今日の臨床サポート

拡張型心筋症

著者: 朝倉正紀1) 兵庫医科大学 循環器内科

著者: 北風政史2) 国立循環器病研究センター 心臓血管内科

監修: 伊藤浩 岡山大学循環器内科

著者校正/監修レビュー済:2020/05/14
患者向け説明資料

概要・推奨   

  1. 拡張型心筋症の患者には、慢性心不全治療のため利尿薬を投与することが勧められる(推奨度1)
  1. 拡張型心筋症患者には、ACE阻害薬の投与が勧められる(推奨度1)
  1. ACE阻害薬に忍容性のない症例ではARBを投与する。またACE阻害薬使用例においても効果が不十分な場合はARBの追加投与を検討する(推奨度1)
  1. 拡張型心筋症の患者にはミネラルコルチコイド受容体拮抗薬(MRA)の投与が勧められる(推奨度1)
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。 閲覧にはご契約が必要となります。閲覧にはご
  1. 拡張型心筋症患者にはβ遮断薬の投与が勧められる(推奨度1)
  1. ACE阻害薬、β遮断薬、利尿薬などで心不全が十分コントロールされない症例ではジゴキシンの追加投与を検討する(推奨度1)
  1. 心房細動や肺血栓塞栓症の既往のある症例では、ワルファリンの投与が勧められる(推奨度1)。
  1. 心房細動や心室性不整脈を有する低心機能例では、アミオダロンの投与が勧められる(推奨度1)
  1. ACE阻害薬、β遮断薬などの内科的治療によってもコントロールが不良な症例や、カテコラミン静脈投与からの離脱が困難な症例に対して経口強心薬の投与を検討する(推奨度2)
  1. 内科的治療によってもNYHA以上の症状が残る低心機能症例や、失神の既往のある症例では、ICDもしくはCRT-Dの導入を検討する(推奨度2)
  1. 内科的治療に抵抗性の症例では、心移植を考慮する(推奨度1)
  1. 原因が明らかでない拡張型心筋症に対しては、心筋生検を考慮する(推奨度2)
  1. 拡張型心筋症の診断時には、虚血性心筋症の除外診断が必要である(推奨度1)
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:
朝倉正紀 : 講演料(大塚製薬(株),小野薬品工業(株),アストラゼネカ(株),ノバルティスファーマ(株),第一三共(株),バイエル薬品(株)),研究費・助成金など(第一三共(株)),奨学(奨励)寄付など(大塚製薬(株))[2021年]
北風政史 : 未申告[2021年]
監修:伊藤浩 : 講演料(第一三共,興和,アストラゼネカ,小野,ノバルティスファーマ),研究費・助成金など(興和,Canon),奨学(奨励)寄付など(第一三共,田辺三菱,小野薬品,興和,Boston,武田,ベーリンガーインゲルハイム,持田,バイエル),企業などが提供する寄付講座(日本メドトロニック)[2021年]

改訂のポイント:
  1. 心筋症診療ガイドラインに基づき、鑑別診断、薬物治療、非薬物治療の改訂を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 拡張型心筋症のきっちりとした有病率は明らかではないが、平成11年の厚生労働省特定疾患特発性心筋症調査研究班による全国疫学調査では、全国推計患者数は1万7,700人とされ、有病率は14.0人/10万人であった[1][2][3]
  1. 拡張型心筋症は、心室の拡大、心室壁の菲薄化を伴って心収縮能が低下する心筋疾患であり、特定心筋症すなわち、先天性疾患、冠動脈疾患虚血性心不全など)、弁膜症、 高血圧 、その他による二次性心筋症を除外できるものをいう。
  1. 拡張型心筋症と鑑別すべき主な二次性心筋症(特定心筋症):表<図表>
  1. 拡張型心筋症の症状は、むくみ、息切れ、呼吸困難( 起坐呼吸 )、倦怠感など、心不全の症状が主であり、急性増悪期の治療(急性心不全)はその他の原疾患による心不全と同様、病態に即した管理を行う。
  1.  心不全 以外にも、心室性不整脈(非持続性心室頻拍/持続性心室頻拍)、房室ブロック(1度・2度房室ブロック/高度・完全房室ブロック)、失神、突然死(心臓突然死の予防)などが起こり得る。
  1. 根治療法はなく、内科的治療に抵抗性の症例においては、機械的な循環補助装置の導入や心移植が検討される。
  1. 遺伝的背景を有する患者は30~48%とも報告されており、無症状の患者(NYHAⅠ度)も多い。
  1. 特発性拡張型心筋症は、指定難病であり、中等症以上を認める場合などでは、申請し認定されると保険料の自己負担分の一部が公費負担として助成される。([平成27年1月施行 57 特発性拡張型心筋症])
  1. 難病法に基づく医療費助成制度
 
  1. 内科的治療に抵抗性の症例では、心移植を考慮する(推奨度1)
  1. まとめ:拡張型心筋症は進行性の疾患と考えてよく、内科的治療にしばしば抵抗性で、重症例では血行動態が悪化の一途をたどる。こういった症例では早い段階で心移植の適応を見据え、VASなどの橋渡し治療の検討なども必要となる。移植適応は、心臓移植以外に有効な治療手段がなく、患者・家族が移植治療を理解し、免疫抑制療法など移植後の治療を一生涯継続することができること、とされる[4]。実際の対象症例は、緊急度ステータス1である(1)VASを必要とする状態(2)IABPを必要とする状態(3)人工呼吸を必要とする状態(4)ICU、CCUなどの重症室に収容され、カテコラミンなどの強心薬の持続的点滴投与が必要な状態――から選ばれ、今のところ、それ以外の病態(ステータス2)から適応となることはない。しかるにステータス1に該当している、もしくは今後該当する見込みのある症例では心移植を見越した対応が望まれる[5]
  1. 結論:心移植は、移植認定施設の日本臓器移植ネットワーク連絡係を通して待機リストに登録がなされる。すなわち申請自体が移植認定施設で行われることがほとんどであり、適応患者については早めに移植認定施設へコンサルトすることが重要である。
問診・診察のポイント  
  1. ショックの兆候がないか確認する。ショックがあれば迅速に治療を開始する。

