今日の臨床サポート

心房細動

著者: 髙橋尚彦 大分大学 医学部 循環器内科・臨床検査診断学講座

監修: 山下武志 心臓血管研究所付属病院

著者校正/監修レビュー済:2021/05/26
患者向け説明資料

概要・推奨   

  1. 心房細動に関連する自覚症状の評価において、modified EHRAスケールを使用する(推奨度2)。
  1. 心房細動の検出における、65歳以上の高齢者における定期的な検脈および心電図検査(推奨度1)。
  1. 心房細動検出における、潜因性脳梗塞患者への非侵襲的長時間心電図モニターまたは植込み型心電計(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:
髙橋尚彦 : 講演料(第一三共,ファイザー,バイエル薬品,日本ベーリンガーインゲルハイム,トーアエイヨー,ノバルティスファーマ,小野薬品)[2021年]
監修:山下武志 : 講演料(第一三共,ブリストル・マイヤーズスクイブ,バイエル,小野薬品,トーアエイヨー,ノバルティス),原稿料(第一三共,バイエル),研究費・助成金など(第一三共,ブリストルマイヤーズスクイブ)[2021年]

改訂のポイント:
  1. 定期レビューを行い、カテーテルアブレーション、左心耳閉鎖デバイスについて加筆修正を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 心房細動とは、心房に変動する複数のリエントリーが成立し心房が秩序のないまま局所的には250~350回/分またはそれ以上の頻度で興奮している状態である。診断は、心電図でf波と、不規則なRR間隔を持ったnarrow QRSとが認められることでなされる。心房細動はその持続時間から、発作性(7日間以内多くは48時間以内)、持続性(7日間以上)、長期持続性(1年以上継続しているが洞調律維持療法を考慮し得るもの)および永続性(除細動が不能)に分類される。発作性の心房細動は毎年5.0~8.6%で慢性化するとされている。なお、発作性から慢性への移行は初期に多く最初の5年で約25%が永続性の心房細動に移行するとのデータがある[1]
  1. 高齢化で患者数は増加の一途をたどっているといわれる。全国の健診心電図を集計した疫学調査で心房細動有病率は1%前後であり、common diseaseといえるレベルに達している[2][3]
  1. 日本での発症率は欧米より低く日本循環器学会の疫学調査では、有病率は70歳台男性で3.44%、女性で2.19%であり、米国の有病率と比較すると2/3の有病率となっている[4]。米国のフラミンガムスタディによると、生涯の間に一過性および慢性の心房細動を発症するリスクは40歳男性で26%、女性では23%であった[5]
  1. 加齡、高血圧、糖尿病、メタボリックシンドローム、閉塞性睡眠時呼吸障害、慢性腎臓病など、さまざまな心血管リスク因子が心房細動発症と相関する[6][7]
  1. 脳梗塞発症後の心房細動患者の予後はきわめて不良である[8]。抗凝固療法を適切に導入し、脳梗塞予防につとめることが重要である。
病歴・診察のポイント  
  1. 心房細動については、現在持続しているならば、いつから持続していると考えられるかを確認する。また、発作の頻度と自覚症状の強さを把握する。

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文献 

著者: Charles R Kerr, Karin H Humphries, Mario Talajic, George J Klein, Stuart J Connolly, Martin Green, John Boone, Robert Sheldon, Paul Dorian, David Newman
雑誌名: Am Heart J. 2005 Mar;149(3):489-96. doi: 10.1016/j.ahj.2004.09.053.
Abstract/Text BACKGROUND: After its initial diagnosis, atrial fibrillation (AF) may progress from paroxysmal to chronic AF (CAF). The rate of progression and risk factors for progression are not clearly defined.
METHODS: The Canadian Registry of Atrial Fibrillation (CARAF) enrolled patients from 6 Canadian cities at the time of their first electrocardiographic diagnosis of AF. Comprehensive clinical and echocardiographic data were collected and patients were followed annually, carefully documenting clinical outcomes, recurrence of paroxysmal AF, and progression to CAF. Baseline clinical, electrocardiographic, and echocardiographic variables were evaluated by univariate Cox proportionate hazards analysis. A stepwise approach was used to model the association between echocardiographic and clinical variables with progression to CAF.
RESULTS: A total of 757 patients with a baseline diagnosis of paroxysmal AF were evaluated. Median follow-up was 8.0 years (range 2 days to 11.1 years). The probability of progression to CAF by 1 year was 8.6% and thereafter there was a slow but steady progression to 24.7% by 5 years. By 5 years, the probability of documented recurrence of any AF (chronic or paroxysmal) was 63.2%. Increasing age, significant aortic stenosis or mitral regurgitation, left atrial enlargement, and diagnosis of cardiomyopathy were independently associated with progression to CAF. A more rapid heart rate during AF was associated with decreased risk of progression.
CONCLUSIONS: After the initial diagnosis of paroxysmal AF, there is a slow but steady progression to CAF. Baseline echocardiographic variables, age, cardiomyopathy, and heart rate were independently associated with progression to CAF.

PMID 15864238  Am Heart J. 2005 Mar;149(3):489-96. doi: 10.1016/j.ahj.・・・
著者: Masaki Ohsawa, Akira Okayama, Kiyomi Sakata, Karen Kato, Kazuyoshi Itai, Toshiyuki Onoda, Hirotsugu Ueshima
雑誌名: J Epidemiol. 2005 Sep;15(5):194-6.
Abstract/Text
PMID 16195640  J Epidemiol. 2005 Sep;15(5):194-6.
著者: O P Heinonen, S Shapiro, R R Monson, S C Hartz, L Rosenberg, D Slone
雑誌名: Int J Epidemiol. 1973 Autumn;2(3):229-35.
Abstract/Text
PMID 4359832  Int J Epidemiol. 1973 Autumn;2(3):229-35.
著者: Mitsuhiro Yokoyama, Hideki Origasa, Masunori Matsuzaki, Yuji Matsuzawa, Yasushi Saito, Yuichi Ishikawa, Shinichi Oikawa, Jun Sasaki, Hitoshi Hishida, Hiroshige Itakura, Toru Kita, Akira Kitabatake, Noriaki Nakaya, Toshiie Sakata, Kazuyuki Shimada, Kunio Shirato, Japan EPA lipid intervention study (JELIS) Investigators
雑誌名: Lancet. 2007 Mar 31;369(9567):1090-8. doi: 10.1016/S0140-6736(07)60527-3.
Abstract/Text BACKGROUND: Epidemiological and clinical evidence suggests that an increased intake of long-chain n-3 fatty acids protects against mortality from coronary artery disease. We aimed to test the hypothesis that long-term use of eicosapentaenoic acid (EPA) is effective for prevention of major coronary events in hypercholesterolaemic patients in Japan who consume a large amount of fish.
METHODS: 18 645 patients with a total cholesterol of 6.5 mmol/L or greater were recruited from local physicians throughout Japan between 1996 and 1999. Patients were randomly assigned to receive either 1800 mg of EPA daily with statin (EPA group; n=9326) or statin only (controls; n=9319) with a 5-year follow-up. The primary endpoint was any major coronary event, including sudden cardiac death, fatal and non-fatal myocardial infarction, and other non-fatal events including unstable angina pectoris, angioplasty, stenting, or coronary artery bypass grafting. Analysis was by intention-to-treat. The study was registered at ClinicalTrials.gov, number NCT00231738.
FINDINGS: At mean follow-up of 4.6 years, we detected the primary endpoint in 262 (2.8%) patients in the EPA group and 324 (3.5%) in controls-a 19% relative reduction in major coronary events (p=0.011). Post-treatment LDL cholesterol concentrations decreased 25%, from 4.7 mmol/L in both groups. Serum LDL cholesterol was not a significant factor in a reduction of risk for major coronary events. Unstable angina and non-fatal coronary events were also significantly reduced in the EPA group. Sudden cardiac death and coronary death did not differ between groups. In patients with a history of coronary artery disease who were given EPA treatment, major coronary events were reduced by 19% (secondary prevention subgroup: 158 [8.7%] in the EPA group vs 197 [10.7%] in the control group; p=0.048). In patients with no history of coronary artery disease, EPA treatment reduced major coronary events by 18%, but this finding was not significant (104 [1.4%] in the EPA group vs 127 [1.7%] in the control group; p=0.132).
INTERPRETATION: EPA is a promising treatment for prevention of major coronary events, and especially non-fatal coronary events, in Japanese hypercholesterolaemic patients.

PMID 17398308  Lancet. 2007 Mar 31;369(9567):1090-8. doi: 10.1016/S014・・・
著者: Donald M Lloyd-Jones, Thomas J Wang, Eric P Leip, Martin G Larson, Daniel Levy, Ramachandran S Vasan, Ralph B D'Agostino, Joseph M Massaro, Alexa Beiser, Philip A Wolf, Emelia J Benjamin
雑誌名: Circulation. 2004 Aug 31;110(9):1042-6. doi: 10.1161/01.CIR.0000140263.20897.42. Epub 2004 Aug 16.
Abstract/Text BACKGROUND: Atrial fibrillation (AF) is the most common cardiac dysrhythmia and a source of considerable morbidity and mortality, but lifetime risk for AF has not been estimated.
METHODS AND RESULTS: We included all participants in the Framingham Heart Study who were free of AF at index ages of 40 years and older. We estimated lifetime risks for AF (including atrial flutter) to age 95 years, with death free of AF as a competing event. We followed 3999 men and 4726 women from 1968 to 1999 (176 166 person-years); 936 participants had development of AF and 2621 died without prior AF. At age 40 years, lifetime risks for AF were 26.0% (95% CI, 24.0% to 27.0%) for men and 23.0% (21.0% to 24.0%) for women. Lifetime risks did not change substantially with increasing index age despite decreasing remaining years of life because AF incidence rose rapidly with advancing age. At age 80 years, lifetime risks for AF were 22.7% (20.1% to 24.1%) in men and 21.6% (19.3% to 22.7%) in women. In further analyses, counting only those who had development of AF without prior or concurrent congestive heart failure or myocardial infarction, lifetime risks for AF were approximately 16%.
CONCLUSIONS: Lifetime risks for development of AF are 1 in 4 for men and women 40 years of age and older. Lifetime risks for AF are high (1 in 6), even in the absence of antecedent congestive heart failure or myocardial infarction. These substantial lifetime risks underscore the major public health burden posed by AF and the need for further investigation into predisposing conditions, preventive strategies, and more effective therapies.

PMID 15313941  Circulation. 2004 Aug 31;110(9):1042-6. doi: 10.1161/01・・・
著者: Hiroshi Watanabe, Naohito Tanabe, Toru Watanabe, Dawood Darbar, Dan M Roden, Shigeru Sasaki, Yoshifusa Aizawa
雑誌名: Circulation. 2008 Mar 11;117(10):1255-60. doi: 10.1161/CIRCULATIONAHA.107.744466. Epub 2008 Feb 19.
Abstract/Text BACKGROUND: The metabolic syndrome consists of a cluster of atherosclerotic risk factors, many of which also have been implicated in the genesis of atrial fibrillation (AF). However, the precise role of the metabolic syndrome in the development of AF is unknown.
METHODS AND RESULTS: This prospective, community-based, observational cohort study was based on an annual health check-up program in Japan. We studied 28 449 participants without baseline AF. We used 2 different criteria for the metabolic syndrome--the guidelines of the National Cholesterol Education Program Third Adult Treatment Panel (NCEP-ATP III) and those of the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI)--to study the risk of development of new-onset AF. The metabolic syndrome was present in 3716 subjects (13%) and 4544 subjects (16%) using the NCEP-ATP III and AHA/NHLBI definitions, respectively. During a mean follow-up of 4.5 years, AF developed in 265 subjects (105 women). Among the metabolic syndrome components, obesity (age- and sex-adjusted hazard ratio [HR], 1.64), elevated blood pressure (HR, 1.69), low high-density lipoprotein cholesterol (HR, 1.52), and impaired fasting glucose [corrected] (HR, 1.44 [NCEP-ATP III] and 1.35 [AHA/NHLBI]) showed an increased risk for AF. The association between the metabolic syndrome and AF remained significant in subjects without treated hypertension or diabetes by the NCEP-ATP III definition (HR, 1.78) but not by the AHA/NHLBI definition (HR, 1.28).
CONCLUSIONS: The metabolic syndrome was associated with increased risk of AF. The metabolic derangements of the syndrome may be important in the pathogenesis of AF.

PMID 18285562  Circulation. 2008 Mar 11;117(10):1255-60. doi: 10.1161/・・・
著者: Hiroshi Watanabe, Toru Watanabe, Shigeru Sasaki, Kojiro Nagai, Dan M Roden, Yoshifusa Aizawa
雑誌名: Am Heart J. 2009 Oct;158(4):629-36. doi: 10.1016/j.ahj.2009.06.031.
Abstract/Text BACKGROUND: Atrial fibrillation (AF) and chronic kidney disease share risk factors and pathophysiologic mechanisms, suggesting that two conditions have close relationships.
METHODS: This is a prospective community-based observational cohort study including 235,818 subjects based upon a voluntary annual health check-up program in Japan. We studied the association of kidney dysfunction at entry with subsequent new-onset AF and the association of AF at entry with the development of kidney disease.
RESULTS: During a follow-up of 5.9 +/- 2.4 years, AF developed in 2947 subjects (1.3%). Baseline serum creatinine and estimated glomerular filtration rate (GFR) were associated with risk of subsequent AF. The HRs (95% CI) for AF were 1.32 (1.08-1.62) and 1.57 (0.89-2.77) for GFR 30 to 59 and <30 mL/min per 1.73 m(2), respectively. The effect of kidney disease on risk of new-onset AF remained significant in subjects without treated hypertension or diabetes. During the follow-up, 7791 subjects (3.3%) developed kidney dysfunction (GFR <60 mL/min per 1.73 m(2)), and 11 307 subjects (4.9%) developed proteinuria. Atrial fibrillation at entry was associated with development of kidney dysfunction (HRs [95% CI], 1.77 [1.50-2.10]) and proteinuria (HR [95% CI], 2.20 [1.92-2.52]). The association persisted in subjects without treated hypertension or diabetes.
CONCLUSIONS: Kidney dysfunction increased the risk of new onset of AF, and AF increased the risk of development of kidney disease. This finding supports the concept that the two conditions share common abnormal molecular signaling pathways contributing to their pathogenesis.

PMID 19781424  Am Heart J. 2009 Oct;158(4):629-36. doi: 10.1016/j.ahj.・・・
著者: Lars Frost, Ljubica Vukelic Andersen, Peter Vestergaard, Steen Husted, Leif Spange Mortensen
雑誌名: Am J Med. 2007 Jan;120(1):47-53. doi: 10.1016/j.amjmed.2005.12.027.
Abstract/Text PURPOSE: To evaluate trend in mortality in stroke associated with atrial fibrillation, we examined mortality trend after stroke with atrial fibrillation by calendar year period (1980-1984, 1985-1989, 1990-1994, 1995-1999, and 2000-2002). We estimated trends separately for each sex in unadjusted analyses. We also adjusted for age, comorbid conditions, and general trend in mortality in the background population.
METHODS: We identified all individuals, aged 40-89 years, with an incident diagnosis of stroke of any nature (ischemic or hemorrhagic) and no history of heart valve disease and a previous or concomitant diagnosis of atrial fibrillation or flutter in the Danish National Registry of Patients. Subjects were followed in the Danish Civil Registration System for emigration and vital status. We used multivariate Cox proportional hazards regression analysis to estimate trend in mortality.
RESULTS: Incident stroke with a previous or concomitant diagnosis of nonvalvular atrial fibrillation or flutter was diagnosed in 24,470 subjects (11,554 men and 12,916 women). During 34,405 years of observation, 9237 men died, and during 35,381 years of observation, 10,827 women died. The hazard ratio for mortality after stroke in the last 3-year period compared with the first 5-year period was .65 (95% confidence interval [CI], .61-.71) in men and .69 (95% CI, .64-.74) in women.
CONCLUSIONS: We observed a substantially better survival in men and women after stroke associated with atrial fibrillation or flutter in Denmark during the years 1980 to 2002. However, we could not control for changes in admission practice, diagnostic performance, or treatment.

PMID 17208079  Am J Med. 2007 Jan;120(1):47-53. doi: 10.1016/j.amjmed.・・・
著者: E J Benjamin, D Levy, S M Vaziri, R B D'Agostino, A J Belanger, P A Wolf
雑誌名: JAMA. 1994 Mar 16;271(11):840-4.
Abstract/Text OBJECTIVE: To determine the independent risk factors for atrial fibrillation.
DESIGN: Cohort study.
SETTING: The Framingham Heart Study.
SUBJECTS: A total of 2090 men and 2641 women members of the original cohort, free of a history of atrial fibrillation, between the ages of 55 and 94 years.
MAIN OUTCOME MEASURES: Sex-specific multiple logistic regression models to identify independent risk factors for atrial fibrillation, including age, smoking, diabetes, electrocardiographic left ventricular hypertrophy, hypertension, myocardial infarction, congestive heart failure, and valve disease.
RESULTS: During up to 38 years of follow-up, 264 men and 298 women developed atrial fibrillation. After adjusting for age and other risk factors for atrial fibrillation, men had a 1.5 times greater risk of developing atrial fibrillation than women. In the full multivariable model, the odds ratio (OR) of atrial fibrillation for each decade of advancing age was 2.1 for men and 2.2 for women (P < .0001). In addition, after multivariable adjustment, diabetes (OR, 1.4 for men and 1.6 for women), hypertension (OR, 1.5 for men and 1.4 for women), congestive heart failure (OR, 4.5 for men and 5.9 for women), and valve disease (OR, 1.8 for men and 3.4 for women) were significantly associated with risk for atrial fibrillation in both sexes. Myocardial infarction (OR, 1.4) was significantly associated with the development of atrial fibrillation in men. Women were significantly more likely than men to have valvular heart disease as a risk factor for atrial fibrillation. The multivariable models were largely unchanged after eliminating subjects with valvular heart disease.
CONCLUSION: In addition to intrinsic cardiac causes such as valve disease and congestive heart failure, risk factors for cardiovascular disease also predispose to atrial fibrillation. Modification of risk factors for cardiovascular disease may have the added benefit of diminishing the incidence of atrial fibrillation.

PMID 8114238  JAMA. 1994 Mar 16;271(11):840-4.
著者: Thomas J Wang, Martin G Larson, Daniel Levy, Ramachandran S Vasan, Eric P Leip, Philip A Wolf, Ralph B D'Agostino, Joanne M Murabito, William B Kannel, Emelia J Benjamin
雑誌名: Circulation. 2003 Jun 17;107(23):2920-5. doi: 10.1161/01.CIR.0000072767.89944.6E. Epub 2003 May 27.
Abstract/Text BACKGROUND: Atrial fibrillation (AF) and congestive heart failure (CHF) frequently occur together, but there is limited information regarding their temporal relations and the combined influence of these conditions on mortality.
METHODS AND RESULTS: We studied participants in the Framingham Study with new-onset AF or CHF. Multivariable Cox proportional hazards models with time-dependent variables were used to evaluate whether mortality after AF or CHF was affected by the occurrence and timing of the other condition. Hazard ratios (HRs) were adjusted for time period and cardiovascular risk factors. During the study period, 1470 participants developed AF, CHF, or both. Among 382 individuals with both conditions, 38% had AF first, 41% had CHF first, and 21% had both diagnosed on the same day. The incidence of CHF among AF subjects was 33 per 1000 person-years, and the incidence of AF among CHF subjects was 54 per 1000 person-years. In AF subjects, the subsequent development of CHF was associated with increased mortality (men: HR 2.7; 95% CI, 1.9 to 3.7; women: HR 3.1; 95% CI, 2.2 to 4.2). Similarly, in CHF subjects, later development of AF was associated with increased mortality (men: HR 1.6; 95% CI, 1.2 to 2.1; women: HR 2.7, 95% CI, 2.0 to 3.6). Preexisting CHF adversely affected survival in individuals with AF, but preexisting AF was not associated with adverse survival in those with CHF.
CONCLUSIONS: Individuals with AF or CHF who subsequently develop the other condition have a poor prognosis. Additional studies addressing the pathogenesis, prevention, and optimal management of the joint occurrence of AF and CHF appear warranted.

PMID 12771006  Circulation. 2003 Jun 17;107(23):2920-5. doi: 10.1161/0・・・
著者: B F Gage, A D Waterman, W Shannon, M Boechler, M W Rich, M J Radford
雑誌名: JAMA. 2001 Jun 13;285(22):2864-70.
Abstract/Text CONTEXT: Patients who have atrial fibrillation (AF) have an increased risk of stroke, but their absolute rate of stroke depends on age and comorbid conditions.
OBJECTIVE: To assess the predictive value of classification schemes that estimate stroke risk in patients with AF.
DESIGN, SETTING, AND PATIENTS: Two existing classification schemes were combined into a new stroke-risk scheme, the CHADS( 2) index, and all 3 classification schemes were validated. The CHADS( 2) was formed by assigning 1 point each for the presence of congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and by assigning 2 points for history of stroke or transient ischemic attack. Data from peer review organizations representing 7 states were used to assemble a National Registry of AF (NRAF) consisting of 1733 Medicare beneficiaries aged 65 to 95 years who had nonrheumatic AF and were not prescribed warfarin at hospital discharge.
MAIN OUTCOME MEASURE: Hospitalization for ischemic stroke, determined by Medicare claims data.
RESULTS: During 2121 patient-years of follow-up, 94 patients were readmitted to the hospital for ischemic stroke (stroke rate, 4.4 per 100 patient-years). As indicated by a c statistic greater than 0.5, the 2 existing classification schemes predicted stroke better than chance: c of 0.68 (95% confidence interval [CI], 0.65-0.71) for the scheme developed by the Atrial Fibrillation Investigators (AFI) and c of 0.74 (95% CI, 0.71-0.76) for the Stroke Prevention in Atrial Fibrillation (SPAF) III scheme. However, with a c statistic of 0.82 (95% CI, 0.80-0.84), the CHADS( 2) index was the most accurate predictor of stroke. The stroke rate per 100 patient-years without antithrombotic therapy increased by a factor of 1.5 (95% CI, 1.3-1.7) for each 1-point increase in the CHADS( 2) score: 1.9 (95% CI, 1.2-3.0) for a score of 0; 2.8 (95% CI, 2.0-3.8) for 1; 4.0 (95% CI, 3.1-5.1) for 2; 5.9 (95% CI, 4.6-7.3) for 3; 8.5 (95% CI, 6.3-11.1) for 4; 12.5 (95% CI, 8.2-17.5) for 5; and 18.2 (95% CI, 10.5-27.4) for 6.
CONCLUSION: The 2 existing classification schemes and especially a new stroke risk index, CHADS( 2), can quantify risk of stroke for patients who have AF and may aid in selection of antithrombotic therapy.

PMID 11401607  JAMA. 2001 Jun 13;285(22):2864-70.
著者: T Yamashita, Y Murakawa, K Sezaki, M Inoue, N Hayami, Y Shuzui, M Omata
雑誌名: Circulation. 1997 Sep 2;96(5):1537-41.
Abstract/Text BACKGROUND: Circadian variation in the incidence of acute cardiovascular events is well known but has not been extensively investigated in paroxysmal atrial fibrillation, although the significance of this arrhythmia is growing in our society with the increasing number of aged people.
METHODS AND RESULTS: We detected 150 patients with paroxysmal atrial fibrillation in a drug-free state from among 25,500 consecutive Holter recordings. To determine whether the onset, maintenance, and termination of paroxysmal atrial fibrillation were random events, we analyzed the total recorded duration of arrhythmia and the incidence of and number of patients with the onset, maintenance, and termination of this arrhythmia as hourly data and as hourly probabilities. A prominent circadian rhythm of the total duration of atrial fibrillation, approximately 90% of which was well explained by a single cosinusoidal function, was detected with a nadir around 11 AM. Because the onset of the arrhythmia had little or no circadian rhythm, this finding was due to a diurnal pattern of maintenance and termination, both of which were well expressed by a double-harmonic density function. Maintenance showed a trough at 11 AM, and termination showed a peak at the same time, leading to the nonuniform duration of single episodes of atrial fibrillation throughout the 24-hour day.
CONCLUSIONS: Paroxysmal atrial fibrillation showed a unique circadian variation that differed from the well-known pattern for acute cardiovascular events, a point that should be kept in mind when antiarrhythmic therapy is evaluated. Identification of factors that regulate the circadian pattern of the maintenance and termination of paroxysmal atrial fibrillation may lead to better chronotherapy for preventing perpetuation of this arrhythmia.

PMID 9315544  Circulation. 1997 Sep 2;96(5):1537-41.
著者: Carsten W Israel, Gerian Grönefeld, Joachim R Ehrlich, Yi-Gang Li, Stefan H Hohnloser
雑誌名: J Am Coll Cardiol. 2004 Jan 7;43(1):47-52.
Abstract/Text OBJECTIVES: The present study determined the incidence and time course of atrial fibrillation (AF) recurrences in patients with a history of AF and fitted with an implantable monitoring device.
BACKGROUND: The long-term risk of undetected recurrence of AF in patients receiving stable antiarrhythmic therapy remains uncertain.
METHODS: In 110 patients with a class I indication for physiologic pacing and a history of AF, a pacemaker with dedicated functions for AF detection and electrogram storage was implanted, and antiarrhythmic drug treatment was optimized. Patients were regularly followed up with evaluation of AF-related symptoms, a resting electrocardiogram (ECG), and interrogation of device memory. The incidence of AF recurrences lasting >48 h in asymptomatic patients presenting in sinus rhythm (SR) at the respective follow-up visit constituted the primary end point of this prospective study.
RESULTS: During 19 +/- 11 months, 678 follow-up visits were performed. Atrial fibrillation was documented in 51 patients (46%) by ECG recording and in 97 patients (88%) by a review of stored electrograms (p < 0.0001). Device interrogation revealed AF recurrences lasting >48 h in 50 patients, 19 of whom (38%) were completely asymptomatic and in SR at subsequent follow-up. In 11 (16%) of 67 patients with device-confirmed freedom from AF for > or =3 months, AF lasting >48 h recurred subsequently.
CONCLUSIONS: This prospective study demonstrates a high incidence of recurrent AF despite optimized antiarrhythmic therapy. Of particular note, AF relapses >48 h remained totally asymptomatic in a significant proportion of patients. Freedom from AF for > or =3 months did not preclude subsequent long-lasting AF recurrence.

PMID 14715182  J Am Coll Cardiol. 2004 Jan 7;43(1):47-52.
著者: K H Humphries, C R Kerr, S J Connolly, G Klein, J A Boone, M Green, R Sheldon, M Talajic, P Dorian, D Newman
雑誌名: Circulation. 2001 May 15;103(19):2365-70.
Abstract/Text BACKGROUND: Although sex differences in coronary artery disease have received considerable attention, few studies have dealt with sex differences in the most common sustained cardiac arrhythmia, atrial fibrillation (AF). Differences in presentation and clinical course may dictate different approaches to detection and management. We sought to examine sex-related differences in presentation, treatment, and outcome in patients presenting with new-onset AF.
METHODS AND RESULTS: The Canadian Registry of Atrial Fibrillation (CARAF) enrolled subjects at the time of first ECG-confirmed diagnosis of AF. Participants were followed at 3 months, at 1 year, and annually thereafter. Treatment was at the discretion of the patients' physicians and was not directed by CARAF investigators. Baseline and follow-up data collection included a detailed medical history, clinical, ECG, and echocardiographic measures, medication history, and therapeutic interventions. Three hundred thirty-nine women and 560 men were followed for 4.14+/-1.39 years. Compared with men, women were older at the time of presentation, more likely to seek medical advice because of symptoms, and experienced significantly higher heart rates during AF. Compared with older men, older women were half as likely to receive warfarin and twice as likely to receive acetylsalicylic acid. Compared with men on warfarin, women on warfarin were 3.35 times more likely to experience a major bleed.
CONCLUSIONS: Anticoagulants are underused in older women with AF relative to older men with AF, despite comparable risk profiles. Women receiving warfarin have a significantly higher risk of major bleeding, suggesting the need for careful monitoring of anticoagulant intensity in women.

PMID 11352885  Circulation. 2001 May 15;103(19):2365-70.
著者: I C Van Gelder, H J Crijns, R G Tieleman, J Brügemann, P J De Kam, A T Gosselink, F W Verheugt, K I Lie
雑誌名: Arch Intern Med. 1996 Dec 9-23;156(22):2585-92.
Abstract/Text BACKGROUND: Serial electrical cardioversion is often used for treatment of atrial fibrillation, but its long-term efficacy has not been determined prospectively.
OBJECTIVES: To determine the long-term success rate of the serial electrical cardioversion approach in patients with chronic atrial fibrillation, to identify factors that predict its success, and to assess the efficacy and safety of oral anticoagulation in these patients.
METHODS: Patients with chronic (> 24 hours) atrial fibrillation received anticoagulant therapy for at least 4 weeks prior to electrical cardioversion. No prophylactic antiarrhythmic agent was given after the first shock. Relapses were managed by using repeated cardioversions, after which serial antiarrhythmic drug therapy was started. Treatment with anticoagulants was withdrawn after 4 weeks of sinus rhythm.
RESULTS: Two hundred thirty-six patients were followed up for a mean +/- SD of 3.7 +/- 1.6 years. The actuarial cumulative percentages of patients who maintained sinus rhythm after serial cardioversion treatment was 42% and 27% after 1 and 4 years, respectively. Multivariate analysis showed that factors that were associated with failure of this approach included duration of atrial fibrillation that exceeded 36 months (risk ratio, 5.0; P < .001), poor exercise tolerance (functional class III; risk ratio, 1.8; P = .001), and age older than 56 years (risk ratio, 1.5; P = .04). The anticoagulation level (international normalized ratio, 2.4-4.8) was associated with an incidence of thromboembolic events and bleeding complications of 0.2% and 1.5%, respectively.
CONCLUSIONS: Many patients with chronic atrial fibrillation failed to respond to the serial electrical cardioversion strategy. However, in younger patients with a fair exercise tolerance and a duration of atrial fibrillation shorter than 36 months, this approach may be worthwhile. In addition, thromboembolic events were infrequent in the patients who were subjected to this regimen.

