Five-year systolic blood pressures were significantly higher in the amlodipine (0.8 mm Hg, P =.03) and lisinopril (2 mm Hg, P<.001) groups compared with chlorthalidone, and 5-year diastolic blood pressure was significantly lower with amlodipine (0.8 mm Hg, P<.001). For amlodipine vs chlorthalidone, secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine (10.2% vs 7.7%; RR, 1.38; 95% CI, 1.25-1.52). For lisinopril vs chlorthalidone, lisinopril had higher 6-year rates of combined CVD (33.3% vs 30.9%; RR, 1.10; 95% CI, 1.05-1.16); stroke (6.3% vs 5.6%; RR, 1.15; 95% CI, 1.02-1.30); and HF (8.7% vs 7.7%; RR, 1.19; 95% CI, 1.07-1.31).
CONCLUSION: Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.

PMID 12479763  JAMA. 2002 Dec 18;288(23):2981-97.
著者: M Packer, C M O'Connor, J K Ghali, M L Pressler, P E Carson, R N Belkin, A B Miller, G W Neuberg, D Frid, J H Wertheimer, A B Cropp, D L DeMets
雑誌名: N Engl J Med. 1996 Oct 10;335(15):1107-14. doi: 10.1056/NEJM199610103351504.
Abstract/Text BACKGROUND: Previous studies have shown that calcium-channel blockers increase morbidity and mortality in patients with chronic heart failure. We studied the effect of a new calcium-channel blocker, amlodipine, in patients with severe chronic heart failure.
METHODS: We randomly assigned 1153 patients with severe chronic heart failure and ejection fractions of less than 30 percent to double-blind treatment with either placebo (582 patients) or amlodipine (571 patients) for 6 to 33 months, while their usual therapy was continued. The randomization was stratified on the basis of whether patients had ischemic or nonischemic causes of heart failure. The primary end point of the study was death from any cause and hospitalization for major cardiovascular events.
RESULTS: Primary end points were reached in 42 percent of the placebo group and 39 percent of the amlodipine group, representing a 9 percent reduction in the combined risk of fatal and nonfatal events with amlodipine (95 percent confidence interval, 24 percent reduction to 10 percent increase; P=0.31). A total of 38 percent of the patients in the placebo group died, as compared with 33 percent of those in the amlodipine group, representing a 16 percent reduction in the risk of death with amlodipine (95 percent confidence interval, 31 percent reduction to 2 percent increase; P=0.07). Among patients with ischemic heart disease, there was no difference between the amlodipine and placebo groups in the occurrence of either end point. In contrast, among patients with nonischemic cardiomyopathy, amlodipine reduced the combined risk of fatal and nonfatal events by 31 percent (P=0.04) and decreased the risk of death by 46 percent (P<0.001).
CONCLUSIONS: Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study.

PMID 8813041  N Engl J Med. 1996 Oct 10;335(15):1107-14. doi: 10.1056・・・
著者: Paolo Verdecchia, Fabio Angeli, Claudio Cavallini, Roberto Gattobigio, Giorgio Gentile, Jan A Staessen, Gianpaolo Reboldi
雑誌名: Eur Heart J. 2009 Mar;30(6):679-88. doi: 10.1093/eurheartj/ehn575. Epub 2009 Jan 23.
Abstract/Text AIMS: It is unclear whether prevention of congestive heart failure (CHF) by drugs that inhibit the renin-angiotensin system (RAS) occurs over and beyond the reduction in blood pressure (BP) achieved by these drugs.
METHODS AND RESULTS: We conducted a meta-analysis of trials comparing angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), or calcium-channel blockers (CCBs), with diuretics, beta-blockers, or placebo in hypertensive or high-risk subjects without CHF at entry. Both fixed- and random-effect models were used. In trials vs. placebo, the risk of CHF was reduced by 21% with ACEIs (P = 0.007), whereas the effect of ARBs and CCBs was not significant (random-effect models). Thus, CCBs did not increase the risk of CHF. In trials vs. diuretics/beta-blockers, no differences were found between ACEIs and comparators [odds ratio (OR) 1.02; 95% confidence interval (CI) 0.84-1.24], whereas CCBs were associated with an 18% higher risk of CHF (OR 1.18; 95% CI 1.00-1.39; P = 0.048). Therefore, ACEIs were not superior to diuretics/beta-blockers for the prevention of CHF. Because heterogeneity between trials was significant, we investigated potential sources of heterogeneity by meta-regression. The risk of CHF decreased by 24% (P < 0.001) for each 5 mmHg reduction in systolic BP. The risk of CHF was 19% less with ACEIs/ARBs than CCBs (P < 0.001) and 16% less in studies without multiple risk factors required for entry (P = 0.009).
CONCLUSION: BP reduction is beneficial for the prevention of CHF. Over and beyond BP reduction, the protective effect of ACEIs and ARBs is greater than that of CCBs.

PMID 19168534  Eur Heart J. 2009 Mar;30(6):679-88. doi: 10.1093/eurhea・・・
著者: Justin A Ezekowitz, Finlay A McAlister
雑誌名: Eur Heart J. 2009 Feb;30(4):469-77. doi: 10.1093/eurheartj/ehn543. Epub 2008 Dec 9.
Abstract/Text CONTEXT: Aldosterone blockade has been used to treat acute myocardial infarction (MI) and chronic heart failure.
OBJECTIVE: The aim of this study is to summarize the evidence on the efficacy of spironolactone (SP), eplerenone (EP), or canrenoate (CAN) in patients with left ventricular dysfunction.
DATA SOURCES: A search of multiple electronic databases until June 2008 was supplemented by hand searches of reference lists of included studies and review articles, meeting abstracts, FDA reports, and contact with study authors and drug manufacturers.
STUDY SELECTION AND DATA EXTRACTION: Studies were eligible for inclusion if they included patients with left ventricular systolic or diastolic dysfunction, treatment with SP, EP, or CAN vs. control, and reported clinical outcomes. Nineteen randomized controlled trials (four in acute MI and 15 in heart failure, n = 10 807 patients) were included -- 14 of SP, three of EP, and three of CAN. Analysis was performed using relative risks (RRs) with 95% confidence intervals (CIs) and a random effects model with statistical heterogeneity assessed by I(2).
DATA SYNTHESIS: Aldosterone blockade reduced all-cause mortality by 20% (RR 0.80, 95% CI 0.74-0.87). All-cause mortality was reduced in both heart failure (RR = 0.75, 95% CI 0.67-0.84) and post-MI (RR 0.85, 95% CI 0.76-0.95) patients. Only nine trials reported hospitalizations, and the RR reduction was 23% (RR 0.77, 95% CI 0.68-0.87), although 98% of the outcomes came from two trials. Ejection fraction (EF) improved in the seven heart failure trials, which assessed this outcome (weighted mean difference 3.1%, 95% CI 1.6-4.5).
CONCLUSION: We demonstrated a 20% reduction in all-cause mortality with the use of aldosterone blockade in a clinically heterogeneous group of clinical trial participants with heart failure and post-MI. In addition, we found a 3.1% improvement in EF. Further study in those with less severe symptoms or preserved systolic function is warranted.

PMID 19066207  Eur Heart J. 2009 Feb;30(4):469-77. doi: 10.1093/eurhea・・・
著者: Bertram Pitt, Willem Remme, Faiez Zannad, James Neaton, Felipe Martinez, Barbara Roniker, Richard Bittman, Steve Hurley, Jay Kleiman, Marjorie Gatlin, Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators
雑誌名: N Engl J Med. 2003 Apr 3;348(14):1309-21. doi: 10.1056/NEJMoa030207. Epub 2003 Mar 31.
Abstract/Text BACKGROUND: Aldosterone blockade reduces mortality and morbidity among patients with severe heart failure. We conducted a double-blind, placebo-controlled study evaluating the effect of eplerenone, a selective aldosterone blocker, on morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.
METHODS: Patients were randomly assigned to eplerenone (25 mg per day initially, titrated to a maximum of 50 mg per day; 3319 patients) or placebo (3313 patients) [correction] in addition to optimal medical therapy. The study continued until 1012 deaths occurred. The primary end points were death from any cause and death from cardiovascular causes or hospitalization for heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia.
RESULTS: During a mean follow-up of 16 months, there were 478 deaths in the eplerenone group and 554 deaths in the placebo group (relative risk, 0.85; 95 percent confidence interval, 0.75 to 0.96; P=0.008). Of these deaths, 407 in the eplerenone group and 483 in the placebo group were attributed to cardiovascular causes (relative risk, 0.83; 95 percent confidence interval, 0.72 to 0.94; P=0.005). The rate of the other primary end point, death from cardiovascular causes or hospitalization for cardiovascular events, was reduced by eplerenone (relative risk, 0.87; 95 percent confidence interval, 0.79 to 0.95; P=0.002), as was the secondary end point of death from any cause or any hospitalization (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.98; P=0.02). There was also a reduction in the rate of sudden death from cardiac causes (relative risk, 0.79; 95 percent confidence interval, 0.64 to 0.97; P=0.03). The rate of serious hyperkalemia was 5.5 percent in the eplerenone group and 3.9 percent in the placebo group (P=0.002), whereas the rate of hypokalemia was 8.4 percent in the eplerenone group and 13.1 percent in the placebo group (P<0.001).
CONCLUSIONS: The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.

Copyright 2003 Massachusetts Medical Society
PMID 12668699  N Engl J Med. 2003 Apr 3;348(14):1309-21. doi: 10.1056/・・・
著者: B Pitt, F Zannad, W J Remme, R Cody, A Castaigne, A Perez, J Palensky, J Wittes
雑誌名: N Engl J Med. 1999 Sep 2;341(10):709-17. doi: 10.1056/NEJM199909023411001.
Abstract/Text BACKGROUND AND METHODS: Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes.
RESULTS: The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients.
CONCLUSIONS: Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure.

PMID 10471456  N Engl J Med. 1999 Sep 2;341(10):709-17. doi: 10.1056/N・・・
著者: Arnfried U Klingbeil, Markus Schneider, Peter Martus, Franz H Messerli, Roland E Schmieder
雑誌名: Am J Med. 2003 Jul;115(1):41-6.
Abstract/Text PURPOSE: Antihypertensive medications have different effects on left ventricular mass. We conducted a meta-analysis of double-blind trials that measured the effects of antihypertensive therapy on left ventricular mass.
METHODS: Medical databases and review articles were screened for double-blind, randomized controlled trials (through September 2002) that reported the effects of diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor antagonists on echocardiographic left ventricular mass in essential hypertension. Treatment arms of the same drug class, weighted for the number of patients, were combined. Analysis of covariance was performed to detect differences among drug classes in effects on left ventricular structure.
RESULTS: Eighty trials with 146 active treatment arms (n = 3767 patients) and 17 placebo arms (n = 346 patients) were identified. Adjusted for treatment duration and change in diastolic blood pressure, there was a significant difference (P = 0.004) among medication classes: left ventricular mass index decreased by 13% with angiotensin II receptor antagonists (95% confidence interval [CI]: 8% to 18%), by 11% with calcium antagonists (95% CI: 9% to 13%), by 10% with ACE inhibitors (95% CI: 8% to 12%), by 8% with diuretics (95% CI: 5% to 10%), and by 6% with beta-blockers (95% CI: 3% to 8%). In pairwise comparisons, angiotensin II receptor antagonists, calcium antagonists, and ACE inhibitors were more effective at reducing left ventricular mass than were beta-blockers (all P <0.05 with Bonferroni correction).
CONCLUSIONS: Antihypertensive drug classes have different effects on left ventricular mass reduction. Whether a greater reduction of left ventricular mass results in better clinical outcomes remains to be determined.

PMID 12867233  Am J Med. 2003 Jul;115(1):41-6.
著者: P Verdecchia, G Schillaci, C Borgioni, A Ciucci, R Gattobigio, I Zampi, G Reboldi, C Porcellati
雑誌名: Circulation. 1998 Jan 6-13;97(1):48-54.
Abstract/Text BACKGROUND: Increased left ventricular (LV) mass predicts an adverse outcome in patients with essential hypertension. The purpose of this study was to determine the relation between changes in LV mass during antihypertensive treatment and subsequent prognosis.
METHODS AND RESULTS: Procedures including echocardiography and 24-hour ambulatory blood pressure (BP) monitoring were performed in 430 patients with essential hypertension before therapy and after 1217 patient-years. Months or years after the follow-up visit, 31 patients suffered a first cardiovascular morbid event. The patients with a decrease in LV mass from the baseline to follow-up visit were compared with those with an increase in LV mass. There were 15 events (1.78 per 100 person-years) in the group with a decrease in LV mass and 16 events (3.03 per 100 person-years) in the group with an increase in LV mass (P=.029). In a Cox model, the lesser cardiovascular risk in the group with a decrease in LV mass (hazard ratio [HR], 0.46; 95% CI, 0.22 to 0.99) remained significant (P=.04) after adjustment for age (HR, 1.06; 95% CI, 1.03 to 1.10; P=.0008) and baseline LVH at ECG (HR, 3.85; 95% CI, 1.52 to 9.78; P=.012). In that model, baseline LV mass bordered on statistical significance (HR, 1.01; 95% CI, 1.00 to 1.03; P=.06). In the subset with LV mass > 125 g/m2 at the baseline visit (26% of subjects), the event rate was lower among the subjects who achieved regression of LVH than in those who did not (1.58 versus 6.27 events per 100 person-years; P=.002). This difference held in the multivariate analysis (HR, 0.18; 95% CI, 0.05 to 0.68).
CONCLUSIONS: In essential hypertension, a reduction in LV mass during treatment is a favorable prognostic marker that predicts a lesser risk for subsequent cardiovascular morbid events. Such an association is independent of baseline LV mass, baseline clinic and ambulatory BP, and degree of BP reduction.

PMID 9443431  Circulation. 1998 Jan 6-13;97(1):48-54.
著者: Kristian Wachtell, Peter M Okin, Michael H Olsen, Björn Dahlöf, Richard B Devereux, Hans Ibsen, Sverre E Kjeldsen, Lars H Lindholm, Markku S Nieminen, Kristian Thygesen
雑誌名: Circulation. 2007 Aug 14;116(7):700-5. doi: 10.1161/CIRCULATIONAHA.106.666594. Epub 2007 Jul 30.
Abstract/Text BACKGROUND: Sudden cardiac death (SCD) occurs more often in patients with ECG left ventricular (LV) hypertrophy. However, whether LV hypertrophy regression is associated with a reduced risk of SCD remains unclear.
METHODS AND RESULTS: The Losartan Intervention for End Point Reduction in Hypertension (LIFE) study included 9193 patients 55 to 80 years of age with essential hypertension and ECG LV hypertrophy by gender-adjusted Cornell product (CP) (RaVL+SV(3) [+6 mm in women]). QRS duration>2440 mm x ms) and/or Sokolow-Lyon voltage (SLV) (SV1+RV(5/6)>38 mm). During follow-up (mean, 4.8 years), 190 patients (2%) experienced SCD. In time-dependent Cox analyses, absence of in-treatment LV hypertrophy was associated with a decreased risk of SCD: every 1-SD-lower in-treatment CP (1050 mm x ms) was associated with a 28% lower risk of SCD (hazard ratio [HR], 0.72; 95% CI, 0.66 to 0.79) and 1-SD-lower SLV (10.5 mm) with a 26% lower risk (HR, 0.74; 95% CI, 0.65 to 0.84). After adjustment for time-varying systolic and diastolic blood pressures, treatment allocation, age, gender, baseline Framingham risk score, ECG strain, heart rate, urine albumin/creatinine ratio, smoking, diabetes, congestive heart failure, coronary heart disease, atrial fibrillation, and occurrence of myocardial infarction, atrial fibrillation, heart failure, and noncardiovascular death, both in-treatment CP and SLV remained predictive of SCD: each 1-SD-lower CP was associated with a 19% lower risk of SCD (HR, 0.81; 95% CI, 0.73 to 0.90) and 1-SD-lower SLV with an 18% lower risk (HR, 0.82; 95% CI, 0.70 to 0.98). Absence of in-treatment LV hypertrophy by both SLV and CP was associated with a 30% lower risk of SCD (HR, 0.70; 95% CI, 0.54 to 0.92).
CONCLUSIONS: Absence of in-treatment ECG LV hypertrophy is associated with reduced risk of SCD independently of treatment modality, blood pressure reduction, prevalent coronary heart disease, and other cardiovascular risk factors in hypertensive patients with LV hypertrophy.