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文献 

著者: Katsuyuki Miura, Akira Matsumori, Ali Nasermoaddeli, Yoshiyuki Soyama, Yuko Morikawa, Masaru Sakurai, Akira Kitabatake, Masaki Nagai, Yutaka Inaba, Hideaki Nakagawa
雑誌名: Circ J. 2008 Mar;72(3):343-8.
Abstract/Text BACKGROUND: There have been few large-scale nationwide studies investigating both the prognosis and the prognostic factors of idiopathic dilated cardiomyopathy (IDC). A predictive score that can be used in clinical practice has not been established.
METHODS AND RESULTS: A nationwide epidemiological study of the prognosis of IDC was conducted in 1999 among randomly selected hospitals in Japan, and 147 departments participated in the present 5-year follow-up survey. The vital status of 1,554 IDC patients was collected in 2004 using medical records and residence-based registers. The crude 5-year survival rate for those diagnosed in 1998 was 78.6%. Cox's regression model selected 5 independent predictors of mortality: male sex, higher age, higher New York Heart Association functional class, higher left ventricular diameter index, and lower left ventricular ejection fraction. A predictive score using these 5 variables effectively predicted prognosis; 5-year survival rates were 90.6% in patients with a score of 4 or less and 49.0% in patients with a score of 9 or 10.
CONCLUSIONS: This nationwide survey revealed the present prognostic status of IDC in Japan and 5 independent predictors of prognosis that can be used in clinical practice as a predictive score.

PMID 18296827  Circ J. 2008 Mar;72(3):343-8.
著者: R Faris, M D Flather, H Purcell, P A Poole-Wilson, A J S Coats
雑誌名: Cochrane Database Syst Rev. 2006 Jan 25;(1):CD003838. doi: 10.1002/14651858.CD003838.pub2. Epub 2006 Jan 25.
Abstract/Text BACKGROUND: Chronic heart failure is a major cause of morbidity and mortality world-wide. Diuretics are regarded as the first-line treatment for patients with congestive heart failure since they provide symptomatic relief. The effects of diuretics on disease progression and survival remain unclear.
OBJECTIVES: To assess the harms and benefits of diuretics for chronic heart failure
SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (Issue 2 2004), MEDLINE 1966-2004, EMBASE 1980-2004 and HERDIN database. We hand searched pertinent journals and reference lists of papers were inspected. We also contacted manufacturers and researchers in the field.
SELECTION CRITERIA: Only double-blinded randomised controlled trials of diuretic therapy comparing one diuretic with placebo, or one diuretic with another active agent (e.g. ACE inhibitors, digoxin) in patients with chronic heart failure were eligible for inclusion.
DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted the data and assessed the eligibility and methodological quality of each trial. Extracted data were entered into the Review Manager 4.2 computer software, and analysed by determining the odds ratio for dichotomous data, and difference in means for continuous data, of the treated group compared with controls. The likelihood of heterogeneity of the study population was assessed by the Chi-square test. If there was no evidence of statistical heterogeneity and pooling of results was clinically appropriate, a combined estimate was obtained using the fixed-effects model.
MAIN RESULTS: We included 14 trials (525 participants), 7 were placebo-controlled, and 7 compared diuretics against other agents such as ACE inhibitors or digoxin. We analysed the data for mortality and for worsening heart failure. Mortality data were available in 3 of the placebo-controlled trials (202 participants). Mortality was lower for participants treated with diuretics than for placebo, odds ratio (OR) for death 0.24, 95% confidence interval (CI) 0.07 to 0.83; P = 0.02. Admission for worsening heart failure was reduced in those taking diuretics in two trials (169 participants), OR 0.07 (95% CI 0.01 to 0.52; P = 0.01). In four trials comparing diuretics to active control (91 participants), diuretics improved exercise capacity in participants with CHF, difference in means WMD 0.72 , 95% CI 0.40 to 1.04; P < 0.0001.
AUTHORS' CONCLUSIONS: The available data from several small trials show that in patients with chronic heart failure, conventional diuretics appear to reduce the risk of death and worsening heart failure compared to placebo. Compared to active control, diuretics appear to improve exercise capacity.

PMID 16437464  Cochrane Database Syst Rev. 2006 Jan 25;(1):CD003838. d・・・
著者: R Faris, M Flather, H Purcell, M Henein, P Poole-Wilson, A Coats
雑誌名: Int J Cardiol. 2002 Feb;82(2):149-58.
Abstract/Text OBJECTIVE: To summarise the current evidence from randomised controlled trials for diuretics in patients with congestive heart failure (CHF).
DATA SOURCES: English-language randomised controlled trials and review papers referenced in Medline, Embase between 1966 and 1999. General literature review of pertinent journals was carried out and reference lists of papers were inspected.
REVIEW METHOD:
STUDY DESIGN: Meta-analysis of randomised controlled trials of diuretic therapy in patients with CHF.
STUDY SELECTION: Studies were included if they were randomised comparisons of loop or thiazide diuretics and control, or one diuretic and another active agent (e.g. ACE inhibitors, ibopamine and digoxin).
DATA ABSTRACTION: Using a standardised protocol, two reviewers independently abstracted the data and assessed the methodological quality of each paper.
DATA SYNTHESIS: The odds ratio (OR) of treated group compared with control was estimated for each end-point outcome and plotted against each other using the fixed-effects model. THE MAIN OUTCOME MEASURES: The primary outcomes of our analysis were effects of diuretics on mortality and morbidity.
RESULTS: Eighteen trials met our criteria and were eligible for analysis, involving 928 patients. Eight trials were placebo-controlled. We analysed the data for mortality and for worsening heart failure. A further ten trials compared diuretics against other agents such as ACE inhibitors, ibopamine, and digoxin. Mortality data were available in three of the placebo-controlled trials (n=221); the mortality rate was lower for patients treated with diuretics than for control [the odds ratio for death, 0.25; 95% confidence intervals (CI), 0.07-0.84; P=0.03]. Admissions for worsening heart failure in the four small trials (n=448) showed an odds ratio of 0.31 (95% CI 0.15-0.62; P=0.001). In six studies of diuretics compared to active control, diuretics significantly improved exercise capacity in patients with CHF [OR: 0.37; CI: 0.10-0.64, P=0.007].
CONCLUSION: Compared to active control, diuretics appear to reduce the risk of worsening disease and improve exercise capacity. The available data from small studies show that in CHF conventional diuretics reduce the risk of death and worsening heart failure compared to placebo.