PMID 8951302  Arch Intern Med. 1996 Dec 9-23;156(22):2585-92.
著者: Satoshi Ogawa, Takeshi Yamashita, Tsutomu Yamazaki, Yoshifusa Aizawa, Hirotsugu Atarashi, Hiroshi Inoue, Tohru Ohe, Hiroshi Ohtsu, Ken Okumura, Takao Katoh, Shiro Kamakura, Koichiro Kumagai, Yoshihisa Kurachi, Itsuo Kodama, Yukihiro Koretsune, Tetsunori Saikawa, Masayuki Sakurai, Kaoru Sugi, Toshifumi Tabuchi, Haruaki Nakaya, Toshio Nakayama, Makoto Hirai, Masahiko Fukatani, Hideo Mitamura, J-RHYTHM Investigators
雑誌名: Circ J. 2009 Feb;73(2):242-8. Epub 2008 Dec 8.
Abstract/Text Background Although previous clinical trials demonstrated the non-inferiority of a rate control to rhythm control strategy for management of atrial fibrillation (AF), the optimal treatment strategy for paroxysmal AF (PAF) remains unclear. Methods and Results A randomized, multicenter comparison of rate control vs rhythm control in Japanese patients with PAF (the Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM) study) was conducted. The primary endpoint was a composite of total mortality, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for heart failure, or physical/psychological disability requiring alteration of treatment strategy. In the study, 823 patients with PAF were followed for a mean period of 578 days. The primary endpoint occurred in 64 patients (15.3%) assigned to rhythm control and in 89 patients (22.0%) to rate control (P=0.0128). No significant differences between the treatment strategies were observed in the incidences of death, stroke, bleeding and heart failure. Meanwhile, significantly fewer patients requested changes of assigned treatment strategy in the rhythm control vs the rate control group, which was accompanied by improvement in AF-specific quality of life scores. Conclusion The J-RHYTHM study showed that rhythm control was associated with fewer primary endpoints than rate control. However, mortality and cardiovascular morbidity were not affected by the treatment strategy (umin-CTR No. C000000106).

PMID 19060419  Circ J. 2009 Feb;73(2):242-8. Epub 2008 Dec 8.
著者: T Katoh, H Iinuma, H Inoue, T Ohe, S Ogawa, H Kasanuki, T Tanabe, H Hayakawa
雑誌名: Jpn Circ J. 2001 Apr;65(4):275-8.
Abstract/Text Based on the results of the Cardiac Arrhythmia Suppression Trial (CAST), strategies for the treatment of tachyarrhythmias have changed rapidly. The Japanese Antiarrhythmics Long-Term (JALT) study was planned to investigate the present methods for choosing antiarrhythmic drugs, and the effects on long-term prognosis in patients with tachyarrhythmias in Japan. Following a 6-month preliminary study (JALT-1), there was a multicenter nonrandomized prospective study (JALT-2), with a 2-year follow-up, of patients with paroxysmal atrial fibrillation (PAF), sustained ventricular tachycardia (SVT) and nonsustained VT (NSVT). Four hundred fifty-five patients were registered, and 361 of them (79%) were analyzed. Cerebral infarction occurred in 10 of 193 patients (5.2%) with PAF. Transition to chronic AF was observed in 21 patients (10.9%), but in none of the patients receiving Ca antagonist therapy. Twenty-five patients died: 5 deaths were arrhythmic, 10 were because of pump failure, and 9 were noncardiac. The most significant difference in drug selection between JALT-1 and JALT-2 was the increase in the use of slow kinetic Na channel blockers for PAF and the decrease in the use of the same agents for VT in the JALT-2 study. A marked change of therapeutic strategy occurred in JALT-2 compared with JALT-1. Most patients with a poor prognosis had underlying heart diseases and heart failure, but the per annum rate of death by arrhythmia and pump failure in JALT-2 was less than that in JALT-1.

PMID 11316122  Jpn Circ J. 2001 Apr;65(4):275-8.
著者: Alvaro Alonso, Faye L Lopez, Kunihiro Matsushita, Laura R Loehr, Sunil K Agarwal, Lin Y Chen, Elsayed Z Soliman, Brad C Astor, Josef Coresh
雑誌名: Circulation. 2011 Jun 28;123(25):2946-53. doi: 10.1161/CIRCULATIONAHA.111.020982. Epub 2011 Jun 6.
Abstract/Text BACKGROUND: Chronic kidney disease is associated with the incidence of cardiovascular disease. Chronic kidney disease may also increase the risk of atrial fibrillation (AF), but existing studies have reported inconsistent results.
METHODS AND RESULTS: We estimated cystatin C-based glomerular filtration rate (eGFR(cys)) and measured urinary albumin-to-creatinine ratio (ACR) in 10 328 men and women free of AF from the Atherosclerosis Risk in Communities (ARIC) Study in 1996 to 1998. Incidence of AF was ascertained through the end of 2007. During a median follow-up of 10.1 years, we identified 788 incident AF cases. Compared with individuals with eGFR(cys) ≥90 mL · min(-1) · 1.73 m(-2), multivariable hazard ratios and 95% confidence intervals (CIs) of AF were 1.3 (95% CI, 1.1 to 1.6), 1.6 (95% CI, 1.3 to 2.1), and 3.2 (95% CI, 2.0 to 5.0; P for trend <0.0001) in those with eGFR(cys) of 60 to 89, 30 to 59, and 15 to 29 mL · min(-1) · 1.73 m(-2), respectively. Similarly, the presence of macroalbuminuria (ACR ≥300 mg/g; hazard ratio, 3.2; 95% CI, 2.3 to 4.5) and microalbuminuria (ACR, 30 to 299 mg/g; hazard ratio, 2.0; 95% CI, 1.6 to 2.4) was associated with higher AF risk compared with those with ACR <30 mg/g. Risk of AF was particularly elevated in those with both low eGFR(cys) and macroalbuminuria (hazard ratio, 13.1; 95% CI, 6.0 to 28.6, comparing individuals with ACR ≥300 mg/g and eGFR(cys) of 15 to 29 mL · min(-1) · 1.73 m(-2) and those with ACR <30 mg/g and eGFR(cys) ≥90 mL · min(-1) · 1.73 m(-2)).
CONCLUSION: In this large population-based study, reduced kidney function and presence of albuminuria were strongly associated with the incidence of AF independently of other risk factors.

PMID 21646496  Circulation. 2011 Jun 28;123(25):2946-53. doi: 10.1161/・・・
著者: David D McManus, David C M Corteville, Michael G Shlipak, Mary A Whooley, Joachim H Ix
雑誌名: Am J Cardiol. 2009 Dec 1;104(11):1551-5. doi: 10.1016/j.amjcard.2009.07.026.
Abstract/Text Atrial fibrillation (AF) is common in end-stage renal disease, but the relation between more modest decrements in kidney function or albuminuria with AF is uncertain. Among 956 outpatients with coronary artery disease, kidney function was assessed using 3 methods (cystatin C-based estimated glomerular filtration rate [eGFR(cys)], creatinine-based eGFR [eGFR(Cr)], and the urinary albumin/creatinine ratio [ACR]) and prevalent AF using surface electrocardiography. Multivariate logistic regression was used to evaluated the association of each measure of kidney function with AF. The mean eGFR(cys) was 71 +/- 23 ml/min/1.73 m(2), and the median ACR was 10 mg/g (interquartile range 6 to 19). Forty subjects (4%) had prevalent AF. Compared to participants with eGFR(cys) in the highest tertile (eGFR(cys) >79), those with eGFR(cys) in the lowest tertile (eGFR(cys) <62) had more than threefold greater odds of AF (odds ratio [OR] 3.43, 95% confidence interval [CI] 1.18 to 9.97) after multivariate adjustment for traditional cardiovascular disease risk factors. This association remained significant with further adjustment for ACR (OR 3.37, 95% 1.02 to 11.14). Results were similar for eGFR(Cr) but did not reach statistical significance (OR 1.59, 95% CI 0.57 to 4.40). Participants with ACRs in the highest tertile (ACR >15 mg/g) had more than fourfold greater odds of AF compared to participants in the lowest ACR tertile (ACR <7 mg/g); an association that remained significant after adjustment for eGFR(cys) (OR 4.36, 95% CI 1.45 to 13.05) or eGFR(Cr) (OR 4.61, 95% CI 1.56 to 13.66). In conclusion, among outpatients with coronary artery disease, lower eGFR(cys) and higher ACR were associated with prevalent AF, independent of each other.

PMID 19932791  Am J Cardiol. 2009 Dec 1;104(11):1551-5. doi: 10.1016/j・・・
著者: Yasuyuki Iguchi, Kazumi Kimura, Kazuto Kobayashi, Junya Aoki, Yuka Terasawa, Kenichiro Sakai, Junichi Uemura, Kensaku Shibazaki
雑誌名: Am J Cardiol. 2008 Oct 15;102(8):1056-9. doi: 10.1016/j.amjcard.2008.06.018. Epub 2008 Jul 26.
Abstract/Text Although both atrial fibrillation (AF) and decreasing glomerular filtration rate (GFR) are strongly related to advanced age and share common associated vascular risk factors, few studies have explored the relation between AF and GFR. From residents (age >or=40 years) in Kurashiki City, a total of 41,417 subjects (median age 72 years; 13,956 men) were enrolled in the Kurashiki City Annual Medical Survey from May to December 2006. The estimated overall prevalence of AF was 1.6% (2.8% in the low-GFR tertile, 1.2% in the middle tertile, and 0.9% in the high tertile, p <0.001). After all subjects were categorized into age tertiles (age thresholds 68 and 76 years), AF was identified in 0.9% in the low-GFR tertile, 0.6% in the middle tertile, and 0.5% in the high tertile in the low-age tertile (p = 0.018); 2.6% in the low-GFR tertile, 1.2% in the middle tertile, and 1.1% in the high tertile in the middle-age tertile (p <0.001); and 3.9% in the low-GFR tertile, 2.4% in the middle tertile, and 1.7% in the high tertile in the high-age tertile (p <0.001). The odds ratio for AF adjusted for age, gender, vascular risk factors, cardiac disease, and hemoglobin was 1.91 (95% confidence interval 1.54 to 2.38, p <0.001) for the low-GFR tertile versus the high tertile and 1.12 (95% confidence interval 0.88 to 1.42, p = 0.364) for the middle-GFR tertile versus the high tertile. The prevalence of AF gradually increased with decreasing GFR. In conclusion, AF appears to be associated with decreasing GFR.

PMID 18929708  Am J Cardiol. 2008 Oct 15;102(8):1056-9. doi: 10.1016/j・・・
著者: H K Nakazawa, K Sakurai, N Hamada, N Momotani, K Ito
雑誌名: Am J Med. 1982 Jun;72(6):903-6.
Abstract/Text This study was designed to investigate the appropriate timing for cardioversion in patients with chronic atrial fibrillation who had been rendered euthyroid from a thyrotoxic state. We carried out a retrospective study of 163 patients with thyrotoxic atrial fibrillation, with a mean follow-up of 34 months. With control of thyroid function alone, 101 patients had spontaneous reversion of atrial fibrillation to sinus rhythm and 62 patients had persistent atrial fibrillation. In those with spontaneous reversion, the longest duration of atrial fibrillation prior to the euthyroid state was 13 months. In those with persistent fibrillation, the shortest duration of atrial fibrillation prior to the euthyroid state was eight months. Almost three-quarters of those with spontaneous reversion had conversion to sinus rhythm within three weeks of becoming euthyroid. No spontaneous reversion occurred if atrial fibrillation was still present after the patients had been in a euthyroid state for four months. This study suggests that spontaneous reversion of atrial fibrillation to sinus rhythm is highly unlikely if the duration of atrial fibrillation before the euthyroid state is achieved exceeds 13 months, or if it is still present after the patient has been in a euthyroid state for four months, Cardioversion should be performed at about the 16th week after the euthyroid state is achieved.

PMID 7091161  Am J Med. 1982 Jun;72(6):903-6.
著者: H Nakazawa, D A Lythall, J Noh, N Ishikawa, K Sugino, K Ito, S M Hardman
雑誌名: Eur Heart J. 2000 Feb;21(4):327-33. doi: 10.1053/euhj.1999.1956.
Abstract/Text AIMS: As atrial fibrillation is associated with significant mortality and morbidity, restoration of sinus rhythm is desirable. However, previous data suggest that cardioversion should be restricted to patients in whom the fibrillation is of limited duration (<1-2 years) because of high relapse rates. It may be the frequent association with cardiac disease, rather than the duration of fibrillation itself, which determined the high relapse of earlier studies. The aim of this study was to investigate rates of cardioversion, maintenance of sinus rhythm and predictors of subsequent relapse in a homogeneous group of patients without evidence of any co-existent cardiac disease.
METHODS AND RESULTS: We report on a retrospective series of 106 patients with thyrotoxicosis-induced fibrillation but no other heart disease: 87% had been in atrial fibrillation for >12 months (median duration 28.5, interquartile range 15-47 months). Cardioversion was attempted using disopyramide and then electric shock. Ninety-eight patients were successfully cardioverted: at late follow-up, 80.6+/-37 months (mean+/-SD), 67% were in sinus rhythm.
CONCLUSION: Although a relationship between the duration of fibrillation and maintenance of sinus rhythm was found, the high proportion remaining in sinus rhythm, compared with other series, suggests this influence may be less important than the presence or absence of structural heart disease.

Copyright 2000 The European Society of Cardiology.
PMID 10653681  Eur Heart J. 2000 Feb;21(4):327-33. doi: 10.1053/euhj.1・・・
著者: Roberto Fogari, Amedeo Mugellini, Maurizio Destro, Luca Corradi, Annalisa Zoppi, Elena Fogari, Andrea Rinaldi
雑誌名: J Cardiovasc Pharmacol. 2006 Jan;47(1):46-50.
Abstract/Text The aim of the study was to evaluate the effect of losartan as compared with amlodipine, both associated with amiodarone, in preventing the recurrence of atrial fibrillation (AF) in hypertensive patients with a history of recent paroxysmal atrial fibrillation. Two hundred and fifty mild hypertensive (SBP > 140 mm Hg and/or DBP > 90 < 100 mm Hg) outpatients in sinus rhythm but with at least two ECG-documented episodes of symptomatic atrial fibrillation in the previous 6 months and in treatment with amiodarone were randomized to losartan or amlodipine and were followed up for 1 year. Clinic blood pressure (BP) and a 24-hour ECG was evaluated every month; the patients were asked to report any episode of symptomatic atrial fibrillation and to perform an ECG as early as possible. Two hundred and thirteen patients completed the study, 107 in the losartan group and 106 in the amlodipine group. After 12 months the SBP/DBP mean values were significantly reduced by both losartan (from 151.4/95.6 to 135.5/83.7 mm Hg, P < 0.001 versus baseline) and amlodipine (from 152.3/96.5 to 135.2/83.4 mm Hg, P < 0.001 versus baseline), with no difference between the two treatments. At least one ECG-documented episode of atrial fibrillation was reported in 13% of the patients treated with losartan and in 39% of the patients treated with amlodipine. The use of losartan in combination with amiodarone seems more effective than amlodipine/amiodarone combination in preventing new episodes of atrial fibrillation in hypertensive patients with recurrent atrial fibrillation. This might be related to possible favorable impact of angiotensin II receptor blockers (ARB) on the atrial electrical and structural remodeling in this type of patients.

PMID 16424784  J Cardiovasc Pharmacol. 2006 Jan;47(1):46-50.
著者: David Conen, Usha B Tedrow, Bruce A Koplan, Robert J Glynn, Julie E Buring, Christine M Albert
雑誌名: Circulation. 2009 Apr 28;119(16):2146-52. doi: 10.1161/CIRCULATIONAHA.108.830042. Epub 2009 Apr 13.
Abstract/Text BACKGROUND: The influence of systolic and diastolic blood pressure (BP) on incident atrial fibrillation (AF) is not well studied among initially healthy, middle-aged women.
METHODS AND RESULTS: A total of 34,221 women participating in the Women's Health Study were prospectively followed up for incident AF. The risk of AF across categories of systolic and diastolic BP was compared by use of Cox proportional-hazards models. During 12.4 years of follow-up, 644 incident AF events occurred. Using BP measurements at baseline, we discovered that the long-term risk of AF was significantly increased across categories of systolic and diastolic BP. Multivariable-adjusted hazard ratios for systolic BP categories (<120, 120 to 129, 130 to 139, 140 to 159, and > or =160 mm Hg) were 1.0, 1.00 (95% CI, 0.78 to 1.28), 1.28 (95% CI, 1.00 to 1.63), 1.56 (95% CI, 1.22 to 2.01), and 2.74 (95% CI, 1.77 to 4.22) (P for trend <0.0001). Adjusted hazard ratios across baseline diastolic BP categories (<65, 65 to 74, 75 to 84, 85 to 89, 90 to 94, and > or =95 mm Hg) were 1.0, 1.17 (95% CI, 0.81 to 1.69), 1.18 (95% CI, 0.84 to 1.65), 1.53 (95% CI, 1.05 to 2.23), 1.35 (95% CI, 0.82 to 2.22), and 2.15 (95% CI, 1.21 to 3.84) (P for trend=0.004). When BP changes over time were accounted for in updated models, multivariable-adjusted hazard ratios were 1.0, 1.14 (95% CI, 0.89 to 1.46), 1.37 (95% CI, 1.07 to 1.76), 1.71 (95% CI, 1.33 to 2.21), and 2.21 (95% CI, 1.45 to 3.36) (P for trend <0.0001) for systolic BP categories and 1.0, 1.12 (95% CI, 0.82 to 1.52), 1.13 (95% CI, 0.83 to 1.52), 1.30 (95% CI, 0.89 to 1.88), 1.50 (95% CI, 1.01 to 1.88), and 1.54 (95% CI, 0.75 to 3.14) (P for trend=0.026) for diastolic BP categories.
CONCLUSIONS: In this large cohort of initially healthy women, BP was strongly associated with incident AF, and systolic BP was a better predictor than diastolic BP. Systolic BP levels within the nonhypertensive range were independently associated with incident AF even after BP changes over time were taken into account.

PMID 19364977  Circulation. 2009 Apr 28;119(16):2146-52. doi: 10.1161/・・・
著者: Takeshi Yamashita, Hiroshi Inoue, Ken Okumura, Itsuo Kodama, Yoshifusa Aizawa, Hirotsugu Atarashi, Tohru Ohe, Hiroshi Ohtsu, Takao Kato, Shiro Kamakura, Koichiro Kumagai, Yoshihisa Kurachi, Yukihiro Koretsune, Tetsunori Saikawa, Masayuki Sakurai, Toshiaki Sato, Kaoru Sugi, Haruaki Nakaya, Makoto Hirai, Atsushi Hirayama, Masahiko Fukatani, Hideo Mitamura, Tsutomu Yamazaki, Eiichi Watanabe, Satoshi Ogawa, J-RHYTHM II Investigators
雑誌名: Europace. 2011 Apr;13(4):473-9. doi: 10.1093/europace/euq439. Epub 2010 Dec 10.
Abstract/Text AIMS: Atrial fibrillation (AF) is a common arrhythmia frequently associated with hypertension. This study was designed to test the hypothesis that lowering blood pressure by angiotensin II-receptor blockers (ARB) has more beneficial effects than by conventional calcium channel blockers (CCB) on the frequency of paroxysmal AF with hypertension.
METHODS AND RESULTS: The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II study) is an open-label randomized comparison between an ARB (candesartan) and a CCB (amlodipine) in the treatment of paroxysmal AF associated with hypertension. Using daily transtelephonic monitoring, we examined asymptomatic and symptomatic paroxysmal AF episodes during a maximum 1 year treatment. The primary endpoint was the difference in AF frequency between the pre-treatment period and the final month of the follow-up. The secondary endpoints included cardiovascular events, development of persistent AF, left atrial dimension, and quality-of-life (QOL). The study enrolled 318 patients (66 years, male/female 219/99, 158 in the ARB group and 160 in the CCB group) treated at 48 sites throughout Japan. At baseline, the frequency of AF episodes (days/month) was 3.8 ± 5.0 in the ARB group vs. 4.8 ± 6.3 in the CCB group (not significant). During the follow-up, blood pressure was significantly lower in the CCB group than in the ARB group (P < 0.001). The AF frequency decreased similarly in both groups, and there was no significant difference in the primary endpoint between the two groups. There were no significant differences between the two groups in the development of persistent AF, changes in left atrial dimension, occurrence of cardiovascular events, or changes in QOL.
CONCLUSIONS: In patients with paroxysmal AF and hypertension, treatment of hypertension by candesartan did not have an advantage over amlodipine in the reduction in the frequency of paroxysmal AF (umin CTR C000000427).

PMID 21148662  Europace. 2011 Apr;13(4):473-9. doi: 10.1093/europace/e・・・
著者: Kristian Wachtell, Björn Hornestam, Mika Lehto, David J Slotwiner, Eva Gerdts, Michael H Olsen, Peter Aurup, Björn Dahlöf, Hans Ibsen, Stevo Julius, Sverre E Kjeldsen, Lars H Lindholm, Markku S Nieminen, Jens Rokkedal, Richard B Devereux
雑誌名: J Am Coll Cardiol. 2005 Mar 1;45(5):705-11. doi: 10.1016/j.jacc.2004.06.080.
Abstract/Text OBJECTIVES: We assessed the impact of antihypertensive treatment in hypertensive patients with electrocardiographic (ECG) left ventricular (LV) hypertrophy and a history of atrial fibrillation (AF).
BACKGROUND: Optimal treatment of hypertensive patients with AF to reduce the risk of cardiovascular morbidity and mortality remains unclear.
METHODS: As part of the Losartan Intervention For End point reduction in hypertension (LIFE) study, 342 hypertensive patients with AF and LV hypertrophy were assigned to losartan- or atenolol-based therapy for 1,471 patient-years of follow-up.
RESULTS: The primary composite end point (cardiovascular mortality, stroke, and myocardial infarction) occurred in 36 patients in the losartan group versus 67 in the atenolol group (hazard ratio [HR] = 0.58, 95% confidence interval [CI] 0.39 to 0.88, p = 0.009). Cardiovascular deaths occurred in 20 versus 38 patients in the losartan and atenolol groups, respectively (HR = 0.58, 95% CI 0.33 to 0.99, p = 0.048). Stroke occurred in 18 versus 38 patients (HR = 0.55, 95% CI 0.31 to 0.97, p = 0.039), and myocardial infarction in 11 versus 8 patients (p = NS). Losartan-based treatment led to trends toward lower all-cause mortality (30 vs. 49, HR = 0.67, 95% CI 0.42 to 1.06, p = 0.090) and fewer pacemaker implantations (5 vs. 15, p = 0.065), whereas hospitalization for heart failure took place in 15 versus 26 patients and sudden cardiac death in 9 versus 17, respectively (both p = NS). The benefit of losartan was greater in patients with AF than those with sinus rhythm for the primary composite end point (p = 0.019) and cardiovascular mortality (p = 0.039).
CONCLUSIONS: Losartan is more effective than atenolol-based therapy in reducing the risk of the primary composite end point of cardiovascular morbidity and mortality as well as stroke and cardiovascular death in hypertensive patients with ECG LV hypertrophy and AF.

PMID 15734614  J Am Coll Cardiol. 2005 Mar 1;45(5):705-11. doi: 10.101・・・
著者: N Chapman, R Huxley, C Anderson, M G Bousser, J Chalmers, S Colman, S Davis, G Donnan, S MacMahon, B Neal, C Warlow, M Woodward, Writing Committee for the PROGRESS Collaborative Group
雑誌名: Stroke. 2004 Jan;35(1):116-21. doi: 10.1161/01.STR.0000106480.76217.6F. Epub 2003 Dec 11.
Abstract/Text BACKGROUND AND PURPOSE: The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) showed that blood pressure lowering reduced stroke risk in patients with a history of cerebrovascular events. Here, we report the consistency of treatment effects across different stroke subtypes and among major clinical subgroups.
METHODS: PROGRESS was a randomized, double-blind trial among 6105 people with a prior history of cerebrovascular events. Participants were assigned to active treatment (perindopril for all participants and indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo(s).
RESULTS: During a mean of 3.9 years of follow-up, active treatment reduced the absolute rates of ischemic stroke from 10% to 8% (relative risk reduction [RRR], 24%; 95% confidence interval [CI], 10 to 35) and the absolute rates of intracerebral hemorrhage from 2% to 1% (RRR, 50%; 95% CI, 26 to 67). The relative risk of any stroke during follow-up was reduced by 26% (95% CI, 12 to 38) among patients whose baseline cerebrovascular event was an ischemic stroke and by 49% (95% CI, 18 to 68) among those whose baseline event was an intracerebral hemorrhage. There was no evidence that treatment effects were modified by other drug therapies (antiplatelet or other antihypertensive agents), residual neurological signs, atrial fibrillation, or the time since the last cerebrovascular event.
CONCLUSIONS: Beneficial effects of a perindopril-based treatment regimen were observed for all stroke types and all major clinical subgroups studied. These data suggest that effective blood pressure-lowering therapy should be routinely considered for all patients with a history of cerebrovascular events.

PMID 14671247  Stroke. 2004 Jan;35(1):116-21. doi: 10.1161/01.STR.0000・・・
著者: H M Perry, B R Davis, T R Price, W B Applegate, W S Fields, J M Guralnik, L Kuller, S Pressel, J Stamler, J L Probstfield
雑誌名: JAMA. 2000 Jul 26;284(4):465-71.
Abstract/Text CONTEXT: The Systolic Hypertension in the Elderly Program (SHEP) demonstrated that treating isolated systolic hypertension in older patients decreased incidence of total stroke, but whether all types of stroke were reduced was not evaluated.
OBJECTIVE: To investigate antihypertensive drug treatment effects on incidence of stroke by type and subtype, timing of strokes, case-fatality rates, stroke residual effects, and relationship of attained systolic blood pressure to stroke incidence.
DESIGN: The SHEP study, a randomized, double-blind, placebo-controlled trial began March 1, 1985, and had an average follow-up of 4.5 years.
SETTING AND PARTICIPANTS: A total of 4736 men and women aged 60 years or older with isolated systolic hypertension at 16 clinical centers in the United States.
INTERVENTIONS: Patients were randomly assigned to receive treatment with 12.5 mg/d of chlorthalidone (step 1); either 25 mg/d of atenolol or 0.05 mg/d of reserpine (step 2) could be added (n = 2365); or placebo (n = 2371).
MAIN OUTCOME MEASURES: Occurrence, type and subtype, and timing of first strokes and stroke fatalities; and change in stroke incidence for participants (whether in active treatment or placebo groups) reaching study-specific systolic blood pressure goal (decrease of at least 20 mm Hg from baseline to below 160 mm Hg) compared with participants not reaching goal.
RESULTS: A total of 85 and 132 participants in the active treatment and placebo groups, respectively, had ischemic strokes (adjusted relative risk [RR], 0.63; 95% confidence interval [CI], 0.48-0.82); 9 and 19 had hemorrhagic strokes (adjusted RR, 0.46; 95% CI, 0.21-1.02); and 9 and 8 had strokes of unknown type (adjusted RR, 1.05; 95% CI, 0.40-2. 73), respectively. Four subtypes of ischemic stroke were observed in active treatment and placebo group participants, respectively, as follows: for lacunar, n = 23 and n = 43 (adjusted RR, 0.53; 95% CI, 0.32-0.88); for embolic, n = 9 and n = 16 (adjusted RR, 0.56; 95% CI, 0.25-1.27); for atherosclerotic, n = 13 and n = 13 (adjusted RR, 0. 99; 95% CI, 0.46-2.15); and for unknown subtype, n = 40 and n = 60 (adjusted RR, 0.64; 95% CI, 0.43-0.96). Treatment effect was observed within 1 year for hemorrhagic strokes but was not seen until the second year for ischemic strokes. Stroke incidence significantly decreased in participants attaining study-specific systolic blood pressure goals.
CONCLUSIONS: In this study, antihypertensive drug treatment reduced the incidence of both hemorrhagic and ischemic (including lacunar) strokes. Reduction in stroke incidence occurred when specific systolic blood pressure goals were attained. JAMA. 2000;284:465-471

PMID 10904510  JAMA. 2000 Jul 26;284(4):465-71.
著者: Nassir F Marrouche, Johannes Brachmann, Dietrich Andresen, Jürgen Siebels, Lucas Boersma, Luc Jordaens, Béla Merkely, Evgeny Pokushalov, Prashanthan Sanders, Jochen Proff, Heribert Schunkert, Hildegard Christ, Jürgen Vogt, Dietmar Bänsch, CASTLE-AF Investigators
雑誌名: N Engl J Med. 2018 Feb 1;378(5):417-427. doi: 10.1056/NEJMoa1707855.
Abstract/Text BACKGROUND: Mortality and morbidity are higher among patients with atrial fibrillation and heart failure than among those with heart failure alone. Catheter ablation for atrial fibrillation has been proposed as a means of improving outcomes among patients with heart failure who are otherwise receiving appropriate treatment.
METHODS: We randomly assigned patients with symptomatic paroxysmal or persistent atrial fibrillation who did not have a response to antiarrhythmic drugs, had unacceptable side effects, or were unwilling to take these drugs to undergo either catheter ablation (179 patients) or medical therapy (rate or rhythm control) (184 patients) for atrial fibrillation in addition to guidelines-based therapy for heart failure. All the patients had New York Heart Association class II, III, or IV heart failure, a left ventricular ejection fraction of 35% or less, and an implanted defibrillator. The primary end point was a composite of death from any cause or hospitalization for worsening heart failure.
RESULTS: After a median follow-up of 37.8 months, the primary composite end point occurred in significantly fewer patients in the ablation group than in the medical-therapy group (51 patients [28.5%] vs. 82 patients [44.6%]; hazard ratio, 0.62; 95% confidence interval [CI], 0.43 to 0.87; P=0.007). Significantly fewer patients in the ablation group died from any cause (24 [13.4%] vs. 46 [25.0%]; hazard ratio, 0.53; 95% CI, 0.32 to 0.86; P=0.01), were hospitalized for worsening heart failure (37 [20.7%] vs. 66 [35.9%]; hazard ratio, 0.56; 95% CI, 0.37 to 0.83; P=0.004), or died from cardiovascular causes (20 [11.2%] vs. 41 [22.3%]; hazard ratio, 0.49; 95% CI, 0.29 to 0.84; P=0.009).
CONCLUSIONS: Catheter ablation for atrial fibrillation in patients with heart failure was associated with a significantly lower rate of a composite end point of death from any cause or hospitalization for worsening heart failure than was medical therapy. (Funded by Biotronik; CASTLE-AF ClinicalTrials.gov number, NCT00643188 .).