PMID 17664372  Circulation. 2007 Aug 14;116(7):700-5. doi: 10.1161/CIR・・・
著者: Joachim Schrader, Stephan Lüders, Anke Kulschewski, Frank Hammersen, Kerstin Plate, Jürgen Berger, Walter Zidek, Peter Dominiak, Hans Christoph Diener, MOSES Study Group
雑誌名: Stroke. 2005 Jun;36(6):1218-26. doi: 10.1161/01.STR.0000166048.35740.a9. Epub 2005 May 5.
Abstract/Text BACKGROUND AND PURPOSE: In hypertensive stroke patients, for the same level of blood pressure control, eprosartan will be more effective than nitrendipine in reducing cerebrovascular and cardiovascular morbidity and mortality.
METHODS: A total of 1405 well-defined, high-risk hypertensives with cerebral event during the last 24 months (proven by cerebral computed tomography scan or nuclear magnetic resonance) were randomized to eprosartan or nitrendipine (mean follow-up 2.5 years). Primary end point was the composite of total mortality and all cardiovascular and cerebrovascular events, including all recurrent events.
RESULTS: Randomization was successful without significant differences in the baseline characteristics. Blood pressure was reduced to a comparable extent without any significant differences between the 2 groups during the whole study period (150.7/84 mm Hg and 152.0/87.2 mm Hg with eprosartan and nitrendipine therapy to 137.5/80.8 mm Hg and 136.0/80.2 mm Hg, respectively, confirmed by ambulatory blood pressure monitoring). Moreover, already after 3 months, normotensive mean values were achieved, and 75.5% reached values <140/90 mm Hg with the eprosartan regimen and 77.7% with the nitrendipine regimen. During follow-up, in total, 461 primary events occurred: 206 eprosartan and 255 nitrendipine (incidence density ratio [IDR], 0.79; 95% CI, 0.66 to 0.96; P=0.014). Cardiovascular events were: 77 eprosartan and 101 nitrendipine (IDR, 0.75; 95% CI, 0.55 to 1.02; P=0.06); cerebrovascular events: 102 eprosartan and134 nitrendipine (IDR, 0.75; 95% CI, 0.58 to 0.97; P=0.03).
CONCLUSIONS: The Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES) study was the first to compare an angiotensin II type 1 receptor antagonist with a calcium antagonist in secondary stroke prevention. In these high-risk hypertensive stroke patients, an early normotensive and comparable blood pressure was achieved. The combined primary end point was significantly lower in the eprosartan group.

PMID 15879332  Stroke. 2005 Jun;36(6):1218-26. doi: 10.1161/01.STR.000・・・
著者: K Radack, C Deck
雑誌名: Arch Intern Med. 1991 Sep;151(9):1769-76.
Abstract/Text Beta-Adrenergic blockers have been considered relatively contraindicated in peripheral arterial disease because of the perceived risk that these drugs could worsen intermittent claudication. Therefore, we conducted a meta-analysis of available randomized controlled trials from the English-language literature to determine whether or not beta-blockers exacerbate intermittent claudication. The primary focus of this analysis was the effect of beta-blockers on exercise duration, measured as walking capacity or endurance time. Outcomes were pooled where appropriate. Of 11 eligible reports, six included 11 individual controlled treatment comparisons that provided data for an analysis of pain-free exercise capacity; no effect size was statistically significant. The pooled effect size for pain-free walking distance was -0.24 (95% confidence interval, -0.62 to 0.14), indicating no significant impairment of walking capacity compared with placebo. Only one study reported that certain beta-blockers were associated with worsening of intermittent claudication. These results strongly suggest that beta-blockers do not adversely affect walking capacity or symptoms of intermittent claudication in patients with mild to moderate peripheral arterial disease. In the absence of other contraindications, beta-blockers can probably be used safely in such patients.

PMID 1679624  Arch Intern Med. 1991 Sep;151(9):1769-76.
著者: Christine Espinola-Klein, Gerhard Weisser, Annika Jagodzinski, Savvas Savvidis, Ascan Warnholtz, Mir-Abolfazl Ostad, Tommaso Gori, Thomas Munzel
雑誌名: Hypertension. 2011 Aug;58(2):148-54. doi: 10.1161/HYPERTENSIONAHA.110.169169. Epub 2011 Jun 6.
Abstract/Text The use of β-receptor blockers in peripheral arterial disease is controversial for their impact on vasomotor tone. The β-blocker nebivolol possesses vasodilating, endothelium-dependent, NO-releasing properties that might be beneficial in peripheral arterial disease. The aim of the study was to evaluate the effects and tolerability of nebivolol in comparison with metoprolol in these patients. A total of 128 patients with intermittent claudication and essential hypertension were included and double-blind randomized to receive 5 mg of nebivolol (N=65) or 95 mg of metoprolol (N=63) once daily. End points were changes in ankle-brachial index, initial and absolute claudication distance, endothelial function assessed by flow-mediated dilatation of the brachial artery, blood pressure, and quality of life using the claudication scale questionnaire. End point analysis was possible in 109 patients (85.2%). After the 48-week treatment period, ankle-brachial index and absolute claudication distance improved significantly in both patient groups (P<0.05 for both), with no difference across treatments. A significant increase of initial claudication distance was found in the nebivolol group. Adjusted mean change of initial claudication distance was 33.9% after nebivolol (P=0.003) and 16.6% after metoprolol (P=0.12) treatment. Quality of life was not influenced by either treatment, and there was no relevant change in flow-mediated dilatation in patients treated with nebivolol or metoprolol (P=0.16). Both drugs were equally effective in lowering blood pressure. In conclusion, β-blocker therapy was well tolerated in patients with intermittent claudication and arterial hypertension during a treatment period of ≈1 year. In the direct comparison, there was no significant difference between nebivolol and metoprolol.

PMID 21646599  Hypertension. 2011 Aug;58(2):148-54. doi: 10.1161/HYPER・・・
著者: Jackson T Wright, George Bakris, Tom Greene, Larry Y Agodoa, Lawrence J Appel, Jeanne Charleston, DeAnna Cheek, Janice G Douglas-Baltimore, Jennifer Gassman, Richard Glassock, Lee Hebert, Kenneth Jamerson, Julia Lewis, Robert A Phillips, Robert D Toto, John P Middleton, Stephen G Rostand, African American Study of Kidney Disease and Hypertension Study Group
雑誌名: JAMA. 2002 Nov 20;288(19):2421-31.
Abstract/Text CONTEXT: Hypertension is a leading cause of end-stage renal disease (ESRD) in the United States, with no known treatment to prevent progressive declines leading to ESRD.
OBJECTIVE: To compare the effects of 2 levels of blood pressure (BP) control and 3 antihypertensive drug classes on glomerular filtration rate (GFR) decline in hypertension.
DESIGN: Randomized 3 x 2 factorial trial with enrollment from February 1995 to September 1998.
SETTING AND PARTICIPANTS: A total of 1094 African Americans aged 18 to 70 years with hypertensive renal disease (GFR, 20-65 mL/min per 1.73 m(2)) were recruited from 21 clinical centers throughout the United States and followed up for 3 to 6.4 years.
INTERVENTIONS: Participants were randomly assigned to 1 of 2 mean arterial pressure goals, 102 to 107 mm Hg (usual; n = 554) or 92 mm Hg or less (lower; n = 540), and to initial treatment with either a beta-blocker (metoprolol 50-200 mg/d; n = 441), an angiotensin-converting enzyme inhibitor (ramipril 2.5-10 mg/d; n = 436) or a dihydropyridine calcium channel blocker, (amlodipine 5-10 mg/d; n = 217). Open-label agents were added to achieve the assigned BP goals.
MAIN OUTCOME MEASURES: Rate of change in GFR (GFR slope); clinical composite outcome of reduction in GFR by 50% or more (or > or =25 mL/min per 1.73 m2) from baseline, ESRD, or death. Three primary treatment comparisons were specified: lower vs usual BP goal; ramipril vs metoprolol; and amlodipine vs metoprolol.
RESULTS: Achieved BP averaged (SD) 128/78 (12/8) mm Hg in the lower BP group and 141/85 (12/7) mm Hg in the usual BP group. The mean (SE) GFR slope from baseline through 4 years did not differ significantly between the lower BP group (-2.21 [0.17] mL/min per 1.73 m2 per year) and the usual BP group (-1.95 [0.17] mL/min per 1.73 m2 per year; P =.24), and the lower BP goal did not significantly reduce the rate of the clinical composite outcome (risk reduction for lower BP group = 2%; 95% confidence interval [CI], -22% to 21%; P =.85). None of the drug group comparisons showed consistent significant differences in the GFR slope. However, compared with the metoprolol and amlodipine groups, the ramipril group manifested risk reductions in the clinical composite outcome of 22% (95% CI, 1%-38%; P =.04) and 38% (95% CI, 14%-56%; P =.004), respectively. There was no significant difference in the clinical composite outcome between the amlodipine and metoprolol groups.
CONCLUSIONS: No additional benefit of slowing progression of hypertensive nephrosclerosis was observed with the lower BP goal. Angiotensin-converting enzyme inhibitors appear to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline.

PMID 12435255  JAMA. 2002 Nov 20;288(19):2421-31.
著者: Pantelis A Sarafidis, Nitin Khosla, George L Bakris
雑誌名: Am J Kidney Dis. 2007 Jan;49(1):12-26. doi: 10.1053/j.ajkd.2006.10.014.
Abstract/Text The presence of proteinuria is a well-known risk factor for both the progression of renal disease and cardiovascular morbidity and mortality, and decreases in urine protein excretion level were associated with a slower decrease in renal function and decrease in risk of cardiovascular events. Increased blood pressure has a major role in the development of proteinuria in patients with either diabetic or nondiabetic kidney disease, and all recent guidelines recommend a blood pressure goal less than 130/80 mm Hg in patients with proteinuria to achieve maximal renal and cardiovascular protection. Drugs interfering with the renin-angiotensin system, ie, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, should be used as first-line antihypertensive therapy in patients with proteinuria because they seem to have a blood pressure-independent antiproteinuric effect, and if blood pressure levels are still out of goal, a diuretic should be added to this regimen. A combination of an angiotensin-converting enzyme inhibitor with an angiotensin receptor blocker or other classes of medications shown to decrease protein excretion, such as nondihydropyridine calcium antagonists or aldosterone receptor blockers, should be considered to decrease proteinuria further. This review provides an extended summary of current evidence regarding the associations of blood pressure with proteinuria, the rationale for currently recommended blood pressure goals, and the use of various classes of antihypertensive agents in proteinuric patients.

PMID 17185142  Am J Kidney Dis. 2007 Jan;49(1):12-26. doi: 10.1053/j.a・・・
著者: Suetonia C Palmer, Dimitris Mavridis, Eliano Navarese, Jonathan C Craig, Marcello Tonelli, Georgia Salanti, Natasha Wiebe, Marinella Ruospo, David C Wheeler, Giovanni F M Strippoli
雑誌名: Lancet. 2015 May 23;385(9982):2047-56. doi: 10.1016/S0140-6736(14)62459-4.
Abstract/Text BACKGROUND: The comparative efficacy and safety of pharmacological agents to lower blood pressure in adults with diabetes and kidney disease remains controversial. We aimed to investigate the benefits and harms of blood pressure-lowering drugs in this population of patients.
METHODS: We did a network meta-analysis of randomised trials from around the world comparing blood pressure-lowering agents in adults with diabetic kidney disease. Electronic databases (the Cochrane Collaboration, Medline, and Embase) were searched systematically up to January, 2014, for trials in adults with diabetes and kidney disease comparing orally administered blood pressure-lowering drugs. Primary outcomes were all-cause mortality and end-stage kidney disease. We also assessed secondary safety and cardiovascular outcomes. We did random-effects network meta-analysis to obtain estimates for primary and secondary outcomes and we presented these estimates as odds ratios or standardised mean differences with 95% CIs. We ranked the comparative effects of all drugs against placebo with surface under the cumulative ranking (SUCRA) probabilities.
FINDINGS: 157 studies comprising 43,256 participants, mostly with type 2 diabetes and chronic kidney disease, were included in the network meta-analysis. No drug regimen was more effective than placebo for reducing all-cause mortality. However, compared with placebo, end-stage renal disease was significantly less likely after dual treatment with an angiotensin-receptor blocker (ARB) and an angiotensin-converting-enzyme (ACE) inhibitor (odds ratio 0·62, 95% CI 0·43-0·90) and after ARB monotherapy (0·77, 0·65-0·92). No regimen significantly increased hyperkalaemia or acute kidney injury, although combined ACE inhibitor and ARB treatment had the lowest rank among all interventions because of borderline increases in estimated risks of these harms (odds ratio 2·69, 95% CI 0·97-7·47 for hyperkalaemia; 2·69, 0·98-7·38 for acute kidney injury).
INTERPRETATION: No blood pressure-lowering strategy prolonged survival in adults with diabetes and kidney disease. ACE inhibitors and ARBs, alone or in combination, were the most effective strategies against end-stage kidney disease. Any benefits of combined ACE inhibitor and ARB treatment need to be balanced against potential harms of hyperkalaemia and acute kidney injury.
FUNDING: Canterbury Medical Research Foundation, Italian Medicines Agency.

Copyright © 2015 Elsevier Ltd. All rights reserved.
PMID 26009228  Lancet. 2015 May 23;385(9982):2047-56. doi: 10.1016/S01・・・
著者: Hans-Henrik Parving, Barry M Brenner, John J V McMurray, Dick de Zeeuw, Steven M Haffner, Scott D Solomon, Nish Chaturvedi, Frederik Persson, Akshay S Desai, Maria Nicolaides, Alexia Richard, Zhihua Xiang, Patrick Brunel, Marc A Pfeffer, ALTITUDE Investigators
雑誌名: N Engl J Med. 2012 Dec 6;367(23):2204-13. doi: 10.1056/NEJMoa1208799. Epub 2012 Nov 3.
Abstract/Text BACKGROUND: This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both.
METHODS: In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level.
RESULTS: The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons).
CONCLUSIONS: The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.).