PMID 11853901  Int J Cardiol. 2002 Feb;82(2):149-58.
著者: G Y Lip, C R Gibbs
雑誌名: Cochrane Database Syst Rev. 2001;(4):CD003336. doi: 10.1002/14651858.CD003336.
Abstract/Text BACKGROUND: Patients with chronic heart failure (heart failure) are at risk of thromboembolic events, including stroke, pulmonary embolism and peripheral arterial embolism, whilst coronary ischaemic events also contribute to the progression of heart failure. Long-term oral anticoagulation is established in certain groups, including patients with heart failure and atrial fibrillation but there is wide variation in the indications and use of oral anticoagulation in the broader heart failure population.
OBJECTIVES: To determine whether long-term oral anticoagulation reduces total deaths and/or major thromboembolic events in patients with heart failure, when compared to placebo.
SEARCH STRATEGY: Reference lists of papers resulting from this search, electronic database searching (MEDLINE, EMBASE, DARE), and abstracts from national and international cardiovascular meetings were studied to identify unpublished studies. Relevant authors of these studies were contacted to obtain further data.
SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing oral anticoagulants with control or placebo. Non-randomised studies were included as they may help in assessing side-effects. Duration of treatment at least 1 month, adults with heart failure due to any underlying cause. Inclusion decisions were duplicated, disagreement resolved by discussion or a third party.
DATA COLLECTION AND ANALYSIS: Data were collected by two reviewers independently and where appropriate data from RCTs were meta-analysed.
MAIN RESULTS: One recent pilot RCT compared warfarin, aspirin and no antithrombotic therapy, but no definitive data have yet been published. Three small prospective studies of warfarin in heart failure were also identified, but were over 50 years old with methods not considered reliable by modern standards. Anticoagulation was more efficacious than control for the reduction of all cause death (odds ratio 0.64 95% CI 0.45,0.90) and the reduction of cardiovascular events (0.26 95% CI 0.16, 0.43). Four retrospective non-randomised cohort analyses and three small observational studies of oral anticoagulation in heart failure included differing populations of heart failure patients and reported contradictory results.
REVIEWER'S CONCLUSIONS: Evidence from the RCTs and observational studies found a reduction in mortality and cardiovascular events with anticoagulants compared to control. This evidence needs to be interpreted with caution. Although oral anticoagulation is indicated in certain groups of patients with heart failure (eg atrial fibrillation), the data available does not support its routine use in heart failure patients who remain in sinus rhythm. A large randomised trial of warfarin in heart failure patients in sinus rhythm is currently in progress data from which will be useful addition to this story.

PMID 11687190  Cochrane Database Syst Rev. 2001;(4):CD003336. doi: 10.・・・
著者: M Piepoli, G Q Villani, P Ponikowski, A Wright, M D Flather, A J Coats
雑誌名: Int J Cardiol. 1998 Sep 1;66(1):1-10.
Abstract/Text Unlike other antiarrhythmic class I drugs, amiodarone showed in preliminary studies, benefits also in patients with left ventricular dysfunction. These positive results have induced the development of large randomised controlled studies: their results are reviewed and the controversial points are discussed. In a meta-analysis of randomised controlled trials the use of amiodarone in heart failure was associated with an approximate 20 to 25% reduction in deaths. However, amiodarone was also associated with a 120 to 124% increase in side effects.

PMID 9781781  Int J Cardiol. 1998 Sep 1;66(1):1-10.
著者:
雑誌名: Lancet. 1997 Nov 15;350(9089):1417-24.
Abstract/Text BACKGROUND: There have been 13 randomised controlled trials of prophylactic amiodarone in patients with recent myocardial infarction (MI) or congestive heart failure (CHF). None of these was powered to detect a mortality reduction of about 20%. We undertook a meta-analysis, based on data from individual patients, to provide a more sensitive and accurate assessment of the benefits and risks of prophylactic amiodarone.
METHODS: Individual data from the studies were abstracted according to a predefined protocol. The summary odds ratios were calculated according to standard methods.
FINDINGS: There were eight post-MI and five CHF trials; nine trials were double-blind and placebo-controlled, and four compared amiodarone with usual care. 6553 patients were randomly assigned treatment, of which 78% were in post-MI trials and 22% in CHF trials. 89% had had previous MI. The mean left-ventricular ejection fraction was 31%, and median frequency of ventricular premature depolarisation 18 per h. Total mortality was reduced by 13% (odds ratio 0.87 [95% CI 0.78-0.99], p = 0.030) based on classic fixed-effects meta-analysis and by 15% (0.85 [0.71-1.02], p = 0.081) with the more conservative random-effects approach. Arrhythmic/sudden death was reduced by 29% (0.71 [0.59-0.85], p = 0.0003). There was no effect on non-arrhythmic deaths (1.02 [0.87-1.19], p = 0.84). There was no difference in treatment effect between post-MI and CHF studies. The risk of arrhythmic/sudden death in control-group patients was higher in CHF than in post-MI studies (10.7 vs 4.1%), and the best single predictor of risk of arrhythmic/sudden death among all patients was symptomatic CHF. The excess (amiodarone minus control) risk of pulmonary toxicity was 1% per year.
INTERPRETATION: Prophylactic amiodarone reduces the rate of arrhythmic/sudden death in high-risk patients with recent MI or CHF and this effect results in an overall reduction of 13% in total mortality.