PMID 29385358  N Engl J Med. 2018 Feb 1;378(5):417-427. doi: 10.1056/N・・・
著者: Willem J M Dewilde, Tom Oirbans, Freek W A Verheugt, Johannes C Kelder, Bart J G L De Smet, Jean-Paul Herrman, Tom Adriaenssens, Mathias Vrolix, Antonius A C M Heestermans, Marije M Vis, Jan G P Tijsen, Arnoud W van 't Hof, Jurriën M ten Berg, WOEST study investigators
雑誌名: Lancet. 2013 Mar 30;381(9872):1107-15. doi: 10.1016/S0140-6736(12)62177-1. Epub 2013 Feb 13.
Abstract/Text BACKGROUND: If percutaneous coronary intervention (PCI) is required in patients taking oral anticoagulants, antiplatelet therapy with aspirin and clopidogrel is indicated, but such triple therapy increases the risk of serious bleeding. We investigated the safety and efficacy of clopidogrel alone compared with clopidogrel plus aspirin.
METHODS: We did an open-label, multicentre, randomised, controlled trial in 15 centres in Belgium and the Netherlands. From November, 2008, to November, 2011, adults receiving oral anticoagulants and undergoing PCI were assigned clopidogrel alone (double therapy) or clopidogrel plus aspirin (triple therapy). The primary outcome was any bleeding episode within 1 year of PCI, assessed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00769938.
FINDINGS: 573 patients were enrolled and 1-year data were available for 279 (98·2%) patients assigned double therapy and 284 (98·3%) assigned triple therapy. Mean ages were 70·3 (SD 7·0) years and 69·5 (8·0) years, respectively. Bleeding episodes were seen in 54 (19·4%) patients receiving double therapy and in 126 (44·4%) receiving triple therapy (hazard ratio [HR] 0·36, 95% CI 0·26-0·50, p<0·0001). In the double-therapy group, six (2·2%) patients had multiple bleeding events, compared with 34 (12·0%) in the triple-therapy group. 11 (3·9%) patients receiving double therapy required at least one blood transfusion, compared with 27 (9·5%) patients in the triple-therapy group (odds ratio from Kaplan-Meier curve 0·39, 95% CI 0·17-0·84, p=0·011).
INTERPRETATION: Use of clopiogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events.
FUNDING: Antonius Ziekenhuis Foundation, Strect Foundation.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23415013  Lancet. 2013 Mar 30;381(9872):1107-15. doi: 10.1016/S01・・・
著者: C Michael Gibson, Roxana Mehran, Christoph Bode, Jonathan Halperin, Freek W Verheugt, Peter Wildgoose, Mary Birmingham, Juliana Ianus, Paul Burton, Martin van Eickels, Serge Korjian, Yazan Daaboul, Gregory Y H Lip, Marc Cohen, Steen Husted, Eric D Peterson, Keith A Fox
雑誌名: N Engl J Med. 2016 Dec 22;375(25):2423-2434. doi: 10.1056/NEJMoa1611594. Epub 2016 Nov 14.
Abstract/Text BACKGROUND: In patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) with placement of stents, standard anticoagulation with a vitamin K antagonist plus dual antiplatelet therapy (DAPT) with a P2Y12 inhibitor and aspirin reduces the risk of thrombosis and stroke but increases the risk of bleeding. The effectiveness and safety of anticoagulation with rivaroxaban plus either one or two antiplatelet agents are uncertain.
METHODS: We randomly assigned 2124 participants with nonvalvular atrial fibrillation who had undergone PCI with stenting to receive, in a 1:1:1 ratio, low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months (group 1), very-low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months (group 2), or standard therapy with a dose-adjusted vitamin K antagonist (once daily) plus DAPT for 1, 6, or 12 months (group 3). The primary safety outcome was clinically significant bleeding (a composite of major bleeding or minor bleeding according to Thrombolysis in Myocardial Infarction [TIMI] criteria or bleeding requiring medical attention).
RESULTS: The rates of clinically significant bleeding were lower in the two groups receiving rivaroxaban than in the group receiving standard therapy (16.8% in group 1, 18.0% in group 2, and 26.7% in group 3; hazard ratio for group 1 vs. group 3, 0.59; 95% confidence interval [CI], 0.47 to 0.76; P<0.001; hazard ratio for group 2 vs. group 3, 0.63; 95% CI, 0.50 to 0.80; P<0.001). The rates of death from cardiovascular causes, myocardial infarction, or stroke were similar in the three groups (Kaplan-Meier estimates, 6.5% in group 1, 5.6% in group 2, and 6.0% in group 3; P values for all comparisons were nonsignificant).
CONCLUSIONS: In participants with atrial fibrillation undergoing PCI with placement of stents, the administration of either low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low-dose rivaroxaban plus DAPT for 1, 6, or 12 months was associated with a lower rate of clinically significant bleeding than was standard therapy with a vitamin K antagonist plus DAPT for 1, 6, or 12 months. The three groups had similar efficacy rates, although the observed broad confidence intervals diminish the surety of any conclusions regarding efficacy. (Funded by Janssen Scientific Affairs and Bayer Pharmaceuticals; PIONEER AF-PCI ClinicalTrials.gov number, NCT01830543 .).

PMID 27959713  N Engl J Med. 2016 Dec 22;375(25):2423-2434. doi: 10.10・・・
著者: Christopher P Cannon, Deepak L Bhatt, Jonas Oldgren, Gregory Y H Lip, Stephen G Ellis, Takeshi Kimura, Michael Maeng, Bela Merkely, Uwe Zeymer, Savion Gropper, Matias Nordaby, Eva Kleine, Ruth Harper, Jenny Manassie, James L Januzzi, Jurrien M Ten Berg, P Gabriel Steg, Stefan H Hohnloser, RE-DUAL PCI Steering Committee and Investigators
雑誌名: N Engl J Med. 2017 Oct 19;377(16):1513-1524. doi: 10.1056/NEJMoa1708454. Epub 2017 Aug 27.
Abstract/Text BACKGROUND: Triple antithrombotic therapy with warfarin plus two antiplatelet agents is the standard of care after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, but this therapy is associated with a high risk of bleeding.
METHODS: In this multicenter trial, we randomly assigned 2725 patients with atrial fibrillation who had undergone PCI to triple therapy with warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and aspirin (for 1 to 3 months) (triple-therapy group) or dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and no aspirin (110-mg and 150-mg dual-therapy groups). Outside the United States, elderly patients (≥80 years of age; ≥70 years of age in Japan) were randomly assigned to the 110-mg dual-therapy group or the triple-therapy group. The primary end point was a major or clinically relevant nonmajor bleeding event during follow-up (mean follow-up, 14 months). The trial also tested for the noninferiority of dual therapy with dabigatran (both doses combined) to triple therapy with warfarin with respect to the incidence of a composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization.
RESULTS: The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group as compared with 26.9% in the triple-therapy group (hazard ratio, 0.52; 95% confidence interval [CI], 0.42 to 0.63; P<0.001 for noninferiority; P<0.001 for superiority) and 20.2% in the 150-mg dual-therapy group as compared with 25.7% in the corresponding triple-therapy group, which did not include elderly patients outside the United States (hazard ratio, 0.72; 95% CI, 0.58 to 0.88; P<0.001 for noninferiority). The incidence of the composite efficacy end point was 13.7% in the two dual-therapy groups combined as compared with 13.4% in the triple-therapy group (hazard ratio, 1.04; 95% CI, 0.84 to 1.29; P=0.005 for noninferiority). The rate of serious adverse events did not differ significantly among the groups.
CONCLUSIONS: Among patients with atrial fibrillation who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y12 inhibitor than among those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events. (Funded by Boehringer Ingelheim; RE-DUAL PCI ClinicalTrials.gov number, NCT02164864 .).

PMID 28844193  N Engl J Med. 2017 Oct 19;377(16):1513-1524. doi: 10.10・・・
著者: Renato D Lopes, Gretchen Heizer, Ronald Aronson, Amit N Vora, Tyler Massaro, Roxana Mehran, Shaun G Goodman, Stephan Windecker, Harald Darius, Jia Li, Oleg Averkov, M Cecilia Bahit, Otavio Berwanger, Andrzej Budaj, Ziad Hijazi, Alexander Parkhomenko, Peter Sinnaeve, Robert F Storey, Holger Thiele, Dragos Vinereanu, Christopher B Granger, John H Alexander, AUGUSTUS Investigators
雑誌名: N Engl J Med. 2019 Apr 18;380(16):1509-1524. doi: 10.1056/NEJMoa1817083. Epub 2019 Mar 17.
Abstract/Text BACKGROUND: Appropriate antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear.
METHODS: In an international trial with a two-by-two factorial design, we randomly assigned patients with atrial fibrillation who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y12 inhibitor to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events.
RESULTS: Enrollment included 4614 patients from 33 countries. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P<0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P = 0.002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the placebo group.
CONCLUSIONS: In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both. (Funded by Bristol-Myers Squibb and Pfizer; AUGUSTUS ClinicalTrials.gov number, NCT02415400.).

Copyright © 2019 Massachusetts Medical Society.
PMID 30883055  N Engl J Med. 2019 Apr 18;380(16):1509-1524. doi: 10.10・・・
著者: Pascal Vranckx, Marco Valgimigli, Lars Eckardt, Jan Tijssen, Thorsten Lewalter, Giuseppe Gargiulo, Valerii Batushkin, Gianluca Campo, Zoreslava Lysak, Igor Vakaliuk, Krzysztof Milewski, Petra Laeis, Paul-Egbert Reimitz, Rüdiger Smolnik, Wolfgang Zierhut, Andreas Goette
雑誌名: Lancet. 2019 Oct 12;394(10206):1335-1343. doi: 10.1016/S0140-6736(19)31872-0. Epub 2019 Sep 3.
Abstract/Text BACKGROUND: We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI).
METHODS: ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web-based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1-12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed.
FINDINGS: From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2-76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65-1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority).
INTERPRETATION: In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events.
FUNDING: Daiichi Sankyo.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 31492505  Lancet. 2019 Oct 12;394(10206):1335-1343. doi: 10.1016/・・・
著者: Yukiko Matsumura-Nakano, Satoshi Shizuta, Akihiro Komasa, Takeshi Morimoto, Hisaki Masuda, Hiroki Shiomi, Koji Goto, Kentaro Nakai, Hisashi Ogawa, Atsushi Kobori, Yutaka Kono, Kazuaki Kaitani, Satoru Suwa, Takeshi Aoyama, Mamoru Takahashi, Yasuhiro Sasaki, Yuko Onishi, Toshiaki Mano, Mitsuo Matsuda, Makoto Motooka, Hirofumi Tomita, Moriaki Inoko, Takatoshi Wakeyama, Nobuhisa Hagiwara, Kengo Tanabe, Masaharu Akao, Katsumi Miyauchi, Junji Yajima, Keiichi Hanaoka, Yoshihiro Morino, Kenji Ando, Yutaka Furukawa, Yoshihisa Nakagawa, Koichi Nakao, Ken Kozuma, Kazushige Kadota, Kazuo Kimura, Kazuya Kawai, Takafumi Ueno, Ken Okumura, Takeshi Kimura, OAC-ALONE Study Investigators
雑誌名: Circulation. 2019 Jan 29;139(5):604-616. doi: 10.1161/CIRCULATIONAHA.118.036768.
Abstract/Text BACKGROUND: Despite recommendations in the guidelines and consensus documents, there has been no randomized controlled trial evaluating oral anticoagulation (OAC) alone without antiplatelet therapy (APT) in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after coronary stenting.
METHODS: This study was a prospective, multicenter, open-label, noninferiority trial comparing OAC alone to combined OAC and single APT among patients with atrial fibrillation beyond 1 year after stenting in a 1:1 randomization fashion. The primary end point was a composite of all-cause death, myocardial infarction, stroke, or systemic embolism. The major secondary end point was a composite of the primary end point or major bleeding according to the International Society on Thrombosis and Haemostasis classification. Although the trial was designed to enroll 2000 patients during 12 months, enrollment was prematurely terminated after enrolling 696 patients in 38 months.
RESULTS: Mean age was 75.0±7.6 years, and 85.2% of patients were men. OAC was warfarin in 75.2% and direct oral anticoagulants in 24.8% of patients. The mean CHADS2 score was 2.5±1.2. During a median follow-up interval of 2.5 years, the primary end point occurred in 54 patients (15.7%) in the OAC-alone group and in 47 patients (13.6%) in the combined OAC and APT group (hazard ratio, 1.16; 95% CI, 0.79-1.72; P=0.20 for noninferiority, P=0.45 for superiority). The major secondary end point occurred in 67 patients (19.5%) in the OAC-alone group and in 67 patients (19.4%) in the combined OAC and APT group (hazard ratio, 0.99; 95% CI, 0.71-1.39; P=0.016 for noninferiority, P=0.96 for superiority). Myocardial infarction occurred in 8 (2.3%) and 4 (1.2%) patients, whereas stroke or systemic embolism occurred in 13 (3.8%) and 19 (5.5%) patients, respectively. Major bleeding occurred in 27 (7.8%) and 36 (10.4%) patients, respectively.
CONCLUSIONS: This randomized trial did not establish noninferiority of OAC alone to combined OAC and APT in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after stenting. Because patient enrollment was prematurely terminated, the study was underpowered and inconclusive. Future larger studies are required to establish the optimal antithrombotic regimen in this population.
CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01962545.

PMID 30586700  Circulation. 2019 Jan 29;139(5):604-616. doi: 10.1161/C・・・
著者: Morten Lamberts, Gunnar H Gislason, Gregory Y H Lip, Jens Flensted Lassen, Jonas Bjerring Olesen, Anders P Mikkelsen, Rikke Sørensen, Lars Køber, Christian Torp-Pedersen, Morten Lock Hansen
雑誌名: Circulation. 2014 Apr 15;129(15):1577-85. doi: 10.1161/CIRCULATIONAHA.113.004834. Epub 2014 Jan 27.
Abstract/Text BACKGROUND: The optimal long-term antithrombotic treatment of patients with coexisting atrial fibrillation and stable coronary artery disease is unresolved, and commonly, a single antiplatelet agent is added to oral anticoagulation. We investigated the effectiveness and safety of adding antiplatelet therapy to vitamin K antagonist (VKA) in atrial fibrillation patents with stable coronary artery disease.
METHODS AND RESULTS: Atrial fibrillation patients with stable coronary artery disease (defined as 12 months from an acute coronary event) between 2002 and 2011 were identified. The subsequent risk of cardiovascular events and serious bleeding events (those that required hospitalization) was examined with adjusted Cox regression models according to ongoing antithrombotic therapy. A total of 8700 patients were included (mean age, 74.2 years; 38% women). During a mean follow-up of 3.3 years, crude incidence rates were 7.2, 3.8, and 4.0 events per 100 person-years for myocardial infarction/coronary death, thromboembolism, and serious bleeding, respectively. Relative to VKA monotherapy, the risk of myocardial infarction/coronary death was similar for VKA plus aspirin (hazard ratio, 1.12 [95% confidence interval, 0.94-1.34]) and VKA plus clopidogrel (hazard ratio, 1.53 [95% confidence interval, 0.93-2.52]). The risk of thromboembolism was comparable in all regimens that included VKA, whereas the risk of bleeding increased when aspirin (hazard ratio, 1.50 [95% confidence interval, 1.23-1.82]) or clopidogrel (hazard ratio, 1.84 [95% confidence interval, 1.11-3.06]) was added to VKA.
CONCLUSIONS: In atrial fibrillation patients with stable coronary artery disease, the addition of antiplatelet therapy to VKA therapy is not associated with a reduction in risk of recurrent coronary events or thromboembolism, whereas risk of bleeding is increased significantly. The common practice of adding antiplatelet therapy to oral VKA anticoagulation in patients with atrial fibrillation and stable coronary artery disease warrants reassessment.

PMID 24470482  Circulation. 2014 Apr 15;129(15):1577-85. doi: 10.1161/・・・
著者: Satoshi Yasuda, Koichi Kaikita, Masaharu Akao, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa, AFIRE Investigators
雑誌名: N Engl J Med. 2019 Sep 19;381(12):1103-1113. doi: 10.1056/NEJMoa1904143. Epub 2019 Sep 2.
Abstract/Text BACKGROUND: There are limited data from randomized trials evaluating the use of antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease.
METHODS: In a multicenter, open-label trial conducted in Japan, we randomly assigned 2236 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring revascularization to receive monotherapy with rivaroxaban (a non-vitamin K antagonist oral anticoagulant) or combination therapy with rivaroxaban plus a single antiplatelet agent. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause; this end point was analyzed for noninferiority with a noninferiority margin of 1.46. The primary safety end point was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis; this end point was analyzed for superiority.
RESULTS: The trial was stopped early because of increased mortality in the combination-therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point, with event rates of 4.14% and 5.75% per patient-year, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P<0.001 for noninferiority). Rivaroxaban monotherapy was superior to combination therapy for the primary safety end point, with event rates of 1.62% and 2.76% per patient-year, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P = 0.01 for superiority).
CONCLUSIONS: As antithrombotic therapy, rivaroxaban monotherapy was noninferior to combination therapy for efficacy and superior for safety in patients with atrial fibrillation and stable coronary artery disease. (Funded by the Japan Cardiovascular Research Foundation; AFIRE UMIN Clinical Trials Registry number, UMIN000016612; and ClinicalTrials.gov number, NCT02642419.).

Copyright © 2019 Massachusetts Medical Society.
PMID 31475793  N Engl J Med. 2019 Sep 19;381(12):1103-1113. doi: 10.10・・・
著者: Hiroshi Inoue, Ken Okumura, Hirotsugu Atarashi, Takeshi Yamashita, Hideki Origasa, Naoko Kumagai, Masayuki Sakurai, Yuichiro Kawamura, Isao Kubota, Kazuo Matsumoto, Yoshiaki Kaneko, Satoshi Ogawa, Yoshifusa Aizawa, Masaomi Chinushi, Itsuo Kodama, Eiichi Watanabe, Yukihiro Koretsune, Yuji Okuyama, Akihiko Shimizu, Osamu Igawa, Shigenobu Bando, Masahiko Fukatani, Tetsunori Saikawa, Akiko Chishaki, J-RHYTHM Registry Investigators
雑誌名: Circ J. 2013;77(9):2264-70. doi: 10.1253/circj.cj-13-0290. Epub 2013 May 25.
Abstract/Text BACKGROUND: Target anticoagulation levels for warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF) are unclear.
METHODS AND RESULTS: Of 7,527 patients with NVAF, 1,002 did not receive warfarin (non-warfarin group), and the remaining patients receiving warfarin were divided into 5 groups based on their baseline international normalized ratio (INR) of prothrombin time (≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0). Patients were followed-up prospectively for 2 years. Primary endpoints were thromboembolic events (cerebral infarction, transient ischemic attack, and systemic embolism), and major hemorrhage requiring hospital admission. During the follow-up period, thromboembolic events occurred in 3.0% of non-warfarin group, but at lower frequencies in the warfarin groups (2.0, 1.3, 1.5, 0.6, and 1.8%/2 years for INR values of ≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0, respectively; P=0.0059). Major hemorrhage occurred more frequently in warfarin groups (1.5, 1.8, 2.4, 3.3, and 4.1% for INR values ≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0, respectively; P=0.0041) than in non-warfarin group (0.8%/2 years). These trends were maintained when the analyses were confined to patients aged ≥70 years.
CONCLUSIONS: An INR of 1.6-2.6 is safe and effective at preventing thromboembolic events in patients with NVAF, particularly patients aged ≥70 years. An INR of 2.6-2.99 is also effective, but associated with a slightly increased risk in major hemorrhage. (UMIN Clinical Trials Registry UMIN000001569)

PMID 23708863  Circ J. 2013;77(9):2264-70. doi: 10.1253/circj.cj-13-02・・・
著者: Takeshi Yamashita, Hiroshi Inoue, Ken Okumura, Hirotsugu Atarashi, Hideki Origasa, J-RHYTHM Registry Investigators
雑誌名: J Cardiol. 2015 Mar;65(3):175-7. doi: 10.1016/j.jjcc.2014.07.013. Epub 2014 Aug 26.
Abstract/Text BACKGROUND: To maximize protection against stroke with minimal bleeding, warfarin therapy in nonvalvular atrial fibrillation (NVAF) requires tight control within a narrow therapeutic range, which might depend on racial variations.
METHODS: The J-RHYTHM Registry followed 6404 NVAF patients treated with warfarin for 2 years. Using international normalized ratios (INRs) at or closest to the embolic and intracranial hemorrhagic (ICH) events, we determined odds ratios for ischemic stroke/systemic embolism (SE) and ICH according to any given INR with a reference INR range including 2.0.
RESULTS: Ischemic stroke and SE occurred in 97 of the patients and ICH occurred in 49. The estimated INR-risk relationships showed characteristics of Japanese NVAF patients. Compared to INR-risk relationships reported for Westerners, those observed in Japanese patients were virtually identical for ischemic stroke/SE and shifted leftward by approximately 0.5 INR for ICH.
CONCLUSION: This is the largest Japanese study providing fundamental data necessary to establish optimal anticoagulation intensities. Japanese NVAF patients may require narrower therapeutic ranges than Westerners.

Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
PMID 25169015  J Cardiol. 2015 Mar;65(3):175-7. doi: 10.1016/j.jjcc.20・・・
著者: Eitaro Kodani, Hirotsugu Atarashi, Hiroshi Inoue, Ken Okumura, Takeshi Yamashita, J-RHYTHM Registry Investigators
雑誌名: Circ J. 2015;79(2):325-30. doi: 10.1253/circj.CJ-14-1057. Epub 2014 Dec 10.
Abstract/Text BACKGROUND: Warfarin is widely used for prevention of thromboembolism in patients with valvular atrial fibrillation (AF), and an international normalized ratio (INR) of prothrombin time between 2.0 and 3.0 is recommended. Optimal intensity of anticoagulation with warfarin in Japanese patients with valvular AF, however, has not been clarified thoroughly as yet.
METHODS AND RESULTS: We evaluated the status of anti-thrombotic therapy and incidence rates of events in 410 patients with mitral stenosis and/or mechanical valve replacement (valvular AF) among 7,816 patients with AF followed in the J-RHYTHM Registry. Patients were divided into 5 groups based on INR (<1.6, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0) at the time of event or at the end of follow-up in order to determine the target INR for patients with valvular AF. Warfarin was prescribed in 407 (99.3%) of valvular AF patients. During a 2-year follow-up period, thromboembolism and major hemorrhage occurred in 12 (2.9%) and in 15 (3.7%) patients, respectively. Among patients receiving warfarin, 2-year incidence rates of thromboembolism were 10.3%, 1.6%, 0.6%, 3.0%, and 0.0% (P=0.003 for trend), and those of major hemorrhage were 1.5%, 1.6%, 3.2%, 6.1%, and 21.1% (P<0.001 for trend), respectively.
CONCLUSIONS: I NR between 1.6 and 2.6 could be optimal to prevent thromboembolism without increasing major hemorrhage in Japanese patients with valvular AF. INR 2.6-2.99 would also be effective, but is associated with a modestly increased risk of major hemorrhage.

PMID 25492037  Circ J. 2015;79(2):325-30. doi: 10.1253/circj.CJ-14-105・・・
著者: M Yasaka, K Minematsu, T Yamaguchi
雑誌名: Intern Med. 2001 Dec;40(12):1183-8.
Abstract/Text OBJECTIVE: To determine optimal intensity of international normalized ratio (INR) of warfarin therapy for the prevention of ischemic events in patients with non-valvular atrial fibrillation (NVAF), we evaluated the risk of severe recurrent stroke, systemic embolism and major hemorrhagic complications according to INR and age.
METHODS: We carried out the National Cardiovascular Center (NCVC) NVAF Secondary Prevention Study and analyzed data with those of Japanese Nonvaluvular Atrial Fibrillation-embolism Secondary Prevention Cooperative Study to elucidate relationships of major stroke and hemorrhage with INR and age. In both studies, all patients with cardioembolic stroke were given warfarin, monitored with INR every month, and followed up for primary endpoints of stroke and embolism to other parts of the body, and for secondary endpoints of major hemorrhagic complications requiring blood transfusion or hospitalization. We regarded ischemic stroke with NIH stroke scale (NIHSS) score > or = 10 or systemic embolism as a major ischemic event and ischemic stroke with NIHSS score <10 as a minor ischemic event. There were 203 patients enrolled in total (152 men and 51 women). We investigated the relationship of occurrence of the events with INR and age, and calculated the incidence rates of major and minor ischemic events and major hemorrhagic events.
RESULTS: During the mean follow-up of 653 days, major ischemic stroke and systemic embolism occurred in only 4 patients with INR <1.6, minor ischemic stroke in 10 patients with INR 1.50-2.66, and major hemorrhage in 9 patients with INR 2.30-3.56. Patients with major ischemic or hemorrhagic events were significantly older than those without any events (75+/-4 years vs. 67+/-7 years, p<0.001 unpaired t test). Incidence rates of any events at INR < or = 1.59, 1.60-1.99, 2.00-2.59 and > or = 2.60 were 8.6%, 3.8%, 4.9%, and 25.7%/year, respectively.
CONCLUSIONS: Major ischemic or hemorrhagic events occur often in the elderly NVAF patients, in whom an INR value of between 1.6 and 2.6 seems optimal to prevent such events.

PMID 11813841  Intern Med. 2001 Dec;40(12):1183-8.
著者: Mari Matsumoto, Manabu Sakaguchi, Shuhei Okazaki, Kazuo Hashikawa, Tsutomu Takahashi, Masayasu Matsumoto, Toshiho Ohtsuki, Takeshi Shimazu, Toshiki Yoshimine, Hideki Mochizuki, Kazuo Kitagawa
雑誌名: Circ J. 2017 Feb 24;81(3):391-396. doi: 10.1253/circj.CJ-16-0707. Epub 2017 Jan 31.
Abstract/Text BACKGROUND: In Japan, warfarin treatment at prothrombin time-international normalized ratio (PT-INR) of 1.60-2.60 is recommended for elderly patients with nonvalvular atrial fibrillation (NVAF). But it remains unknown whether PT-INR 1.60-1.99 has a similar effect on stroke severity as a value >2.0. The purpose of this study was to clarify the association between infarct volume and PT-INR levels.Methods and Results:The 180 patients (mean age, 76 years [SD, 10 years], 53% male) selected from 429 consecutive ischemic stroke patients admitted within 48 h of onset between 2004 and 2014 with NVAF were included. We classified them into 4 groups according to their PT-INR values on admission: no warfarin (NW), 129 patients; PT-INR <1.60 (poor control: PC), 29 patients; PT-INR 1.60-1.99 (low-intensity control: LC), 14 patients; and PT-INR ≥2.00 (high-intensity control: HC), 8 patients. Median (interquartile range: IQR) of infarct volume was 55 mL (IQR 14-175) in the NW, 42 mL (IQR 27-170) in the PC, 36 mL (IQR 6-130) in the LC, and 11 mL (IQR 0-39) in the HC groups. The infarct volume of the HC group was significantly smaller than in the other 3 groups, but no difference existed between the LC and PC groups or the LC and NW groups.
CONCLUSIONS: Warfarin control at PT-INR of 1.60-1.99 is not effective for reducing the severity of ischemic stroke in NVAF patients.