PMID 23121378  N Engl J Med. 2012 Dec 6;367(23):2204-13. doi: 10.1056/・・・
著者:
雑誌名: Diabetes Care. 2007 Jun;30(6):1577-8. Epub 2007 Mar 26.
Abstract/Text
PMID 17389334  Diabetes Care. 2007 Jun;30(6):1577-8. Epub 2007 Mar 26・・・
著者: Sripal Bangalore, Robert Fakheri, Bora Toklu, Franz H Messerli
雑誌名: BMJ. 2016 Feb 11;352:i438. Epub 2016 Feb 11.
Abstract/Text OBJECTIVE:  To evaluate the outcomes with use of renin angiotensin system (RAS) blockers compared with other antihypertensive agents in people with diabetes.
DESIGN:  Meta-analysis.
DATA SOURCES AND STUDY SELECTION:  PubMed, Embase, and the Cochrane central register of controlled trials databases for randomized trials of RAS blockers versus other antihypertensive agents in people with diabetes mellitus. Outcomes were death, cardiovascular death, myocardial infarction, angina, stroke, heart failure, revascularization, and end stage renal disease.
RESULTS:  The search yielded 19 randomized controlled trials that enrolled 25 414 participants with diabetes for a total of 95 910 patient years of follow-up. When compared with other antihypertensive agents, RAS blockers were associated with a similar risk of death (relative risk 0.99, 95% confidence interval 0.93 to 1.05), cardiovascular death (1.02, 0.83 to 1.24), myocardial infarction (0.87, 0.64 to 1.18), angina pectoris (0.80, 0.58 to 1.11), stroke (1.04, 0.92 to 1.17), heart failure (0.90, 0.76 to 1.07), and revascularization (0.97, 0.77 to 1.22). There was also no difference in the hard renal outcome of end stage renal disease (0.99, 0.78 to 1.28) (power of 94% to show a 23% reduction in end stage renal disease).
CONCLUSIONS:  In people with diabetes, RAS blockers are not superior to other antihypertensive drug classes such as thiazides, calcium channel blockers, and β blockers at reducing the risk of hard cardiovascular and renal endpoints. These findings support the recommendations of the guidelines of the European Society of Cardiology/European Society of Hypertension and eighth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure to also use other antihypertensive agents in people with diabetes but without kidney disease.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
PMID 26868137  BMJ. 2016 Feb 11;352:i438. Epub 2016 Feb 11.
著者: Kazuomi Kario, Kenta Okada, Mitsutoshi Kato, Masafumi Nishizawa, Tetsuro Yoshida, Tsuguyoshi Asano, Kazuaki Uchiyama, Yawara Niijima, Tomohiro Katsuya, Hidenori Urata, Jun-Ichi Osuga, Takeshi Fujiwara, Shoji Yamazaki, Naoko Tomitani, Hiroshi Kanegae
雑誌名: Circulation. 2018 Nov 29;. doi: 10.1161/CIRCULATIONAHA.118.037076. Epub 2018 Nov 29.
Abstract/Text BACKGROUND: The risk of cardiovascular disease and mortality in salt-sensitive patients with diabetes mellitus and uncontrolled nocturnal hypertension is high. The SGLT2 inhibitor and ARB Combination theRapy in pAtients with diabetes and uncontrolled nocturnal hypertension (SACRA) study investigated changes in blood pressure (BP) with empagliflozin plus existing antihypertensive therapy.
METHODS: This multicenter, double-blind, parallel study was conducted in Japan. Adult patients with type 2 diabetes mellitus and uncontrolled nocturnal hypertension receiving stable antihypertensive therapy including angiotensin receptor blockers were randomized to 12 weeks' treatment with empagliflozin 10 mg once daily or placebo. Clinic BP was measured at baseline, and weeks 4, 8 and 12; 24-hour ambulatory BP monitoring (ABPM) was performed at baseline and week 12; and morning home BP was determined for 5 days before each visit. Primary efficacy end point was change from baseline in nighttime BP (ABPM).
RESULTS: 132 non-obese, older patients with well-controlled blood glucose were randomized (mean age 70 years, mean body mass index 26 kg/m2). Empagliflozin, but not placebo, significantly reduced nighttime systolic BP versus baseline (-6.3 mmHg; p=0.004); between-group difference in change from baseline -4.3 mmHg (p=0.159). Reductions in daytime, 24-hour, morning home and clinic systolic BP at 12 weeks with empagliflozin were significantly greater than with placebo (-9.5, -7.7, -7.5 and -8.6 mmHg, respectively; all p≤0.002). Between-group differences in body weight and glycosylated hemoglobin reductions were significant, but small (-1.3 kg and -0.33%; both p<0.001). At 4-weeks, amino terminal pro-B-type natriuretic peptide levels were reduced to a greater extent in the empagliflozin versus placebo group (-12.1%; p=0.013); atrial natriuretic peptide levels decreased with empagliflozin versus placebo at weeks 4 and 12 (-8.2% [p=0.008] and -9.7% [p=0.019]). Changes in antihypertensive medication during the study did not differ significantly between groups.
CONCLUSIONS: Non-severely obese older diabetes patients with uncontrolled nocturnal hypertension showed significant BP reductions without marked reductions in glucose with the addition of empagliflozin to existing antihypertensive and antidiabetic therapy. Use of SGLT2 inhibitors in specific groups (e.g. those with nocturnal hypertension, diabetes, and high salt sensitivity) could help reduce the risk of heart failure and cardiovascular mortality.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov Unique identifier: NCT03050229.

PMID 30586745  Circulation. 2018 Nov 29;. doi: 10.1161/CIRCULATIONAHA.・・・
著者: Takashi Iwanaga, Masanobu Sato, Tomoji Maeda, Toshio Ogihara, Ikumi Tamai
雑誌名: J Pharmacol Exp Ther. 2007 Jan;320(1):211-7. doi: 10.1124/jpet.106.112755. Epub 2006 Oct 16.
Abstract/Text Serum uric acid (SUA) is currently recognized as a risk factor for cardiovascular disease. It has been reported that an angiotensin II receptor blocker (ARB), losartan, decreases SUA level, whereas other ARBs, such as candesartan, have no lowering effect. Because the renal uric acid transporter (URAT1) is an important factor controlling the SUA level, we examined the involvement of URAT1 in those differential effects of various ARBs on SUA level at clinically relevant concentrations. This study was done by using URAT1-expressing Xenopus oocytes. Losartan, pratosartan, and telmisartan exhibited cis-inhibitory effects on the uptake of uric acid by URAT1, whereas at higher concentrations, only telmisartan did, and these ARBs reduced the uptake in competitive inhibition kinetics. On the other hand, candesartan, EXP3174 [2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yI)methyl]imidazole-5-carboxylic acid] (a major metabolite of losartan), olmesartan, and valsartan were not inhibitory. Preloading of those ARBs in the oocytes enhanced the URAT1-mediated uric acid uptake, showing a trans-stimulatory effect. The present study is a first demonstration of the differential effects of ARBs on URAT1 that some ARBs are both cis-inhibitory and trans-stimulatory, depending on concentration, whereas others exhibit either a trans-stimulatory or cis-inhibitory effect alone, which could explain the clinically observed differential effects of ARBs on SUA level. Furthermore, it was found that such differential effects of ARBs on URAT1 could be predicted from the partial chemical structures of ARBs, which will be useful information for the appropriate use and development of ARBs without an increase of SUA.

PMID 17043154  J Pharmacol Exp Ther. 2007 Jan;320(1):211-7. doi: 10.11・・・
著者: Hiroaki Naritomi, Toshiro Fujita, Sadayoshi Ito, Toshio Ogihara, Kazuyuki Shimada, Kazuaki Shimamoto, Heizo Tanaka, Nobuo Yoshiike
雑誌名: Hypertens Res. 2008 Feb;31(2):295-304. doi: 10.1291/hypres.31.295.
Abstract/Text The Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH) study is a nationwide, prospective, multicentered, observational study that was designed to enroll 30,000 hypertensive Japanese patients from more than 3,000 private practitioners. It is the first large-scale observational study to assess the efficacy and safety of losartan, an angiotensin II receptor antagonist, in Japan. Patients were enrolled between June 2000 and May 2002, and followed up to June 2005. The data from 29,850 patients were used for the analysis of safety and efficacy. These patients were treated with losartan mostly at a daily dose of 25-50 mg. The mean follow-up period was 2.9 years. The patients were aged 62.4+/-12.1 years (mean+/-SD) and their mean systolic/diastolic blood pressure was 165.3+/-17.2/94.3+/-11.7 mmHg (mean+/-SD). Mean blood pressure in patients who were evaluated for efficacy decreased from 165.8/94.8 mmHg (n=26,512) at baseline to 145.5/84.4 mmHg after 3 months (n=21,269) and 138.6/80.0 mmHg after 36 months of treatment (n=13,879). Blood pressure was well controlled during the study period by losartan alone or losartan-based combination therapy. In nearly half of the patients, blood pressure was reduced to less than 140/90 mmHg during the study period. In addition to its antihypertensive effect, losartan reduced the uric acid level in patients whose baseline uric acid level was > or =7 mg/dL. Losartan also prevented acceleration of proteinuria. Adverse drug reactions occurred in 1,081 of the 29,850 patients. Long-term losartan therapy was effective and well tolerated in Japanese clinical practice.

PMID 18360050  Hypertens Res. 2008 Feb;31(2):295-304. doi: 10.1291/hyp・・・
著者: Atsushi Enomoto, Hiroaki Kimura, Arthit Chairoungdua, Yasuhiro Shigeta, Promsuk Jutabha, Seok Ho Cha, Makoto Hosoyamada, Michio Takeda, Takashi Sekine, Takashi Igarashi, Hirotaka Matsuo, Yuichi Kikuchi, Takashi Oda, Kimiyoshi Ichida, Tatsuo Hosoya, Kaoru Shimokata, Toshimitsu Niwa, Yoshikatsu Kanai, Hitoshi Endou
雑誌名: Nature. 2002 May 23;417(6887):447-52. doi: 10.1038/nature742. Epub 2002 Apr 14.
Abstract/Text Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes, as demonstrated by its capacity of neuroprotection. It is present at higher levels in human blood (200 500 microM) than in other mammals, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences. Here we identify the long-hypothesized urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate anion exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.

PMID 12024214  Nature. 2002 May 23;417(6887):447-52. doi: 10.1038/natu・・・
著者: Sadayoshi Ito, Hiroaki Naritomi, Toshio Ogihara, Kazuyuki Shimada, Kazuaki Shimamoto, Heizo Tanaka, Nobuo Yoshiike
雑誌名: Hypertens Res. 2012 Aug;35(8):867-73. doi: 10.1038/hr.2012.59. Epub 2012 May 10.
Abstract/Text High serum uric acid level (SUA) and chronic kidney disease (CKD) are risk factors for cardiovascular events (CVEs). However, their interactions as cardiovascular risk factors remain unknown. This subanalysis of the Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH) study included 7629 patients, in whom the serum creatinine level was measured at least twice. The study examined the impact of hyperuricemia (SUA ≥7 mg dl(-1)) on CVE according to the level of renal dysfunction and whether early changes in SUA predicted future glomerular filtration rates (GFRs). The mean follow-up period was 3.1 years. The patients were divided into three groups according to the baseline estimated GFR (eGFR): groups A, B and C with eGFR <45, 45-59 and ≥60 ml min(-1) per 1.73 m(2), respectively. eGFR increased from 38.1 to 57.6, from 52.8 to 67.5 and from 74.7 to 80.7 ml min(-1) per 1.73 m(2) in groups A, B and C, respectively. In non-hyperuricemic patients, the CVE rate was 10.83, 4.98 and 4.21/1000 person-years in groups A, B and C, respectively, while in hyperuricemic patients, the corresponding values were 14.18, 17.02 and 5.93. Thus, hyperuricemia increased the risk of CVE only in group B (relative risk (RR) 3.43 (95% confidence interval (CI) 1.55 to 7.60); P<0.002). The final change in the eGFR was negatively correlated with the change in SUA from baseline to year 1 (P<0.001). CVEs were more frequent in those with a decrease in eGFR. Hyperuricemia may be a major determinant of increased cardiovascular risk in CKD stage 3A, and SUA may be involved in the progression of CKD. Changes in the GFR influence the rate of CVE.

PMID 22573200  Hypertens Res. 2012 Aug;35(8):867-73. doi: 10.1038/hr.2・・・
著者: Kazuomi Kario
雑誌名: Hypertension. 2018 Jun;71(6):997-1009. doi: 10.1161/HYPERTENSIONAHA.118.10971. Epub 2018 Apr 30.
Abstract/Text
PMID 29712746  Hypertension. 2018 Jun;71(6):997-1009. doi: 10.1161/HYP・・・
著者: Norman M Kaplan
雑誌名: Hypertension. 2011 Dec;58(6):994-5. doi: 10.1161/HYPERTENSIONAHA.111.183525. Epub 2011 Oct 24.
Abstract/Text
PMID 22025371  Hypertension. 2011 Dec;58(6):994-5. doi: 10.1161/HYPERT・・・
著者: G L Bakris, R D Toto, P A McCullough, R Rocha, D Purkayastha, P Davis, GUARD (Gauging Albuminuria Reduction With Lotrel in Diabetic Patients With Hypertension) Study Investigators
雑誌名: Kidney Int. 2008 Jun;73(11):1303-9. doi: 10.1038/ki.2008.102. Epub 2008 Mar 19.
Abstract/Text Clinical practice guidelines recommend blockers of the renin-angiotensin system alone or in combination with other agents to reduce blood pressure and albuminuria in patients with type 2 diabetes. Dihydropyridine calcium channel blockers, however, may lower blood pressure but not albuminuria in these patients. Here we tested the hypothesis that combining an ACE inhibitor with either a thiazide diuretic or a calcium channel blocker will cause similar reductions in blood pressure and albuminuria in hypertensive type 2 diabetics. We conducted a double blind randomized controlled trial on 332 hypertensive, albuminuric type 2 diabetic patients treated with benazepril with either amlodipine or hydrochlorothiazide for 1 year. The trial employed a non-inferiority design. Both combinations significantly reduced the urinary albumin to creatinine ratio and sitting blood pressure of the entire cohort. The percentage of patients progressing to overt proteinuria was similar for both groups. When we examined patients who had only microalbuminuria and hypertension we found that a larger percentage of the diuretic and ACE inhibitor normalized their albuminuria. We conclude that initial treatment using benzaepril with a diuretic resulted in a greater reduction in albuminuria compared to the group of ACE inhibitor and calcium channel blocker. In contrast, blood pressure reduction, particularly the diastolic component, favored the combination with amilodipine. The dissociation between reductions in blood pressure and albuminuria may be related to factors other than blood pressure.