PMID 9371164  Lancet. 1997 Nov 15;350(9089):1417-24.
著者: S N Singh, R D Fletcher, S G Fisher, B N Singh, H D Lewis, P C Deedwania, B M Massie, C Colling, D Lazzeri
雑誌名: N Engl J Med. 1995 Jul 13;333(2):77-82. doi: 10.1056/NEJM199507133330201.
Abstract/Text BACKGROUND: Asymptomatic ventricular arrhythmias in patients with congestive heart failure are associated with increased rates of overall mortality and sudden death. Amiodarone is now used widely to prevent ventricular tachycardia and fibrillation. We conducted a trial to determine whether amiodarone can reduce overall mortality in patients with congestive heart failure and asymptomatic ventricular arrhythmias.
METHODS: We used a double-blind, placebo-controlled protocol in which 674 patients with symptoms of congestive heart failure, cardiac enlargement, 10 or more premature ventricular contractions per hour, and a left ventricular ejection fraction of 40 percent or less were randomly assigned to receive amiodarone (336 patients) or placebo (338 patients). The primary end point was overall mortality, and the median follow-up was 45 months (range, 0 to 54).
RESULTS: There was no significant difference in overall mortality between the two treatment groups (P = 0.6). The two-year actuarial survival rate was 69.4 percent (95 percent confidence interval, 64.2 to 74.6) for the patients in the amiodarone group and 70.8 percent (95 percent confidence interval, 65.7 to 75.9) for those in the placebo group. At two years, the rate of sudden death was 15 percent in the amiodarone group and 19 percent in the placebo group (P = 0.43). There was a trend toward a reduction in overall mortality among the patients with nonischemic cardiomyopathy who received amiodarone (P = 0.07). Amiodarone was significantly more effective in suppressing ventricular arrhythmias and increased the left ventricular ejection fraction by 42 percent at two years.
CONCLUSIONS: Although amiodarone was effective in suppressing ventricular arrhythmias and improving ventricular function, it did not reduce the incidence of sudden death or prolong survival among patients with heart failure, except for a trend toward reduced mortality among those with nonischemic cardiomyopathy.

PMID 7539890  N Engl J Med. 1995 Jul 13;333(2):77-82. doi: 10.1056/NE・・・
著者: H C Doval, D R Nul, H O Grancelli, S V Perrone, G R Bortman, R Curiel
雑誌名: Lancet. 1994 Aug 20;344(8921):493-8.
Abstract/Text In severe heart failure many deaths are sudden and are presumed to be due to ventricular arrhythmias. The GESICA trial evaluated the effect of low-dose amiodarone on two-year mortality in patients with severe heart failure. Our prospective multicentre trial included 516 patients on optimal standard treatment for heart failure. Patients were randomised to 300 mg/day amiodarone (260) or to standard treatment (256). Intention-to-treat analysis showed 87 deaths in the amiodarone group (33.5%) compared with 106 in the control group (41.4%) (risk reduction 28%; 95% CI 4%-45%; log rank test p = 0.024). There were reductions in both sudden death (risk reduction 27%; p = 0.16) and death due to progressive heart failure (risk reduction 23%; p = 0.16). Fewer patients in the amiodarone group died or were admitted to hospital due to worsening heart failure (119 versus 149 in the control group; risk reduction 31%; 95% CI 13-46%; p = 0.0024). The decrease in mortality and hospital admission was present in all subgroups examined and independent of the presence of non-sustained ventricular tachycardia. Side-effects were reported in 17 patients (6.1%); amiodarone was withdrawn in 12. Low-dose amiodarone proved to be an effective and reliable treatment, reducing mortality and hospital admission in patients with severe heart failure independently of the presence of complex ventricular arrhythmias.

PMID 7914611  Lancet. 1994 Aug 20;344(8921):493-8.
著者: Stuart J Connolly, Paul Dorian, Robin S Roberts, Michael Gent, Steven Bailin, Eric S Fain, Kevin Thorpe, Jean Champagne, Mario Talajic, Benoit Coutu, Gerian C Gronefeld, Stefan H Hohnloser, Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) Investigators
雑誌名: JAMA. 2006 Jan 11;295(2):165-71. doi: 10.1001/jama.295.2.165.
Abstract/Text CONTEXT: Implantable cardioverter defibrillator (ICD) therapy is effective but is associated with high-voltage shocks that are painful.
OBJECTIVE: To determine whether amiodarone plus beta-blocker or sotalol are better than beta-blocker alone for prevention of ICD shocks.
DESIGN, SETTING, AND PATIENTS: A randomized controlled trial with blinded adjudication of events of 412 patients from 39 outpatient ICD clinical centers located in Canada, Germany, United States, England, Sweden, and Austria, conducted from January 13, 2001, to September 28, 2004. Patients were eligible if they had received an ICD within 21 days for inducible or spontaneously occurring ventricular tachycardia or fibrillation.
INTERVENTION: Patients were randomized to treatment for 1 year with amiodarone plus beta-blocker, sotalol alone, or beta-blocker alone.
MAIN OUTCOME MEASURE: Primary outcome was ICD shock for any reason.
RESULTS: Shocks occurred in 41 patients (38.5%) assigned to beta-blocker alone, 26 (24.3%) assigned to sotalol, and 12 (10.3%) assigned to amiodarone plus beta-blocker. A reduction in the risk of shock was observed with use of either amiodarone plus beta-blocker or sotalol vs beta-blocker alone (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.28-0.68; P<.001). Amiodarone plus beta-blocker significantly reduced the risk of shock compared with beta-blocker alone (HR, 0.27; 95% CI, 0.14-0.52; P<.001) and sotalol (HR, 0.43; 95% CI, 0.22-0.85; P = .02). There was a trend for sotalol to reduce shocks compared with beta-blocker alone (HR, 0.61; 95% CI, 0.37-1.01; P = .055). The rates of study drug discontinuation at 1 year were 18.2% for amiodarone, 23.5% for sotalol, and 5.3% for beta-blocker alone. Adverse pulmonary and thyroid events and symptomatic bradycardia were more common among patients randomized to amiodarone.
CONCLUSIONS: Despite use of advanced ICD technology and treatment with a beta-blocker, shocks occur commonly in the first year after ICD implant. Amiodarone plus beta-blocker is effective for preventing these shocks and is more effective than sotalol but has an increased risk of drug-related adverse effects.Clinical Trials Registration ClinicalTrials.gov Identifier: NCT00257959.