PMID 28154247  Circ J. 2017 Feb 24;81(3):391-396. doi: 10.1253/circj.C・・・
著者: Asako Nakamura, Tetsuro Ago, Masahiro Kamouchi, Jun Hata, Ryu Matsuo, Junya Kuroda, Takahiro Kuwashiro, Hiroshi Sugimori, Takanari Kitazono, Fukuoka Stroke Registry Investigators
雑誌名: Stroke. 2013 Nov;44(11):3239-42. doi: 10.1161/STROKEAHA.113.002523. Epub 2013 Aug 20.
Abstract/Text BACKGROUND AND PURPOSE: The relationship between the intensity of anticoagulation at the onset of acute cardioembolic stroke and clinical outcome after stroke is unclear. Here, we elucidated the relationship between prothrombin time-international normalized ratio (PT-INR) values on admission and clinical outcomes in patients with acute cardioembolic stroke.
METHODS: A total of 602 patients from the Fukuoka Stroke Registry in Japan who had been treated with warfarin but developed cardioembolic stroke were enrolled. The patients were classified into 3 groups according to their PT-INR values on admission: PT-INR <1.50, 411 patients; PT-INR 1.50 to 1.99, 146 patients; and PT-INR ≥2.00, 45 patients. The associations between PT-INR categories and severe neurological deficits (National Institutes of Health Stroke Scale ≥10) on admission and poor functional outcome (modified Rankin scale 4-6) at discharge were investigated using a logistic regression analysis.
RESULTS: Neurological deficits on admission were less severe, and functional outcome at discharge was more favorable as the PT-INR level on admission increased. The multivariate analysis revealed that severe neurological deficits were inversely associated with PT-INR on admission (PT-INR 1.50-1.99: odds ratio, 0.66; 95% confidence interval, 0.43-1.00; PT-INR ≥2.00: odds ratio, 0.41; 95% confidence interval, 0.20-0.83; compared with a reference group of PT-INR <1.50). Poor functional outcome was less likely in patients with PT-INR ≥2.00 (odds ratio, 0.20; 95% confidence interval, 0.06-0.55) after adjustment for confounders.
CONCLUSIONS: Prestroke PT-INR ≥2.0 is associated with favorable clinical outcomes after acute cardioembolic stroke.

PMID 23963334  Stroke. 2013 Nov;44(11):3239-42. doi: 10.1161/STROKEAHA・・・
著者: Stefan H Hohnloser, Dimitri Pajitnev, Janice Pogue, Jeff S Healey, Marc A Pfeffer, Salim Yusuf, Stuart J Connolly, ACTIVE W Investigators
雑誌名: J Am Coll Cardiol. 2007 Nov 27;50(22):2156-61. doi: 10.1016/j.jacc.2007.07.076. Epub 2007 Nov 13.
Abstract/Text OBJECTIVES: Our goal was to determine the risk of stroke or non-cerebral embolism associated with paroxysmal compared with sustained atrial fibrillation (AF).
BACKGROUND: The risk of stroke and non-cerebral embolism and the efficacy of oral anticoagulation (OAC) in paroxysmal AF as compared with sustained AF are not precisely known.
METHODS: The ACTIVE W (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events) was a trial comparing OAC to combined antiplatelet therapy with aspirin and clopidogrel for prevention of vascular events in 6,706 AF patients. The incidence of thromboembolic events and major bleeds were compared in patients with paroxysmal AF (n = 1,202) and persistent or permanent AF (n = 5,495).
RESULTS: Patients with paroxysmal AF were younger, had a shorter AF history, more hypertension, and less valvular disease, heart failure, and diabetes mellitus than patients with sustained AF. At baseline, patients with paroxysmal AF had a CHADS2 (cardiac failure, hypertension, age, diabetes, stroke [doubled]) risk score of 1.79 +/- 1.03 compared with 2.04 +/- 1.12 in patients with sustained AF (p < 0.00001). The annualized risk of stroke or non-central nervous system (CNS) systemic embolism was 2.0 in paroxysmal AF compared with 2.2 in sustained AF (relative risk 0.87, 95% confidence interval [CI] 0.59 to 1.30, p = 0.496). After adjusting for confounding baseline variables, the relative risk was 0.94 (95% CI 0.63 to 1.40, p = 0.755). The incidence of stroke and non-CNS embolism was lower for patients treated with OAC irrespective of type of AF. There were more bleedings of any type in patients receiving clopidogrel plus aspirin, irrespective of the type of AF.
CONCLUSIONS: Patients with paroxysmal AF treated with aspirin plus clopidogrel or OAC have a similar risk for thromboembolic events than patients with sustained AF. This risk can be significantly lowered with OAC. (The ACTIVE W trial; http://www.clinicaltrials.gov/ct/show/NCT00243178;NCT00243178).

PMID 18036454  J Am Coll Cardiol. 2007 Nov 27;50(22):2156-61. doi: 10.・・・
著者: Stuart J Connolly, Michael D Ezekowitz, Salim Yusuf, John Eikelboom, Jonas Oldgren, Amit Parekh, Janice Pogue, Paul A Reilly, Ellison Themeles, Jeanne Varrone, Susan Wang, Marco Alings, Denis Xavier, Jun Zhu, Rafael Diaz, Basil S Lewis, Harald Darius, Hans-Christoph Diener, Campbell D Joyner, Lars Wallentin, RE-LY Steering Committee and Investigators
雑誌名: N Engl J Med. 2009 Sep 17;361(12):1139-51. doi: 10.1056/NEJMoa0905561. Epub 2009 Aug 30.
Abstract/Text BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor.
METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism.
RESULTS: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051).
CONCLUSIONS: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)

2009 Massachusetts Medical Society
PMID 19717844  N Engl J Med. 2009 Sep 17;361(12):1139-51. doi: 10.1056・・・
著者: Shimoli V Shah, Brian F Gage
雑誌名: Circulation. 2011 Jun 7;123(22):2562-70. doi: 10.1161/CIRCULATIONAHA.110.985655. Epub 2011 May 23.
Abstract/Text BACKGROUND: Recent studies have investigated alternatives to warfarin for stroke prophylaxis in patients with atrial fibrillation (AF), but whether these alternatives are cost-effective is unknown.
METHODS AND RESULTS: On the basis of the results from Randomized Evaluation of Long Term Anticoagulation Therapy (RE-LY) and other trials, we developed a decision-analysis model to compare the cost and quality-adjusted survival of various antithrombotic therapies. We ran our Markov model in a hypothetical cohort of 70-year-old patients with AF using a cost-effectiveness threshold of $50 000/quality-adjusted life-year. We estimated the cost of dabigatran as US $9 a day. For a patient with an average risk of major hemorrhage (≈3%/y), the most cost-effective therapy depended on stroke risk. For patients with the lowest stroke rate (CHADS2 stroke score of 0), only aspirin was cost-effective. For patients with a moderate stroke rate (CHADS2 score of 1 or 2), warfarin was cost-effective unless the risk of hemorrhage was high or quality of international normalized ratio control was poor (time in the therapeutic range <57.1%). For patients with a high stroke risk (CHADS(2) stroke score ≥3), dabigatran 150 mg (twice daily) was cost-effective unless international normalized ratio control was excellent (time in the therapeutic range >72.6%). Neither dabigatran 110 mg nor dual therapy (aspirin and clopidogrel) was cost-effective.
CONCLUSIONS: Dabigatran 150 mg (twice daily) was cost-effective in AF populations at high risk of hemorrhage or high risk of stroke unless international normalized ratio control with warfarin was excellent. Warfarin was cost-effective in moderate-risk AF populations unless international normalized ratio control was poor.

PMID 21606397  Circulation. 2011 Jun 7;123(22):2562-70. doi: 10.1161/C・・・
著者: Jonas Bjerring Olesen, Gregory Y H Lip, Morten Lock Hansen, Peter Riis Hansen, Janne Schurmann Tolstrup, Jesper Lindhardsen, Christian Selmer, Ole Ahlehoff, Anne-Marie Schjerning Olsen, Gunnar Hilmar Gislason, Christian Torp-Pedersen
雑誌名: BMJ. 2011 Jan 31;342:d124. Epub 2011 Jan 31.
Abstract/Text OBJECTIVES: To evaluate the individual risk factors composing the CHADS(2) (Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes, previous Stroke) score and the CHA(2)DS(2)-VASc (CHA(2)DS(2)-Vascular disease, Age 65-74 years, Sex category) score and to calculate the capability of the schemes to predict thromboembolism.
DESIGN: Registry based cohort study.
SETTING: Nationwide data on patients admitted to hospital with atrial fibrillation. Population All patients with atrial fibrillation not treated with vitamin K antagonists in Denmark in the period 1997-2006.
MAIN OUTCOME MEASURES: Stroke and thromboembolism.
RESULTS: Of 121,280 patients with non-valvular atrial fibrillation, 73,538 (60.6%) fulfilled the study inclusion criteria. In patients at "low risk" (score = 0), the rate of thromboembolism per 100 person years was 1.67 (95% confidence interval 1.47 to 1.89) with CHADS(2) and 0.78 (0.58 to 1.04) with CHA(2)DS(2)-VASc at one year's follow-up. In patients at "intermediate risk" (score = 1), this rate was 4.75 (4.45 to 5.07) with CHADS(2) and 2.01 (1.70 to 2.36) with CHA(2)DS(2)-VASc. The rate of thromboembolism depended on the individual risk factors composing the scores, and both schemes underestimated the risk associated with previous thromboembolic events. When patients were categorised into low, intermediate, and high risk groups, C statistics at 10 years' follow-up were 0.812 (0.796 to 0.827) with CHADS(2) and 0.888 (0.875 to 0.900) with CHA(2)DS(2)-VASc.
CONCLUSIONS: The risk associated with a specific risk stratification score depended on the risk factors composing the score. CHA(2)DS(2)-VASc performed better than CHADS(2) in predicting patients at high risk, and those categorised as low risk by CHA(2)DS(2)-VASc were truly at low risk for thromboembolism.

PMID 21282258  BMJ. 2011 Jan 31;342:d124. Epub 2011 Jan 31.
著者: Gregory Y H Lip, Robby Nieuwlaat, Ron Pisters, Deirdre A Lane, Harry J G M Crijns
雑誌名: Chest. 2010 Feb;137(2):263-72. doi: 10.1378/chest.09-1584. Epub 2009 Sep 17.
Abstract/Text BACKGROUND: Contemporary clinical risk stratification schemata for predicting stroke and thromboembolism (TE) in patients with atrial fibrillation (AF) are largely derived from risk factors identified from trial cohorts. Thus, many potential risk factors have not been included.
METHODS: We refined the 2006 Birmingham/National Institute for Health and Clinical Excellence (NICE) stroke risk stratification schema into a risk factor-based approach by reclassifying and/or incorporating additional new risk factors where relevant. This schema was then compared with existing stroke risk stratification schema in a real-world cohort of patients with AF (n = 1,084) from the Euro Heart Survey for AF.
RESULTS: Risk categorization differed widely between the different schemes compared. Patients classified as high risk ranged from 10.2% with the Framingham schema to 75.7% with the Birmingham 2009 schema. The classic CHADS(2) (Congestive heart failure, Hypertension, Age > 75, Diabetes, prior Stroke/transient ischemic attack) schema categorized the largest proportion (61.9%) into the intermediate-risk strata, whereas the Birmingham 2009 schema classified 15.1% into this category. The Birmingham 2009 schema classified only 9.2% as low risk, whereas the Framingham scheme categorized 48.3% as low risk. Calculated C-statistics suggested modest predictive value of all schema for TE. The Birmingham 2009 schema fared marginally better (C-statistic, 0.606) than CHADS(2). However, those classified as low risk by the Birmingham 2009 and NICE schema were truly low risk with no TE events recorded, whereas TE events occurred in 1.4% of low-risk CHADS(2) subjects. When expressed as a scoring system, the Birmingham 2009 schema (CHA(2)DS(2)-VASc acronym) showed an increase in TE rate with increasing scores (P value for trend = .003).
CONCLUSIONS: Our novel, simple stroke risk stratification schema, based on a risk factor approach, provides some improvement in predictive value for TE over the CHADS(2) schema, with low event rates in low-risk subjects and the classification of only a small proportion of subjects into the intermediate-risk category. This schema could improve our approach to stroke risk stratification in patients with AF.

PMID 19762550  Chest. 2010 Feb;137(2):263-72. doi: 10.1378/chest.09-15・・・
著者: Hiroshi Sato, Kinji Ishikawa, Akira Kitabatake, Satoshi Ogawa, Yukio Maruyama, Yoshiyuki Yokota, Takaya Fukuyama, Yoshinori Doi, Seibu Mochizuki, Tohru Izumi, Noboru Takekoshi, Kiyoshi Yoshida, Katsuhiko Hiramori, Hideki Origasa, Shinichiro Uchiyama, Masayasu Matsumoto, Takenori Yamaguchi, Masatsugu Hori, Japan Atrial Fibrillation Stroke Trial Group
雑誌名: Stroke. 2006 Feb;37(2):447-51. doi: 10.1161/01.STR.0000198839.61112.ee. Epub 2005 Dec 29.
Abstract/Text BACKGROUND AND PURPOSE: Although the efficacy of anticoagulant therapy for primary prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF) has been established, efficacy of antiplatelet therapy for low-risk patients is disputable in Japanese patients because of the frequent hemorrhagic complications. We examined the efficacy and safety of aspirin therapy in Japanese patients with NVAF in a prospective randomized multicenter trial.
METHODS: Patients with NVAF were randomized to an aspirin group (aspirin at 150 to 200 mg per day) or a control group without antiplatelet or anticoagulant therapy. Primary end points included cardiovascular death, symptomatic brain infarction, or transient ischemic attack.
RESULTS: A total of 426 patients were randomized to aspirin group and 445 to no treatment. The trial was stopped earlier because there were 27 primary end point events (3.1% per year; 95% CI, 2.1% to 4.6% per year) in the aspirin group versus 23 (2.4% per year; 95% CI, 1.5% to 3.5% per year) in the control group, suggesting a low possibility of superiority of the aspirin treatment for prevention of the primary end point. In addition, treatment with aspirin caused a marginally increased risk of major bleeding (7 patients; 1.6%) compared with the control group (2 patients; 0.4%; Fisher exact test P=0.101).
CONCLUSIONS: For prevention of stroke in patients with NVAF, aspirin at 150 to 200 mg per day does not seem to be either effective or safe. Further prospective studies are needed to determine the best preventive therapy for cerebrovascular events in Japanese patients with NVAF.

PMID 16385088  Stroke. 2006 Feb;37(2):447-51. doi: 10.1161/01.STR.0000・・・
著者: ACTIVE Writing Group of the ACTIVE Investigators, S Connolly, J Pogue, R Hart, M Pfeffer, S Hohnloser, S Chrolavicius, M Pfeffer, S Hohnloser, S Yusuf
雑誌名: Lancet. 2006 Jun 10;367(9526):1903-12. doi: 10.1016/S0140-6736(06)68845-4.
Abstract/Text BACKGROUND: Oral anticoagulation therapy reduces risk of vascular events in patients with atrial fibrillation. However, long-term monitoring is necessary and many patients cannot achieve optimum anticoagulation. We assessed whether clopidogrel plus aspirin was non-inferior to oral anticoagulation therapy for prevention of vascular events.
METHODS: Patients were enrolled if they had atrial fibrillation plus one or more risk factor for stroke, and were randomly allocated to receive oral anticoagulation therapy (target international normalised ratio of 2.0-3.0; n=3371) or clopidogrel (75 mg per day) plus aspirin (75-100 mg per day recommended; n=3335). Outcome events were adjudicated by a blinded committee. Primary outcome was first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. Analyses were by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00243178.
RESULTS: The study was stopped early because of clear evidence of superiority of oral anticoagulation therapy. There were 165 primary events in patients on oral anticoagulation therapy (annual risk 3.93%) and 234 in those on clopidogrel plus aspirin (annual risk 5.60%; relative risk 1.44 (1.18-1.76; p=0.0003). Patients on oral anticoagulation therapy who were already receiving this treatment at study entry had a trend towards a greater reduction in vascular events (relative risk 1.50, 95% CI 1.19-1.89) and a significantly (p=0.03 for interaction) lower risk of major bleeding with oral anticoagulation therapy (1.30; 0.94-1.79) than patients not on this treatment at study entry (1.27, 0.85-1.89 and 0.59, 0.32-1.08, respectively).
CONCLUSION: Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke, especially in those already taking oral anticoagulation therapy.

PMID 16765759  Lancet. 2006 Jun 10;367(9526):1903-12. doi: 10.1016/S01・・・
著者: E N Prystowsky, D W Benson, V Fuster, R G Hart, G N Kay, R J Myerburg, G V Naccarelli, D G Wyse
雑誌名: Circulation. 1996 Mar 15;93(6):1262-77.
Abstract/Text
PMID 8653857  Circulation. 1996 Mar 15;93(6):1262-77.
著者: R G Hart, J L Halperin
雑誌名: Ann Intern Med. 1999 Nov 2;131(9):688-95.
Abstract/Text Atrial fibrillation is associated with a sixfold increased risk for stroke. More than a dozen published randomized trials of anticoagulants or antiplatelet agents for stroke prevention provide solid evidence on which to base antithrombotic prophylaxis. Adjusted-dose warfarin reduces risk for stroke by about 60% compared with placebo, aspirin reduces this risk (primarily for nondisabling stroke) by about 20% compared with placebo, and warfarin reduces it by about 40% compared with aspirin. Warfarin provides maximal protection against stroke at international normalized ratios of 2.0 to 3.0. Risk stratification of patients with atrial fibrillation identifies those who potentially benefit most or least from anticoagulation; this is important because a substantial percentage of patients with atrial fibrillation have relatively low rates of stroke if they are given aspirin. Many elderly patients with recurrent intermittent atrial fibrillation experience high rates of stroke and benefit from anticoagulation. The value of precordial or transesophageal echocardiography in addition to clinical risk stratifiers for stratifying stroke risk is controversial. Altered hemostasis favoring thrombosis may contribute to formation of atrial appendage thrombus, but these conditions remain ill defined. The past decade has brought unprecedented progress toward understanding thromboembolism in patients with atrial fibrillation and has changed the clinical perspective of a prevalent cardiac arrhythmia into an important opportunity for stroke prevention. Making the most of this promise calls for appreciation of the epidemiology of atrial fibrillation and the concept of risk specificity in the face of diverse therapeutic options.

PMID 10577332  Ann Intern Med. 1999 Nov 2;131(9):688-95.
著者: G B Mancini, A L Goldberger
雑誌名: Am Heart J. 1982 Sep;104(3):617-21.
Abstract/Text
PMID 7113903  Am Heart J. 1982 Sep;104(3):617-21.
著者: H Atarashi, H Inoue, K Hiejima, H Hayakawa
雑誌名: Am J Cardiol. 1996 Sep 15;78(6):694-7.
Abstract/Text The efficacy and safety of a single oral dose of 150-mg pilsicainide, a new class Ic antiarrhythmic drug, in converting recent-onset atrial fibrillation to sinus rhythm were evaluated in 75 patients (51 men, 24 women; age 23 to 74 years). Conversion to sinus rhythm was achieved within 90 minutes in 45% of patients given pilsicainide and in 8.6% of those on placebo (p < 0.01), with no major adverse effects.

PMID 8831412  Am J Cardiol. 1996 Sep 15;78(6):694-7.
著者: Akira Fujiki, Takayuki Tsuneda, Masataka Sugao, Koichi Mizumaki, Hiroshi Inoue
雑誌名: Am J Cardiol. 2003 Aug 15;92(4):472-5.
Abstract/Text The aim of this study was to investigate the efficacy and safety of bepridil (a multichannel blocker including several potassium channels) for conversion of long-lasting atrial fibrillation (AF). Bepridil restored sinus rhythm alone or in combination with aprindine in 69% of 32 patients with persistent AF lasting > or = 3 months. The time to conversion after starting bepridil was 30 +/- 12 days. An increase in fibrillation cycle length with bepridil was greater in responders (31 +/- 10%), but an increase in QTc did not differ between responders and nonresponders. Bepridil is effective and safe for terminating long-lasting persistent AF.

PMID 12914884  Am J Cardiol. 2003 Aug 15;92(4):472-5.
著者: Isabelle C Van Gelder, D George Wyse, Mary L Chandler, Howard A Cooper, Brian Olshansky, Vincent E Hagens, Harry J G M Crijns, RACE and AFFIRM Investigators
雑誌名: Europace. 2006 Nov;8(11):935-42. doi: 10.1093/europace/eul106. Epub 2006 Sep 14.
Abstract/Text AIMS: The AFFIRM and RACE studies showed that rate control is an acceptable treatment strategy for atrial fibrillation (AF). We examined whether strict rate control offers benefit over more lenient rate control.
METHODS AND RESULTS: We compared the outcome of patients enrolled in the rate-control arms of AFFIRM and RACE, using data from patients who met a composite of overlapping inclusion and exclusion criteria. We evaluated 1091 patients, 874 from AFFIRM and 217 from RACE. In AFFIRM, the rate-control strategy aimed for a resting heart rate < or =80 bpm and heart rate during daily activity of < or =110 bpm. In RACE, a more lenient approach was taken: resting heart rate <100 bpm. Primary endpoint was a composite of mortality, cardiovascular hospitalization, and myocardial infarction. Mean heart rate across all follow-up visits for patients in AF was lower in AFFIRM (76.1 vs. 83.4 bpm). Event-free survival for the occurrence of the primary endpoint did not differ (64% in AFFIRM vs. 66% in RACE). Patients with mean heart rates during AF within the AFFIRM (< or =80) or RACE (<100) criteria had a better outcome than patients with heart rates > or =100 (hazard ratios 0.69 and 0.58, respectively, for < or =80 and <100 compared with > or =100 bpm).
CONCLUSION: Stringency of the approach to rate control, based on the comparison of the AFFIRM and RACE studies, was not associated with an important difference in clinical events.

PMID 16973686  Europace. 2006 Nov;8(11):935-42. doi: 10.1093/europace/・・・
著者: Isabelle C Van Gelder, Hessel F Groenveld, Harry J G M Crijns, Ype S Tuininga, Jan G P Tijssen, A Marco Alings, Hans L Hillege, Johanna A Bergsma-Kadijk, Jan H Cornel, Otto Kamp, Raymond Tukkie, Hans A Bosker, Dirk J Van Veldhuisen, Maarten P Van den Berg, RACE II Investigators
雑誌名: N Engl J Med. 2010 Apr 15;362(15):1363-73. doi: 10.1056/NEJMoa1001337. Epub 2010 Mar 15.
Abstract/Text BACKGROUND: Rate control is often the therapy of choice for atrial fibrillation. Guidelines recommend strict rate control, but this is not based on clinical evidence. We hypothesized that lenient rate control is not inferior to strict rate control for preventing cardiovascular morbidity and mortality in patients with permanent atrial fibrillation.
METHODS: We randomly assigned 614 patients with permanent atrial fibrillation to undergo a lenient rate-control strategy (resting heart rate <110 beats per minute) or a strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The duration of follow-up was at least 2 years, with a maximum of 3 years.
RESULTS: The estimated cumulative incidence of the primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group, with an absolute difference with respect to the lenient-control group of -2.0 percentage points (90% confidence interval, -7.6 to 3.5; P<0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets (304 [97.7%], vs. 203 [67.0%] in the strict-control group; P<0.001) with fewer total visits (75 [median, 0], vs. 684 [median, 2]; P<0.001). The frequencies of symptoms and adverse events were similar in the two groups.
CONCLUSIONS: In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve. (ClinicalTrials.gov number, NCT00392613.)

2010 Massachusetts Medical Society
PMID 20231232  N Engl J Med. 2010 Apr 15;362(15):1363-73. doi: 10.1056・・・
著者: Takeshi Yamashita, Takanori Ikeda, Yasuhiko Akita
雑誌名: J Cardiol. 2019 May;73(5):386-393. doi: 10.1016/j.jjcc.2018.11.009. Epub 2018 Dec 24.
Abstract/Text BACKGROUND: TY-0201 (TY) is a transdermal patch containing bisoprolol. The objectives of this study were to evaluate the noninferiority of TY to bisoprolol oral formulation (BO) in patients with persistent or permanent atrial fibrillation (AF).
METHODS: In this multicenter, double-blind, comparative study, Japanese patients with persistent or permanent AF were randomized to TY 4-mg (n=55), TY 8-mg (n=55), BO 2.5-mg (n=55), or BO 5-mg (n=55) groups. All patients were administered TY 4mg or BO 2.5mg once a day for the first 2 weeks. Patients in the TY 8-mg or BO 5-mg group, in whom dose escalation was required, were administered TY 8mg or BO 5mg for a further 2 weeks, and the other patients continued to receive TY 4mg or BO 2.5mg. The primary endpoint was a change in 24-h mean heart rate (mHR) from baseline by Holter electrocardiogram, and the noninferiority of the TY 4-mg to the BO 2.5-mg groups and that of the TY 8-mg to the BO 5-mg groups were evaluated.
RESULTS: Adjusted means of changes in 24-h mHR from baseline in the TY 4-mg, TY 8-mg, BO 2.5-mg, and BO 5-mg groups were -12.3, -13.8, -12.7, and -14.3bpm, respectively. Differences between values for the TY 4-mg and BO 2.5-mg groups and between values for the TY 8-mg and BO 5-mg groups were estimated to be 0.5 (95% CI: -1.9 to 2.9) and 0.5 (-1.9 to 2.9)bpm, respectively, which did not exceed the predefined noninferiority margins. The incidence of adverse events did not differ between the groups.
CONCLUSIONS: In Japanese patients with persistent or permanent AF, TY 4mg and TY 8mg had heart rate-reducing effects similar to those of BO 2.5mg and BO 5mg, respectively.

Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.
PMID 30591320  J Cardiol. 2019 May;73(5):386-393. doi: 10.1016/j.jjcc.・・・
著者: Matthew G Whitbeck, Richard J Charnigo, Paul Khairy, Khaled Ziada, Alison L Bailey, Milagros M Zegarra, Jignesh Shah, Gustavo Morales, Tracy Macaulay, Vincent L Sorrell, Charles L Campbell, John Gurley, Paul Anaya, Hafez Nasr, Rong Bai, Luigi Di Biase, David C Booth, Guillaume Jondeau, Andrea Natale, Denis Roy, Susan Smyth, David J Moliterno, Claude S Elayi
雑誌名: Eur Heart J. 2013 May;34(20):1481-8. doi: 10.1093/eurheartj/ehs348. Epub 2012 Nov 27.
Abstract/Text AIMS: Digoxin is frequently used for rate control of atrial fibrillation (AF). It has, however, been associated with increased mortality. It remains unclear whether digoxin itself is responsible for the increased mortality (toxic drug effect) or whether it is prescribed to sicker patients with inherently higher mortality due to comorbidities. The goal of our study was to determine the relationship between digoxin and mortality in patients with AF.
METHODS AND RESULTS: The association between digoxin and mortality was assessed in patients enrolled in the AF Follow-Up Investigation of Rhythm Management (AFFIRM) trial using multivariate Cox proportional hazards models. Analyses were conducted in all patients and in subsets according to the presence or absence of heart failure (HF), as defined by a history of HF and/or an ejection fraction <40%. Digoxin was associated with an increase in all-cause mortality [estimated hazard ratio (EHR) 1.41, 95% confidence interval (CI) 1.19-1.67, P < 0.001], cardiovascular mortality (EHR 1.35, 95% CI 1.06-1.71, P = 0.016), and arrhythmic mortality (EHR 1.61, 95% CI 1.12-2.30, P = 0.009). The all-cause mortality was increased with digoxin in patients without or with HF (EHR 1.37, 95% CI 1.05-1.79, P = 0.019 and EHR 1.41, 95% CI 1.09-1.84, P = 0.010, respectively). There was no significant digoxin-gender interaction for all-cause (P = 0.70) or cardiovascular (P = 0.95) mortality.
CONCLUSION: Digoxin was associated with a significant increase in all-cause mortality in patients with AF after correcting for clinical characteristics and comorbidities, regardless of gender or of the presence or absence of HF. These findings call into question the widespread use of digoxin in patients with AF.