PMID 18354383  Kidney Int. 2008 Jun;73(11):1303-9. doi: 10.1038/ki.200・・・
著者: Kenneth Jamerson, Michael A Weber, George L Bakris, Björn Dahlöf, Bertram Pitt, Victor Shi, Allen Hester, Jitendra Gupte, Marjorie Gatlin, Eric J Velazquez, ACCOMPLISH Trial Investigators
雑誌名: N Engl J Med. 2008 Dec 4;359(23):2417-28. doi: 10.1056/NEJMoa0806182.
Abstract/Text BACKGROUND: The optimal combination drug therapy for hypertension is not established, although current U.S. guidelines recommend inclusion of a diuretic. We hypothesized that treatment with the combination of an angiotensin-converting-enzyme (ACE) inhibitor and a dihydropyridine calcium-channel blocker would be more effective in reducing the rate of cardiovascular events than treatment with an ACE inhibitor plus a thiazide diuretic.
METHODS: In a randomized, double-blind trial, we assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. The primary end point was the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization.
RESULTS: The baseline characteristics of the two groups were similar. The trial was terminated early after a mean follow-up of 36 months, when the boundary of the prespecified stopping rule was exceeded. Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-hydrochlorothiazide group. There were 552 primary-outcome events in the benazepril-amlodipine group (9.6%) and 679 in the benazepril-hydrochlorothiazide group (11.8%), representing an absolute risk reduction with benazepril-amlodipine therapy of 2.2% and a relative risk reduction of 19.6% (hazard ratio, 0.80, 95% confidence interval [CI], 0.72 to 0.90; P<0.001). For the secondary end point of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke, the hazard ratio was 0.79 (95% CI, 0.67 to 0.92; P=0.002). Rates of adverse events were consistent with those observed from clinical experience with the study drugs.
CONCLUSIONS: The benazepril-amlodipine combination was superior to the benazepril-hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events. (ClinicalTrials.gov number, NCT00170950.)

2008 Massachusetts Medical Society
PMID 19052124  N Engl J Med. 2008 Dec 4;359(23):2417-28. doi: 10.1056/・・・
著者: George L Bakris, Pantelis A Sarafidis, Matthew R Weir, Björn Dahlöf, Bertram Pitt, Kenneth Jamerson, Eric J Velazquez, Linda Staikos-Byrne, Roxzana Y Kelly, Victor Shi, Yann-Tong Chiang, Michael A Weber, ACCOMPLISH Trial investigators
雑誌名: Lancet. 2010 Apr 3;375(9721):1173-81. doi: 10.1016/S0140-6736(09)62100-0. Epub 2010 Feb 18.
Abstract/Text BACKGROUND: The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed that initial antihypertensive therapy with benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing cardiovascular morbidity and mortality. We assessed the effects of these drug combinations on progression of chronic kidney disease.
METHODS: ACCOMPLISH was a double-blind, randomised trial undertaken in five countries (USA, Sweden, Norway, Denmark, and Finland). 11 506 patients with hypertension who were at high risk for cardiovascular events were randomly assigned via a central, telephone-based interactive voice response system in a 1:1 ratio to receive benazepril (20 mg) plus amlodipine (5 mg; n=5744) or benazepril (20 mg) plus hydrochlorothiazide (12.5 mg; n=5762), orally once daily. Drug doses were force-titrated for patients to attain recommended blood pressure goals. Progression of chronic kidney disease, a prespecified endpoint, was defined as doubling of serum creatinine concentration or end-stage renal disease (estimated glomerular filtration rate <15 mL/min/1.73 m(2) or need for dialysis). Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00170950.
FINDINGS: The trial was terminated early (mean follow-up 2.9 years [SD 0.4]) because of superior efficacy of benazepril plus amlodipine compared with benazepril plus hydrochlorothiazide. At trial completion, vital status was not known for 143 (1%) patients who were lost to follow-up (benazepril plus amlodipine, n=70; benazepril plus hydrochlorothiazide, n=73). All randomised patients were included in the ITT analysis. There were 113 (2.0%) events of chronic kidney disease progression in the benazepril plus amlodipine group compared with 215 (3.7%) in the benazepril plus hydrochlorothiazide group (HR 0.52, 0.41-0.65, p<0.0001). The most frequent adverse event in patients with chronic kidney disease was peripheral oedema (benazepril plus amlodipine, 189 of 561, 33.7%; benazepril plus hydrochlorothiazide, 85 of 532, 16.0%). In patients with chronic kidney disease, angio-oedema was more frequent in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. In patients without chronic kidney disease, dizziness, hypokalaemia, and hypotension were more frequent in the benazepril plus hydrochlorothiazide group than in the benazepril plus amlodipine group.
INTERPRETATION: Initial antihypertensive treatment with benazepril plus amlodipine should be considered in preference to benazepril plus hydrochlorothiazide since it slows progression of nephropathy to a greater extent.
FUNDING: Novartis.

Copyright 2010 Elsevier Ltd. All rights reserved.
PMID 20170948  Lancet. 2010 Apr 3;375(9721):1173-81. doi: 10.1016/S014・・・
著者: T Fujita, K Ando, H Nishimura, T Ideura, G Yasuda, M Isshiki, K Takahashi, Cilnidipine versus Amlodipine Randomised Trial for Evaluation in Renal Desease(CARTER) Study Investigators
雑誌名: Kidney Int. 2007 Dec;72(12):1543-9. doi: 10.1038/sj.ki.5002623. Epub 2007 Oct 17.
Abstract/Text Cilnidipine, a dual L-/N-type calcium channel blocker, dilates both efferent and afferent arterioles and is renoprotective. Our multi-center, open-labeled, and randomized trial compared the antiproteinuric effect of cilnidipine with that of amlodipine in hypertensive patients with kidney disease. A group of 339 patients, already receiving renin-angiotensin system inhibitor treatment, were randomly assigned to cilnidipine or amlodipine. The primary endpoint was a decrease in the urinary protein to creatinine ratio. After 1-year of treatment, systolic and diastolic blood pressures were significantly reduced in both groups which did not differ between them. The urinary protein to creatinine ratio significantly decreased in the cilnidipine compared to the amlodipine group. Cilnidipine exerted a greater antiproteinuric effect than amlodipine even in the subgroup whose blood pressure fell below the target level. This study suggests that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in hypertensive patients when coupled with a renin-angiotensin system inhibitor.

PMID 17943080  Kidney Int. 2007 Dec;72(12):1543-9. doi: 10.1038/sj.ki.・・・
著者: Toshihiko Ishimitsu, Tomoko Kameda, Akira Akashiba, Toshiaki Takahashi, Satoshi Ohta, Masayoshi Yoshii, Junichi Minami, Hidehiko Ono, Atsushi Numabe, Hiroaki Matsuoka
雑誌名: Hypertens Res. 2007 Jul;30(7):621-6. doi: 10.1291/hypres.30.621.
Abstract/Text Efonidipine, a dihydropirydine calcium channel blocker, has been shown to dilate the efferent glomerular arterioles as effectively as the afferent arterioles. The present study compared the chronic effects of efonidipine and amlodipine on proteinuria in patients with chronic glomerulonephritis. The study subjects were 21 chronic glomerulonephritis patients presenting with spot proteinuria greater than 30 mg/dL and serum creatinine concentrations of or=130/85 mmHg. Efonidipine 20-60 mg twice daily and amlodipine 2.5-7.5 mg once daily were given for 4 months each in a random crossover manner. In both periods, calcium channel blockers were titrated when the BP exceeded 130/85 mmHg. Blood sampling and urinalysis were performed at the end of each treatment period. The average blood pressure was comparable between the efonidipine and the amlodipine periods (133+/-10/86+/-5 vs. 132+/-8/86+/-5 mmHg). Urinary protein excretion was significantly less in the efonidipine period than in the amlodipine period (1.7+/-1.5 vs. 2.0+/-1.6 g/g creatinine, p=0.04). Serum albumin was significantly higher in the efonidipine period than the amlodipine period (4.0+/-0.5 vs. 3.8+/-0.5 mEq/L, p=0.03). Glomerular filtration rate was not significantly different between the two periods. Plasma aldosterone was lower in the efonidipine period than in the amlodipine period (52+/-46 vs. 72+/-48 pg/mL, p=0.009). It may be concluded that efonidipine results in a greater reduction of plasma aldosterone and proteinuria than amlodipine, and that these effects occur by a mechanism independent of blood pressure reduction. A further large-scale clinical trial will be needed in order to apply the findings of this study to the treatment of patients with renal disease.

PMID 17785930  Hypertens Res. 2007 Jul;30(7):621-6. doi: 10.1291/hypre・・・
著者: Tsukasa Nakamura, Takeshi Sugaya, Yasuhiro Kawagoe, Tsukasa Suzuki, Yoshihiko Ueda, Hikaru Koide, Teruo Inoue, Koichi Node
雑誌名: Am J Med Sci. 2007 Jun;333(6):321-6. doi: 10.1097/MAJ.0b013e318065c254.
Abstract/Text BACKGROUND: Hypoxia plays a significant role in the pathogenesis and progression of chronic renal disease. Urinary liver-type fatty acid binding protein (L-FABP) levels reflect the clinical prognosis of chronic renal disease. The calcium channel blocker azelnidipine has anti-oxidative properties and these may contribute to the beneficial effects of this drug. The aim of the present study was to determine whether azelnidipine and/or amlodipine affected urinary protein excretion or the urinary levels of 8-OHdG and L-FABP in hypertensive patients with mild chronic kidney disease (CKD).
METHODS: Thirty moderately hypertensive chronic kidney disease patients were randomly assigned to 2 treatment groups: azelnidipine 16 mg once daily or amlodipine 5 mg once daily. Treatment was continued for 6 months. Urinary protein excretion and urinary levels of 8-OHdG and urinary L-FABP were measured before 3 and 6 months after the treatment period.
RESULTS: Both drugs exhibited comparable and significant effects on the systolic and diastolic blood pressure. Azelnidipine decreased heart rate significantly after 3 and 6 months whereas amlodipine increased it significantly after 3 and 6 months. Urinary protein excretion, urinary 8-OHdG and urinary L-FABP levels decreased significantly after 3 months (p < 0.05) and 6 months (p < 0.05) in the azelnidipine group. In contrast, amlodipine showed little effect on urinary protein excretion or the urinary levels of 8-OHdG and L-FABP throughout the experimental period.
CONCLUSIONS: Azelnidipine is renoprotective in hypertensive patients with mild CKD and this action is, at least in part, due to the anti-oxidative effect.

PMID 17570983  Am J Med Sci. 2007 Jun;333(6):321-6. doi: 10.1097/MAJ.0・・・
著者: Mitsuru Ohishi, Takashi Takagi, Norihisa Ito, Minako Terai, Yuji Tatara, Norihiro Hayashi, Atsushi Shiota, Tomohiro Katsuya, Hiromi Rakugi, Toshio Ogihara
雑誌名: Hypertens Res. 2007 Sep;30(9):797-806. doi: 10.1291/hypres.30.797.
Abstract/Text Both strict blood pressure control and efferent artery dilatation are critical in reducing proteinuria, which in turn helps to regulate blood pressure. Benidipine, an L- and T-type calcium channel blocker, has the potential for increased effectiveness compared with L-type-dominant calcium channel blockers such as amlodipine. Therefore, we evaluated blood pressure and proteinuria after changeover from amlodipine to benidipine in poorly controlled hypertensive patients. Fifty-eight hypertensive outpatients undergoing amlodipine treatment and unable to achieve optimal blood pressure as determined by Japanese Society of Hypertension Guidelines for the Management of Hypertention (JSH 2004) were changed over to benidipine treatment. We measured blood pressure and pulse rate and assessed urinary protein excretion before and after changeover. Systolic and diastolic blood pressure dropped from 151/90 mmHg to 140/81 mmHg (p<0.0001). Mean blood pressure (p<0.0001) and pulse pressure (p=0.0069) were also reduced, but pulse rate increased from 75 bpm to 78 bpm (p=0.0047). Urinary protein excretion adjusted for urinary creatinine was reduced from 0.35 +/- 0.82 to 0.22 +/- 0.55 g/g creatinine (p=0.0119). The urinary protein reduction was observed only in patients with renin-angiotensin inhibition (p=0.0216). By switching from amlodipine to benidipine treatment, more than 80% of patients reduced their blood pressure, and more than 40% achieved optimal blood pressure. Higher urinary protein excretion (p<0.0001), lower glomerular filtration rate (p=0.0011) and presence of diabetes (p=0.0284) were correlated with reduction of urinary proteins during changeover. Taken together, our results suggest that benidipine may have greater efficacy than amlodipine in reducing blood pressure and proteinuria.

PMID 18037772  Hypertens Res. 2007 Sep;30(9):797-806. doi: 10.1291/hyp・・・
著者: Ilse-Nirmala Bähr, Patrizia Tretter, Janine Krüger, Renee G Stark, Julia Schimkus, Thomas Unger, Kai Kappert, Jürgen Scholze, Klaus G Parhofer, Ulrich Kintscher
雑誌名: Hypertension. 2011 Oct;58(4):725-32. doi: 10.1161/HYPERTENSIONAHA.111.173542. Epub 2011 Aug 29.
Abstract/Text The present study aimed to explore the anti-inflammatory effects and peroxisome proliferator-activated receptor-γ (PPARγ)-activating properties of the angiotensin type 1 receptor blocker telmisartan by analysis of serum interleukin 6 levels and monocytic PPARγ target gene expression in drug-naïve patients with the metabolic syndrome. This was a 14-week, randomized, double-blind, placebo-controlled 2-center study with telmisartan 80 mg/d and telmisartan 160 mg/d in 54 patients with the metabolic syndrome. In addition to clinical laboratory measurements, peripheral monocytes were extracted by negative isolation using a Dynal Monocyte kit to evaluate ligand-activated PPARγ target gene expression (CD36 and CD163) at baseline and study end using quantitative real-time RT-PCR. In this low-risk patient population, telmisartan (80 and 160 mg) treatment did not significantly affect serum interleukin 6 levels. Expression of the PPARγ target gene CD36 in monocytes was markedly induced by telmisartan from baseline to study end (telmisartan 80 mg: 2.3±1.5-fold change versus placebo [P value not significant]; telmisartan 160 mg: 3.5±0.9-fold change versus placebo [P<0.05]). The recently reported PPARγ target gene CD163 was slightly induced by telmisartan (telmisartan 80 mg: 1.1±0.3-fold change versus placebo [P value not significant]; telmisartan 160 mg: 1.4±0.4-fold change versus placebo [P value not significant]), which did not reach statistical significance. This is the first clinical description of monocytic PPARγ target gene regulation with high-dose telmisartan treatment. These data implicate that the angiotensin type 1 receptor blocker telmisartan activates PPARγ in circulating monocytes of patients with the metabolic syndrome.