PMID 16403928  JAMA. 2006 Jan 11;295(2):165-71. doi: 10.1001/jama.295.・・・
著者: R Garg, S Yusuf
雑誌名: JAMA. 1995 May 10;273(18):1450-6.
Abstract/Text OBJECTIVE: To evaluate the effect of angiotensin-converting enzyme (ACE) inhibitors on mortality and morbidity in patients with symptomatic congestive heart failure.
DATA SOURCE AND STUDY SELECTION: Data were obtained for all completed, published or unpublished, randomized, placebo-controlled trials of ACE inhibitors that were at least 8 weeks in duration and had determined total mortality by intention to treat, regardless of sample size. Trials were identified based on literature review and correspondence with investigators and pharmaceutical firms.
DATA EXTRACTION: Using standard tables, data were extracted by one author and confirmed where necessary by the other author or the principal investigator of the trial. Unpublished data were obtained by direct correspondence with the principal investigator of each study or pharmaceutical firm.
DATA SYNTHESIS: The data for each outcome were combined using the Yusuf-Peto adaptation of the Mantel-Haenszel method. Overall, there was a statistically significant reduction in total mortality (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.67 to 0.88; P < .001) and in the combined endpoint of mortality or hospitalization for congestive heart failure (OR, 0.65; 95% CI, 0.57 to 0.74; P < .001). Similar benefits were observed with several different ACE inhibitors, although the data were largely based on enalapril maleate, captopril, ramipril, quinapril hydrochloride, and lisinopril. Reductions for total mortality and the combined endpoint were similar for various subgroups examined (age, sex, etiology, and New York Heart Association class). However, patients with the lowest ejection fraction appeared to have the greatest benefit. The greatest effect was seen during the first 3 months, but additional benefit was observed during further treatment. The reduction in mortality was primarily due to fewer deaths from progressive heart failure (OR, 0.69; 95% CI, 0.58 to 0.83); point estimates for effects on sudden or presumed arrhythmic deaths (OR, 0.91; 95% CI, 0.73 to 1.12) and fatal myocardial infarction (OR, 0.82; 95% CI, 0.60 to 1.11) were less than 1 but were not significant.
CONCLUSIONS: Total mortality and hospitalization for congestive heart failure are significantly reduced by ACE inhibitors with consistent effects in a broad range of patients.

PMID 7654275  JAMA. 1995 May 10;273(18):1450-6.
著者: M Packer, P A Poole-Wilson, P W Armstrong, J G Cleland, J D Horowitz, B M Massie, L Rydén, K Thygesen, B F Uretsky
雑誌名: Circulation. 1999 Dec 7;100(23):2312-8.
Abstract/Text BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are generally prescribed by physicians in doses lower than the large doses that have been shown to reduce morbidity and mortality in patients with heart failure. It is unclear, however, if low doses and high doses of ACE inhibitors have similar benefits.
METHODS AND RESULTS: We randomly assigned 3164 patients with New York Heart Association class II to IV heart failure and an ejection fraction < or = 30% to double-blind treatment with either low doses (2.5 to 5.0 mg daily, n=1596) or high doses (32.5 to 35 mg daily, n=1568) of the ACE inhibitor, lisinopril, for 39 to 58 months, while background therapy for heart failure was continued. When compared with the low-dose group, patients in the high-dose group had a nonsignificant 8% lower risk of death (P=0.128) but a significant 12% lower risk of death or hospitalization for any reason (P=0.002) and 24% fewer hospitalizations for heart failure (P=0.002). Dizziness and renal insufficiency was observed more frequently in the high-dose group, but the 2 groups were similar in the number of patients requiring discontinuation of the study medication. Conclusions-These findings indicate that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor (unless these are the only doses that can be tolerated) and suggest that the difference in efficacy between intermediate and high doses of an ACE inhibitor (if any) is likely to be very small.

PMID 10587334  Circulation. 1999 Dec 7;100(23):2312-8.
著者: Philip Jong, Salim Yusuf, Michel F Rousseau, Sylvie A Ahn, Shrikant I Bangdiwala
雑誌名: Lancet. 2003 May 31;361(9372):1843-8. doi: 10.1016/S0140-6736(03)13501-5.
Abstract/Text BACKGROUND: In the studies of left ventricular dysfunction (SOLVD), enalapril reduced mortality in patients with symptomatic but not asymptomatic left ventricular systolic dysfunction during the trial. We did a 12-year follow-up of SOLVD to establish if the mortality reduction with enalapril among patients with heart failure was sustained, and whether a subsequent reduction in mortality would emerge among those with asymptomatic ventricular dysfunction.
METHODS: Of the 6797 patients previously enrolled in the SOLVD prevention and treatment trials, we ascertained the subsequent vital status of 5165 individuals who were alive when the trials had been completed. Follow-up was done through direct contacts in Belgium and linkages with national death registries and federal beneficiary or historic tax summary files in the USA and Canada.
FINDINGS: Follow-up was 99.8% (6784/6797) complete. In the prevention trial, 50.9% (1074/2111) of the enalapril group had died compared with 56.4% (1195/2117) of the placebo group (generalised Wilcoxon p=0.001). In the treatment trial, 79.8% (1025/1285) of the enalapril group had died compared with 80.8% (1038/1284) of the placebo group (generalised Wilcoxon p=0.01). The reductions in cardiac deaths were significant and similar in both trials. When data for the prevention and treatment trials were combined, the hazard ratio for death was 0.90 for the enalapril group compared with the placebo group (95% CI 0.84-0.95, generalised Wilcoxon p=0.0003). Enalapril extended median survival by 9.4 months in the combined trials (95% CI 2.8-16.5, p=0.004).
INTERPRETATION: Treatment with enalapril for 3-4 years led to a sustained improvement in survival beyond the original trial period in patients with left ventricular systolic dysfunction, with an important increase in life expectancy.