PMID 23186806  Eur Heart J. 2013 May;34(20):1481-8. doi: 10.1093/eurhe・・・
著者: D G Wyse, A L Waldo, J P DiMarco, M J Domanski, Y Rosenberg, E B Schron, J C Kellen, H L Greene, M C Mickel, J E Dalquist, S D Corley, Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators
雑誌名: N Engl J Med. 2002 Dec 5;347(23):1825-33. doi: 10.1056/NEJMoa021328.
Abstract/Text BACKGROUND: There are two approaches to the treatment of atrial fibrillation: one is cardioversion and treatment with antiarrhythmic drugs to maintain sinus rhythm, and the other is the use of rate-controlling drugs, allowing atrial fibrillation to persist. In both approaches, the use of anticoagulant drugs is recommended.
METHODS: We conducted a randomized, multicenter comparison of these two treatment strategies in patients with atrial fibrillation and a high risk of stroke or death. The primary end point was overall mortality.
RESULTS: A total of 4060 patients (mean [+/-SD] age, 69.7+/-9.0 years) were enrolled in the study; 70.8 percent had a history of hypertension, and 38.2 percent had coronary artery disease. Of the 3311 patients with echocardiograms, the left atrium was enlarged in 64.7 percent and left ventricular function was depressed in 26.0 percent. There were 356 deaths among the patients assigned to rhythm-control therapy and 310 deaths among those assigned to rate-control therapy (mortality at five years, 23.8 percent and 21.3 percent, respectively; hazard ratio, 1.15 [95 percent confidence interval, 0.99 to 1.34]; P=0.08). More patients in the rhythm-control group than in the rate-control group were hospitalized, and there were more adverse drug effects in the rhythm-control group as well. In both groups, the majority of strokes occurred after warfarin had been stopped or when the international normalized ratio was subtherapeutic.
CONCLUSIONS: Management of atrial fibrillation with the rhythm-control strategy offers no survival advantage over the rate-control strategy, and there are potential advantages, such as a lower risk of adverse drug effects, with the rate-control strategy. Anticoagulation should be continued in this group of high-risk patients.

Copyright 2002 Massachusetts Medical Society
PMID 12466506  N Engl J Med. 2002 Dec 5;347(23):1825-33. doi: 10.1056/・・・
著者: Isabelle C Van Gelder, Vincent E Hagens, Hans A Bosker, J Herre Kingma, Otto Kamp, Tsjerk Kingma, Salah A Said, Julius I Darmanata, Alphons J M Timmermans, Jan G P Tijssen, Harry J G M Crijns, Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group
雑誌名: N Engl J Med. 2002 Dec 5;347(23):1834-40. doi: 10.1056/NEJMoa021375.
Abstract/Text BACKGROUND: Maintenance of sinus rhythm is the main therapeutic goal in patients with atrial fibrillation. However, recurrences of atrial fibrillation and side effects of antiarrhythmic drugs offset the benefits of sinus rhythm. We hypothesized that ventricular rate control is not inferior to the maintenance of sinus rhythm for the treatment of atrial fibrillation.
METHODS: We randomly assigned 522 patients who had persistent atrial fibrillation after a previous electrical cardioversion to receive treatment aimed at rate control or rhythm control. Patients in the rate-control group received oral anticoagulant drugs and rate-slowing medication. Patients in the rhythm-control group underwent serial cardioversions and received antiarrhythmic drugs and oral anticoagulant drugs. The end point was a composite of death from cardiovascular causes, heart failure, thromboembolic complications, bleeding, implantation of a pacemaker, and severe adverse effects of drugs.
RESULTS: After a mean (+/-SD) of 2.3+/-0.6 years, 39 percent of the 266 patients in the rhythm-control group had sinus rhythm, as compared with 10 percent of the 256 patients in the rate-control group. The primary end point occurred in 44 patients (17.2 percent) in the rate-control group and in 60 (22.6 percent) in the rhythm-control group. The 90 percent (two-sided) upper boundary of the absolute difference in the primary end point was 0.4 percent (the prespecified criterion for noninferiority was 10 percent or less). The distribution of the various components of the primary end point was similar in the rate-control and rhythm-control groups.
CONCLUSIONS: Rate control is not inferior to rhythm control for the prevention of death and morbidity from cardiovascular causes and may be appropriate therapy in patients with a recurrence of persistent atrial fibrillation after electrical cardioversion.

Copyright 2002 Massachusetts Medical Society
PMID 12466507  N Engl J Med. 2002 Dec 5;347(23):1834-40. doi: 10.1056/・・・
著者: Denis Roy, Mario Talajic, Stanley Nattel, D George Wyse, Paul Dorian, Kerry L Lee, Martial G Bourassa, J Malcolm O Arnold, Alfred E Buxton, A John Camm, Stuart J Connolly, Marc Dubuc, Anique Ducharme, Peter G Guerra, Stefan H Hohnloser, Jean Lambert, Jean-Yves Le Heuzey, Gilles O'Hara, Ole Dyg Pedersen, Jean-Lucien Rouleau, Bramah N Singh, Lynne Warner Stevenson, William G Stevenson, Bernard Thibault, Albert L Waldo, Atrial Fibrillation and Congestive Heart Failure Investigators
雑誌名: N Engl J Med. 2008 Jun 19;358(25):2667-77. doi: 10.1056/NEJMoa0708789.
Abstract/Text BACKGROUND: It is common practice to restore and maintain sinus rhythm in patients with atrial fibrillation and heart failure. This approach is based in part on data indicating that atrial fibrillation is a predictor of death in patients with heart failure and suggesting that the suppression of atrial fibrillation may favorably affect the outcome. However, the benefits and risks of this approach have not been adequately studied.
METHODS: We conducted a multicenter, randomized trial comparing the maintenance of sinus rhythm (rhythm control) with control of the ventricular rate (rate control) in patients with a left ventricular ejection fraction of 35% or less, symptoms of congestive heart failure, and a history of atrial fibrillation. The primary outcome was the time to death from cardiovascular causes.
RESULTS: A total of 1376 patients were enrolled (682 in the rhythm-control group and 694 in the rate-control group) and were followed for a mean of 37 months. Of these patients, 182 (27%) in the rhythm-control group died from cardiovascular causes, as compared with 175 (25%) in the rate-control group (hazard ratio in the rhythm-control group, 1.06; 95% confidence interval, 0.86 to 1.30; P=0.59 by the log-rank test). Secondary outcomes were similar in the two groups, including death from any cause (32% in the rhythm-control group and 33% in the rate-control group), stroke (3% and 4%, respectively), worsening heart failure (28% and 31%), and the composite of death from cardiovascular causes, stroke, or worsening heart failure (43% and 46%). There were also no significant differences favoring either strategy in any predefined subgroup.
CONCLUSIONS: In patients with atrial fibrillation and congestive heart failure, a routine strategy of rhythm control does not reduce the rate of death from cardiovascular causes, as compared with a rate-control strategy. (ClinicalTrials.gov number, NCT00597077.)

2008 Massachusetts Medical Society
PMID 18565859  N Engl J Med. 2008 Jun 19;358(25):2667-77. doi: 10.1056・・・
著者: Carlos A Morillo, Atul Verma, Stuart J Connolly, Karl H Kuck, Girish M Nair, Jean Champagne, Laurence D Sterns, Heather Beresh, Jeffrey S Healey, Andrea Natale, RAAFT-2 Investigators
雑誌名: JAMA. 2014 Feb 19;311(7):692-700. doi: 10.1001/jama.2014.467.
Abstract/Text IMPORTANCE: Atrial fibrillation (AF) is the most common rhythm disorder seen in clinical practice. Antiarrhythmic drugs are effective for reduction of recurrence in patients with symptomatic paroxysmal AF. Radiofrequency ablation is an accepted therapy in patients for whom antiarrhythmic drugs have failed; however, its role as a first-line therapy needs further investigation.
OBJECTIVE: To compare radiofrequency ablation with antiarrhythmic drugs (standard therapy) in treating patients with paroxysmal AF as a first-line therapy.
DESIGN, SETTING, AND PATIENTS: A randomized clinical trial involving 127 treatment-naive patients with paroxysmal AF were randomized at 16 centers in Europe and North America to received either antiarrhythmic therapy or ablation. The first patient was enrolled July 27, 2006; the last patient, January 29, 2010. The last follow-up was February 16, 2012.
INTERVENTIONS: Sixty-one patients in the antiarrhythmic drug group and 66 in the radiofrequency ablation group were followed up for 24 months.
MAIN OUTCOMES AND MEASURES: The time to the first documented atrial tachyarrhythmia of more than 30 seconds (symptomatic or asymptomatic AF, atrial flutter, or atrial tachycardia), detected by either scheduled or unscheduled electrocardiogram, Holter, transtelephonic monitor, or rhythm strip, was the primary outcome. Secondary outcomes included symptomatic recurrences of atrial tachyarrhythmias and quality of life measures assessed by the EQ-5D tool.
RESULTS: Forty-four patients (72.1%) in the antiarrhythmic group and in 36 patients (54.5%) in the ablation group experienced the primary efficacy outcome (hazard ratio [HR], 0.56 [95% CI, 0.35-0.90]; P = .02). For the secondary outcomes, 59% in the drug group and 47% in the ablation group experienced the first recurrence of symptomatic AF, atrial flutter, atrial tachycardia (HR, 0.56 [95% CI, 0.33-0.95]; P = .03). No deaths or strokes were reported in either group; 4 cases of cardiac tamponade were reported in the ablation group. In the standard treatment group, 26 patients (43%) underwent ablation after 1-year. Quality of life was moderately impaired at baseline in both groups and improved at the 1 year follow-up. However, improvement was not significantly different among groups.
CONCLUSIONS AND RELEVANCE: Among patients with paroxysmal AF without previous antiarrhythmic drug treatment, radiofrequency ablation compared with antiarrhythmic drugs resulted in a lower rate of recurrent atrial tachyarrhythmias at 2 years. However, recurrence was frequent in both groups.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00392054.

PMID 24549549  JAMA. 2014 Feb 19;311(7):692-700. doi: 10.1001/jama.201・・・
著者: Douglas L Packer, Daniel B Mark, Richard A Robb, Kristi H Monahan, Tristram D Bahnson, Jeanne E Poole, Peter A Noseworthy, Yves D Rosenberg, Neal Jeffries, L Brent Mitchell, Greg C Flaker, Evgeny Pokushalov, Alexander Romanov, T Jared Bunch, Georg Noelker, Andrey Ardashev, Amiran Revishvili, David J Wilber, Riccardo Cappato, Karl-Heinz Kuck, Gerhard Hindricks, D Wyn Davies, Peter R Kowey, Gerald V Naccarelli, James A Reiffel, Jonathan P Piccini, Adam P Silverstein, Hussein R Al-Khalidi, Kerry L Lee, CABANA Investigators
雑誌名: JAMA. 2019 Apr 2;321(13):1261-1274. doi: 10.1001/jama.2019.0693.
Abstract/Text Importance: Catheter ablation is effective in restoring sinus rhythm in atrial fibrillation (AF), but its effects on long-term mortality and stroke risk are uncertain.
Objective: To determine whether catheter ablation is more effective than conventional medical therapy for improving outcomes in AF.
Design, Setting, and Participants: The Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation trial is an investigator-initiated, open-label, multicenter, randomized trial involving 126 centers in 10 countries. A total of 2204 symptomatic patients with AF aged 65 years and older or younger than 65 years with 1 or more risk factors for stroke were enrolled from November 2009 to April 2016, with follow-up through December 31, 2017.
Interventions: The catheter ablation group (n = 1108) underwent pulmonary vein isolation, with additional ablative procedures at the discretion of site investigators. The drug therapy group (n = 1096) received standard rhythm and/or rate control drugs guided by contemporaneous guidelines.
Main Outcomes and Measures: The primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Among 13 prespecified secondary end points, 3 are included in this report: all-cause mortality; total mortality or cardiovascular hospitalization; and AF recurrence.
Results: Of the 2204 patients randomized (median age, 68 years; 37.2% female; 42.9% had paroxysmal AF and 57.1% had persistent AF), 89.3% completed the trial. Of the patients assigned to catheter ablation, 1006 (90.8%) underwent the procedure. Of the patients assigned to drug therapy, 301 (27.5%) ultimately received catheter ablation. In the intention-to-treat analysis, over a median follow-up of 48.5 months, the primary end point occurred in 8.0% (n = 89) of patients in the ablation group vs 9.2% (n = 101) of patients in the drug therapy group (hazard ratio [HR], 0.86 [95% CI, 0.65-1.15]; P = .30). Among the secondary end points, outcomes in the ablation group vs the drug therapy group, respectively, were 5.2% vs 6.1% for all-cause mortality (HR, 0.85 [95% CI, 0.60-1.21]; P = .38), 51.7% vs 58.1% for death or cardiovascular hospitalization (HR, 0.83 [95% CI, 0.74-0.93]; P = .001), and 49.9% vs 69.5% for AF recurrence (HR, 0.52 [95% CI, 0.45-0.60]; P < .001).
Conclusions and Relevance: Among patients with AF, the strategy of catheter ablation, compared with medical therapy, did not significantly reduce the primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest. However, the estimated treatment effect of catheter ablation was affected by lower-than-expected event rates and treatment crossovers, which should be considered in interpreting the results of the trial.
Trial Registration: ClinicalTrials.gov Identifier: NCT00911508.

PMID 30874766  JAMA. 2019 Apr 2;321(13):1261-1274. doi: 10.1001/jama.2・・・
著者: Daniel B Mark, Kevin J Anstrom, Shubin Sheng, Jonathan P Piccini, Khaula N Baloch, Kristi H Monahan, Melanie R Daniels, Tristram D Bahnson, Jeanne E Poole, Yves Rosenberg, Kerry L Lee, Douglas L Packer, CABANA Investigators
雑誌名: JAMA. 2019 Apr 2;321(13):1275-1285. doi: 10.1001/jama.2019.0692.
Abstract/Text Importance: Catheter ablation is more effective than drug therapy in restoring sinus rhythm in patients with atrial fibrillation (AF), but its incremental effect on long-term quality of life (QOL) is uncertain.
Objective: To determine whether catheter ablation is more beneficial than conventional drug therapy for improving QOL in patients with AF.
Design, Setting, and Participants: An open-label randomized clinical trial of catheter ablation vs drug therapy in 2204 symptomatic patients with AF older than 65 years or 65 years or younger with at least 1 risk factor for stroke. Patients were enrolled from November 2009 to April 2016 from 126 centers in 10 countries. Follow-up ended in December 2017.
Interventions: Pulmonary vein isolation, with additional ablation procedures at the discretion of the investigators, for the catheter ablation group (n = 1108) and standard rhythm and/or rate-control drugs selected and managed by investigators for the drug therapy group (n = 1096).
Main Outcomes and Measures: Prespecified co-primary QOL end points at 12 months, including the Atrial Fibrillation Effect on Quality of Life (AFEQT) summary score (range, 0-100; 0 indicates complete disability and 100 indicates no disability; patient-level clinically important difference, ≥5 points) and the Mayo AF-Specific Symptom Inventory (MAFSI) frequency score (range, 0-40; 0 indicates no symptoms and 40 indicates the most severe symptoms; patient-level clinically important difference, ≤-1.6 points) and severity score (range, 0-30; 0 indicates no symptoms and 30 indicates the most severe symptoms; patient-level clinically important difference, ≤-1.3 points).
Results: Among 2204 randomized patients (median age, 68 years; 1385 patients [63%] were men, 946 [43%] had paroxysmal AF, and 1256 [57%] had persistent AF), the median follow-up was 48.5 months, and 1968 (89%) completed the trial. The mean AFEQT summary score was more favorable in the catheter ablation group than the drug therapy group at 12 months (86.4 points vs 80.9 points) (adjusted difference, 5.3 points [95% CI, 3.7-6.9]; P < .001). The mean MAFSI frequency score was more favorable for the catheter ablation group than the drug therapy group at 12 months (6.4 points vs 8.1 points) (adjusted difference, -1.7 points [95% CI, -2.3 to -1.2]; P < .001) and the mean MAFSI severity score was more favorable for the catheter ablation group than the drug therapy group at 12 months (5.0 points vs 6.5 points) (adjusted difference, -1.5 points [95% CI, -2.0 to -1.1]; P < .001).
Conclusions and Relevance: Among patients with symptomatic atrial fibrillation, catheter ablation, compared with medical therapy, led to clinically important and significant improvements in quality of life at 12 months. These findings can help guide decisions regarding management of atrial fibrillation.
Trial Registration: ClinicalTrials.gov Identifier: NCT00911508.

PMID 30874716  JAMA. 2019 Apr 2;321(13):1275-1285. doi: 10.1001/jama.2・・・
著者: Michiel Rienstra, Anne H Hobbelt, Marco Alings, Jan G P Tijssen, Marcelle D Smit, Johan Brügemann, Bastiaan Geelhoed, Robert G Tieleman, Hans L Hillege, Raymond Tukkie, Dirk J Van Veldhuisen, Harry J G M Crijns, Isabelle C Van Gelder, RACE 3 Investigators
雑誌名: Eur Heart J. 2018 Aug 21;39(32):2987-2996. doi: 10.1093/eurheartj/ehx739.
Abstract/Text Aims: Atrial fibrillation (AF) is a progressive disease. Targeted therapy of underlying conditions refers to interventions aiming to modify risk factors in order to prevent AF. We hypothesised that targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent AF.
Methods and results: We randomized patients with early persistent AF and mild-to-moderate heart failure (HF) to targeted therapy of underlying conditions or conventional therapy. Both groups received causal treatment of AF and HF, and rhythm control therapy. In the intervention group, on top of that, four therapies were started: (i) mineralocorticoid receptor antagonists (MRAs), (ii) statins, (iii) angiotensin converting enzyme inhibitors and/or receptor blockers, and (iv) cardiac rehabilitation including physical activity, dietary restrictions, and counselling. The primary endpoint was sinus rhythm at 1 year during 7 days of Holter monitoring. Of 245 patients, 119 were randomized to targeted and 126 to conventional therapy. The intervention led to a contrast in MRA (101 [85%] vs. 5 [4%] patients, P < 0.001) and statin use (111 [93%] vs. 61 [48%], P < 0.001). Angiotensin converting enzyme inhibitors/angiotensin receptor blockers were not different. Cardiac rehabilitation was completed in 109 (92%) patients. Underlying conditions were more successfully treated in the intervention group. At 1 year, sinus rhythm was present in 89 (75%) patients in the intervention vs. 79 (63%) in the conventional group (odds ratio 1.765, lower limit of 95% confidence interval 1.021, P = 0.042).
Conclusions: RACE 3 confirms that targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent AF.
Trial Registration number: Clinicaltrials.gov NCT00877643.

PMID 29401239  Eur Heart J. 2018 Aug 21;39(32):2987-2996. doi: 10.1093・・・
著者: O D Pedersen, H Bagger, L Kober, C Torp-Pedersen
雑誌名: Circulation. 1999 Jul 27;100(4):376-80.
Abstract/Text BACKGROUND: Studies have suggested that ACE inhibitors have an antiarrhythmic effect on ventricular arrhythmias. Whether they have an effect on atrial fibrillation is unknown.
METHODS AND RESULTS: We investigated the effect of ACE inhibition with trandolapril on the incidence of atrial fibrillation in patients with reduced left ventricular function secondary to acute myocardial infarction. The patients in this study were those who qualified for inclusion into the TRAndolapril Cardiac Evaluation (TRACE) study, a randomized double-blind placebo-controlled study and who had sinus rhythm on the ECG obtained at randomization. Patients who fulfilled the criteria for inclusion were randomized to treatment with the ACE inhibitor trandolapril or placebo and were followed up for 2 to 4 years. Development and time to occurrence of atrial fibrillation in one 12-lead ECG recorded at the outpatient visits was the primary end point of this investigation. Of the 1749 patients included in the TRACE study, 1577 had sinus rhythm on the ECG recorded at randomization. Of these patients, 790 were randomized to trandolapril treatment and 787 to placebo treatment. The groups differed only slightly with respect to baseline characteristics. A total of 64 patients developed atrial fibrillation during the 2- to 4-year follow-up period. Significantly more patients developed atrial fibrillation in the placebo group than in the trandolapril group, 5.3% (n=42) versus 2.8% (n=22), respectively, P<0.05. Cox multivariable regression analysis, adjusting for important baseline characteristics, revealed that trandolapril treatment significantly reduced the risk of developing atrial fibrillation (RR, 0.45; 95% CI, 0.26 to 0.76; P<0.01).
CONCLUSIONS: The results from the present study demonstrate that trandolapril treatment reduces the incidence of atrial fibrillation in patients with left ventricular dysfunction after acute myocardial infarction.

PMID 10421597  Circulation. 1999 Jul 27;100(4):376-80.
著者: Emmanuelle Vermes, Jean-Claude Tardif, Martial G Bourassa, Normand Racine, Sylvie Levesque, Michel White, Peter G Guerra, Anique Ducharme
雑誌名: Circulation. 2003 Jun 17;107(23):2926-31. doi: 10.1161/01.CIR.0000072793.81076.D4. Epub 2003 May 27.
Abstract/Text BACKGROUND: Atrial fibrillation (AF) is frequently encountered in patients with heart failure (HF) and is also a predictor of morbidity and mortality in this population. Recent experimental studies have shown electrical and structural atrial remodeling with increased fibrosis in animals with HF and have suggested a preventive effect of ACE inhibitors (ACEi) on the development of AF. To verify the hypothesis that ACEi prevent the development of AF in patients with HF, we conducted a retrospective analysis of the patients from the Montreal Heart Institute (MHI) included in the Studies Of Left Ventricular Dysfunction (SOLVD).
METHODS AND RESULTS: Clinical charts were reviewed and serial ECGs interpreted by a single cardiologist blinded to drug allocation. Patients with AF or flutter on the baseline ECG were excluded. Baseline characteristics were obtained from the SOLVD databases. The mean follow-up was 2.9+/-1.0 years. Of the 391 patients randomly assigned at MHI, 374 were in sinus rhythm at the time of random assignment, with 186 taking enalapril and 188 taking placebo. Baseline characteristics were similar in the two groups except for a higher incidence of previous myocardial infarction in the enalapril group. Fifty-five patients had AF during the follow-up: 10 (5.4%) in the enalapril group and 45 (24%) in the placebo group (P<0.0001). By Cox multivariate analysis, enalapril was the most powerful predictor for risk reduction of AF (hazard ratio, 0.22; 95% CI, 0.11 to 0.44; P<0.0001).
CONCLUSIONS: Treatment with the ACEi enalapril markedly reduces the risk of development of atrial fibrillation in patients with left ventricular dysfunction.

PMID 12771010  Circulation. 2003 Jun 17;107(23):2926-31. doi: 10.1161/・・・
著者: Aldo P Maggioni, Roberto Latini, Peter E Carson, Steven N Singh, Simona Barlera, Robert Glazer, Serge Masson, Elisabetta Cerè, Gianni Tognoni, Jay N Cohn, Val-HeFT Investigators
雑誌名: Am Heart J. 2005 Mar;149(3):548-57. doi: 10.1016/j.ahj.2004.09.033.
Abstract/Text BACKGROUND: Atrial fibrillation (AF) in heart failure (HF) is generally considered a negative prognostic factor. Recent studies indicate that the incidence of AF might be decreased by renin angiotensin aldosterone system inhibitors. The identification of a treatment to prevent its occurrence is likely to improve patients outcome. The aims of these subanalyses of Val-HeFT were to assess (a) the effects of valsartan in the prevention of AF, (b) the independent predictors of this event, and (c) the prognostic role of AF occurrence.
METHODS AND RESULTS: The occurrence of AF was evaluated based on adverse event reports in the patients with HF enrolled in Val-HeFT. Patients were randomized to valsartan or placebo on top of their prescribed treatments for HF. During the mean 23 months of follow-up, AF was reported in 287/4395 patients (6.53%) in sinus rhythm at baseline, of whom 113/2205 (5.12%) were allocated to valsartan and 174/2190 (7.95%) to placebo (P = .0002). Multivariable analysis showed that brain natriuretic peptide (BNP) levels at baseline above the median value (HR 2.28, 95% CI 1.75-2.98), age over 70 years (HR 1.51, 95% CI 1.17-1.95), male sex (HR 1.53, 95% CI 1.07-2.18), and the valsartan treatment (HR 0.63, 95% CI 0.49-0.81) were independently associated with AF occurrence. Cox multivariable regression analysis showed that occurrence of AF was independently associated with a worse prognosis, with the adjusted hazard risks for all-cause mortality and combined mortality/morbidity of 1.40 (95% CI 1.16-1.58) and 1.38 (95% CI 1.12-1.70), respectively.
CONCLUSIONS: The results of the present study demonstrate that (a) adding valsartan to prescribed therapy for HF significantly reduces the incidence of AF by 37%; (b) BNP level and advanced age were the strongest independent predictors for AF occurrence; and (c) AF occurrence further worsens the outcome in patients with HF.

PMID 15864246  Am Heart J. 2005 Mar;149(3):548-57. doi: 10.1016/j.ahj.・・・
著者: Anique Ducharme, Karl Swedberg, Marc A Pfeffer, Alain Cohen-Solal, Christopher B Granger, Aldo P Maggioni, Eric L Michelson, John J V McMurray, Lars Olsson, Jean L Rouleau, James B Young, Bertil Olofsson, Margareta Puu, Salim Yusuf, CHARM Investigators
雑誌名: Am Heart J. 2006 Jul;152(1):86-92.
Abstract/Text BACKGROUND: Atrial fibrillation (AF) is frequent in patients with chronic heart failure (CHF). Experimental and small patient studies have demonstrated that blocking the renin-angiotensin-aldosterone system may prevent AF. In the CHARM program, the effects of the angiotensin receptor blocker candesartan on cardiovascular mortality and morbidity were evaluated in a broad spectrum of patients with symptomatic CHF. CHARM provided the opportunity to prospectively determine the effect of candesartan on the incidence of new AF in this CHF population.
METHODS: 7601 patients with symptomatic CHF and reduced or preserved left ventricular systolic function were randomized to candesartan (target dose 32 mg once daily, mean dose 24 mg) or placebo in the 3 component trials of CHARM. The major outcomes were cardiovascular death or CHF hospitalization and all-cause mortality. The incidence of new AF was a prespecified secondary outcome. Median follow-up was 37.7 months. A conditional logistic regression model for stratified data was used.
RESULTS: 6379 patients (83.9%) did not have AF on their baseline electrocardiogram. Of these, 392 (6.15%) developed AF during follow-up, 177 (5.55%) in the candesartan group and 215 (6.74%) in the placebo group (odds ratio 0.812, 95% CI 0.662-0.998, P = .048). After adjustment for baseline covariates, the odds ratio was 0.802 (95% CI 0.650-0.990, P = .039). There was no heterogeneity of the effects of candesartan in preventing AF between the 3 component trials (P = .57).
CONCLUSIONS: Treatment with the angiotensin receptor blocker candesartan reduced the incidence of AF in a large, broadly-based, population of patients with symptomatic CHF.

PMID 16838426  Am Heart J. 2006 Jul;152(1):86-92.
著者: Klaus Kettering, Christian Mewis, Volker Dörnberger, Reinhard Vonthein, Ralph F Bosch, Volker Kühlkamp
雑誌名: Pacing Clin Electrophysiol. 2002 Nov;25(11):1571-6. doi: 10.1046/j.1460-9592.2002.01571.x.
Abstract/Text ICDs provide protection against sudden cardiac death in patients with life-threatening ventricular arrhythmias. Nevertheless, most ICD recipients receive adjunctive antiarrhythmic drug therapy to reduce the number of recurrent episodes and ICD discharges. The aim of the study was to compare the efficacy of metoprolol and d,l-sotalol in preventing VT/VF recurrences in patients with an ICD in a prospective, randomized trial. One hundred patients (83 men, 17 women; mean age 59 years, SD +/- 11 years) were randomized to receive metoprolol or sotalol after implantation of an ICD. There were no significant differences between the two groups with regard to age, sex, underlying cardiac disease, left ventricular ejection fraction, NYHA class assessment and clinical arrhythmia. The median follow-up was 728 days (25th percentile: 530 days, 75th percentile: 943 days) in the metoprolol group and 727 days (25th percentile: 472 days, 75th percentile: 1,223 days) in the sotalol group (P = 0.52). Thirty-three patients treated with metoprolol and 30 patients receiving sotalol had at least one episode during the follow-up. Event-free survival curves were generated for the two treatment arms using the Kaplan-Meier method and showed no significant difference (P = 0.68). Eight patients treated with metoprolol and six patients treated with sotalol died during follow-up. Total mortality was not significantly different between the two study groups (P = 0.43). Metoprolol is as efficacious as sotalol in preventing VT/VF recurrences in patients with an ICD.