PMID 21876071  Hypertension. 2011 Oct;58(4):725-32. doi: 10.1161/HYPER・・・
著者: Daniel Caldeira, Joana Alarcão, António Vaz-Carneiro, João Costa
雑誌名: BMJ. 2012 Jul 11;345:e4260. Epub 2012 Jul 11.
Abstract/Text OBJECTIVE: To systematically review longitudinal studies evaluating use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and risk of pneumonia.
DESIGN: Systematic review and meta-analysis.
DATA SOURCES: Medline through PubMed, Web of Science with conference proceedings (inception to June 2011), and US Food and Drug Administration website (June 2011). Systematic reviews and references of retrieved articles were also searched.
STUDY SELECTION: Two reviewers independently selected randomised controlled trials and cohort and case-control studies evaluating the use of ACE inhibitors or ARBs and risk of pneumonia and retrieved characteristics of the studies and data estimates.
DATA SYNTHESIS: The primary outcome was incidence of pneumonia and the secondary outcome was pneumonia related mortality. Subgroup analyses were carried according to baseline morbidities (stroke, heart failure, and chronic kidney disease) and patients' characteristics (Asian and non-Asian). Pooled estimates of odds ratios and 95% confidence intervals were derived by random effects meta-analysis. Adjusted frequentist indirect comparisons between ACE inhibitors and ARBs were estimated and combined with direct evidence whenever available. Heterogeneity was assessed using the I(2) test.
RESULTS: 37 eligible studies were included. ACE inhibitors were associated with a significantly reduced risk of pneumonia compared with control treatment (19 studies: odds ratio 0.66, 95% confidence interval 0.55 to 0.80; I(2) = 79%) and ARBs (combined direct and indirect odds ratio estimate 0.69, 0.56 to 0.85). In patients with stroke, the risk of pneumonia was also lower in those treated with ACE inhibitors compared with control treatment (odds ratio 0.46, 0.34 to 0.62) and ARBs (0.42, 0.22 to 0.80). ACE inhibitors were associated with a significantly reduced risk of pneumonia among Asian patients (0.43, 0.34 to 0.54) compared with non-Asian patients (0.82, 0.67 to 1.00; P<0.001). Compared with control treatments, both ACE inhibitors (seven studies: odds ratio 0.73, 0.58 to 0.92; I(2)=51%) and ARBs (one randomised controlled trial: 0.63, 0.40 to 1.00) were associated with a decrease in pneumonia related mortality, without differences between interventions.
CONCLUSIONS: The best evidence available points towards a putative protective role of ACE inhibitors but not ARBs in risk of pneumonia. Patient populations that may benefit most are those with previous stroke and Asian patients. ACE inhibitors were also associated with a decrease in pneumonia related mortality, but the data lacked strength.

PMID 22786934  BMJ. 2012 Jul 11;345:e4260. Epub 2012 Jul 11.
著者: Blood Pressure Lowering Treatment Trialists' Collaboration, F Turnbull, B Neal, M Pfeffer, J Kostis, C Algert, M Woodward, J Chalmers, A Zanchetti, S MacMahon
雑誌名: J Hypertens. 2007 May;25(5):951-8. doi: 10.1097/HJH.0b013e3280bad9b4.
Abstract/Text OBJECTIVES: To evaluate the blood pressure-dependent and independent effects of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) on major cardiovascular events.
METHODS: Using data from 26 large-scale trials comparing an ACEI or an ARB with placebo or another drug class, meta-regression analyses were conducted in which treatment-specific relative risks for major cause-specific outcomes [stroke, major coronary heart disease (CHD) events and heart failure] were regressed against follow-up blood pressure differences.
RESULTS: From a total of 146 838 individuals with high blood pressure or an elevated risk of cardiovascular disease, 22 666 major cardiovascular events were documented during follow-up. The analyses showed comparable blood pressure-dependent reductions in risk with ACEI and ARB (P >or= 0.3 for all three outcomes). The analyses also showed that ACEI produced a blood pressure-independent reduction in the relative risk of CHD of approximately 9% (95% confidence interval 3-14%). No similar effect was detected for ARB, and there was some evidence of a difference between ACEI and ARB in this regard (P = 0.002). For both stroke and heart failure there was no evidence of any blood pressure-independent effects of either ACEI or ARB.
CONCLUSION: There are similar blood pressure-dependent effects of ACEI and ARB for the risks of stroke, CHD and heart failure. For ACEI, but not ARB, there is evidence of blood pressure-independent effects on the risk of major coronary disease events.

PMID 17414657  J Hypertens. 2007 May;25(5):951-8. doi: 10.1097/HJH.0b0・・・
著者: Kazuomi Kario, Satoshi Hoshide
雑誌名: Hypertension. 2015 Apr;65(4):729-35. doi: 10.1161/HYPERTENSIONAHA.114.04935. Epub 2015 Feb 2.
Abstract/Text Sleep blood pressure (BP), which is partly determined by salt sensitivity and intake, is an important cardiovascular risk in hypertensives. However, there have been no studies on age-related differences in the sleep BP-lowering effect between angiotensin II receptor blockers and calcium channel blockers in Asians. Azilsartan Circadian and Sleep Pressure-the 1st Study was a multicenter, randomized, open-label, 2-parallel-group study conducted to compare the efficacy of 8-week oral treatment with an angiotensin II receptor blocker (azilsartan 20 mg) or a calcium channel blocker (amlodipine 5 mg) on sleep BP as evaluated by ambulatory BP monitoring. Among the overall population, amlodipine treatment achieved significantly greater reduction in sleep BP, awake BP, and 24-hour BP than azilsartan treatment. BP reduction by amlodipine was particularly pronounced in elderly hypertensive patients aged ≥60 years old. Among patients ≥60 years old, the amlodipine group had numerically, but not significantly, higher control rate of sleep BP compared with the azilsartan group. Similar results were found for awake BP and 24-hour BP. These results suggest a greater BP reduction/control by amlodipine compared with azilsartan and that reduction/control of BP by amlodipine was also more effective in the elderly population. As recommended in the American Society of Hypertension/The international Society of Hypertension and the National Institute for Health and Clinical Excellence guidelines for differentiating treatment according to age, amlodipine should be one of the options for starting treatment in the elderly population. CLINICAL TRIAL URL: http://clinicaltrials.gov/show/NCT01762501 CLINICAL TRIAL ID: NCT01762501.

© 2015 American Heart Association, Inc.
PMID 25646296  Hypertension. 2015 Apr;65(4):729-35. doi: 10.1161/HYPER・・・
著者: Aud Høieggen, Michael H Alderman, Sverre E Kjeldsen, Stevo Julius, Richard B Devereux, Ulf De Faire, Frej Fyhrquist, Hans Ibsen, Krister Kristianson, Ole Lederballe-Pedersen, Lars H Lindholm, Markku S Nieminen, Per Omvik, Suzanne Oparil, Hans Wedel, Cong Chen, Björn Dahlöf, LIFE Study Group
雑誌名: Kidney Int. 2004 Mar;65(3):1041-9. doi: 10.1111/j.1523-1755.2004.00484.x.
Abstract/Text BACKGROUND: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study demonstrated the superiority of a losartan-based regimen over atenolol-based regimen for reduction of cardiovascular (CV) morbidity and mortality. It has been suggested that the LIFE study results may be related to the effects of losartan on serum uric acid (SUA). SUA has been proposed as an independent risk factor for CV morbidity and death.
METHODS: Cox regression analysis was used to assess relationship of SUA and treatment regimens with the LIFE primary composite outcome (CV death, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke).
RESULTS: Baseline SUA was significantly associated with increased CV events [hazard ratio (HR) 1.024 (95% CI 1.017-1.032) per 10 micromol/L, P < 0.0001] in the entire study population. The association was significant in women [HR = 1.025 (1.013-1.037), P < 0.0001], but not in men [HR = 1.009 (0.998-1.019), P= 0.108]. After adjustment for Framingham risk score (FRS), SUA was no longer significant in the entire study population [HR = 1.006 (0.998-1.014), P= 0.122] or in men [HR = 1.006 (0.995-1.017), P= 0.291], but was significant in women [HR = 1.013 (1-1.025), P= 0.0457]. The baseline-to-end-of-study increase in SUA (standard deviation, SD) was greater (P < 0.0001) in atenolol-treated subjects (44.4 +/- 72.5 micromol/L) than in losartan-treated subjects (17.0 +/- 69.8 micromol/L). SUA as a time-varying covariate was strongly associated with events (P < 0.0001) in the entire population. The contribution of SUA to the treatment effect of losartan on the primary composite end point was 29% (14%-107%), P= 0.004. The association between time-varying SUA and increased CV risk tended to be stronger in women (P < 0.0001) than in men (P= 0.0658), although the gender-outcome interaction was not significant (P= 0.079).
CONCLUSION: The increase in SUA over 4.8 years in the LIFE study was attenuated by losartan compared with atenolol treatment, appearing to explain 29% of the treatment effect on the primary composite end point. The association between SUA and events was stronger in women than in men with or without adjustment of FRS.

PMID 14871425  Kidney Int. 2004 Mar;65(3):1041-9. doi: 10.1111/j.1523-・・・
著者: Hyon K Choi, Lucia Cea Soriano, Yuqing Zhang, Luis A García Rodríguez
雑誌名: BMJ. 2012 Jan 12;344:d8190. Epub 2012 Jan 12.
Abstract/Text OBJECTIVE: To determine the independent associations of antihypertensive drugs with the risk of incident gout among people with hypertension.
DESIGN: Nested case-control study.
SETTING: UK general practice database, 2000-7.
PARTICIPANTS: All incident cases of gout (n = 24,768) among adults aged 20-79 and a random sample of 50,000 matched controls.
MAIN OUTCOME MEASURE: Relative risk of incident gout associated with use of antihypertensive drugs.
RESULTS: After adjusting for age, sex, body mass index, visits to the general practitioner, alcohol intake, and pertinent drugs and comorbidities, the multivariate relative risks of incident gout associated with current use of antihypertensive drugs among those with hypertension (n = 29,138) were 0.87 (95% confidence interval 0.82 to 0.93) for calcium channel blockers, 0.81 (0.70 to 0.94) for losartan, 2.36 (2.21 to 2.52) for diuretics, 1.48 (1.40 to 1.57) for β blockers, 1.24 (1.17 to 1.32) for angiotensin converting enzyme inhibitors, and 1.29 (1.16 to 1.43) for non-losartan angiotensin II receptor blockers. Similar results were obtained among those without hypertension. The multivariate relative risks for the duration of use of calcium channel blockers among those with hypertension were 1.02 for less than one year, 0.88 for 1-1.9 years, and 0.75 for two or more years and for use of losartan they were 0.98, 0.87, and 0.71, respectively (both P<0.05 for trend).
CONCLUSIONS: Compatible with their urate lowering properties, calcium channel blockers and losartan are associated with a lower risk of incident gout among people with hypertension. By contrast, diuretics, β blockers, angiotensin converting enzyme inhibitors, and non-losartan angiotensin II receptor blockers are associated with an increased risk of gout.

PMID 22240117  BMJ. 2012 Jan 12;344:d8190. Epub 2012 Jan 12.
著者: Thomas Unger, Elena Kaschina
雑誌名: Drug Saf. 2003;26(10):707-20.
Abstract/Text The ever-increasing introduction of new therapeutic agents means that the potential for drug interactions is likely to escalate. Numerous different classes of drugs are currently used to treat hypertension. The angiotensin receptor blockers offer one of the newest approaches to the management of patients with high blood pressure. Compared with other classes of antihypertensive agents, the angiotensin receptor blockers appear overall to have a low potential for drug interactions, but variations within the class have been detected. Losartan and irbesartan have a greater affinity for cytochrome p450 (CYP) isoenzymes and, thus, are more likely to be implicated in drug interactions. There is pharmacokinetic evidence to suggest that such interactions could have a clinical impact. Candesartan cilexetil, valsartan and eprosartan have variable but generally modest affinity and telmisartan has no affinity for any of the CYP isoenzymes. In vitro studies and pharmacokinetic/pharmacodynamic evaluation can provide evidence for some interactions, but only a relatively small number of drug combinations are usually studied in this way. The absence of any pharmacokinetic evidence of drug interaction, however, should not lead to complacency. Patients should be made aware of possible interactions, especially involving the concurrent use of over-the-counter products, and it may be prudent for all patients receiving antihypertensive treatment to be monitored for possible drug interactions at their regular check-ups. The physician can help by prescribing agents with a low potential for interaction, such as angiotensin receptor blockers.

PMID 12862505  Drug Saf. 2003;26(10):707-20.
著者: J Stangier, C A Su, M G Hendriks, J J van Lier, F A Sollie, B Oosterhuis, J H Jonkman
雑誌名: J Clin Pharmacol. 2000 Dec;40(12 Pt 1):1373-9.
Abstract/Text A multiple-dose, open-label, two-period, crossover randomized study was conducted in 12 healthy male volunteers to investigate the effect of multiple-dose telmisartan on the steady-state pharmacokinetics of digoxin. On day 1 of a 7-day medication period, subjects received a loading dose of digoxin 0.5 mg in the morning, followed by an evening dose of digoxin 0.25 mg, either alone or together with telmisartan 120 mg administered in the morning. On the subsequent 6 days, either digoxin 0.25 mg or digoxin 0.25 mg together with telmisartan 120 mg was administered once daily in the morning. Each 7-day medication period was separated by a washout period of > or = 14 days. A steady-state plasma concentration-time profile was assessed for digoxin during each period and for telmisartan during the period with the combined treatment. Multiple-dose telmisartan administered with digoxin resulted in higher serum digoxin concentrations than those observed after digoxin given alone. Geometric mean AUC144-168, Cmax, and Cmin values for digoxin when given in combination with telmisartan were higher by 22%, 50%, and 13%, respectively, compared with values when given alone. However, the 90% confidence interval for the geometric mean of Cmin was within the predefined 80% to 125% range of no interaction. During combination medication, digoxin tmax was shorter and Cmax/AUC144-168 increased, suggesting that the rise in digoxin Cmax may be due to more rapid drug absorption. Study medications were well tolerated, with the incidence, nature, and intensity of adverse events being similar during both medication periods. Also, no changes in vital signs or clinical laboratory tests were observed during the study. Although there was some evidence for a pharmacokinetic interaction between digoxin and telmisartan found in this study, the safety and tolerability of digoxin were unaffected by concurrent administration of telmisartan in the study population. Since any symptoms of overdose are related only to steady state and not peak concentrations and due to the fact that there was a lack of effect on serum trough levels of digoxin in this study, it is unlikely that the findings have any clinical relevance. The magnitude of increase in digoxin concentrations is comparable with increases observed with administration of calcium antagonists, carvedilol, ACE inhibitors such as captopril, and antiarrhythmic drugs such as amiodarone, quinidine, and propafenone. Monitoring of serum digoxin concentrations should be considered when patients first receive telmisartan and in the event of any changes in telmisartan dose.

PMID 11185636  J Clin Pharmacol. 2000 Dec;40(12 Pt 1):1373-9.
著者: T W Gress, F J Nieto, E Shahar, M R Wofford, F L Brancati
雑誌名: N Engl J Med. 2000 Mar 30;342(13):905-12. doi: 10.1056/NEJM200003303421301.
Abstract/Text BACKGROUND: Previous research has suggested that thiazide diuretics and beta-blockers may promote the development of type 2 diabetes mellitus. However, the results of previous studies have been inconsistent, and many studies have been limited by inadequate data on outcomes and by potential confounding.
METHODS: We conducted a prospective study of 12,550 adults 45 to 64 years old who did not have diabetes. An extensive health evaluation conducted at base line included assessment of medication use and measurement of blood pressure with a random-zero sphygmomanometer. The incidence of new cases of diabetes was assessed after three years and after six years by measurement of serum glucose concentrations while the subjects were fasting.
RESULTS: After simultaneous adjustment for age, sex, race, education, adiposity, family history with respect to diabetes, physical-activity level, other health-related behavior, and coexisting illnesses, subjects with hypertension who were taking thiazide diuretics were not at greater risk for the subsequent development of diabetes than were subjects with hypertension who were not receiving any antihypertensive therapy (relative hazard, 0.91; 95 percent confidence interval, 0.73 to 1.13). Likewise, subjects who were taking angiotensin-converting-enzyme inhibitors and calcium-channel antagonists were not at greater risk than those not taking any medication. In contrast, subjects with hypertension who were taking beta-blockers had a 28 percent higher risk of subsequent diabetes (relative hazard, 1.28; 95 percent confidence interval, 1.04 to 1.57).
CONCLUSIONS: Concern about the risk of diabetes should not discourage physicians from prescribing thiazide diuretics to nondiabetic adults who have hypertension. The use of beta-blockers appears to increase the risk of diabetes, but this adverse effect must be weighed against the proven benefits of beta-blockers in reducing the risk of cardiovascular events.