PMID 12788569  Lancet. 2003 May 31;361(9372):1843-8. doi: 10.1016/S014・・・
著者: K Swedberg, J Kjekshus
雑誌名: Am J Cardiol. 1988 Jul 11;62(2):60A-66A.
Abstract/Text To evaluate the influence of the angiotensin-converting enzyme inhibitor, enalapril (2.5 to 40 mg/day), on the prognosis of severe congestive heart failure, defined as New York Heart Association functional class IV, a double-blind study was undertaken in which 253 patients were randomized to receive either placebo (n = 126) or enalapril (n = 127) in addition to conventional treatment, including vasodilators. Follow-up averaged 188 days (range 1 day to 20 months). The reduction in crude mortality within 6 months (primary objective) was 40% in the enalapril-treated group (from 44 to 26%, p = 0.002) and within 1 year 31% (p = 0.001). By the end of the study, 68 subjects in the placebo group and 50 in the enalapril group had died--a reduction of 27% (p = 0.003). The entire reduction in total mortality (50%) was found in patients dying from progressive heart failure, whereas no difference was seen in the incidence of sudden cardiac death. There was a significant improvement in New York Heart Association classification in the enalapril group, together with a reduction in heart size and a reduced requirement for other heart failure medication. It is concluded that the addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms. The effect seems to be due to a reduction in death from progression of heart failure.

PMID 2839019  Am J Cardiol. 1988 Jul 11;62(2):60A-66A.
著者: Philip Jong, Catherine Demers, Robert S McKelvie, Peter P Liu
雑誌名: J Am Coll Cardiol. 2002 Feb 6;39(3):463-70.
Abstract/Text OBJECTIVES: We sought to determine the effect of angiotensin receptor blockers (ARBs) on mortality and hospitalization in patients with heart failure (HF).
BACKGROUND: There is uncertainty regarding the efficacy of ARBs as substitute or adjunctive therapy to angiotensin-converting enzyme inhibitors (ACEIs) in the treatment of HF.
METHODS: We conducted a meta-analysis of all randomized controlled trials that compared ARBs with either placebo or ACEIs in patients with symptomatic HF. The pooled outcomes were all-cause mortality and hospitalization for HF.
RESULTS: Seventeen trials involving 12,469 patients were included. Overall, ARBs were not superior to controls in the pooled rates of death (odds ratio: 0.96; 95% confidence interval: 0.75 to 1.23) or hospitalization (0.86; 0.69 to 1.06). Stratified analysis, however, showed a non-significant trend in benefit of ARBs over placebo in reducing mortality (0.68; 0.38 to 1.22) and hospitalization (0.67; 0.29 to 1.51) when given in the absence of background ACEI therapy. When compared directly with ACEIs, ARBs were not superior in reducing either mortality (1.09; 0.92 to 1.29) or hospitalization (0.95; 0.80 to 1.13). In contrast, the combination therapy of ARBs and ACEIs was superior to ACEIs alone in reducing hospitalization (0.74; 0.64 to 0.86) but not mortality (1.04; 0.91 to 1.20).
CONCLUSIONS: This meta-analysis cannot confirm that ARBs are superior in reducing all-cause mortality or HF hospitalization in patients with symptomatic HF, particularly when compared with ACEIs. However, the use of ARBs as monotherapy in the absence of ACEIs or as combination therapy with ACEIs appears promising.

PMID 11823085  J Am Coll Cardiol. 2002 Feb 6;39(3):463-70.
著者: Christopher B Granger, John J V McMurray, Salim Yusuf, Peter Held, Eric L Michelson, Bertil Olofsson, Jan Ostergren, Marc A Pfeffer, Karl Swedberg, CHARM Investigators and Committees
雑誌名: Lancet. 2003 Sep 6;362(9386):772-6. doi: 10.1016/S0140-6736(03)14284-5.
Abstract/Text BACKGROUND: Angiotensin-converting-enzyme (ACE) inhibitors improve outcome of patients with chronic heart failure (CHF). A substantial proportion of patients, however, experience no benefit from ACE inhibitors because of previous intolerance. We aimed to find out whether candesartan, an angiotensin-receptor blocker, could improve outcome in such patients not taking an ACE inhibitor.
METHODS: Between March, 1999, and March, 2001, we enrolled 2028 patients with symptomatic heart failure and left-ventricular ejection fraction 40% or less who were not receiving ACE inhibitors because of previous intolerance. Patients were randomly assigned candesartan (target dose 32 mg once daily) or matching placebo. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. Analysis was by intention to treat.
FINDINGS: The most common manifestation of ACE-inhibitor intolerance was cough (72%), followed by symptomatic hypotension (13%) and renal dysfunction (12%). During a median follow-up of 33.7 months, 334 (33%) of 1013 patients in the candesartan group and 406 (40%) of 1015 in the placebo group had cardiovascular death or hospital admission for CHF (unadjusted hazard ratio 0.77 [95% CI 0.67-0.89], p=0.0004; covariate adjusted 0.70 [0.60-0.81], p<0.0001). Each component of the primary outcome was reduced, as was the total number of hospital admissions for CHF. Study-drug discontinuation rates were similar in the candesartan (30%) and placebo (29%) groups.
INTERPRETATION: Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic heart failure and intolerance to ACE inhibitors.

PMID 13678870  Lancet. 2003 Sep 6;362(9386):772-6. doi: 10.1016/S0140-・・・
著者: B Pitt, F Zannad, W J Remme, R Cody, A Castaigne, A Perez, J Palensky, J Wittes
雑誌名: N Engl J Med. 1999 Sep 2;341(10):709-17. doi: 10.1056/NEJM199909023411001.
Abstract/Text BACKGROUND AND METHODS: Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes.
RESULTS: The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients.
CONCLUSIONS: Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure.