PMID 12494613  Pacing Clin Electrophysiol. 2002 Nov;25(11):1571-6. doi・・・
著者: Jonathan P Piccini, Jeffrey S Berger, Christopher M O'Connor
雑誌名: Eur Heart J. 2009 May;30(10):1245-53. doi: 10.1093/eurheartj/ehp100. Epub 2009 Mar 31.
Abstract/Text AIMS: Not all patients at risk for sudden cardiac death (SCD) are eligible for, or have access to implantable cardioverter defibrillator (ICD) implantation. There are conflicting data regarding the efficacy and safety of amiodarone for the prevention of SCD.
METHODS AND RESULTS: We conducted a meta-analysis of all randomized controlled trials examining the use of amiodarone vs. placebo/control for the prevention of SCD. We identified 15 trials, which randomized 8522 patients to amiodarone or placebo/control. Amiodarone decreased the incidence of SCD [7.1 vs. 9.7%; OR 0.71 (0.61-0.84), P < 0.001] and cardiovascular death (CVD) [14.0 vs. 16.3%; OR 0.82 (0.71-0.94), P = 0.004]. There was a 1.5% absolute risk reduction in all-cause mortality which did not meet statistical significance (P = 0.093). Amiodarone therapy increased the risk of pulmonary [2.9 vs. 1.5%; OR 1.97, (1.27-3.04), P = 0.002], and thyroid [3.6 vs. 0.4%; OR 5.68, (2.94-10.98), P < 0.001] toxicity.
CONCLUSION: Amiodarone reduces the risk of SCD by 29% and CVD by 18%, and therefore, represents a viable alternative in patients who are not eligible for or who do not have access to ICD therapy for the prevention of SCD. However, amiodarone therapy is neutral with respect to all-cause mortality and is associated with a two- and five-fold increased risk of pulmonary and thyroid toxicity.

PMID 19336434  Eur Heart J. 2009 May;30(10):1245-53. doi: 10.1093/eurh・・・
著者: J W Mason
雑誌名: N Engl J Med. 1993 Aug 12;329(7):445-51. doi: 10.1056/NEJM199308123290701.
Abstract/Text BACKGROUND: Invasive electrophysiologic study and noninvasive Holter monitoring (in conjunction with exercise testing) have both been used to evaluate the efficacy of antiarrhythmic drugs in patients with sustained ventricular tachycardia and in survivors of cardiac arrest. We directly compared these two approaches to the prediction of drug efficacy.
METHODS: A total of 486 patients who had documented ventricular tachyarrhythmias that were inducible during electrophysiologic study and 10 or more premature ventricular complexes per hour during Holter monitoring were randomly assigned to undergo serial testing of antiarrhythmic-drug efficacy by electrophysiologic study or Holter monitoring. The patients received up to six drugs in random order until one was predicted to be effective either in suppressing inducible arrhythmia (in the electrophysiologic-study group) or in suppressing premature ventricular complexes (in the Holter-monitoring group). The patients were then followed for recurrences of arrhythmia or death.
RESULTS: In the electrophysiologic-study group, 108 of 242 patients (45 percent) received a prediction of efficacy, as compared with 188 of 244 patients (77 percent) in the Holter-monitoring group (P < 0.001). Over a six-year follow-up period, there were 150 recurrences of arrhythmia and 46 deaths among the 296 patients receiving drugs predicted to be effective. Thirty-four of the deaths were from arrhythmic causes, and eight were from cardiac causes. There was no significant difference between the two study groups in the actuarial probabilities of these events. The risk of a recurrence of arrhythmia was significantly lower in patients who received sotalol than in those who received other antiarrhythmic drugs, and the risk was lower in those who had not previously failed to respond to antiarrhythmic drugs than in those who had.
CONCLUSIONS: Although Holter monitoring led to predictions of antiarrhythmic-drug efficacy more often than did electrophysiologic study in patients with sustained ventricular tachyarrhythmias, there was no significant difference in the success of drug therapy as selected by the two methods.

PMID 8332149  N Engl J Med. 1993 Aug 12;329(7):445-51. doi: 10.1056/N・・・
著者: Takeshi Aiba, Kenichiro Yamagata, Wataru Shimizu, Atsushi Taguchi, Kazuhiro Satomi, Takashi Noda, Hideo Okamura, Kazuhiro Suyama, Naohiko Aihara, Shiro Kamakura, Takashi Kurita
雑誌名: Circ J. 2008 Jan;72(1):88-93. doi: 10.1253/circj.72.88.
Abstract/Text BACKGROUND: Although an electrophysiologic study (EPS) and Holter-monitoring are often helpful in evaluating the efficacy of antiarrhythmic drugs in patients with ventricular tachyarrhythmias (ventricular tachycardia/fibrillation (VT/VF)), the efficacy of EPS- or Holter-guided oral amiodarone therapy in Japanese patients is still unclear.
METHODS AND RESULTS: EPS was performed 1 month after starting amiodarone, and Holter-monitoring was recorded before and 1 month after amiodarone in 188 patients with sustained VT/VF because of structural heart diseases. In spite of the judgment of EPS (n=89) or Holter (n=75), all patients continued amiodarone. Patients were followed up to 3 years and the primary endpoint was VT/VF recurrence and secondary endpoint was death by all cause. Kaplan-Meier estimated the risk of VT/VF recurrence was significantly smaller with EPS-guided amiodarone (p<0.01) but not with Holter-guided amiodarone. Multivariate Cox hazard analysis revealed that EPS-guided amiodarone was an independent factor suppressing the recurrence of VT/VF (p<0.05, 95% confidence interval =0.15 to 0.96). In the subgroup analysis, EPS-guided amiodarone was effective in patients with relatively well-preserved left ventricular ejection fraction (LVEF > or =0.30) but not in patients with lower LVEF (LVEF <0.30).
CONCLUSION: EPS-guided amiodarone was useful for preventing recurrence of VT/VF in patients with a relatively well-preserved LVEF, but not always beneficial in patients with a lower LVEF.

PMID 18159106  Circ J. 2008 Jan;72(1):88-93. doi: 10.1253/circj.72.88.・・・
著者: Karl-Heinz Kuck, Josep Brugada, Alexander Fürnkranz, Andreas Metzner, Feifan Ouyang, K R Julian Chun, Arif Elvan, Thomas Arentz, Kurt Bestehorn, Stuart J Pocock, Jean-Paul Albenque, Claudio Tondo, FIRE AND ICE Investigators
雑誌名: N Engl J Med. 2016 Jun 9;374(23):2235-45. doi: 10.1056/NEJMoa1602014. Epub 2016 Apr 4.
Abstract/Text BACKGROUND: Current guidelines recommend pulmonary-vein isolation by means of catheter ablation as treatment for drug-refractory paroxysmal atrial fibrillation. Radiofrequency ablation is the most common method, and cryoballoon ablation is the second most frequently used technology.
METHODS: We conducted a multicenter, randomized trial to determine whether cryoballoon ablation was noninferior to radiofrequency ablation in symptomatic patients with drug-refractory paroxysmal atrial fibrillation. The primary efficacy end point in a time-to-event analysis was the first documented clinical failure (recurrence of atrial fibrillation, occurrence of atrial flutter or atrial tachycardia, use of antiarrhythmic drugs, or repeat ablation) following a 90-day period after the index ablation. The noninferiority margin was prespecified as a hazard ratio of 1.43. The primary safety end point was a composite of death, cerebrovascular events, or serious treatment-related adverse events.
RESULTS: A total of 762 patients underwent randomization (378 assigned to cryoballoon ablation and 384 assigned to radiofrequency ablation). The mean duration of follow-up was 1.5 years. The primary efficacy end point occurred in 138 patients in the cryoballoon group and in 143 in the radiofrequency group (1-year Kaplan-Meier event rate estimates, 34.6% and 35.9%, respectively; hazard ratio, 0.96; 95% confidence interval [CI], 0.76 to 1.22; P<0.001 for noninferiority). The primary safety end point occurred in 40 patients in the cryoballoon group and in 51 patients in the radiofrequency group (1-year Kaplan-Meier event rate estimates, 10.2% and 12.8%, respectively; hazard ratio, 0.78; 95% CI, 0.52 to 1.18; P=0.24).
CONCLUSIONS: In this randomized trial, cryoballoon ablation was noninferior to radiofrequency ablation with respect to efficacy for the treatment of patients with drug-refractory paroxysmal atrial fibrillation, and there was no significant difference between the two methods with regard to overall safety. (Funded by Medtronic; FIRE AND ICE ClinicalTrials.gov number, NCT01490814.).

PMID 27042964  N Engl J Med. 2016 Jun 9;374(23):2235-45. doi: 10.1056/・・・
著者: G Borea, L Montebugnoli, P Capuzzi, C Magelli
雑誌名: Oral Surg Oral Med Oral Pathol. 1993 Jan;75(1):29-31. doi: 10.1016/0030-4220(93)90401-o.
Abstract/Text A double-blind randomized study was carried out to evaluate the clinical hemostatic effect of tranexamic acid mouthwash after dental extraction in 30 patients who received anticoagulant agents. Surgery was performed with a reduction in the level of anticoagulant therapy in the control group and with no change in the level of anticoagulant therapy in the group who received the tranexamic acid. After the extraction the surgical field was irrigated with a 5% solution of tranexamic acid in the group of 15 patients whose anticoagulant treatment had not been discontinued and with a placebo solution in the group of 15 patients for whom the anticoagulant therapy was reduced. Patients were instructed to rinse their mouths with 10 ml of the assigned solution for 2 minutes four times a day for 7 days. There was no significant difference between the two treatment groups in the bleeding incidence after oral surgery. We conclude that the anticoagulant treatment does not need to be withdrawn before oral surgery provided that local antifibrinolytic therapy is instituted.

PMID 8419869  Oral Surg Oral Med Oral Pathol. 1993 Jan;75(1):29-31. d・・・
著者: I L Evans, M S Sayers, A J Gibbons, G Price, H Snooks, A W Sugar
雑誌名: Br J Oral Maxillofac Surg. 2002 Jun;40(3):248-52. doi: 10.1054/bjom.2001.0773.
Abstract/Text A randomized controlled trial was set up to investigate whether patients who were taking warfarin and had an International Normalised Ratio (INR) within the normal therapeutic range require cessation of their anticoagulation drugs before dental extractions. Of 109 patients who completed the trial, 52 were allocated to the control group (warfarin stopped 2 days before extraction) and 57 patients were allocated to the intervention group (warfarin continued). The incidence of bleeding complications in the intervention group was higher (15/57, 26%) than in the control group (7/52, 14%) but this difference was not significant. Two patients in the study required hospital review for bleeding and all other episodes of bleeding were controlled by patients at home. Continuing warfarin when the INR is < 4.1 may lead to an increase in minor post-extraction bleeding after dental extractions but we found no evidence of an increase in clinically important bleeding. As there are risks associated with stopping warfarin, the practice of routinely discontinuing it before dental extractions should be reconsidered.

Copyright 2002 The British Association of Oral and Maxillofacial Surgeons.
PMID 12054719  Br J Oral Maxillofac Surg. 2002 Jun;40(3):248-52. doi: ・・・
著者: S Al-Mubarak, N Al-Ali, M Abou-Rass, A Al-Sohail, A Robert, K Al-Zoman, A Al-Suwyed, S Ciancio
雑誌名: Br Dent J. 2007 Oct 13;203(7):E15; discussion 410-1. doi: 10.1038/bdj.2007.725. Epub 2007 Aug 10.
Abstract/Text OBJECTIVES: To examine the consequences of temporary withdrawal of warfarin and/or suturing on bleeding and healing pattern following dental extractions.
METHODS: Two hundred and fourteen patients on long-term oral anticoagulation (warfarin) therapy scheduled for dental extraction were randomly divided into four groups: no suturing and discontinued (group 1) or continued warfarin (group 2), and suturing and discontinued (group 3) or continued warfarin (group 4). International normalised ratio (INR) was determined at different time points (baseline, days 1, 3 and 7).
RESULTS: Discontinuing warfarin reduced INR level significantly at day 1, which subsequently reached <1.5 in 96 out of 104 patients (group 1 and 3). Statistical comparisons among the different treatment groups did not reveal any significant difference regarding bleeding status or healing pattern. Interestingly, patients who received sutures showed higher but insignificant incidence of bleeding postoperatively compared to their respective controls.
CONCLUSION: Dental extractions may be safely performed for patients on anticoagulation therapy provided the INR level is kept <3.0 and effective measures of local haemostasis are administered. The decision to suture should be made on case-by-case basis, as the trauma associated with soft tissue handling might outweigh its advantages in certain situations like simple extractions.

PMID 17694045  Br Dent J. 2007 Oct 13;203(7):E15; discussion 410-1. do・・・
著者: R Sacco, M Sacco, M Carpenedo, P M Mannucci
雑誌名: Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 Jul;104(1):e18-21. doi: 10.1016/j.tripleo.2006.12.035. Epub 2007 May 7.
Abstract/Text OBJECTIVE: To evaluate whether or not it is possible to perform oral surgery in patients on oral anticoagulant therapy (OAT) without stopping treatment.
STUDY DESIGN: A prospective randomized open-label study was designed to evaluate the outcome of oral surgery in patients on OAT, operated upon in conditions of reduced international normalized ratio (INR), compared with patients maintained in their usual therapeutic ranges of the prothrombin time INR. The INR target in the group with reduced OAT was 1.8, and the INR target of the group without reduced OAT was 2.5 or more in carriers of artificial valves.
RESULTS: One hundred thirty-one patients on OAT were randomized to reduced anticoagulation or to full anticoagulation, and 511 teeth were extracted by the same surgeon. Mild bleeding, but excessive enough to warrant adoption of supplementary local hemostatic measures, was observed in 10 cases (15.1%) in the reduced dosage group and in 6 cases (9.2%) in the unmodified dosage group, which was a nonsignificant difference. There were no thrombotic complications in either group.
CONCLUSIONS: This randomized study shows that, using simple measures for local hemostasis, it is not necessary to reduce OAT in patients undergoing routine dental extractions.

PMID 17482846  Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 ・・・
著者: Adeela Nematullah, Abdullah Alabousi, Nick Blanas, James D Douketis, Susan E Sutherland
雑誌名: J Can Dent Assoc. 2009 Feb;75(1):41.
Abstract/Text PURPOSE: To evaluate the effect of continuing warfarin therapy on the bleeding risk of patients undergoing elective dental surgical procedures.
METHODS: Data sources were the MEDLINE and EMBASE databases, the Cochrane Central Register of Controlled Trials, a manual citation review of the relevant literature, content experts and relevant abstracts from the proceedings of the International Association for Dental Research. Study selection was carried out independently by 2 reviewers, as was quality assessment. Data extraction was done by 3 reviewers. Differences were resolved by consensus. Eligible studies were randomized controlled trials that compared the effects of continuing the regular dose of warfarin therapy with the effects of discontinuing or modifying the dose on the incidence of bleeding in patients undergoing dental procedures.
RESULTS: Five trials (a total of 553 patients) met the inclusion criteria. Compared with interrupting warfarin therapy (either partial or complete), perioperative continuation of warfarin with patients" usual dose was not associated with an increased risk for clinically significant nonmajor bleeding (relative risk [RR], 0.71; 95% confidence interval [CI]: 0.39-1.28; p = 0.65; I2 = 0%) or an increased risk for minor bleeding (RR, 1.19; 95% CI: 0.90-1.58; p = 0.22; I2 = 0%).
CONCLUSIONS: Continuing the regular dose of warfarin therapy does not seem to confer an increased risk of bleeding compared with discontinuing or modifying the warfarin dose for patients undergoing minor dental procedures.

PMID 19239742  J Can Dent Assoc. 2009 Feb;75(1):41.
著者: M J Wahl
雑誌名: Arch Intern Med. 1998 Aug 10-24;158(15):1610-6.
Abstract/Text Continuous oral anticoagulant therapy has been used to decrease the risk of thromboembolism for more than half a century, prolonging the lives of thousands of patients. Many physicians recommend interrupting continuous anticoagulant therapy for dental surgery to prevent hemorrhage. In reviewing the available literature, there are no well-documented cases of serious bleeding problems from dental surgery in patients receiving therapeutic levels of continuous warfarin sodium therapy, but there were several documented cases of serious embolic complications in patients whose warfarin therapy was withdrawn for dental treatment. Many authorities state that dental extractions can be performed with minimal risk in patients who are at or above therapeutic levels of anticoagulation. There are sound legal reasons to continue therapeutic levels of warfarin for dental treatment. Although there is a theoretical risk of hemorrhage after dental surgery in patients who are at therapeutic levels of anticoagulation, the risk appears to be minimal, the bleeding usually can be easily treated with local measures, and this risk may be greatly outweighed by the risk of thromboembolism after withdrawal of anticoagulant therapy.

PMID 9701094  Arch Intern Med. 1998 Aug 10-24;158(15):1610-6.
著者: Jeff S Healey, John Eikelboom, James Douketis, Lars Wallentin, Jonas Oldgren, Sean Yang, Ellison Themeles, Hein Heidbuchel, Hein Heidbuchle, Alvaro Avezum, Paul Reilly, Stuart J Connolly, Salim Yusuf, Michael Ezekowitz, RE-LY Investigators
雑誌名: Circulation. 2012 Jul 17;126(3):343-8. doi: 10.1161/CIRCULATIONAHA.111.090464. Epub 2012 Jun 14.
Abstract/Text BACKGROUND: Dabigatran reduces ischemic stroke in comparison with warfarin; however, given the lack of antidote, there is concern that it might increase bleeding when surgery or invasive procedures are required.
METHODS AND RESULTS: The current analysis was undertaken to compare the periprocedural bleeding risk of patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial treated with dabigatran and warfarin. Bleeding rates were evaluated from 7 days before until 30 days after invasive procedures, considering only the first procedure for each patient. A total of 4591 patients underwent at least 1 invasive procedure: 24.7% of patients received dabigatran 110 mg, 25.4% received dabigatran 150 mg, and 25.9% received warfarin, P=0.34. Procedures included: pacemaker/defibrillator insertion (10.3%), dental procedures (10.0%), diagnostic procedures (10.0%), cataract removal (9.3%), colonoscopy (8.6%), and joint replacement (6.2%). Among patients assigned to either dabigatran dose, the last dose of study drug was given 49 (35-85) hours before the procedure on comparison with 114 (87-144) hours in patients receiving warfarin, P<0.001. There was no significant difference in the rates of periprocedural major bleeding between patients receiving dabigatran 110 mg (3.8%) or dabigatran 150 mg (5.1%) or warfarin (4.6%); dabigatran 110 mg versus warfarin: relative risk, 0.83; 95% CI, 0.59 to 1.17; P=0.28; dabigatran 150 mg versus warfarin: relative risk, 1.09; 95% CI, 0.80 to 1.49; P=0.58. Among patients having urgent surgery, major bleeding occurred in 17.8% with dabigatran 110 mg, 17.7% with dabigatran 150 mg, and 21.6% with warfarin: dabigatran 110 mg; relative risk, 0.82; 95% CI, 0.48 to 1.41; P=0.47; dabigatran 150 mg: relative risk, 0.82; 95% CI, 0.50 to 1.35; P=0.44.
CONCLUSIONS: Dabigatran and warfarin were associated with similar rates of periprocedural bleeding, including patients having urgent surgery. Dabigatran facilitated a shorter interruption of oral anticoagulation.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

PMID 22700854  Circulation. 2012 Jul 17;126(3):343-8. doi: 10.1161/CIR・・・
著者: H Yoshikawa, M Yoshida, M Yasaka, H Yoshida, Y Murasato, D Fukunaga, A Shintani, Y Okada
雑誌名: Int J Oral Maxillofac Surg. 2019 Aug;48(8):1102-1108. doi: 10.1016/j.ijom.2019.01.013. Epub 2019 Feb 8.
Abstract/Text The aim of this study was to compare the safety of tooth extraction in patients receiving direct oral anticoagulants (DOACs) or warfarin without cessation of their antithrombotic treatment. This prospective observational study included 367 patients undergoing tooth extraction (119 receiving DOACs and 248 receiving warfarin). All extractions in DOAC patients were performed 6-7h after taking DOACs in consideration of the half-life in blood under continued antithrombotic treatment. To examine the potential postoperative bleeding risk related to the time of extraction and the drug concentration of blood, activated partial thromboplastin time (APTT) in dabigatran and prothrombin time (PT) in rivaroxaban were measured three times after administration. A total of 390 tooth extractions were performed: 128 in the DOAC patients and 262 in warfarin patients. Postoperative bleeding occurred in four extractions (3.1%) in the DOAC group and in 23 (8.8%) in the warfarin group. There was no statistically significant difference between the two groups (odds ratio: 2.362, 95% confidence interval (CI) 0.819-6.815, p=0.112). APTT and PT prolongation in almost all cases decreased with time after taking the medicine. Our findings suggest that interruption of DOAC therapy is not necessary for tooth extraction if the procedure is performed at least 6h after the last dose.

Copyright © 2019 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
PMID 30745243  Int J Oral Maxillofac Surg. 2019 Aug;48(8):1102-1108. d・・・
著者: David J Blacker, Eelco F M Wijdicks, Robyn L McClelland
雑誌名: Neurology. 2003 Oct 14;61(7):964-8. doi: 10.1212/01.wnl.0000086817.54076.eb.
Abstract/Text OBJECTIVE: To determine the risk of stroke in anticoagulated patients with atrial fibrillation (AF) when anticoagulation is adjusted for bronchoscopy, gastroscopy, or colonoscopy, and to identify factors that could modify this risk.
METHODS: The authors reviewed patients with AF undergoing endoscopies between 1995 and 2001, with specific analysis of patients with AF in whom anticoagulation was adjusted for the procedures. The authors calculated the stroke rate within 30 days of the procedures.
RESULTS: Twelve strokes occurred in 987 patients undergoing 1,137 procedures (1.06%/procedure). The risk ranged from 0.31% for patients with nonvalvular AF undergoing routine procedures to 2.93% for complex patients undergoing endoscopies combined with other procedures or with comorbid illnesses. Patients with stroke were more likely to be complex (7/12 vs 219/975, p = 0.04); to be older than 80 years (6/12 vs 187/975, p = 0.017); to have a history of stroke (7/12 vs 194/975, p = 0.004), hypertension (10/12 vs 508/975, p = 0.04), or hyperlipidemia (9/12 vs 334/975, p = 0.005); or to have a family history of vascular disease (10/12 vs 502/975, p = 0.039).
CONCLUSIONS: The risk of stroke in patients with AF whose anticoagulation is adjusted for endoscopies is low, but almost tenfold higher in patients with complex clinical situations. Age, history of stroke, hypertension, hyperlipidemia, and family history of vascular disease may increase the risk of stroke.

PMID 14557569  Neurology. 2003 Oct 14;61(7):964-8. doi: 10.1212/01.wnl・・・
著者: Lauren B Gerson, LeAnn Michaels, Nighat Ullah, Brian Gage, Luke Williams
雑誌名: Gastrointest Endosc. 2010 Jun;71(7):1211-1217.e2. doi: 10.1016/j.gie.2009.12.054.
Abstract/Text BACKGROUND: Chronic anticoagulation has been demonstrated to be a risk factor for GI bleeding (GIB) in patients undergoing endoscopic procedures.
OBJECTIVE: The aim of this study was to determine the incidence of GIB prospectively in a large cohort of patients enrolled in the Clinical Outcomes Research Initiative (CORI) database.
DESIGN: Anticoagulated patients undergoing endoscopic procedures were interviewed by phone 30 to 45 days after the procedure to determine potential adverse events and management of warfarin therapy in the periendoscopic period.
SETTING: Participating CORI sites, Stanford University Hospital, Veterans Administration Palo Alto Health Care System.
MAIN OUTCOME MEASUREMENT: Postprocedural hemorrhagic or thrombotic events.
RESULTS: Thirteen CORI sites agreed to participate, including 120,886 procedures in 95,807 patients. We contacted 929 patients on warfarin therapy and enrolled 483 patients (52%). The majority of the patients were men with atrial fibrillation undergoing colonoscopy. Warfarin was temporarily suspended in 437 (90%) of the patients before the procedure, and 114 (22%) received periprocedural heparin therapy. There were 10 major hemorrhagic events (2%), and the rate of hemorrhage was not higher in the patients receiving periprocedural heparin therapy (P = .1). However, polypectomy was a risk factor for postprocedural hemorrhage (P = .02). One fatal stroke (0.2%) occurred in a patient 2 weeks after endoscopy; however, information regarding warfarin management was not available.
LIMITATIONS: Small number of enrolled patients and lack of control group. Lack of information regarding prothrombin time before procedure, concurrent antiplatelet agents, and timing of bleeding in 50% of the cases. The study was underpowered to definitively conclude benefits of current guidelines regarding thrombosis or bleeding.
CONCLUSIONS: Postprocedural hemorrhagic events were not increased in anticoagulated patients. Most patients receiving bridging therapy were managed according to current society guidelines.

Copyright 2010 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.
PMID 20598248  Gastrointest Endosc. 2010 Jun;71(7):1211-1217.e2. doi: ・・・
著者: Katsuhiro Mabe, Mototsugu Kato, Koji Oba, Soichi Nakagawa, Hideyuki Seki, Shinichi Katsuki, Kentaro Yamashita, Shoko Ono, Yuichi Shimizu, Naoya Sakamoto, Sapporo Consensus Study Group
雑誌名: J Gastroenterol. 2017 Jan;52(1):50-60. doi: 10.1007/s00535-016-1203-3. Epub 2016 Apr 16.
Abstract/Text BACKGROUND: The management of antithrombotic agents for endoscopic procedures has recently focused on preventing periprocedural thrombosis in Western countries. However, this focus on shorter cessation of antithrombotic agents needs to be examined for its implications for post-procedural bleeding, with potential risk factors for such bleeding clarified in real-world clinical settings in Japan.
METHODS: A Sapporo consensus group convened and developed a consensus document on the criteria for cessation of antithrombotic agents. In the multicenter, prospective, observational study that followed to validate the criteria in a real-world clinical setting, of all patients ≥20 years of age receiving antithrombotic agents and undergoing endoscopic procedures, all consenting patients were enrolled. All participating facilities were followed up on their adherence to the criteria and clinical outcomes, such as the occurrence of post-procedural bleeding and thrombosis.
RESULTS: A total of 5250 patients, who accounted for 6944 endoscopic procedures, were enrolled from 19 study sites. The consensus criteria, which proved to be nearly consistent with the JSGE criteria revised in 2012, had been adhered to in a total of 6531 procedures performed in 4921 patients. Bleeding and thrombosis were reported in 53 (0.76 %) and two (0.03 %) patients, respectively, among those receiving antithrombotic agents. Post-procedural bleeding was significantly associated with high-bleeding-risk procedures, a high thromboembolic risk with heparin bridging, and the presence of renal failure/dialysis.
CONCLUSIONS: With the new criteria in place for cessation of antithrombotic agents focused on prevention of periprocedural thrombosis, endoscopic procedures may be safely performed without substantially increasing bleeding in clinical practice in Japan.

PMID 27085338  J Gastroenterol. 2017 Jan;52(1):50-60. doi: 10.1007/s00・・・
著者: Glenn M Eisen, Todd H Baron, Jason A Dominitz, Douglas O Faigel, Jay L Goldstein, John F Johanson, J Shawn Mallery, Hareth M Raddawi, John J Vargo, J Patrick Waring, Robert D Fanelli, Jo Wheeler-Harbough, American Society for Gastrointestinal Endoscopy
雑誌名: Gastrointest Endosc. 2002 Jun;55(7):775-9. doi: 10.1016/s0016-5107(02)70402-1.
Abstract/Text This is one of a series of statements discussing the practice of gastrointestinal endoscopy in common clinical situations. It is intended to aid endoscopists in determining the appropriate use of endoscopic procedures in conjunction with anticoagulation and/or antiplatelet therapy. Guidelines for the appropriate practice of endoscopy are based on critical review of the available data and expert consensus. Controlled clinical studies would be beneficial to clarify some aspects of this statement and revision might be necessary as new data appear. Clinical consideration may justify a course of action at variance from these specific recommendations.

PMID 12024126  Gastrointest Endosc. 2002 Jun;55(7):775-9. doi: 10.1016・・・
著者: Axel Hittelet, Jacques Devière
雑誌名: Can J Gastroenterol. 2003 May;17(5):329-32. doi: 10.1155/2003/182398.
Abstract/Text The risk of procedure-related bleeding while taking anticoagulants needs to be weighed against the risk of thromboembolism from discontinuing these drugs. It is not necessary to adjust anticoagulation for low-risk procedures, such as upper endoscopy with biopsy, colonoscopy with biopsy or endoscopic retrograde cholangiopancreatography with stent insertion (but without sphincterotomy). Procedures that incur a high risk of bleeding include polypectomy, endoscopic sphincterotomy, laser therapy, mucosal ablation and treatment of varices. For these procedures, warfarin should be discontinued four to five days beforehand. Depending on the risk of thromboembolism, that is based on the nature of the underlying condition, the patient may require vitamin K and/or fresh frozen plasma (to ensure that coagulation parameters are within the normal range) or heparin infusions (to ensure that some degree of anticoagulation is maintained). Low molecular weight heparin is an alternative to unfractionated heparin for select cases with a high risk of thromboembolism. Warfarin therapy may generally be resumed on the night of the procedure and may be supplemented by heparin in patients with a high risk of thromboembolism. It is not necessary to discontinue acetylsalicylic acid or nonsteroidal anti-inflammatory drugs, when used in standard doses, for endoscopic procedures. There are insufficient data to make recommendations regarding newer antiplatelet drugs, such as ticlopidine or clopidogrel, but it is prudent to discontinue these medications seven to 10 days before a high-risk procedure.