PMID 10738048  N Engl J Med. 2000 Mar 30;342(13):905-12. doi: 10.1056/・・・
著者: Camila Manrique, Megan Johnson, James R Sowers
雑誌名: Hypertension. 2010 Jan;55(1):15-7. doi: 10.1161/HYPERTENSIONAHA.109.142620. Epub 2009 Nov 16.
Abstract/Text
PMID 19917873  Hypertension. 2010 Jan;55(1):15-7. doi: 10.1161/HYPERTE・・・
著者: GianLuca Colussi, Cristiana Catena, Leonardo A Sechi
雑誌名: J Hypertens. 2013 Jan;31(1):3-15. doi: 10.1097/HJH.0b013e3283599b6a.
Abstract/Text Mineralocorticoid receptor antagonists (MRAs) are commonly used to reduce blood pressure, left-ventricular hypertrophy, and urinary albumin excretion in patients with essential hypertension or primary aldosteronism. Effects of MRAs on hypertensive organ damage seem to occur beyond what is expected from the mere reduction of blood pressure. This suggests that activation of the mineralocorticoid receptor plays a central role in the development of cardiac and renal abnormalities in hypertensive patients. However, broad use of classic MRAs such as spironolactone has been limited by significant incidence of gynecomastia and other sex-related adverse effects. To overcome these problems, new aldosterone blockers have been developed with different strategies that include use of nonsteroidal MRAs and inhibition of aldosterone synthesis. Both strategies have been designed to avoid the steroid receptor cross-reactivity of classic MRAs that accounts for most adverse effects. Moreover, inhibition of aldosterone synthesis could have an additional benefit due to blockade of the mineralocorticoid receptor-independent pathways that might account for some of the untoward effects of aldosterone. The new aldosterone blockers are currently having extensive preclinical evaluation, and one of these compounds has passed phase 2 trials showing promising results in patients with primary hypertension and primary aldosteronism. This narrative review summarizes the knowledge on the use of classic MRAs in hypertension and covers the evidence currently available on new aldosterone blockers.

PMID 23011526  J Hypertens. 2013 Jan;31(1):3-15. doi: 10.1097/HJH.0b01・・・
著者: Andrew S Bomback, Abhijit V Kshirsagar, M Ahinee Amamoo, Philip J Klemmer
雑誌名: Am J Kidney Dis. 2008 Feb;51(2):199-211. doi: 10.1053/j.ajkd.2007.10.040.
Abstract/Text BACKGROUND: The use of mineralocorticoid receptor blockers (MRBs) in patients with chronic kidney disease is growing, but data for efficacy in decreasing proteinuria are limited by a relative paucity of studies, many of which are small and uncontrolled.
STUDY DESIGN: We performed a systematic review using the MEDLINE database (inception to November 1, 2006), abstracts from national meetings, and selected reference lists.
SETTING & POPULATION: Adult patients with chronic kidney disease and proteinuria.
SELECTION CRITERIA FOR STUDIES: English-language studies investigating the use of MRBs added to long-term angiotensin-converting enzyme (ACE)-inhibitor and/or angiotensin receptor blocker (ARB) therapy in adult patients with proteinuric kidney disease.
INTERVENTION: MRBs as additive therapy to conventional renin-angiotensin-aldosterone system blockade in patients with chronic kidney disease.
OUTCOMES: Changes in proteinuria as the primary outcome; rates of hyperkalemia, changes in blood pressure, and changes in glomerular filtration rate as secondary outcomes.
RESULTS: 15 studies met inclusion criteria for our review; 4 were parallel-group randomized controlled trials, 4 were crossover randomized controlled trials, 2 were pilot studies, and 5 were case series. When MRBs were added to ACE-inhibitor and/or ARB therapy, the reported proteinuria decreases from baseline ranged from 15% to 54%, with most estimates in the 30% to 40% range. Hyperkalemic events were significant in only 1 of 8 randomized controlled trials. MRB therapy was associated with statistically significant decreases in blood pressure and glomerular filtration rate in approximately 40% and 25% of included studies, respectively.
LIMITATIONS: Reported results were insufficient for meta-analysis, with only 2 studies reporting sufficient data to calculate SEs of their published estimates. We were unable to locate studies that showed no effect of MRB treatment over placebo, raising concern for publication bias.
CONCLUSIONS: Although data suggest that adding MRBs to ACE-inhibitor and/or ARB therapy yields significant decreases in proteinuria without adverse effects of hyperkalemia and impaired renal function, routine use of MRBs as additive therapy in patients with chronic kidney disease cannot be recommended yet. However, the findings of this review promote interesting hypotheses for future study.

PMID 18215698  Am J Kidney Dis. 2008 Feb;51(2):199-211. doi: 10.1053/j・・・
著者: Sankar D Navaneethan, Sagar U Nigwekar, Ashwini R Sehgal, Giovanni F M Strippoli
雑誌名: Clin J Am Soc Nephrol. 2009 Mar;4(3):542-51. doi: 10.2215/CJN.04750908. Epub 2009 Mar 4.
Abstract/Text BACKGROUND AND OBJECTIVES: Addition of aldosterone antagonists (AA) might provide renal benefits to proteinuric chronic kidney disease (CKD) patients over and above the inhibition of renin-angiotensin system blockers (RAS). We evaluated the benefits and harms of adding selective and nonselective AA in CKD patients already on RAS.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: MEDLINE, EMBASE, and Renal Health Library were searched for relevant randomized clinical trials in adult CKD patients. Results were summarized using the random-effects model.
RESULTS: Eleven trials (991 patients) were included. In comparison to angiotensin- converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARB) plus placebo, nonselective AA along with ACEi and/or ARB significantly reduced 24 h proteinuria (seven trials, 372 patients, weighted mean difference [WMD] -0.80 g, 95% CI -1.27, -0.33) and BP. This did not translate into an improvement in GFR (WMD -0.70 ml/min/1.73m(2), 95% CI -4.73, 3.34). There was a significant increase in the risk of hyperkalemia with the addition of nonselective AA to ACEi and/or ARB (relative risk 3.06, 95% CI 1.26, 7.41). In two trials, addition of selective AA to ACEi resulted in an additional reduction in 24 h proteinuria, without any impact on BP and renal function. Data on cardiovascular outcomes, long-term renal outcomes and mortality were not available in any of the trials.
CONCLUSIONS: Aldosterone antagonists reduce proteinuria in CKD patients already on ACEis and ARBs but increase the risk of hyperkalemia. Long-term effects of these agents on renal outcomes, mortality, and safety need to be established.

PMID 19261819  Clin J Am Soc Nephrol. 2009 Mar;4(3):542-51. doi: 10.22・・・
著者: Linda Shavit, Meyer D Lifschitz, Murray Epstein
雑誌名: Kidney Int. 2012 May;81(10):955-68. doi: 10.1038/ki.2011.505. Epub 2012 Feb 15.
Abstract/Text The past two decades have witnessed a striking paradigm shift with respect to our understanding of the widespread effects of aldosterone. There is substantive evidence that mineralocorticoid receptor (MR) activation promotes myriad 'off target' effects on the heart, the vasculature, and importantly the kidney. In the present review, we summarize the expanding role of MR activation in promoting both vascular and renal injury. We review the recent clinical studies that investigated the efficacy of MR antagonism (MRA) in reducing proteinuria and attenuating progressive renal disease. We also review in-depth both the utility and safety of MRA in the end-stage renal disease (ESRD) patient undergoing dialysis. Because the feasibility of add-on MRA is critically dependent on our ability to minimize or avoid hyperkalemia, and because controversy centers on the incidence of hyperkalemia, we critically review the risk of hyperkalemia with add-on MRA. Our present analysis suggests that hyperkalemia supervening in MRA-treated patients is overstated. Furthermore, recent studies demonstrating the efficacy of new non-absorbed, orally administered, potassium [K+]-binding polymers suggest that a multi-pronged approach encompassing adequate surveillance, moderate or low-dose MRA, and K-binding polymers may adequately control serum K in both chronic kidney disease and ESRD patients.

PMID 22336987  Kidney Int. 2012 May;81(10):955-68. doi: 10.1038/ki.201・・・
著者: Ajay K Gupta, Shazia Arshad, Neil R Poulter
雑誌名: Hypertension. 2010 Feb;55(2):399-407. doi: 10.1161/HYPERTENSIONAHA.109.139816. Epub 2009 Dec 21.
Abstract/Text Two or more antihypertensive agents are increasingly used to control blood pressure (BP) in hypertensive patients. However, it is unclear whether fixed-dose combinations (FDCs) of 2 antihypertensive agents in a single tablet provide greater benefits than the corresponding free-drug components given separately. A meta-analysis was performed to assess compliance, persistence, BP control, and safety associated with FDCs in comparison with their free-drug components. Fifteen included studies (n=32331) reported on >or=1 of the evaluated outcomes. In 3 cohort studies and 2 trials reporting on drug compliance (n=17 999), the use of FDCs was associated with significantly better compliance (odds ratio: 1.21 [95% CI: 1.03 to 1.43]; P=0.02) compared with its corresponding free-drug combinations. In 3 cohort studies (n=12 653), there was a nonsignificant improvement in persistence with therapy (odds ratio: 1.54 [95% CI: 0.95 to 2.49]; P=0.08), and in 5 trials (n=1775) the odds ratio for adverse effects for FDC use compared with free-drug combination use was 0.80 (95% CI: 0.58 to 1.11; P=0.19). In 9 trials (n=1671) with BP data, use of an FDC was associated with nonsignificant changes in systolic and diastolic BPs of 4.1 mm Hg (95% CI: -9.8 to 1.5; P=0.15) and 3.1 mm Hg (95% CI: -7.1 to 0.9; P=0.13), respectively. In these BP-lowering comparisons, there was heterogeneity associated with differences in study design but no publication bias. In conclusion, compared with free-drug combinations, FDCs of antihypertensive agents are associated with a significant improvement in compliance and with nonsignificant beneficial trends in BP and adverse effects.

PMID 20026768  Hypertension. 2010 Feb;55(2):399-407. doi: 10.1161/HYPE・・・
著者: David E Kandzari, Michael Böhm, Felix Mahfoud, Raymond R Townsend, Michael A Weber, Stuart Pocock, Konstantinos Tsioufis, Dimitrios Tousoulis, James W Choi, Cara East, Sandeep Brar, Sidney A Cohen, Martin Fahy, Garrett Pilcher, Kazuomi Kario, SPYRAL HTN-ON MED Trial Investigators
雑誌名: Lancet. 2018 Jun 9;391(10137):2346-2355. doi: 10.1016/S0140-6736(18)30951-6. Epub 2018 May 23.
Abstract/Text BACKGROUND: Previous catheter-based renal denervation studies have reported variable efficacy results. We aimed to evaluate safety and blood pressure response after renal denervation or sham control in patients with uncontrolled hypertension on antihypertensive medications with drug adherence testing.
METHODS: In this international, randomised, single-blind, sham-control, proof-of-concept trial, patients with uncontrolled hypertension (aged 20-80 years) were enrolled at 25 centres in the USA, Germany, Japan, UK, Australia, Austria, and Greece. Eligible patients had an office systolic blood pressure of between 150 mm Hg and 180 mm Hg and a diastolic blood pressure of 90 mm Hg or higher; a 24 h ambulatory systolic blood pressure of between 140 mm Hg and 170 mm Hg at second screening; and were on one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned to undergo renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were masked to randomisation assignments. The primary efficacy endpoint was blood pressure change from baseline (measured at screening visit two), based on ambulatory blood pressure measurements assessed at 6 months, as compared between treatment groups. Drug surveillance was used to assess medication adherence. The primary analysis was done in the intention-to-treat population. Safety events were assessed through 6 months as per major adverse events. This trial is registered with ClinicalTrials.gov, number NCT02439775, and follow-up is ongoing.
FINDINGS: Between July 22, 2015, and June 14, 2017, 467 patients were screened and enrolled. This analysis presents results for the first 80 patients randomly assigned to renal denervation (n=38) and sham control (n=42). Office and 24 h ambulatory blood pressure decreased significantly from baseline to 6 months in the renal denervation group (mean baseline-adjusted treatment differences in 24 h systolic blood pressure -7·0 mm Hg, 95% CI -12·0 to -2·1; p=0·0059, 24 h diastolic blood pressure -4·3 mm Hg, -7·8 to -0·8; p=0.0174, office systolic blood pressure -6·6 mm Hg, -12·4 to -0·9; p=0·0250, and office diastolic blood pressure -4·2 mm Hg, -7·7 to -0·7; p=0·0190). The change in blood pressure was significantly greater at 6 months in the renal denervation group than the sham-control group for office systolic blood pressure (difference -6·8 mm Hg, 95% CI -12·5 to -1·1; p=0·0205), 24 h systolic blood pressure (difference -7·4 mm Hg, -12·5 to -2·3; p=0·0051), office diastolic blood pressure (difference -3·5 mm Hg, -7·0 to -0·0; p=0·0478), and 24 h diastolic blood pressure (difference -4·1 mm Hg, -7·8 to -0·4; p=0·0292). Evaluation of hourly changes in 24 h systolic blood pressure and diastolic blood pressure showed blood pressure reduction throughout 24 h for the renal denervation group. 3 month blood pressure reductions were not significantly different between groups. Medication adherence was about 60% and varied for individual patients throughout the study. No major adverse events were recorded in either group.
INTERPRETATION: Renal denervation in the main renal arteries and branches significantly reduced blood pressure compared with sham control with no major safety events. Incomplete medication adherence was common.
FUNDING: Medtronic.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29803589  Lancet. 2018 Jun 9;391(10137):2346-2355. doi: 10.1016/S・・・
著者: Kazuomi Kario, Michael Böhm, Felix Mahfoud, Raymond R Townsend, Michael A Weber, Manesh Patel, Crystal C Tyson, Joachim Weil, Tolga Agdirlioglu, Sidney A Cohen, Martin Fahy, David E Kandzari
雑誌名: Circulation. 2018 Oct 9;138(15):1602-1604. doi: 10.1161/CIRCULATIONAHA.118.035588.
Abstract/Text
PMID 30354518  Circulation. 2018 Oct 9;138(15):1602-1604. doi: 10.1161・・・
著者: Michel Azizi, Roland E Schmieder, Felix Mahfoud, Michael A Weber, Joost Daemen, Justin Davies, Jan Basile, Ajay J Kirtane, Yale Wang, Melvin D Lobo, Manish Saxena, Lida Feyz, Florian Rader, Philipp Lurz, Jeremy Sayer, Marc Sapoval, Terry Levy, Kintur Sanghvi, Josephine Abraham, Andrew S P Sharp, Naomi D L Fisher, Michael J Bloch, Helen Reeve-Stoffer, Leslie Coleman, Christopher Mullin, Laura Mauri, RADIANCE-HTN Investigators
雑誌名: Lancet. 2018 Jun 9;391(10137):2335-2345. doi: 10.1016/S0140-6736(18)31082-1. Epub 2018 May 23.
Abstract/Text BACKGROUND: Early studies suggest that radiofrequency-based renal denervation reduces blood pressure in patients with moderate hypertension. We investigated whether an alternative technology using endovascular ultrasound renal denervation reduces ambulatory blood pressure in patients with hypertension in the absence of antihypertensive medications.
METHODS: RADIANCE-HTN SOLO was a multicentre, international, single-blind, randomised, sham-controlled trial done at 21 centres in the USA and 18 in Europe. Patients with combined systolic-diastolic hypertension aged 18-75 years were eligible if they had ambulatory blood pressure greater than or equal to 135/85 mm Hg and less than 170/105 mm Hg after a 4-week discontinuation of up to two antihypertensive medications and had suitable renal artery anatomy. Patients were randomised (1:1) to undergo renal denervation with the Paradise system (ReCor Medical, Palo Alto, CA, USA) or a sham procedure consisting of renal angiography only. The randomisation sequence was computer generated and stratified by centres with randomised blocks of four or six and permutation of treatments within each block. Patients and outcome assessors were blinded to randomisation. The primary effectiveness endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Patients were to remain off antihypertensive medications throughout the 2 months of follow-up unless specified blood pressure criteria were exceeded. Major adverse events included all-cause mortality, renal failure, an embolic event with end-organ damage, renal artery or other major vascular complications requiring intervention, or admission to hospital for hypertensive crisis within 30 days and new renal artery stenosis within 6 months. This study is registered with ClinicalTrials.gov, number NCT02649426.
FINDINGS: Between March 28, 2016, and Dec 28, 2017, 803 patients were screened for eligibility and 146 were randomised to undergo renal denervation (n=74) or a sham procedure (n=72). The reduction in daytime ambulatory systolic blood pressure was greater with renal denervation (-8·5 mm Hg, SD 9·3) than with the sham procedure (-2·2 mm Hg, SD 10·0; baseline-adjusted difference between groups: -6·3 mm Hg, 95% CI -9·4 to -3·1, p=0·0001). No major adverse events were reported in either group.
INTERPRETATION: Compared with a sham procedure, endovascular ultrasound renal denervation reduced ambulatory blood pressure at 2 months in patients with combined systolic-diastolic hypertension in the absence of medications.
FUNDING: ReCor Medical.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29803590  Lancet. 2018 Jun 9;391(10137):2335-2345. doi: 10.1016/S・・・
著者: Kazuomi Kario, Michael A Weber, Felix Mahfoud, David E Kandzari, Roland E Schmieder, Ajay J Kirtane, Michael Böhm, Douglas A Hettrick, Raymond R Townsend, Konstantinos P Tsioufis
雑誌名: Hypertension. 2019 Jul 1;:HYPERTENSIONAHA11913081. doi: 10.1161/HYPERTENSIONAHA.119.13081. Epub 2019 Jul 1.
Abstract/Text
PMID 31256723  Hypertension. 2019 Jul 1;:HYPERTENSIONAHA11913081. doi:・・・
著者: R E Schmieder, J K Rockstroh, F H Messerli
雑誌名: JAMA. 1991 Mar 27;265(12):1566-71.
Abstract/Text The benefits of continuous antihypertensive therapy have been extensively documented. However, lack of compliance with the prescribed regimen, excessive cost, and troublesome adverse effects of some antihypertensive agents led to the consideration of intermittent therapy or even complete discontinuation of therapy as an effective alternative to lifelong medication. Prospective studies dealing with this subject reported inconsistent results. Nevertheless, they allowed us to identify selection criteria of candidates for step-down or discontinuation of antihypertensive therapy. Such candidates include patients with mild essential hypertension who have one or more of the following characteristics: young age, normal body weight, low salt intake, no alcohol consumption, low pretreatment blood pressure, successful therapy with one drug only, and no or only minimal signs of target organ damage. Stopping antihypertensive therapy without subsequent rise in arterial pressure was shown to be possible in a subset of patients with mild essential hypertension for a period of months to years. This approach appears to be safe, provided that blood pressure is monitored frequently, and may improve compliance, save treatment costs, and reduce adverse effects of certain drugs, although its long-term consequences for morbidity and mortality remain to be determined.