PMID 10471456  N Engl J Med. 1999 Sep 2;341(10):709-17. doi: 10.1056/N・・・
著者: Bertram Pitt, Willem Remme, Faiez Zannad, James Neaton, Felipe Martinez, Barbara Roniker, Richard Bittman, Steve Hurley, Jay Kleiman, Marjorie Gatlin, Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators
雑誌名: N Engl J Med. 2003 Apr 3;348(14):1309-21. doi: 10.1056/NEJMoa030207. Epub 2003 Mar 31.
Abstract/Text BACKGROUND: Aldosterone blockade reduces mortality and morbidity among patients with severe heart failure. We conducted a double-blind, placebo-controlled study evaluating the effect of eplerenone, a selective aldosterone blocker, on morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.
METHODS: Patients were randomly assigned to eplerenone (25 mg per day initially, titrated to a maximum of 50 mg per day; 3319 patients) or placebo (3313 patients) [correction] in addition to optimal medical therapy. The study continued until 1012 deaths occurred. The primary end points were death from any cause and death from cardiovascular causes or hospitalization for heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia.
RESULTS: During a mean follow-up of 16 months, there were 478 deaths in the eplerenone group and 554 deaths in the placebo group (relative risk, 0.85; 95 percent confidence interval, 0.75 to 0.96; P=0.008). Of these deaths, 407 in the eplerenone group and 483 in the placebo group were attributed to cardiovascular causes (relative risk, 0.83; 95 percent confidence interval, 0.72 to 0.94; P=0.005). The rate of the other primary end point, death from cardiovascular causes or hospitalization for cardiovascular events, was reduced by eplerenone (relative risk, 0.87; 95 percent confidence interval, 0.79 to 0.95; P=0.002), as was the secondary end point of death from any cause or any hospitalization (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.98; P=0.02). There was also a reduction in the rate of sudden death from cardiac causes (relative risk, 0.79; 95 percent confidence interval, 0.64 to 0.97; P=0.03). The rate of serious hyperkalemia was 5.5 percent in the eplerenone group and 3.9 percent in the placebo group (P=0.002), whereas the rate of hypokalemia was 8.4 percent in the eplerenone group and 13.1 percent in the placebo group (P<0.001).
CONCLUSIONS: The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.

Copyright 2003 Massachusetts Medical Society
PMID 12668699  N Engl J Med. 2003 Apr 3;348(14):1309-21. doi: 10.1056/・・・
著者: Faiez Zannad, John J V McMurray, Henry Krum, Dirk J van Veldhuisen, Karl Swedberg, Harry Shi, John Vincent, Stuart J Pocock, Bertram Pitt, EMPHASIS-HF Study Group
雑誌名: N Engl J Med. 2011 Jan 6;364(1):11-21. doi: 10.1056/NEJMoa1009492. Epub 2010 Nov 14.
Abstract/Text BACKGROUND: Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms.
METHODS: In this randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.
RESULTS: The trial was stopped prematurely, according to prespecified rules, after a median follow-up period of 21 months. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008); 10.8% and 13.5%, respectively, died of cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001).
CONCLUSIONS: Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (Funded by Pfizer; ClinicalTrials.gov number, NCT00232180.).

PMID 21073363  N Engl J Med. 2011 Jan 6;364(1):11-21. doi: 10.1056/NEJ・・・
著者: J M Brophy, L Joseph, J L Rouleau
雑誌名: Ann Intern Med. 2001 Apr 3;134(7):550-60.
Abstract/Text PURPOSE: Congestive heart failure is an important cause of patient morbidity and mortality. Although several randomized clinical trials have compared beta-blockers with placebo for treatment of congestive heart failure, a meta-analysis quantifying the effect on mortality and morbidity has not been performed recently.
DATA SOURCES: The MEDLINE, Cochrane, and Web of Science electronic databases were searched from 1966 to July 2000. References were also identified from bibliographies of pertinent articles.
STUDY SELECTION: All randomized clinical trials of beta-blockers versus placebo in chronic stable congestive heart failure were included.
DATA EXTRACTION: A specified protocol was followed to extract data on patient characteristics, beta-blocker used, overall mortality, hospitalizations for congestive heart failure, and study quality.
DATA SYNTHESIS: A hierarchical random-effects model was used to synthesize the results. A total of 22 trials involving 10 135 patients were identified. There were 624 deaths among 4862 patients randomly assigned to placebo and 444 deaths among 5273 patients assigned to beta-blocker therapy. In these groups, 754 and 540 patients, respectively, required hospitalization for congestive heart failure. The probability that beta-blocker therapy reduced total mortality and hospitalizations for congestive heart failure was almost 100%. The best estimates of these advantages are 3.8 lives saved and 4 fewer hospitalizations per 100 patients treated in the first year after therapy. The probability that these benefits are clinically significant (>2 lives saved or >2 fewer hospitalizations per 100 patients treated) is 99%. Both selective and nonselective agents produced these salutary effects. The results are robust to any reasonable publication bias.
CONCLUSIONS: beta-Blocker therapy is associated with clinically meaningful reductions in mortality and morbidity in patients with stable congestive heart failure and should be routinely offered to all patients similar to those included in trials.

PMID 11281737  Ann Intern Med. 2001 Apr 3;134(7):550-60.
著者: S L Whorlow, H Krum
雑誌名: Am J Cardiol. 2000 Oct 15;86(8):886-9.
Abstract/Text
PMID 11024409  Am J Cardiol. 2000 Oct 15;86(8):886-9.
著者: Willem J Remme, Guenter Riegger, Per Hildebrandt, Michel Komajda, Wybren Jaarsma, Marco Bobbio, Jordi Soler-Soler, Armin Scherhag, Beatrix Lutiger, Lars Rydén
雑誌名: Cardiovasc Drugs Ther. 2004 Jan;18(1):57-66. doi: 10.1023/B:CARD.0000025756.32499.6f.
Abstract/Text AIMS: Heart failure (HF) treatment guidelines of the ESC recommend ACE-inhibitors (ACE-I) as first-line treatment and beta-blockers added if patients remain symptomatic. CARMEN explored the need for combined treatment for remodelling and order of introduction by comparing the ACE-I enalapril against carvedilol and their combination.
METHODS: In a parallel-group, 3-arm study of 18 months duration, 572 mild heart failure patients were randomly assigned to carvedilol (N = 191), enalapril (N = 190) or their combination (N = 191). In the latter, carvedilol was up-titrated before enalapril. Left ventricular (LV) remodelling was assessed by transthoracic echocardiography (biplane, modified Simpson) at baseline and after 6, 12 and 18 months of maintenance therapy. Primary comparisons considered the change in LV end-systolic volume index (LVESVI) from baseline to month 18 between the combination and enalapril, and between carvedilol and enalapril.
RESULTS: In the first primary comparison, LVESVI was reduced by 5.4 ml/m2 (p = 0.0015) in favour of combination therapy compared to enalapril. The second primary comparison tended to favour carvedilol to enalapril (NS). In the within treatment arm analyses, carvedilol significantly reduced LVESVI by 2.8 ml/m2 (p = 0.018) compared to baseline, whereas enalapril did not. LVESVI decreased by 6.3 ml/m2 (p = 0.0001) with combination therapy. All three arms showed similar safety profiles and withdrawal rates.
CONCLUSION: CARMEN is the first study to demonstrate that early combination of ACE-I and carvedilol reverses LV remodelling in patients with mild to moderate HF and LV systolic dysfunction. The results of the CARMEN study support a therapeutic strategy in which the institution of beta-blockade should not be delayed.