PMID 12772008  Can J Gastroenterol. 2003 May;17(5):329-32. doi: 10.115・・・
著者: Mio Matsumoto, Katsuhiro Mabe, Momoko Tsuda, Masayoshi Ono, Saori Omori, Masakazu Takahashi, Takeshi Yoshida, Shoko Ono, Manabu Nakagawa, Soichi Nakagawa, Yuichi Shimizu, Takahiko Kudo, Naoya Sakamoto, Mototsugu Kato
雑誌名: BMC Gastroenterol. 2015 Jul 28;15:89. doi: 10.1186/s12876-015-0315-1. Epub 2015 Jul 28.
Abstract/Text BACKGROUND: For endoscopic interventions, heparin bridging therapy is recommended in patients who are at high risk from interruption of antithrombotic therapy. Although heparin bridging has been reported to be effective in preventing thrombosis, several reports have raised concerns about increased risk of bleeding. The aim of this study was to clarify complications of hepari bridging therapy in therapeutic endoscopy.
METHODS: A nationwide multicenter survey using questionnaire was performed about patients undergoing therapeutic endoscopy with heparin bridging. Patients who underwent therapeutic endoscopy without heparin bridging therapy were considered as controls. Compliance scores of heparin bridging therapy guideline were employed, and association was analyzed between the score and occurrence of post-procedural bleeding.
RESULTS: The incidence of post-procedural bleeding was significantly higher (13.5%, 33/245) in the heparin group compared with the control group (2.7%, 299/11102)(p < 0.001). Thrombosis occurred in 1 patient each in the two groups. In the heparin group, post-procedural bleeding was more likely to be delayed bleeding. Dose adjustment of heparin was a significant factor contributing to bleeding. The compliance score of heparin bridging therapy guideline was significantly higher in those who suffered bleeding.
CONCLUSIONS: Heparin bridging therapy significantly increased the risk of post-procedural bleeding compared with the control. The bleeding risk was associated with greater adherence with guidelines for heparin bridging therapy.

PMID 26215103  BMC Gastroenterol. 2015 Jul 28;15:89. doi: 10.1186/s128・・・
著者: Toshiyuki Yoshio, Tsutomu Nishida, Naoki Kawai, Kiyonori Yuguchi, Takuya Yamada, Takamasa Yabuta, Masato Komori, Shinjiro Yamaguchi, Shinji Kitamura, Hideki Iijima, Shusaku Tsutsui, Tomoki Michida, Eiji Mita, Masahiko Tsujii, Tetsuo Takehara
雑誌名: Gastroenterol Res Pract. 2013;2013:365830. doi: 10.1155/2013/365830. Epub 2013 Jun 13.
Abstract/Text Objectives. Heparin replacement (HR) is often performed in patients with a high risk of thrombosis undergoing endoscopic procedures. However, information about the influence of HR is scarce. The aim of this study is to assess the clinical impact of HR for gastric endoscopic submucosal dissection (ESD). Methods. This is a retrospective study comprising approximately 1310 consecutive gastric neoplasms in 1250 patients, who underwent ESD in 5 institutes. We assessed the clinical findings and outcomes of ESD under HR, compared to ESD without HR as control. Results. A total of 24 EGC lesions in 24 patients were treated by ESD under HR. In the HR group, the complete en-bloc resection rate was 100%. The delayed bleeding rate was, however, higher in the HR group than in the controls (38% versus 4.6%). The timing of bleeding in the HR group was significantly later than in controls. In the control group, 209 patients discontinued antithrombotic therapy during perioperative period, and their delayed bleeding rate was not different from those without antithrombotic therapy (5.7% versus. 4.4%). A thromboembolic event was encountered in 1 patient under HR after delayed bleeding. Conclusion. ESD under HR is technically feasible but has a high risk of delayed bleeding.

PMID 23843783  Gastroenterol Res Pract. 2013;2013:365830. doi: 10.1155・・・
著者: Mototsugu Kato, Noriya Uedo, Seiji Hokimoto, Masahiro Ieko, Kazuhide Higuchi, Kazunari Murakami, Kazuma Fujimoto
雑誌名: Dig Endosc. 2018 Jul;30(4):433-440. doi: 10.1111/den.13184.
Abstract/Text In 2012, the Japan Gastroenterological Endoscopy Society published "Guidelines for Gastroenterological Endoscopy in Patients Undergoing Antithrombotic Treatment" concerning thromboembolism associated with antithrombotic therapy withdrawal. Since then, physicians have started prescribing oral anticoagulants, creating a need for standards reflecting their use in clinical practice. Therefore, new findings regarding anticoagulants are included in this appendix. However, the evidence levels are low for many statements contained herein and these appended guidelines still need to be verified in clinical settings.

© 2018 Japan Gastroenterological Endoscopy Society.
PMID 29733468  Dig Endosc. 2018 Jul;30(4):433-440. doi: 10.1111/den.13・・・
著者: James D Douketis, Alex C Spyropoulos, Scott Kaatz, Richard C Becker, Joseph A Caprini, Andrew S Dunn, David A Garcia, Alan Jacobson, Amir K Jaffer, David F Kong, Sam Schulman, Alexander G G Turpie, Vic Hasselblad, Thomas L Ortel, BRIDGE Investigators
雑誌名: N Engl J Med. 2015 Aug 27;373(9):823-33. doi: 10.1056/NEJMoa1501035. Epub 2015 Jun 22.
Abstract/Text BACKGROUND: It is uncertain whether bridging anticoagulation is necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective operation or other elective invasive procedure. We hypothesized that forgoing bridging anticoagulation would be noninferior to bridging with low-molecular-weight heparin for the prevention of perioperative arterial thromboembolism and would be superior to bridging with respect to major bleeding.
METHODS: We performed a randomized, double-blind, placebo-controlled trial in which, after perioperative interruption of warfarin therapy, patients were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin (100 IU of dalteparin per kilogram of body weight) or matching placebo administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after the procedure. Warfarin treatment was stopped 5 days before the procedure and was resumed within 24 hours after the procedure. Follow-up of patients continued for 30 days after the procedure. The primary outcomes were arterial thromboembolism (stroke, systemic embolism, or transient ischemic attack) and major bleeding.
RESULTS: In total, 1884 patients were enrolled, with 950 assigned to receive no bridging therapy and 934 assigned to receive bridging therapy. The incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (risk difference, 0.1 percentage points; 95% confidence interval [CI], -0.6 to 0.8; P=0.01 for noninferiority). The incidence of major bleeding was 1.3% in the no-bridging group and 3.2% in the bridging group (relative risk, 0.41; 95% CI, 0.20 to 0.78; P=0.005 for superiority).
CONCLUSIONS: In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism and decreased the risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health; BRIDGE ClinicalTrials.gov number, NCT00786474.).

PMID 26095867  N Engl J Med. 2015 Aug 27;373(9):823-33. doi: 10.1056/N・・・
著者: T-H Kim, J-Y Kim, H-S Mun, H-Y Lee, Y H Roh, J-S Uhm, H-N Pak, M-H Lee, B Joung
雑誌名: J Thromb Haemost. 2015 Feb;13(2):182-90. doi: 10.1111/jth.12810. Epub 2015 Jan 7.
Abstract/Text BACKGROUND: The efficacy of heparin-bridging therapy during the initiation of oral anticoagulation therapy (OAC) in non-valvular atrial fibrillation (NVAF) is unclear.
OBJECTIVES: To evaluate the efficacy and the safety of heparin-bridging therapy during OAC initiation in NVAF patients.
PATIENTS/METHODS: This study included 5327 consecutive warfarin-naïve NVAF patients who received OAC that was initiated with (n = 1053) or without (n = 4274) heparin bridging at four tertiary hospitals. Stroke and bleeding events within 30 days of OAC were evaluated.
RESULTS: While there was no difference in the incidence of stroke (0.5% vs. 0.3%, P = 0.381), major bleeding rate (0.9% vs. 0.3%, P = 0.004) was higher in heparin-bridged than in non-bridged patients. This trend remained in the propensity score-matched population (stroke 0.5% vs. 0.6%, P = 0.762; major bleeding 0.8% vs. 0.1%, P = 0.019). A high CHA2 DS2 -VASc score was an independent predictor for stroke, whereas bridging therapy had no beneficial effect in preventing stroke regardless of CHADS2 or CHA2 DS2 -VASc scores. The HAS-BLED score had a predictive value for major bleeding (odds ratio 1.80, 95% confidence interval 1.11-2.92, P = 0.018), and heparin-bridging therapy was associated with a higher major bleeding rate (odds ratio 4.44, 95% confidence interval 1.68-11.72, P = 0.003), especially in patients with a HAS-BLED score of ≥ 1.
CONCLUSIONS: The heparin-bridging therapy increased bleeding without the benefit of preventing stroke at the initiation of OAC in NVAF. Our data suggest that heparin bridging should not be considered at the initiation of OAC in NVAF patients.

© 2014 International Society on Thrombosis and Haemostasis.
PMID 25472735  J Thromb Haemost. 2015 Feb;13(2):182-90. doi: 10.1111/j・・・
著者: Benjamin A Steinberg, Sunghee Kim, Jonathan P Piccini, Gregg C Fonarow, Renato D Lopes, Laine Thomas, Michael D Ezekowitz, Jack Ansell, Peter Kowey, Daniel E Singer, Bernard Gersh, Kenneth W Mahaffey, Elaine Hylek, Alan S Go, Paul Chang, Eric D Peterson, ORBIT-AF Investigators and Patients
雑誌名: Circulation. 2013 Aug 13;128(7):721-8. doi: 10.1161/CIRCULATIONAHA.113.002927. Epub 2013 Jul 16.
Abstract/Text BACKGROUND: The role of concomitant aspirin (ASA) therapy in patients with atrial fibrillation (AF) receiving oral anticoagulation (OAC) is unclear. We assessed concomitant ASA use and its association with clinical outcomes among AF patients treated with OAC.
METHODS AND RESULTS: The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry enrolled 10 126 AF patients from 176 US practices from June 2010 through August 2011. The study population was limited to those on OAC (n=7347). Hierarchical multivariable logistic regression models were used to assess factors associated with concomitant ASA therapy. Primary outcomes were 6-month bleeding, hospitalization, ischemic events, and mortality. Overall, 35% of AF patients (n=2543) on OAC also received ASA (OAC+ASA). Patients receiving OAC+ASA were more likely to be male (66% versus 53%; P<0.0001) and had more comorbid illness than those on OAC alone. More than one third of patients (39%) receiving OAC+ASA did not have a history of atherosclerotic disease, yet 17% had elevated Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) bleeding risk scores (≥5). Major bleeding (adjusted hazard ratio, 1.53; 95% confidence interval, 1.20-1.96) and bleeding hospitalizations (adjusted hazard ratio, 1.52; 95% confidence interval, 1.17-1.97) were significantly higher in those on OAC+ASA compared with those on OAC alone. Rates of ischemic events were low.
CONCLUSIONS: Patients with AF receiving OAC are often treated with concomitant ASA, even when they do not have cardiovascular disease. Use of OAC+ASA was associated with significantly increased risk for bleeding, emphasizing the need to carefully determine if and when the benefits of concomitant ASA outweigh the risks in AF patients already on OAC.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01165710.

PMID 23861512  Circulation. 2013 Aug 13;128(7):721-8. doi: 10.1161/CIR・・・
著者: Simon van der Pol, Maartje S Jacobs, Karina Meijer, Margriet G Piersma-Wichers, Robert G Tieleman, Maarten J Postma, Marinus van Hulst
雑誌名: Europace. 2019 May 1;21(5):716-723. doi: 10.1093/europace/euy308.
Abstract/Text AIMS: Bridging anticoagulation in atrial fibrillation (AF) patients who need to interrupt vitamin K antagonists for procedures is a clinical dilemma. Currently, guidelines recommend clinicians to take the stroke and bleeding risk into consideration, but no clear thresholds are advised. To aid clinical decision making, we aimed to develop a model in which periprocedural bridging therapy is compared with withholding anticoagulation in AF patients, for several bleeding and stroke risk groups.
METHODS AND RESULTS: A model was developed to simulate both a bridge and a non-bridge cohort, using simulated international normalized ratio (INR) values for patients on warfarin, acenocoumarol, and phenprocoumon. For both clinical strategies, stroke and bleeding risks were included and outcomes were stratified by CHA2DS2-VASc or CHADS2 and HAS-BLED groups. Quality-adjusted life expectancy was the main outcome considered. Our analyses show bridging to only be beneficial for patients with HAS-BLED scores equal or lower to 2 and with CHA2DS2-VASc scores of 6 or higher. For patients using acenocoumarol bridging may be beneficial starting at a CHA2DS2-VASc score of 7. Post-procedural time to therapeutic INR has a significant influence on the results: no significant benefit of bridging was found for patients reaching therapeutic INR values within 5 days.
CONCLUSION: When deciding whether to bridge anticoagulation, clinicians should consider the patient's individual stroke and bleeding risk, while also considering the patient's post-procedural INR management. In practice, only a small subset of patients is expected to benefit from bridging anticoagulation treatment.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
PMID 30649301  Europace. 2019 May 1;21(5):716-723. doi: 10.1093/europa・・・
著者: James D Douketis, Sabina A Murphy, Elliott M Antman, Laura T Grip, Michele F Mercuri, Christian T Ruff, Jeffrey I Weitz, Eugene Braunwald, Robert P Giugliano
雑誌名: Thromb Haemost. 2018 Jun;118(6):1001-1008. doi: 10.1055/s-0038-1645856. Epub 2018 May 3.
Abstract/Text BACKGROUND: Peri-operative management of anticoagulated patients with atrial fibrillation (AF) is challenging. To gain information on the peri-operative management of edoxaban, we compared outcomes in patients on warfarin or edoxaban enrolled in ENGAGE AF-TIMI 48 who underwent a surgery or invasive procedure.
METHODS: Data from patients undergoing their first surgery/procedure were analysed and results compared by anticoagulant (warfarin vs. higher- or lower-dose edoxaban regimen [HDER and LDER, respectively]). Patients were classified by procedural management: anticoagulant interrupted (last dose 4-10 days pre-procedure) or anticoagulant continued (last dose ≤ 3 days pre-procedure). Stroke/systemic embolism (SSE), major bleeding (MB), MB or clinically relevant non-MB (CRNMB) and death were assessed from 7 days pre- until 30 days post-procedure. The chi-square test was used to compare outcomes across treatment groups.
RESULTS: A total of 7,193 patients (34%) underwent surgery/procedure: 3,116 had anticoagulant interrupted, 4,077 had anticoagulant continued. Among patients on warfarin, HDER and LDER who had anticoagulant interrupted, rates of SSE were 0.6, 0.5 and 0.9% (p = 0.53), rates of MB were 1.0, 1.2 and 1.1% (p = 0.94) and rates of MB or CRNMB were 3.9, 4.2 and 3.6% (p = 0.78); among patients on warfarin, HDER and LDER who had anticoagulant continued, rates of SSE were 1.1, 0.7 and 0.9% (p = 0.51), rates of MB were 3.6, 2.6 and 2.4% (p = 0.13) and rates of MB or CRNMB were 8.5, 7.9 and 6.6% (p = 0.17).
CONCLUSION: In patients requiring surgery/procedure in ENGAGE AF-TIMI 48, peri-operative rates of SSE, MB and death were not significantly different in patients who received edoxaban or warfarin.

Schattauer GmbH Stuttgart.
PMID 29723874  Thromb Haemost. 2018 Jun;118(6):1001-1008. doi: 10.1055・・・
著者: David Garcia, John H Alexander, Lars Wallentin, Daniel M Wojdyla, Laine Thomas, Michael Hanna, Sana M Al-Khatib, Paul Dorian, Jack Ansell, Patrick Commerford, Greg Flaker, Fernando Lanas, Dragos Vinereanu, Denis Xavier, Elaine M Hylek, Claes Held, Freek W A Verheugt, Christopher B Granger, Renato D Lopes
雑誌名: Blood. 2014 Dec 11;124(25):3692-8. doi: 10.1182/blood-2014-08-595496. Epub 2014 Oct 15.
Abstract/Text Using data from ARISTOTLE, we describe the periprocedural management of anticoagulation and rates of subsequent clinical outcomes among patients chronically anticoagulated with warfarin or apixaban. We recorded whether (and for how long) anticoagulant therapy was interrupted preprocedure, whether bridging therapy was used, and the proportion of patients who experienced important clinical outcomes during the 30 days postprocedure. Of 10 674 procedures performed during follow-up in 5924 patients, 9260 were included in this analysis. Anticoagulant treatment was not interrupted preprocedure 37.5% of the time. During the 30 days postprocedure, stroke or systemic embolism occurred after 16/4624 (0.35%) procedures among apixaban-treated patients and 26/4530 (0.57%) procedures among warfarin-treated patients (odds ratio [OR] 0.601; 95% confidence interval [CI] 0.322-1.120). Major bleeding occurred in 74/4560 (1.62%) procedures in the apixaban arm and 86/4454 (1.93%) in the warfarin arm (OR 0.846; 95% CI 0.614-1.166). The risk of death was similar with apixaban (54/4624 [1.17%]) and warfarin (49/4530 [1.08%]) (OR 1.082; 95% CI 0.733-1.598). Among patients in ARISTOTLE, the 30-day postprocedure stroke, death, and major bleeding rates were low and similar in apixaban- and warfarin-treated patients, regardless of whether anticoagulation was stopped beforehand. Our findings suggest that many patients on chronic anticoagulation can safely undergo procedures; some will not require a preprocedure interruption of anticoagulation. ARISTOTLE was registered at www.clinicaltrials.gov as #NCT00412984.

© 2014 by The American Society of Hematology.
PMID 25320240  Blood. 2014 Dec 11;124(25):3692-8. doi: 10.1182/blood-2・・・
著者: Matthew W Sherwood, James D Douketis, Manesh R Patel, Jonathan P Piccini, Anne S Hellkamp, Yuliya Lokhnygina, Alex C Spyropoulos, Graeme J Hankey, Daniel E Singer, Christopher C Nessel, Kenneth W Mahaffey, Keith A A Fox, Robert M Califf, Richard C Becker, ROCKET AF Investigators
雑誌名: Circulation. 2014 May 6;129(18):1850-9. doi: 10.1161/CIRCULATIONAHA.113.005754. Epub 2014 Feb 19.
Abstract/Text BACKGROUND: During long-term anticoagulation in atrial fibrillation, temporary interruptions (TIs) of therapy are common, but the relationship between patient outcomes and TIs has not been well studied. We sought to determine reasons for TI, the characteristics of patients undergoing TI, and the relationship between anticoagulant and outcomes among patients with TI.
METHODS AND RESULTS: In the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), a randomized, double-blind, double-dummy study of rivaroxaban and warfarin in nonvalvular atrial fibrillation, baseline characteristics, management, and outcomes, including stroke, non-central nervous system systemic embolism, death, myocardial infarction, and bleeding, were reported in participants who experienced TI (3-30 days) for any reason. The at-risk period for outcomes associated with TI was from TI start to 30 days after resumption of study drug. In 14 236 participants who received at least 1 dose of study drug, 4692 (33%) experienced TI. Participants with TI were similar to the overall ROCKET AF population in regard to baseline clinical characteristics. Only 6% (n=483) of TI incidences involved bridging therapy. Stroke/systemic embolism rates during the at-risk period were similar in rivaroxaban-treated and warfarin-treated participants (0.30% versus 0.41% per 30 days; hazard ratio [confidence interval]=0.74 [0.36-1.50]; P=0.40). Risk of major bleeding during the at-risk period was also similar in rivaroxaban-treated and warfarin-treated participants (0.99% versus 0.79% per 30 days; hazard ratio [confidence interval]=1.26 [0.80-2.00]; P=0.32).
CONCLUSIONS: TI of oral anticoagulation is common and is associated with substantial stroke risks and bleeding risks that were similar among patients treated with rivaroxaban or warfarin. Further investigation is needed to determine the optimal management strategy in patients with atrial fibrillation requiring TI of anticoagulation.
CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

PMID 24552831  Circulation. 2014 May 6;129(18):1850-9. doi: 10.1161/CI・・・
著者: Joseph R Shaw, Jason D Woodfine, James Douketis, Sam Schulman, Marc Carrier
雑誌名: Res Pract Thromb Haemost. 2018 Apr;2(2):282-290. doi: 10.1002/rth2.12076. Epub 2018 Feb 16.
Abstract/Text
Background: Patients with atrial fibrillation (AF) frequently undergo invasive procedures that require temporary interruption of anticoagulation. There is little evidence to guide the perioperative interruption of direct oral anticoagulants (DOACs).
Methods: A systematic literature search including studies that evaluated the perioperative interruption of DOACs for non-emergent invasive procedures in patients with AF was performed. The primary outcomes of interest were the 30-day risk of thromboembolic events and major bleeding. Secondary outcomes of interest included the 30-day risk of minor bleeding and overall mortality. The systematic review protocol and search strategy were registered online (PROSPERO January 27th 2017:CRD42017056124).
Results: A total of 8 publications encompassing 14 446 patients and 17 107 periprocedural interruptions were included in our study. Our analysis revealed a pooled postoperative 30-day thromboembolic complication risk of 0.41% (95% CI 0.29- 0.54), and a pooled 30-day postoperative major bleeding risk of 1.81% (95% CI 0.84-3.13). Pooled 30-day postoperative risks of minor bleeding and overall mortality were 3.08% (95% CI 1.02-6.20) and 0.67% (95% CI 0.29-1.23), respectively. Meta-analysis of the included comparative studies did not reveal any significant differences in these postoperative outcomes following the perioperative interruption of DOACs or vitamin K antagonists.
Conclusions: The perioperative interruption of DOACs in patients with AF was associated with 0.4% thromboembolic and 1.8% major bleeding events at 30 days post surgery. These findings seem reassuring, but require validation in large prospective management studies where pre-operative DOAC levels are measured and compared with clinical outcomes in this patient population.

PMID 30046730  Res Pract Thromb Haemost. 2018 Apr;2(2):282-290. doi: 1・・・
著者: Jan Steffel, Peter Verhamme, Tatjana S Potpara, Pierre Albaladejo, Matthias Antz, Lien Desteghe, Karl Georg Haeusler, Jonas Oldgren, Holger Reinecke, Vanessa Roldan-Schilling, Nigel Rowell, Peter Sinnaeve, Ronan Collins, A John Camm, Hein Heidbüchel, ESC Scientific Document Group
雑誌名: Eur Heart J. 2018 Apr 21;39(16):1330-1393. doi: 10.1093/eurheartj/ehy136.
Abstract/Text The current manuscript is the second update of the original Practical Guide, published in 2013 [Heidbuchel et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625-651; Heidbuchel et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17:1467-1507]. Non-vitamin K antagonist oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with atrial fibrillation (AF) and have emerged as the preferred choice, particularly in patients newly started on anticoagulation. Both physicians and patients are becoming more accustomed to the use of these drugs in clinical practice. However, many unresolved questions on how to optimally use these agents in specific clinical situations remain. The European Heart Rhythm Association (EHRA) set out to coordinate a unified way of informing physicians on the use of the different NOACs. A writing group identified 20 topics of concrete clinical scenarios for which practical answers were formulated, based on available evidence. The 20 topics are as follows i.e., (1) Eligibility for NOACs; (2) Practical start-up and follow-up scheme for patients on NOACs; (3) Ensuring adherence to prescribed oral anticoagulant intake; (4) Switching between anticoagulant regimens; (5) Pharmacokinetics and drug-drug interactions of NOACs; (6) NOACs in patients with chronic kidney or advanced liver disease; (7) How to measure the anticoagulant effect of NOACs; (8) NOAC plasma level measurement: rare indications, precautions, and potential pitfalls; (9) How to deal with dosing errors; (10) What to do if there is a (suspected) overdose without bleeding, or a clotting test is indicating a potential risk of bleeding; (11) Management of bleeding under NOAC therapy; (12) Patients undergoing a planned invasive procedure, surgery or ablation; (13) Patients requiring an urgent surgical intervention; (14) Patients with AF and coronary artery disease; (15) Avoiding confusion with NOAC dosing across indications; (16) Cardioversion in a NOAC-treated patient; (17) AF patients presenting with acute stroke while on NOACs; (18) NOACs in special situations; (19) Anticoagulation in AF patients with a malignancy; and (20) Optimizing dose adjustments of VKA. Additional information and downloads of the text and anticoagulation cards in different languages can be found on an EHRA website (www.NOACforAF.eu).

PMID 29562325  Eur Heart J. 2018 Apr 21;39(16):1330-1393. doi: 10.1093・・・
著者: James D Douketis, Jeff S Healey, Martina Brueckmann, John W Eikelboom, Michael D Ezekowitz, Mandy Fraessdorf, Herbert Noack, Jonas Oldgren, Paul Reilly, Alex C Spyropoulos, Lars Wallentin, Stuart J Connolly
雑誌名: Thromb Haemost. 2015 Mar;113(3):625-32. doi: 10.1160/TH14-04-0305. Epub 2014 Dec 4.
Abstract/Text In patients with atrial fibrillation (AF) who require interruption of dabigatran or warfarin for an elective surgery/procedure, the risks and benefits of perioperative bridging anticoagulation is uncertain.We accessed the database from RE-LY, a randomised trial comparing dabigatran with warfarin for stroke prevention in AF, to assess the potential benefits and risks of bridging. In patients who had a first interruption of dabigatran or warfarin for an elective surgery/procedure, we compared the risk for major bleeding (MB), stroke or systemic embolism (SSE) and any thromboembolism (TE) in patients who were bridged or not bridged during the period of seven days before until 30 days after surgery/procedure. We used multivariable Cox regression to adjust for potential confounders.Bridging was used more during warfarin interruption than dabigatran interruption (27.5 % vs 15.4 %; p< 0.001). With dabigatran interruption, bridged patients had more MB (6.5 % vs 1.8 %, p< 0.001) than those not bridged but bridged and not bridged groups did not differ for any TE (1.2 % vs 0.6 %, p=0.16) and SSE (0.5 % vs 0.3 %, p=0.46). With warfarin interruption, bridged patients had more MB (6.8 % vs 1.6 %, p< 0.001) and any TE (1.8 % vs 0.3 %, p=0.007) than those not bridged but bridged and not bridged groups did not differ for SSE (0.5 % vs 0.2 %, p=0.321). In conclusion, in patients who interrupted dabigatran or warfarin for a surgery/ procedure in the RE-LY trial, use of bridging anticoagulation appeared to increase the risk for major bleeding irrespective of dabigatran or warfarin interruption.

PMID 25472710  Thromb Haemost. 2015 Mar;113(3):625-32. doi: 10.1160/TH・・・
著者: David H Birnie, Jeff S Healey, George A Wells, Atul Verma, Anthony S Tang, Andrew D Krahn, Christopher S Simpson, Felix Ayala-Paredes, Benoit Coutu, Tiago L L Leiria, Vidal Essebag, BRUISE CONTROL Investigators
雑誌名: N Engl J Med. 2013 May 30;368(22):2084-93. doi: 10.1056/NEJMoa1302946. Epub 2013 May 9.
Abstract/Text BACKGROUND: Many patients requiring pacemaker or implantable cardioverter-defibrillator (ICD) surgery are taking warfarin. For patients at high risk for thromboembolic events, guidelines recommend bridging therapy with heparin; however, case series suggest that it may be safe to perform surgery without interrupting warfarin treatment. There have been few results from clinical trials to support the safety and efficacy of this approach.
METHODS: We randomly assigned patients with an annual risk of thromboembolic events of 5% or more to continued warfarin treatment or to bridging therapy with heparin. The primary outcome was clinically significant device-pocket hematoma, which was defined as device-pocket hematoma that necessitated prolonged hospitalization, interruption of anticoagulation therapy, or further surgery (e.g., hematoma evacuation).
RESULTS: The data and safety monitoring board recommended termination of the trial after the second prespecified interim analysis. Clinically significant device-pocket hematoma occurred in 12 of 343 patients (3.5%) in the continued-warfarin group, as compared with 54 of 338 (16.0%) in the heparin-bridging group (relative risk, 0.19; 95% confidence interval, 0.10 to 0.36; P<0.001). Major surgical and thromboembolic complications were rare and did not differ significantly between the study groups. They included one episode of cardiac tamponade and one myocardial infarction in the heparin-bridging group and one stroke and one transient ischemic attack in the continued-warfarin group.
CONCLUSIONS: As compared with bridging therapy with heparin, a strategy of continued warfarin treatment at the time of pacemaker or ICD surgery markedly reduced the incidence of clinically significant device-pocket hematoma. (Funded by the Canadian Institutes of Health Research and the Ministry of Health and Long-Term Care of Ontario; BRUISE CONTROL ClinicalTrials.gov number, NCT00800137.).