PMID 1999906  JAMA. 1991 Mar 27;265(12):1566-71.
著者: E D Freis, J R Thomas, S G Fisher, R Hamburger, R E Borreson, K C Mezey, B Mukherji, W W Neal, H M Perry, J T Taguchi
雑誌名: Am J Cardiol. 1989 Mar 15;63(11):702-8.
Abstract/Text The possibility of discontinuing--compared to reducing--antihypertensive drug treatment was investigated in 606 male hypertensive patients with entry diastolic blood pressure (BP) in the range of 90 to 114 mm Hg. Diastolic BP was controlled at less than 90 mm Hg with 1 of 4 regimens: low dose hydrochlorothiazide (HCTZ), 25 mg twice daily; high dose HCTZ, 50 mg twice daily; or high dose HCTZ plus a low or high dose of a step II drug (propranolol, clonidine or reserpine). After 6 months of treatment that controlled BP, dosages were reduced in two-thirds of the patients. In those patients receiving low dose HCTZ and randomized to dose reduction, antihypertensive drugs were completely discontinued. Although approximately half of these patients remained normotensive for the first 6 months, a significantly greater proportion had elevation of BP compared to the control group, which continued to receive treatment (p less than 0.0001). In the high dose HCTZ drug group, the proportion of patients remaining normotensive did not differ among those stepped down to low dose HCTZ and the fully treated control group. While not achieving significance the trend was similar with the step II regimens. Although some patients remained normotensive after discontinuation of step II drugs, a greater proportion returned to elevated BP than when step II dosage was unchanged. Therefore, while stopping therapy may be effective in some patients, a decreased dosage is significantly more effective as a method for maintaining an antihypertensive effect. Decreasing drug dosages offers the dual benefit of minimizing side effects and reducing drug costs.

PMID 2646896  Am J Cardiol. 1989 Mar 15;63(11):702-8.
著者: Mark R Nelson, Chris M Reid, Henry Krum, Philip Ryan, Lindon M H Wing, John J McNeil, Management Committee, Second Australian National Blood Pressure Study
雑誌名: Am J Hypertens. 2003 Jan;16(1):39-45.
Abstract/Text BACKGROUND: Antihypertensive drug therapy is considered lifelong but in the family practice environment drug cessation may provide an opportunity to attempt nonpharmacologic strategies for blood pressure (BP) control with a clear outcome, maintaining drug-free status. The identification of simple predictors would assist the family physician to select who may or may not have their medication ceased.
METHODS: To monitor a drug cessation program in currently treated hypertensive patients in Australian family practice, 25,826 patients aged 65 to 84 years currently receiving antihypertensive medication, were offered drug withdrawal as part of the run-in phase of a large clinical trial. Outcomes investigated were the proportion of patients completing drug withdrawal and maintaining short-term BP control and factors that predicted these patients.
RESULTS: A total of 18,993 patients did not enter the withdrawal program; 6291 (92% of those who entered) completed drug withdrawal. In comparison to patients who did not complete drug withdrawal, they were younger and more likely male. A total of 1,228 (18% of those who entered) ceased medication and maintained adequate BP control for 0 to 76 weeks (median, 4 weeks). Cox regression analysis identified lower on therapy systolic and diastolic BP, younger age, type of agent, and monotherapy as predictors of successful drug withdrawal and maintenance of BP control.
CONCLUSIONS: Cessation of antihypertensive drug therapy is possible in a substantial proportion (18%) of patients attending family practice who are willing to do so and is most successful in those who are younger with BP controlled on monotherapy. Where this strategy is initiated, use of such predictors, effective behavioral change, and systematic follow-up is recommended.

PMID 12517681  Am J Hypertens. 2003 Jan;16(1):39-45.
著者: Mark R Nelson, Chris M Reid, Henry Krum, Tui Muir, Philip Ryan, John J McNeil
雑誌名: BMJ. 2002 Oct 12;325(7368):815.
Abstract/Text OBJECTIVES: To identify simple long term predictors of maintenance of normotension after withdrawal of antihypertensive drugs in elderly patients in general practice.
DESIGN: Prospective cohort study.
SETTING: 169 general practices in Victoria, Australia.
PARTICIPANTS: 503 patients aged 65-84 with treated hypertension who were withdrawn from all antihypertensive drugs and remained drug free and normotensive for an initial two week period; all were followed for a further 12 months.
MAIN OUTCOME MEASURES: Relative likelihood of maintaining normotension 12 months after drug withdrawal; relative likelihood of early return to hypertension after drug withdrawal.
RESULTS: The likelihood of remaining normotensive at 12 months was greater among younger patients (65-74 years), patients with lower "on-treatment" systolic blood pressure, patients on single agent treatment, and patients with a greater waist:hip ratio. The likelihood of return to hypertension was greatest for patients with higher "on-treatment" systolic blood pressure.
CONCLUSIONS: Age, blood pressure control, and the number of antihypertensive drugs are important factors in the clinical decision to withdraw drug treatment. Because of consistent rates of return to antihypertensive treatment, all patients from whom such treatment is withdrawn should be monitored indefinitely to detect a recurrence of hypertension.

PMID 12376444  BMJ. 2002 Oct 12;325(7368):815.
著者: T Sugiyama, J Kiraku, T Ashida, J Fujii
雑誌名: Hypertens Res. 1998 Jun;21(2):103-8.
Abstract/Text To clarify the background and outcome of hypertensive patients who have remission of their elevated blood pressure (BP) after a course of antihypertensive drug therapy, we designed a retrospective observational study. The clinical records of 106 hypertensive men and women (BP, 164.3/104.4 mmHg) given antihypertensive drug treatment and subsequently examined every 1 to 3 mo for more than 20 yr were reviewed. The patients were divided into two groups: those who had remission (R-group) and those who did not have remission (N-group). Patients were considered in remission if no significant elevation in BP was observed for more than 1 yr after withdrawing their medication. Remissions ranging in duration from 1.6 to 21.7 yr (average duration, 6.3 yr) occurred in 19 of 106 patients (17.9%). However, anti-hypertensive drug treatment was eventually restarted in 17 of the 19 patients. Before treatment, comparison of the R-group and N-group revealed no differences with respect to age, body weight, BP, or serum creatinine. In contrast, the proportion of patients who lacked high-voltage deflections in their electrocardiograms (ECG) as well as that of patients whose BP was well-controlled by a single medication was significantly greater in the R-group than in the N-group (12/19 vs. 22/87, p < 0.05 and 10/19 vs. 13/87, p < 0.001, respectively). In addition, body weight in the R-group decreased significantly by the time drug therapy was withdrawn (p < 0.01). Finally, significantly more patients (14 of 19 patients) entered remission in the spring and summer (p < 0.05) than at other times of the year. We conclude that remission occurs in a subset of well-controlled hypertensive patients and may persist for several years or more. However, in the majority of patients, antihypertensive drug treatment will usually need to be restarted at some point. Patients who lack ECG high-voltage deflections and who are successfully treated with a single therapeutic agent are most likely to experience remission. Moreover, it appears that withdrawing patients from drug therapy in the spring or summer is more likely to yield a favorable outcome than at other times of the year.

PMID 9661806  Hypertens Res. 1998 Jun;21(2):103-8.
著者: K Kario, T G Pickering, T Matsuo, S Hoshide, J E Schwartz, K Shimada
雑誌名: Hypertension. 2001 Oct;38(4):852-7.
Abstract/Text It remains uncertain whether abnormal dipping patterns of nocturnal blood pressure influence the prognosis for stroke. We studied stroke events in 575 older Japanese patients with sustained hypertension determined by ambulatory blood pressure monitoring (without medication). They were subclassified by their nocturnal systolic blood pressure fall (97 extreme-dippers, with >/=20% nocturnal systolic blood pressure fall; 230 dippers, with >/=10% but <20% fall; 185 nondippers, with >/=0% but <10% fall; and 63 reverse-dippers, with <0% fall) and were followed prospectively for an average duration of 41 months. Baseline brain magnetic resonance imaging (MRI) disclosed that the percentages with multiple silent cerebral infarct were 53% in extreme-dippers, 29% in dippers, 41% in nondippers, and 49% in reverse-dippers. There was a J-shaped relationship between dipping status and stroke incidence (extreme-dippers, 12%; dippers, 6.1%; nondippers, 7.6%; and reverse-dippers, 22%), and this remained significant in a Cox regression analysis after controlling for age, gender, body mass index, 24-hour systolic blood pressure, and antihypertensive medication. Intracranial hemorrhage was more common in reverse-dippers (29% of strokes) than in other subgroups (7.7% of strokes, P=0.04). In the extreme-dipper group, 27% of strokes were ischemic strokes that occurred during sleep (versus 8.6% of strokes in the other 3 subgroups, P=0.11). In conclusion, in older Japanese hypertensive patients, extreme dipping of nocturnal blood pressure may be related to silent and clinical cerebral ischemia through hypoperfusion during sleep or an exaggerated morning rise of blood pressure, whereas reverse dipping may pose a risk for intracranial hemorrhage.

PMID 11641298  Hypertension. 2001 Oct;38(4):852-7.
著者: Kazuomi Kario, Hiroshi Kanegae, Naoko Tomitani, Yukie Okawara, Takeshi Fujiwara, Yuichiro Yano, Satoshi Hoshide
雑誌名: Hypertension. 2019 Jun;73(6):1240-1248. doi: 10.1161/HYPERTENSIONAHA.118.12740.
Abstract/Text We developed an innovative automated home blood pressure (BP) monitoring method that measures BP while asleep repeatedly over several days. Our aim was to assess the predictive ability of nighttime BP obtained using the home BP device for incident cardiovascular disease (CVD) in general practice patients. We used data from the nationwide practice-based J-HOP (Japan Morning Surge-Home Blood Pressure) Nocturnal BP Study, which recruited 2545 Japanese with a history of or risk factors for CVD (mean age 63 years; antihypertensive medication use 83%). The associations between nighttime home BPs (measured at 2:00, 3:00, and 4:00 am using validated, automatic, and oscillometric home BP devices) and incident CVD, including coronary disease and stroke events, were assessed with Cox proportional hazards models. The mean±SD office, morning home, and nighttime home systolic BP (SBP)/diastolic BP were 140±15/82±10, 137±15/79±10, and 121±15/70±9 mm Hg, respectively. During a follow-up of 7.1±3.8 years (18,116 person-years), 152 CVD events occurred. A 10-mm Hg increase of nighttime home SBP was associated with an increased risk of CVD events (hazard ratios [95% CIs]: 1.201 [1.046-1.378]), after adjustments for covariates including office and morning home SBPs. The model fit assessed by the change in Goodness-of-Fit was improved when we added nighttime home SBP into the base models including office and morning home SBPs (Δ6.838 [5.6%]; P=0.009). This is among the first and largest nationwide practice-based study demonstrating that nighttime SBP obtained using a home device is a predictor of incident CVD events, independent of in-office and morning in-home SBP measurement. Clinical Trial Registration- URL: http://www.umin.ac.jp/icdr/index.html . Unique identifier: UMIN000000894.

