今日の臨床サポート

降圧薬(薬理)

著者: 前田智司1) 日本薬科大薬学部

著者: 松浦誠2) 岩手医科大学 薬学部 臨床薬学講座 地域医療薬学分野

監修: 中原 保裕 (有)ファーマシューティカルケア研究所

著者校正/監修レビュー済:2021/11/10

概要・推奨   

  1. 降圧薬の種類には、Ca拮抗薬、ACE(アンジオテンシン変換酵素)阻害薬/ARB(アンジオテンシン受容体拮抗薬)、アルドステロン阻害薬、直接的レニン阻害薬、利尿薬(サイアザイド系・非サイアザイド系・ループ利尿薬・カリウム保持性)、β遮断薬、αβ遮断薬、α遮断薬、レセルピン系、中枢性交感神経抑制薬、血管拡張薬MR阻害薬などが存在する。
  1. 生活習慣の改善のみでは目標降圧レベルに達することは困難と判断された場合、降圧薬による治療考慮する
  1. 多くの研究にて、降圧薬で血圧を下降させることにより、心血管疾患の発症を予防できることが示されている。そして、この効果は降圧薬の種類によらず降圧の大きさに帰因することが、大規模臨床試験のメタ解析から示されている。したがって、薬剤の選択は、目標降圧作用を到達できるのに十分な降圧効果が高く、また、合併する種々の病態に適した降圧薬を選択することにな(推奨度1)
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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:
前田智司 : 未申告[2021年]
松浦誠 : 未申告[2021年]
監修:中原 保裕 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 販売中止になった薬を削除
  1. ARB・ネプリライシン阻害薬配合薬、降圧薬3剤合剤および小児に適応がある降圧薬を追加

各論

合併症に基づく治療薬選択のまとめ  
  1. 以下の一覧のような背景を認める場合には適応・禁忌に沿った薬剤治療を行うことが望ましい。
 
  1. 患者の背景と適応禁忌薬剤治療の一覧:
  1. 年齢・性別・既往歴:
  1. 高齢者:
  1. 適応:Ca拮抗薬、ACE阻害薬/ARB、利尿薬
  1. 妊娠:
  1. 禁忌:ACE阻害薬/ARB
  1. 慎重使用例:サイアザイド系/サイアザイド類似利尿薬
  1. 血管神経性浮腫:
  1. 禁忌:ACE阻害薬
  1. 脳・心臓血管疾患:(*はACE阻害薬に対し忍容性が悪い場合のみ)
  1. 脳血管障害慢性期:
  1. 適応:Ca拮抗薬、ACE阻害薬/ARB、サイアザイド類似薬
  1. 労作性狭心症:
  1. 適応:Ca拮抗薬、β遮断薬、ACE阻害薬
  1. 冠れん縮型狭心症:
  1. 適応:Ca拮抗薬
  1. 心筋梗塞後:
  1. 適応:ACE阻害薬/ARB、β遮断薬
  1. 左室肥大:
  1. 適応:Ca拮抗薬、ACE阻害薬/ARB
  1. 心不全:
  1. 適応:ACE阻害薬/ARB、利尿薬、β遮断薬
  1. 慎重使用例:Ca拮抗薬
  1. 頻脈:
  1. 適応:非ジヒドロピリジン系Ca拮抗薬、β遮断薬
  1. 徐脈:
  1. 禁忌:非ジヒドロピリジン系Ca拮抗薬
  1. 高度徐脈:
  1. 禁忌:β遮断薬
  1. 起立性低血圧:
  1. 禁忌:α1阻害薬
  1. 末梢動脈疾患:
  1. 慎重投与:β遮断薬
  1. 腎疾患:
  1. 蛋白尿:
  1. 適応:ACE阻害薬/ARB
  1. 慢性腎疾患(蛋白尿-):
  1. 適応:ACE阻害薬/ARB、ジヒドロピリジン系Ca拮抗薬、サイアザイド系/サイアザイド類似利尿薬(ただし中程度以上の腎障害では使わない)
  1. 両側腎動脈狭窄症:
  1. 禁忌:ACE阻害薬/ARB
  1. 片側腎動脈狭窄症:
  1. 慎重使用例:ACE阻害薬/ARB
  1. 前立腺肥大症:
  1. 適応:α1阻害薬
  1. 重症の肝機能障害:
  1. 慎重投与:肝代謝の薬剤一般、利尿薬
  1. 代謝性疾患:
  1. 糖尿病:
  1. 適応:ACE阻害薬/ARB
  1. 慎重使用例:サイアザイド系/サイアザイド類似利尿薬、β遮断薬
  1. 耐糖能異常:
  1. 適応:ACE阻害薬/ARB
  1. 慎重使用例:サイアザイド系/サイアザイド類似利尿薬、β遮断薬
  1. メタボリックシンドローム:
  1. 適応:ACE阻害薬/ARB
  1. 痛風:
  1. 適応:ロサルタン、Ca拮抗薬
  1. 慎重投与:サイアザイド系/サイアザイド類似利尿薬
  1. 骨粗鬆症:
  1. 適応:サイアザイド系/サイアザイド類似利尿薬
  1. 呼吸器疾患:
  1. 喘息:
  1. 禁忌:β遮断薬
  1. 閉塞性肺疾患:
  1. 慎重使用例:β遮断薬
  1. 誤嚥性肺炎:
  1. 適応:ACE阻害薬
  1. 電解質異常:
  1. 高K血症:
  1. 禁忌:ACE阻害薬/ARB
  1. 低K血症:
  1. 禁忌:サイアザイド系/サイアザイド類似利尿薬
併用療法  
 
  1. ポイント:
  1. 降圧目標を達成するためには、多くの場合2、3剤の併用が必要となる。その際、少量利尿薬を積極的に併用すべきである。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

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: 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: 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: 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: 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: 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・・・

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