PMID 23659733  N Engl J Med. 2013 May 30;368(22):2084-93. doi: 10.1056・・・
著者: Alan Cheng, Saman Nazarian, Jeffrey A Brinker, Christine Tompkins, David D Spragg, Charles T Leng, Henry Halperin, Harikrishna Tandri, Sunil K Sinha, Joseph E Marine, Hugh Calkins, Gordon F Tomaselli, Ronald D Berger, Charles A Henrikson
雑誌名: Heart Rhythm. 2011 Apr;8(4):536-40. doi: 10.1016/j.hrthm.2010.12.016. Epub 2010 Dec 13.
Abstract/Text BACKGROUND: Management of oral anticoagulation in patients undergoing pacemaker (PPM) or implantable cardioverter-defibrillator (ICD) implantation remains controversial. Prior studies demonstrate that continuation of warfarin may be safer when compared with strategies requiring interruption and/or heparin bridging. Limited data from randomized trials exist.
OBJECTIVE: We conducted a randomized trial to determine whether warfarin continuation is superior to warfarin interruption during PPM or ICD implantation.
METHODS: Patients on oral anticoagulation referred for PPM or ICD implantation were randomized to warfarin continuation versus interruption. Patients randomized to warfarin interruption were further stratified into two groups based on their risk for thromboembolic events in the absence of warfarin. Moderate-risk patients were randomized to warfarin continuation versus warfarin interruption. High-risk patients were randomized to warfarin continuation versus warfarin interruption with heparin bridging. The primary combined outcome included thromboembolic events, anticoagulant-related complications, or any significant bleeding necessitating additional intervention or discontinuation of anticoagulation.
RESULTS: We studied 100 patients (average age 70.8 years, 21% female, mean body mass index 28.4) who underwent 64 ICD and 36 PPM implantations. Fifty patients were assigned to continue warfarin. The randomized groups were well matched. Among patients randomized to warfarin interruption, there were two pocket hematomas, one pericardial effusion, one transient ischemic attack, and one patient who developed heparin-induced thrombocytopenia. No events were noted among patients continuing warfarin (P = .056).
CONCLUSIONS: While the results were not statistically significant, there was a trend toward reduced complications in patients randomized to warfarin continuation. This strategy should be considered in patients undergoing PPM or ICD implantation.

Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
PMID 21147261  Heart Rhythm. 2011 Apr;8(4):536-40. doi: 10.1016/j.hrth・・・
著者: Vidal Essebag, Atul Verma, Jeff S Healey, Andrew D Krahn, Eli Kalfon, Benoit Coutu, Felix Ayala-Paredes, Anthony S Tang, John Sapp, Marcio Sturmer, Arieh Keren, George A Wells, David H Birnie, BRUISE CONTROL Investigators
雑誌名: J Am Coll Cardiol. 2016 Mar 22;67(11):1300-8. doi: 10.1016/j.jacc.2016.01.009.
Abstract/Text BACKGROUND: The BRUISE CONTROL trial (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial) demonstrated that a strategy of continued warfarin during cardiac implantable electronic device surgery was safe and reduced the incidence of clinically significant pocket hematoma (CSH). CSH was defined as a post-procedure hematoma requiring further surgery and/or resulting in prolongation of hospitalization of at least 24 h, and/or requiring interruption of anticoagulation. Previous studies have inconsistently associated hematoma with the subsequent development of device infection; reasons include the retrospective nature of many studies, lack of endpoint adjudication, and differing subjective definitions of hematoma.
OBJECTIVES: The BRUISE CONTROL INFECTION (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial Extended Follow-Up for Infection) prospectively examined the association between CSH and subsequent device infection.
METHODS: The study included 659 patients with a primary outcome of device-related infection requiring hospitalization, defined as 1 or more of the following: pocket infection; endocarditis; and bloodstream infection. Outcomes were verified by a blinded adjudication committee. Multivariable analysis was performed to identify predictors of infection.
RESULTS: The overall 1-year device-related infection rate was 2.4% (16 of 659). Infection occurred in 11% of patients (7 of 66) with previous CSH and in 1.5% (9 of 593) without CSH. CSH was the only independent predictor and was associated with a >7-fold increased risk of infection (hazard ratio: 7.7; 95% confidence interval: 2.9 to 20.5; p < 0.0001). Empiric antibiotics upon development of hematoma did not reduce long-term infection risk.
CONCLUSIONS: CSH is associated with a significantly increased risk of infection requiring hospitalization within 1 year following cardiac implantable electronic device surgery. Strategies aimed at reducing hematomas may decrease the long-term risk of infection. (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial [BRUISE CONTROL]; NCT00800137).

Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
PMID 26988951  J Am Coll Cardiol. 2016 Mar 22;67(11):1300-8. doi: 10.1・・・
著者: John M Jennings, Robert Robichaux, H Thomas McElderry, Vance J Plumb, Alicia Gunter, Harish Doppalapudi, Jose Osorio, Takumi Yamada, G Neal Kay
雑誌名: J Cardiovasc Electrophysiol. 2013 Oct;24(10):1125-9. doi: 10.1111/jce.12214. Epub 2013 Jul 25.
Abstract/Text BACKGROUND: While continuation of oral anticoagulation (OAC) with warfarin may be preferable to interruption and bridging with heparin for patients undergoing cardiovascular implantable electronic device (CIED) implantation, it is uncertain whether the same strategy can be safely used with dabigatran.
OBJECTIVE AND METHODS: To determine the risk of bleeding and thromboembolic complications associated with uninterrupted OAC during CIED implantation, replacement, or revision, the outcomes of patients receiving uninterrupted dabigatran (D) were compared to those receiving warfarin (W).
RESULTS: D was administered the day of CIED implant in 48 patients (age 66 ± 12.4 years, 13 F and 35 M, 21 ICDs and 27 PMs), including new implant in 25 patients, replacement in 14 patients, and replacement plus lead revision in 9 patients. D was held the morning of the procedure in 14 patients (age 70 ± 11 years, 4 F and 10 M, 5 ICDs and 9 PMs). W was continued in 195 patients (age 60 ± 14.4 years, 54 F, and 141 M), including new implant in 122 patients, replacement in 33 patients, and replacement plus lead revision or upgrade in 40 patients. Bleeding complications occurred in 1 of 48 patients (2.1%) with uninterrupted dabigatran (a late pericardial effusion), 0 of 14 with interrupted D, and 9 of 195 patients (4.6%) on W (9 pocket hematomas), P = 0.69. Fifty percent of bleeding complications were associated with concomitant antiplatelet medications.
CONCLUSIONS: The incidence of bleeding complications is similar during CIED implantation with uninterrupted D or W. The risks are higher when OAC is combined with antiplatelet drugs.

© 2013 Wiley Periodicals, Inc.
PMID 23889767  J Cardiovasc Electrophysiol. 2013 Oct;24(10):1125-9. do・・・
著者: Jedrzej Kosiuk, Emmanuel Koutalas, Michael Doering, Sotirios Nedios, Philipp Sommer, Sascha Rolf, Angeliki Darma, Ole A Breithardt, Borislav Dinov, Gerhard Hindricks, Sergio Richter, Andreas Bollmann
雑誌名: Circ J. 2014;78(10):2402-7. Epub 2014 Aug 22.
Abstract/Text BACKGROUND: The incidence of postoperative complications following pacemaker or implantable cardioverter-defibrillator implantations in patients treated with new oral anticoagulation agents has not been studied. Here we present a first comparison of complications after cardiac rhythm device (CRD) implantations in patients with atrial fibrillation (AF) treated with dabigatran or uninterrupted warfarin.
METHODS AND RESULTS: Using a case-control study design, we compared complications within 30 days after 236 CRD procedures performed under uninterrupted warfarin (n=118) or interrupted dabigatran (n=118).There were no significant differences in the baseline characteristics of both groups. In the warfarin group, 9 (8%) pocket hematomas were observed vs. 3 (3%) in the dabigatran group (P=0.075). Two complications in the warfarin group necessitated surgical intervention as opposed to none in the dabigatran group (P=0.156). The postprocedural blood loss expressed as a drop in hemoglobin was significantly greater in the warfarin group (-0.9±0.7 vs. -0.5±0.4 mmol/L, P=0.023). In the dabigatran group, 1 case of transient ischemic attack occurred. The mean time to hospital discharge was shorter in patients treated with dabigatran (2.5±2.3 vs. 3.8±4.1 days, P=0.02).
CONCLUSIONS: The incidence and severity of bleeding complications may be lower in patients treated with periprocedurally discontinued dabigatran when compared with uninterrupted warfarin therapy. Further evaluation of peri-interventional complications and establishment of an optimal anticoagulation management protocol are needed.

PMID 25253506  Circ J. 2014;78(10):2402-7. Epub 2014 Aug 22.
著者: Christopher P Rowley, Michael L Bernard, William W Brabham, Peter C Netzler, Darren S Sidney, Frank Cuoco, J Lacy Sturdivant, Robert B Leman, J Marcus Wharton, Michael R Gold
雑誌名: Am J Cardiol. 2013 Apr 15;111(8):1165-8. doi: 10.1016/j.amjcard.2012.12.046. Epub 2013 Jan 26.
Abstract/Text The perioperative bleeding risk associated with therapeutic anticoagulation at cardiac implantable electronic device implantation has previously been demonstrated to vary by the specific anticoagulant used. Although uninterrupted anticoagulation with warfarin appears to be safe, heparin products have been shown to increase the risk of perioperative bleeding. However, the risk associated with cardiac implantable electronic device implantation with anticoagulation using dabigatran, a novel oral direct thrombin inhibitor, is not known. We performed a prospective observational study of patients receiving dabigatran for anticoagulation who underwent cardiac implantable electronic device implantation from June 2011 through May 2012. The study end points included thromboembolic and bleeding complications within 30 days of surgery. Major bleeding complications were defined as bleeding requiring surgical intervention, prolongation of hospitalization, and discontinuation of the anticoagulant or transfusion of blood products within 30 days of surgery. Minor bleeding complications included the development of a hematoma not requiring additional intervention. The thrombotic end points included stroke, transient ischemic attack, myocardial infarction, pulmonary embolism, and deep vein thrombosis. A total of 25 patients were identified for inclusion. During the index hospitalization, no thromboembolic or bleeding complications developed. No major bleeding complications occurred within 30 days of surgery. One minor bleeding event (4%) occurred within 30 days of surgery in 1 patient who was also receiving dual antiplatelet therapy. In conclusion, although no thromboembolic or major bleeding events were observed, additional studies are required to define the optimal antithrombotic management in the perioperative period.

Copyright © 2013 Elsevier Inc. All rights reserved.
PMID 23360767  Am J Cardiol. 2013 Apr 15;111(8):1165-8. doi: 10.1016/j・・・
著者: Luigi Di Biase, J David Burkhardt, Pasquale Santangeli, Prasant Mohanty, Javier E Sanchez, Rodney Horton, G Joseph Gallinghouse, Sakis Themistoclakis, Antonio Rossillo, Dhanunjaya Lakkireddy, Madhu Reddy, Steven Hao, Richard Hongo, Salwa Beheiry, Jason Zagrodzky, Bai Rong, Sanghamitra Mohanty, Claude S Elayi, Giovanni Forleo, Gemma Pelargonio, Maria Lucia Narducci, Antonio Dello Russo, Michela Casella, Gaetano Fassini, Claudio Tondo, Robert A Schweikert, Andrea Natale
雑誌名: Circulation. 2014 Jun 24;129(25):2638-44. doi: 10.1161/CIRCULATIONAHA.113.006426. Epub 2014 Apr 17.
Abstract/Text BACKGROUND: Periprocedural thromboembolic and hemorrhagic events are worrisome complications of catheter ablation for atrial fibrillation (AF). The periprocedural anticoagulation management could play a role in the incidence of these complications. Although ablation procedures performed without warfarin discontinuation seem to be associated with lower thromboembolic risk, no randomized study exists.
METHODS AND RESULTS: This was a prospective, open-label, randomized, parallel-group, multicenter study assessing the role of continuous warfarin therapy in preventing periprocedural thromboembolic and hemorrhagic events after radiofrequency catheter ablation. Patients with CHADS2 score ≥1 were included. Patients were randomly assigned in a 1:1 ratio to the off-warfarin or on-warfarin arm. The incidence of thromboembolic events in the 48 hours after ablation was the primary end point of the study. The study enrolled 1584 patients: 790 assigned to discontinue warfarin (group 1) and 794 assigned to continuous warfarin (group 2). No statistical difference in baseline characteristics was observed. There were 39 thromboembolic events (3.7% strokes [n=29] and 1.3% transient ischemic attacks [n=10]) in group 1: two events (0.87%) in patients with paroxysmal AF, 4 (2.3%) in patients with persistent AF, and 33 (8.5%) in patients with long-standing persistent AF. Only 2 strokes (0.25%) in patients with long-standing persistent AF were observed in group 2 (P<0.001). Warfarin discontinuation emerged as a strong predictor of periprocedural thromboembolism (odds ratio, 13; 95% confidence interval, 3.1-55.6; P<0.001).
CONCLUSION: This is the first randomized study showing that performing catheter ablation of AF without warfarin discontinuation reduces the occurrence of periprocedural stroke and minor bleeding complications compared with bridging with low-molecular-weight heparin.
CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01006876.

© 2014 American Heart Association, Inc.
PMID 24744272  Circulation. 2014 Jun 24;129(25):2638-44. doi: 10.1161/・・・
著者: Hugh Calkins, Stephan Willems, Edward P Gerstenfeld, Atul Verma, Richard Schilling, Stefan H Hohnloser, Ken Okumura, Harvey Serota, Matias Nordaby, Kelly Guiver, Branislav Biss, Marc A Brouwer, Massimo Grimaldi, RE-CIRCUIT Investigators
雑誌名: N Engl J Med. 2017 Apr 27;376(17):1627-1636. doi: 10.1056/NEJMoa1701005. Epub 2017 Mar 19.
Abstract/Text BACKGROUND: Catheter ablation of atrial fibrillation is typically performed with uninterrupted anticoagulation with warfarin or interrupted non-vitamin K antagonist oral anticoagulant therapy. Uninterrupted anticoagulation with a non-vitamin K antagonist oral anticoagulant, such as dabigatran, may be safer; however, controlled data are lacking. We investigated the safety of uninterrupted dabigatran versus warfarin in patients undergoing ablation of atrial fibrillation.
METHODS: In this randomized, open-label, multicenter, controlled trial with blinded adjudicated end-point assessments, we randomly assigned patients scheduled for catheter ablation of paroxysmal or persistent atrial fibrillation to receive either dabigatran (150 mg twice daily) or warfarin (target international normalized ratio, 2.0 to 3.0). Ablation was performed after 4 to 8 weeks of uninterrupted anticoagulation, which was continued during and for 8 weeks after ablation. The primary end point was the incidence of major bleeding events during and up to 8 weeks after ablation; secondary end points included thromboembolic and other bleeding events.
RESULTS: The trial enrolled 704 patients across 104 sites; 635 patients underwent ablation. Baseline characteristics were balanced between treatment groups. The incidence of major bleeding events during and up to 8 weeks after ablation was lower with dabigatran than with warfarin (5 patients [1.6%] vs. 22 patients [6.9%]; absolute risk difference, -5.3 percentage points; 95% confidence interval, -8.4 to -2.2; P<0.001). Dabigatran was associated with fewer periprocedural pericardial tamponades and groin hematomas than warfarin. The two treatment groups had a similar incidence of minor bleeding events. One thromboembolic event occurred in the warfarin group.
CONCLUSIONS: In patients undergoing ablation for atrial fibrillation, anticoagulation with uninterrupted dabigatran was associated with fewer bleeding complications than uninterrupted warfarin. (Funded by Boehringer Ingelheim; RE-CIRCUIT ClinicalTrials.gov number, NCT02348723 .).

PMID 28317415  N Engl J Med. 2017 Apr 27;376(17):1627-1636. doi: 10.10・・・
著者: Riccardo Cappato, Francis E Marchlinski, Stefan H Hohnloser, Gerald V Naccarelli, Jim Xiang, David J Wilber, Chang-Sheng Ma, Susanne Hess, Darryl S Wells, George Juang, Johan Vijgen, Burkhard J Hügl, Richard Balasubramaniam, Christian De Chillou, D Wyn Davies, L Eugene Fields, Andrea Natale, VENTURE-AF Investigators
雑誌名: Eur Heart J. 2015 Jul 21;36(28):1805-11. doi: 10.1093/eurheartj/ehv177. Epub 2015 May 14.
Abstract/Text AIMS: VENTURE-AF is the first prospective randomized trial of uninterrupted rivaroxaban and vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF) undergoing catheter ablation (CA).
METHODS AND RESULTS: Trial size was administratively set at 250, the protocol-specified target. Events were independently and blindly adjudicated. We randomly assigned 248 NVAF patients to uninterrupted rivaroxaban (20 mg once-daily) or to an uninterrupted VKA prior to CA and for 4 weeks afterwards. The primary endpoint was major bleeding events after CA. Secondary endpoints included thromboembolic events (composite of stroke, systemic embolism, myocardial infarction, and vascular death) and other bleeding or procedure-attributable events. Patients were 59.5 ± 10 years of age, 71% male, 74% paroxysmal AF, and had a CHA2DS2-VASc score of 1.6. The average total heparin dose used to manage activated clotting time (ACT) was slightly higher (13 871 vs. 10 964 units; P < 0.001) and the mean ACT level attained slightly lower (302 vs. 332 s; P < 0.001) in rivaroxaban and VKA arms, respectively. The incidence of major bleeding was low (0.4%; 1 major bleeding event). Similarly, thromboembolic events were low (0.8%; 1 ischemic stroke and 1 vascular death). All events occurred in the VKA arm and all after CA. The number of any adjudicated events (26 vs. 25), any bleeding events (21 vs. 18), and any other procedure-attributable events (5 vs. 5) were similar.
CONCLUSION: In patients undergoing CA for AF, the use of uninterrupted oral rivaroxaban was feasible and event rates were similar to those for uninterrupted VKA therapy.
NAME OF THE TRIAL REGISTRY: Clinicaltrials.gov trial registration number is NCT01729871.

© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.
PMID 25975659  Eur Heart J. 2015 Jul 21;36(28):1805-11. doi: 10.1093/e・・・
著者: Paulus Kirchhof, Karl Georg Haeusler, Benjamin Blank, Joseph De Bono, David Callans, Arif Elvan, Thomas Fetsch, Isabelle C Van Gelder, Philip Gentlesk, Massimo Grimaldi, Jim Hansen, Gerhard Hindricks, Hussein R Al-Khalidi, Tyler Massaro, Lluis Mont, Jens Cosedis Nielsen, Georg Nölker, Jonathan P Piccini, Tom De Potter, Daniel Scherr, Ulrich Schotten, Sakis Themistoclakis, Derick Todd, Johan Vijgen, Luigi Di Biase
雑誌名: Eur Heart J. 2018 Aug 21;39(32):2942-2955. doi: 10.1093/eurheartj/ehy176.
Abstract/Text Aims: It is recommended to perform atrial fibrillation ablation with continuous anticoagulation. Continuous apixaban has not been tested.
Methods and results: We compared continuous apixaban (5 mg b.i.d.) to vitamin K antagonists (VKA, international normalized ratio 2-3) in atrial fibrillation patients at risk of stroke a prospective, open, multi-centre study with blinded outcome assessment. Primary outcome was a composite of death, stroke, or bleeding (Bleeding Academic Research Consortium 2-5). A high-resolution brain magnetic resonance imaging (MRI) sub-study quantified acute brain lesions. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) at baseline and at end of follow-up. Overall, 674 patients (median age 64 years, 33% female, 42% non-paroxysmal atrial fibrillation, 49 sites) were randomized; 633 received study drug and underwent ablation; 335 undertook MRI (25 sites, 323 analysable scans). The primary outcome was observed in 22/318 patients randomized to apixaban, and in 23/315 randomized to VKA {difference -0.38% [90% confidence interval (CI) -4.0%, 3.3%], non-inferiority P = 0.0002 at the pre-specified absolute margin of 0.075}, including 2 (0.3%) deaths, 2 (0.3%) strokes, and 24 (3.8%) ISTH major bleeds. Acute small brain lesions were found in a similar number of patients in each arm [apixaban 44/162 (27.2%); VKA 40/161 (24.8%); P = 0.64]. Cognitive function increased at the end of follow-up (median 1 MoCA unit; P = 0.005) without differences between study groups.
Conclusions: Continuous apixaban is safe and effective in patients undergoing atrial fibrillation ablation at risk of stroke with respect to bleeding, stroke, and cognitive function. Further research is needed to reduce ablation-related acute brain lesions.

PMID 29579168  Eur Heart J. 2018 Aug 21;39(32):2942-2955. doi: 10.1093・・・
著者: Akihiko Nogami, Tomoo Harada, Yukio Sekiguchi, Ryuji Otani, Yukihiko Yoshida, Kentaro Yoshida, Yukiko Nakano, Norihito Nuruki, Shiro Nakahara, Masahiko Goya, Hideki Origasa, Yasuki Kihara, Kenzo Hirao, Kazutaka Aonuma, ABRIDGE-J (ABlation peRIoperative DabiGatran in use Envisioning in Japan) Investigators
雑誌名: JAMA Netw Open. 2019 Apr 5;2(4):e191994. doi: 10.1001/jamanetworkopen.2019.1994. Epub 2019 Apr 5.
Abstract/Text Importance: Uninterrupted dabigatran therapy reduces stroke risk in patients with nonvalvular atrial fibrillation (NVAF) undergoing ablation and is associated with a lower bleeding risk than uninterrupted warfarin therapy. Minimally interrupted direct oral anticoagulant therapy is widely used, but data from controlled studies are insufficient.
Objective: To compare the safety and efficacy of minimally interrupted dabigatran vs uninterrupted warfarin therapy in patients undergoing catheter ablation for NVAF.
Design, Setting, and Participants: The ABRIDGE-J (ABlation peRIoperative DabiGatran in use Envisioning in Japan) trial is a open-label, randomized clinical trial performed in 28 Japanese treatment centers. A total of 504 patients scheduled for NVAF ablation were enrolled; 500 were randomized to the study treatments; 499 received at least 1 dose of dabigatran etexilate (n = 248) or warfarin potassium (n = 251); and 442 underwent ablation (220 in the dabigatran group and 222 in the warfarin group). Data were collected from May 1, 2014, through September 14, 2015, and analyzed from March 7, 2017, through January 28, 2019.
Interventions: Appropriate dose anticoagulation was administered 4 weeks before and at least 3 months after ablation in all patients. Dabigatran therapy was interrupted before catheter ablation (holding of 1-2 doses) and resumed after ablation.
Main Outcomes and Measures: Primary end points were the incidence of embolism during the perioperative period and atrial thrombus just before the ablation. The main secondary end point was the incidence of major bleeding events until 3 months after ablation.
Results: Of the 442 patients who underwent ablation, 74.9% were men and the median age was 66 years (interquartile range, 59-71 years). Before ablation, 1 cerebral infarction and 1 thrombus in the left atrium occurred in the warfarin group, but no events occurred in the interrupted dabigatran group. After ablation, the mean (SD) incidence of major bleeding events was significantly lower with dabigatran (3 patients [1.4% {0.8%}; 95% CI, 0.4%-4.2%]) vs warfarin (11 patients [5.0% {1.5%}; 95% CI, 2.8%-8.8%]; P = .03). No thromboembolic events occurred after ablation in the dabigatran group; 1 (0.5%) occurred in the warfarin group.
Conclusions and Relevance: In patients undergoing ablation for NVAF, anticoagulation with minimally interrupted dabigatran therapy did not increase thromboembolic events and was associated with fewer bleeding complications than uninterrupted warfarin therapy.
Trial Registration: umin.ac.jp Identifier: UMIN000013129.

PMID 31002317  JAMA Netw Open. 2019 Apr 5;2(4):e191994. doi: 10.1001/j・・・
著者: Kohki Nakamura, Shigeto Naito, Takehito Sasaki, Yutaka Take, Kentaro Minami, Yoshiyuki Kitagawa, Hiroyuki Motoda, Mitsuho Inoue, Yoshimitsu Otsuka, Katsura Niijima, Eiji Yamashita, Yoshinao Sugai, Koji Kumagai, Keiko Koyama, Nobusada Funabashi, Shigeru Oshima
雑誌名: Europace. 2019 Feb 1;21(2):259-267. doi: 10.1093/europace/euy148.
Abstract/Text Aims: This prospective, randomized, single-centre study aimed to directly compare the safety and efficacy of uninterrupted and interrupted periprocedural anticoagulation protocols with direct oral anticoagulants (DOACs) in patients undergoing catheter ablation of non-valvular atrial fibrillation (NVAF).
Methods and results: We randomly assigned 846 NVAF patients receiving DOACs prior to ablation to uninterruption (n = 422) or interruption (n = 424) of the DOACs on the day of the procedure. The primary endpoint was a composite of symptomatic thromboembolisms and major bleeding events within 30 days after the ablation. Secondary endpoints included symptomatic and silent thromboembolisms and major and minor bleeding events. The primary endpoint occurred in 0.7% of the uninterrupted DOAC group [1 transient ischaemic attack (TIA) and 2 major bleeding events] and 1.2% of the interrupted DOAC group (1 TIA and 4 major bleeding events) (P = 0.480). The incidence of major and minor bleeding was comparable between the two groups (0.5% vs. 0.9%, P = 0.345; 5.9% vs. 5.4%, P = 0.753). Silent cerebral ischaemic lesions (SCILs) were observed in 138 (20.9%) of the 661 patients undergoing post-ablation magnetic resonance (MR) imaging. The uninterrupted and interrupted DOAC groups revealed a similar incidence of SCILs (19.8% vs. 22.0%, P = 0.484) and percentage of SCILs with disappearance on follow-up MR imaging (77.8% vs. 82.1%, P = 0.428).
Conclusion: Both the uninterrupted and interrupted DOAC protocols revealed a low risk of symptomatic thromboembolisms and major bleeding events and similar incidence of SCILs and minor bleeding events and may be feasible for periprocedural anticoagulation in NVAF patients undergoing catheter ablation.

PMID 29982562  Europace. 2019 Feb 1;21(2):259-267. doi: 10.1093/europa・・・
著者: Naohiko Takahashi, Yasushi Mukai, Tetsuya Kimura, Keita Yamaguchi, Takuyuki Matsumoto, Hideki Origasa, Ken Okumura, KYU-RABLE Investigators
雑誌名: Circ J. 2019 Sep 25;83(10):2017-2024. doi: 10.1253/circj.CJ-19-0535. Epub 2019 Sep 12.
Abstract/Text BACKGROUND: The KYU-RABLE study, a prospective, multicenter, single-arm interventional study, evaluated the efficacy and safety of uninterrupted oral edoxaban in patients undergoing catheter ablation (CA) for atrial fibrillation (AF).Methods and Results:We enrolled patients with AF from 23 centers in Japan. Edoxaban 60 mg (30 mg in patients indicated for dose adjustment) was administered uninterrupted, once daily in the morning for ≥4 weeks before CA and 4 weeks ±7 days after CA with one dose delayed on the procedural day. The primary endpoint was a composite of thromboembolism and major bleeding during 4 weeks from the procedural day. Among the 513 eligible patients who underwent CA, 63.5% received edoxaban 60 mg/day and 36.1% received 30 mg/day. For the primary endpoint, no thromboembolism and 1 major bleeding event (0.2%, cardiac tamponade) were observed. The plasma edoxaban concentration decreased depending on the time from the last administration to the CA procedure. However, plasma levels of coagulative biomarkers were within appropriate ranges regardless of the interval from the last administration of edoxaban.
CONCLUSIONS: The present study provided evidence of the efficacy and safety of uninterrupted edoxaban administered once daily in the morning, with one dose delayed on procedural day, in patients with AF undergoing CA. Edoxaban was associated with a low risk of periprocedural thromboembolic and bleeding complications.

PMID 31511436  Circ J. 2019 Sep 25;83(10):2017-2024. doi: 10.1253/circ・・・
著者: Charles V Pollack, Paul A Reilly, Joanne van Ryn, John W Eikelboom, Stephan Glund, Richard A Bernstein, Robert Dubiel, Menno V Huisman, Elaine M Hylek, Chak-Wah Kam, Pieter W Kamphuisen, Jörg Kreuzer, Jerrold H Levy, Gordon Royle, Frank W Sellke, Joachim Stangier, Thorsten Steiner, Peter Verhamme, Bushi Wang, Laura Young, Jeffrey I Weitz
雑誌名: N Engl J Med. 2017 Aug 3;377(5):431-441. doi: 10.1056/NEJMoa1707278. Epub 2017 Jul 11.
Abstract/Text BACKGROUND: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran.
METHODS: We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures.
RESULTS: A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals.
CONCLUSIONS: In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947 .).

PMID 28693366  N Engl J Med. 2017 Aug 3;377(5):431-441. doi: 10.1056/N・・・
著者: Stuart J Connolly, Truman J Milling, John W Eikelboom, C Michael Gibson, John T Curnutte, Alex Gold, Michele D Bronson, Genmin Lu, Pamela B Conley, Peter Verhamme, Jeannot Schmidt, Saskia Middeldorp, Alexander T Cohen, Jan Beyer-Westendorf, Pierre Albaladejo, Jose Lopez-Sendon, Shelly Goodman, Janet Leeds, Brian L Wiens, Deborah M Siegal, Elena Zotova, Brandi Meeks, Juliet Nakamya, W Ting Lim, Mark Crowther, ANNEXA-4 Investigators
雑誌名: N Engl J Med. 2016 Sep 22;375(12):1131-41. doi: 10.1056/NEJMoa1607887. Epub 2016 Aug 30.
Abstract/Text BACKGROUND: Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers.
METHODS: In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication.
RESULTS: The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up.
CONCLUSIONS: On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

PMID 27573206  N Engl J Med. 2016 Sep 22;375(12):1131-41. doi: 10.1056・・・

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