PMID 31006331  Hypertension. 2019 Jun;73(6):1240-1248. doi: 10.1161/HY・・・
著者: Kazuomi Kario, Chen-Huan Chen, Sungha Park, Chang-Gyu Park, Satoshi Hoshide, Hao-Min Cheng, Qi-Fang Huang, Ji-Guang Wang
雑誌名: Hypertension. 2018 Mar;71(3):375-382. doi: 10.1161/HYPERTENSIONAHA.117.10238. Epub 2018 Jan 8.
Abstract/Text
PMID 29311253  Hypertension. 2018 Mar;71(3):375-382. doi: 10.1161/HYPE・・・
著者: Satoshi Hoshide, Kazuomi Kario, Alejandro de la Sierra, Grzegorz Bilo, Giuseppe Schillaci, José Ramón Banegas, Manuel Gorostidi, Julian Segura, Carolina Lombardi, Stefano Omboni, Luis Ruilope, Giuseppe Mancia, Gianfranco Parati
雑誌名: Hypertension. 2015 Oct;66(4):750-6. doi: 10.1161/HYPERTENSIONAHA.115.05958. Epub 2015 Aug 24.
Abstract/Text Morning blood pressure (BP) surge has been reported to be a prognostic factor for cardiovascular events. Its determinants are still poorly defined, however. In particular, it is not clear whether ethnic differences play a role in determining morning surge (MS) size. Aim of our study was to explore whether differences exist in the size of MS between Japanese and Western European hypertensive patients. We included 2887 untreated hypertensive patients (age 62.3±8.8 years) from a European ambulatory BP monitoring database and 811 hypertensive patients from a Japanese database (Jichi Medical School Ambulatory Blood Pressure Monitoring WAVE1, age 72.3±9.8 years) following the same inclusion criteria. Their 24-hour ambulatory BP monitoring recordings were analyzed focusing on MS. Sleep-trough MS was defined as the difference between mean systolic BP during the 2 hours after awakening and mean systolic BP during the 1-hour night period that included the lowest sleep BP level. The sleep-trough MS was higher in Japanese than in European hypertensive patients after adjusting for age and 24-hour mean BP levels (40.1 [95% confidence interval 39.0-41.2] versus 23.0 [22.4-23.5] mm Hg; P<0.001). This difference remained significant after accounting for differences in night-time BP dipping. Age was independently associated with MS in the Japanese database, but not in the European subjects. Our results for the first time show the occurrence of substantial ethnic differences in the degree of MS. These findings may help in understanding the role of ethnic factors in cardiovascular risk assessment and in identifying possible ethnicity-related differences in the most effective measures to be implemented for prevention of BP-related cardiovascular events.

© 2015 American Heart Association, Inc.
PMID 26303289  Hypertension. 2015 Oct;66(4):750-6. doi: 10.1161/HYPERT・・・
著者: Kazuomi Kario, Daichi Shimbo, Satoshi Hoshide, Ji-Guang Wang, Kei Asayama, Takayoshi Ohkubo, Yutaka Imai, Richard J McManus, Anastasios Kollias, Teemu J Niiranen, Gianfranco Parati, Bryan Williams, Michael A Weber, Wanpen Vongpatanasin, Paul Muntner, George S Stergiou
雑誌名: Hypertension. 2019 Jul 1;:HYPERTENSIONAHA11912630. doi: 10.1161/HYPERTENSIONAHA.119.12630. Epub 2019 Jul 1.
Abstract/Text
PMID 31256719  Hypertension. 2019 Jul 1;:HYPERTENSIONAHA11912630. doi:・・・
著者: Takeshi Fujiwara, Satoshi Hoshide, Hiroshi Kanegae, Masafumi Nishizawa, Kazuomi Kario
雑誌名: J Clin Hypertens (Greenwich). 2018 Feb;20(2):315-323. doi: 10.1111/jch.13165. Epub 2018 Jan 6.
Abstract/Text The authors evaluated differences in the reliability of home blood pressure measurements taken in the morning, before dinner, and at bedtime. Forty-eight patients with hypertension (age range, 50-89 years; mean age, 76.4 years) measured their home blood pressure using a validated automatic information/communication technology-based device for 14 consecutive days. Those days were divided into the first seven days (1-7) and the following 8 to 14 days (days 8-14) and compared systolic blood pressure (SBP) reliability in the two periods for each measurement time point. In Bland-Altman analyses, morning SBP showed the least standard error of measurement (3.0 mm Hg). There were fixed biases in morning and before-dinner SBP with average limits of agreement of 3.9 and 6.4 mm Hg, respectively. For at-bedtime SBP, a random error was detected and the minimal detectable change was 13.8 mm Hg. The percentage of near-maximal variation of morning SBP was the smallest at 18.1%. Morning SBP therefore provided the most reliable home blood pressure value in the day.

©2018 Wiley Periodicals, Inc.
PMID 29316183  J Clin Hypertens (Greenwich). 2018 Feb;20(2):315-323. d・・・
著者: Kei Asayama, Takeshi Fujiwara, Satoshi Hoshide, Takayoshi Ohkubo, Kazuomi Kario, George S Stergiou, Gianfranco Parati, William B White, Michael A Weber, Yutaka Imai, International Expert Group of Nocturnal Home Blood Pressure
雑誌名: J Hypertens. 2019 May;37(5):905-916. doi: 10.1097/HJH.0000000000001987.
Abstract/Text : Studies using ambulatory blood pressure (BP) monitoring have shown that BP during night-time sleep is a stronger predictor of cardiovascular outcomes than daytime ambulatory or conventional office BP. However, night-time ambulatory BP recordings may interfere with sleep quality because of the device cuff inflation and frequency of measurements. Hence, there is an unmet need for obtaining high quality BP values during sleep. In the last two decades, technological development of home BP devices enabled automated BP measurements during night-time. Preliminary data suggest that nocturnal home BP measurements yield similar BP values and show good agreement in detecting nondippers when compared with ambulatory BP monitoring. Thus, nocturnal home BP measurements might be a reliable and practical alternative to ambulatory BP monitoring to evaluate BP during sleep. As the use of home BP devices is widespread, well accepted by users and has relatively low cost, it may prove to be more feasible and widely available for routine clinical assessment of nocturnal BP. At present, however, data on the prognostic relevance of nocturnal BP measured by home devices, the optimal measurement schedule, and other methodological issues are lacking and await further investigation. This article offers a systematic review of the current evidence on nocturnal home BP, highlights the remaining research questions, and provides preliminary recommendations for application of this novel approach in BP management.

PMID 30394982  J Hypertens. 2019 May;37(5):905-916. doi: 10.1097/HJH.0・・・
著者: Kazuomi Kario
雑誌名: Prog Cardiovasc Dis. 2016 Nov - Dec;59(3):262-281. doi: 10.1016/j.pcad.2016.04.001. Epub 2016 Apr 11.
Abstract/Text There are notable differences between Asians and Westerners regarding hypertension (HTN) and the relationship between HTN and cardiovascular disease (CVD). Asians show greater morning surges in blood pressure (BP) and a steeper slope illustrating the link between higher BP and the risk of CVD events. It is thus particularly important for Asian hypertensives to achieve 24-h BP control, including morning and night-time control. There are three components of 'perfect 24-h BP control:' the 24-h BP level, nocturnal BP dipping, and BP variability (BPV), such as the morning BP surge that can be assessed by ambulatory BP monitoring. The morning BP-guided approach using home BP monitoring (HBPM) is the first step toward perfect 24-h BP control, followed by the control of nocturnal HTN. We have been developing new HBPM devices that can measure nocturnal BP. BPV includes different time-phase variability from the shortest beat-by-beat, positional, diurnal, day-by-day, visit-to-visit, seasonal, and yearly changes. The synergistic resonance of each type of BPV would produce a great dynamic BP surge (resonance hypothesis), which triggers a CVD event, especially in the high-risk patients with systemic hemodynamic atherothrombotic syndrome (SHATS). In the future, the innovative management of HTN based on the simultaneous assessment of the resonance of all of the BPV phenotypes using a beat by beat wearable 'surge' BP monitoring device (WSP) and an information and communication technology (ICT)-based data analysis system will produce a paradigm shift from 'dots' BP management to 'seamless' ultimate individualized 'anticipation medication' for reaching a zero CVD event rate.

Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.
PMID 27080202  Prog Cardiovasc Dis. 2016 Nov - Dec;59(3):262-281. doi:・・・
著者: Ramón C Hermida, Diana E Ayala, Artemio Mojón, José R Fernández
雑誌名: Chronobiol Int. 2010 Sep;27(8):1629-51. doi: 10.3109/07420528.2010.510230.
Abstract/Text Clinical studies have documented morning-evening, administration-time differences of several different classes of hypertension medications in blood pressure (BP)-lowering efficacy, duration of action, safety profile, and/or effects on the circadian BP pattern. In spite of these published findings, most hypertensive subjects, including those under combination therapy, are instructed by their physicians and pharmacists to ingest all of their BP-lowering medications in the morning. The potential differential reduction of cardiovascular (CVD) morbidity and mortality risk by a bedtime versus upon-awakening treatment schedule has never been evaluated prospectively. The prospective MAPEC study was specifically designed to test the hypothesis that bedtime chronotherapy with ≥1 hypertension medications exerts better BP control and CVD risk reduction than conventional therapy, i.e., all medications ingested in the morning. A total of 2156 hypertensive subjects, 1044 men/1112 women, 55.6 ± 13.6 (mean ± SD) yrs of age, were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00 h and at 30-min intervals at night for 48 h. Physical activity was simultaneously monitored every min by wrist actigraphy to accurately determine the beginning and end of daytime activity and nocturnal sleep. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Despite lack of differences in ambulatory BP between groups at baseline, subjects ingesting medication at bedtime showed at their last available evaluation significantly lower mean sleep-time BP, higher sleep-time relative BP decline, reduced prevalence of non-dipping (34% versus 62%; p < .001), and higher prevalence of controlled ambulatory BP (62% versus 53%; p < .001). After a median follow-up of 5.6 yrs, subjects ingesting ≥1 BP-lowering medications at bedtime exhibited a significantly lower relative risk of total CVD events than those ingesting all medications upon awakening (0.39 [0.29-0.51]; number of events 187 versus 68; p < .001). The difference between the treatment-time groups in the relative risk of major events (including CVD death, myocardial infarction, ischemic stroke, and hemorrhagic stroke) was also highly statistically significant (0.33 [0.19-0.55]; number of events: 55 versus 18; p < .001). The progressive decrease in asleep BP and increase in sleep-time relative BP decline towards a more normal dipping pattern, two novel therapeutic targets requiring proper patient evaluation by ambulatory BP, were best achieved with bedtime therapy, and they were the most significant predictors of event-free survival. Bedtime chronotherapy with ≥1 BP-lowering medications, compared to conventional upon-waking treatment with all medications, more effectively improved BP control, better decreased the prevalence of non-dipping, and, most importantly, significantly reduced CVD morbidity and mortality.

PMID 20854139  Chronobiol Int. 2010 Sep;27(8):1629-51. doi: 10.3109/07・・・
著者: Satoshi Hoshide, Kazuomi Kario, Yoko Hoshide, Yuji Umeda, Toru Hashimoto, Osamu Kunii, Toshiyuki Ojima, Kazuyuki Shimada
雑誌名: Am J Hypertens. 2003 Jun;16(6):434-8. doi: 10.1016/s0895-7061(03)00567-3.
Abstract/Text BACKGROUND: In hypertensives, nondippers are more likely than dippers to suffer silent, as well as overt, hypertensive target organ damage. In this study, we investigated whether a nondipper status was associated with target organ damage in normotensives.
METHODS: We performed ambulatory blood pressure (BP) monitoring, echocardiography, and carotid ultrasonography and measured natriuretic peptides and urinary albumin (UAE) in 74 normotensive subjects with the following criteria: 1) clinical BP <140/90 mm Hg; 2) average 24-h ambulatory BP <125/80 mm Hg.
RESULTS: The left ventricular mass index (LVMI) and the relative wall thickness (RWT) measured by echocardiography were greater in nondippers than dippers (LVMI: 103 +/- 26 v 118 +/- 34 g/m(2), P <.05; RWT: 0.38 +/- 0.07 v 0.43 +/- 0.09, P <.01). Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were higher in nondippers than dippers (ANP: 14 +/- 10 v 36 +/- 63 pg/mL, P <.01; BNP: 16 +/- 12 v 62 +/- 153 pg/mL, P <.05). There were no significant differences in UAE and intima-media thickness measured by carotid ultrasonography.
CONCLUSIONS: Normotensive nondipping may not reflect renal damage, but may have a predominant effect on cardiac damage. Nondipping of nocturnal BP seems to be a determinant of cardiac hypertrophy and remodeling, and may result in a cardiovascular risk independent of ambulatory BP levels in normotensives.

PMID 12799090  Am J Hypertens. 2003 Jun;16(6):434-8. doi: 10.1016/s089・・・
著者: M Yakovlevitch, H R Black
雑誌名: Arch Intern Med. 1991 Sep;151(9):1786-92.
Abstract/Text STUDY OBJECTIVE: --To determine the prevalence of resistant hypertension in a tertiary care facility, the frequency of its various causes, and the results of treatment.
DESIGN: --Review of clinic records of all patients seen for the first time between January 1, 1986, and December 31, 1988.
METHODS: --Patients meeting criteria for resistant hypertension were examined for appropriateness of their medical regimen, presence of secondary causes of hypertension, noncompliance, interfering substances, drug interactions, office resistance (elevated blood pressure in the office only while receiving treatment), and other potential causes of resistance.
RESULTS: --Of the 436 charts reviewed, 91 were those of patients who met criteria for resistant hypertension and were seen more than once. The most common cause was a suboptimal medical regimen (39 patients), followed by medication intolerance (13 patients), previously undiagnosed secondary hypertension (10 patients), noncompliance (nine patients), psychiatric causes (seven patients), office resistance (two patients), an interfering substance (two patients), and drug interaction (one patient). Blood pressure control, defined as diastolic blood pressure of 90 mm Hg or less and systolic blood pressure of 140 mm Hg or less for patients aged 50 years or less (less than or equal to 150 mm Hg for those aged 51 to 60 years and less than or equal to 160 mm Hg for those aged greater than 60 years), was achieved in 48 (53%) of those 91 patients. Another 10 had significant improvement in their blood pressure (greater than or equal to 15% decrease in diastolic blood pressure). Of patients whose blood pressure was controlled after they had been on a suboptimal regimen, the two most frequently used therapeutic strategies were to add (50%) or modify (24%) diuretic therapy or to add (50%) or increase the dose of (12%) a newer drug, either a calcium entry blocker or angiotensin-converting enzyme inhibitor.
CONCLUSION: --We conclude that resistant hypertension is common in a tertiary care facility and that a suboptimal regimen is the most common reason. Furthermore, in the majority of these patients, the elevated blood pressures can be controlled or significantly improved.

PMID 1888244  Arch Intern Med. 1991 Sep;151(9):1786-92.

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