PMID 15115904  Cardiovasc Drugs Ther. 2004 Jan;18(1):57-66. doi: 10.10・・・
著者: Masatsugu Hori, Shigetake Sasayama, Akira Kitabatake, Teruhiko Toyo-oka, Shunnosuke Handa, Mitsuhiro Yokoyama, Masunori Matsuzaki, Akira Takeshita, Hideki Origasa, Kennichi Matsui, Saichi Hosoda, MUCHA Investigators
雑誌名: Am Heart J. 2004 Feb;147(2):324-30. doi: 10.1016/j.ahj.2003.07.023.
Abstract/Text BACKGROUND: The efficacy and optimum dose of beta-blockers have not been established in Japanese patients with chronic heart failure (CHF). The efficacy and safety of two doses of carvedilol, a beta-blocker with vasodilator and antioxidant actions, were investigated in Japanese patients with CHF.
METHODS: After screening and a carvedilol challenge phase, 174 patients with mild to moderate CHF were randomly assigned (double-blinded) to placebo, 2.5 mg of carvedilol twice daily, or 10 mg of carvedilol twice daily. After a 2- to 4-week uptitration phase, maintenance treatment was continued for 24 to 48 weeks. The primary end point was improvement of the global assessment of CHF by the attending physician. Secondary end points were death or hospitalization for cardiovascular disease, cardiovascular hospitalization, hospitalization for heart failure, change of left ventricular ejection fraction, and change in New York Heart Association class.
RESULTS: Carvedilol therapy achieved dose-dependent improvement of all end points (P for linear trend, range.002 to <.001). Both carvedilol groups showed marked risk reduction (71% to 91%) for cardiovascular and CHF hospitalization and for death or cardiovascular hospitalization (P range,.024 to <.001 for pairwise comparisons with placebo). No significant differences were observed for noncardiovascular hospitalization or adverse events.
CONCLUSIONS: In Japanese patients with mild or moderate CHF, carvedilol achieved dose-related improvement of CHF and left ventricular ejection fraction; cardiovascular hospitalization was markedly reduced. At 5 mg/d, carvedilol conferred an important patient benefit, less than at 20 mg/d.

PMID 14760332  Am Heart J. 2004 Feb;147(2):324-30. doi: 10.1016/j.ahj.・・・
著者: W B Hood, A L Dans, G H Guyatt, R Jaeschke, J J V McMurray
雑誌名: Cochrane Database Syst Rev. 2004;(2):CD002901. doi: 10.1002/14651858.CD002901.pub2.
Abstract/Text BACKGROUND: Digitalis glycosides have been in clinical use in the treatment of congestive heart failure (CHF) for more than 200 years. In recent years several trials have been conducted to address concerns about efficacy and toxicity. Although a systematic review of the literature was published in 1990, an update is required to include more current trials.
OBJECTIVES: To examine the effectiveness of digitalis glycosides in treating CHF in patients with normal sinus rhythm. To examine the effect of digitalis in patients taking diuretics, angiotensin converting enzyme inhibitors, and beta-blockers; patients with varying severity and duration of disease; patients with prior exposure to digitalis vs. no prior exposure; and patients with "CHF due to systolic dysfunction" vs. "CHF with preserved systolic function."
SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) 2003 Issue 4, MEDLINE (1966 to December 2003) and EMBASE (1990 to December 2003) were searched. Dissertation Abstracts and annual meeting abstracts of the American Heart Association, American College of Cardiology, and European Society of Cardiology were also searched from 1996-2003. In addition, reference lists provided by the pharmaceutical industry (Glaxo Wellcome Inc.) were searched.
SELECTION CRITERIA: Included were randomized placebo-controlled trials of 20 or more adult patients of either sex with symptomatic CHF who were studied for seven weeks or more. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of CHF such as acute ischemic heart disease or myocarditis was present.
DATA COLLECTION AND ANALYSIS: Articles selected from the searches described above were evaluated as a joint effort of the coauthors. The staff of the Cochrane Heart Group ran searches on the Cochrane Central Register of Controlled Trials.
MAIN RESULTS: Thirteen articles meeting the defined criteria were identified, and major endpoints of mortality, hospitalization, and clinical status, based respectively upon 8, 4, and 12 of these selected studies, were recorded and analyzed. The data show that there is no evidence of a difference in mortality between treatment and control groups, whereas digitalis therapy is associated with a lower rate of hospitalization and of clinical deterioration.
REVIEWERS' CONCLUSIONS: The literature indicates that digitalis has a useful role in the treatment of patients with CHF who are in normal sinus rhythm.

PMID 15106182  Cochrane Database Syst Rev. 2004;(2):CD002901. doi: 10.・・・
著者: Digitalis Investigation Group
雑誌名: N Engl J Med. 1997 Feb 20;336(8):525-33. doi: 10.1056/NEJM199702203360801.
Abstract/Text BACKGROUND: The role of cardiac glycosides in treating patients with chronic heart failure and normal sinus rhythm remains controversial. We studied the effect of digoxin on mortality and hospitalization in a randomized, double-blind clinical trial.
METHODS: In the main trial, patients with a left ventricular ejection fraction of 0.45 or less were randomly assigned to digoxin (3397 patients) or placebo (3403 patients) in addition to diuretics and angiotensin-converting-enzyme inhibitors (median dose of digoxin, 0.25 mg per day; average follow-up, 37 months). In an ancillary trial of patients with ejection fractions greater than 0.45, 492 patients were randomly assigned to digoxin and 496 to placebo.
RESULTS: In the main trial, mortality was unaffected. There were 1181 deaths (34.8 percent) with digoxin and 1194 deaths (35.1 percent) with placebo (risk ratio when digoxin was compared with placebo, 0.99; 95 percent confidence interval, 0.91 to 1.07; P=0.80). In the digoxin group, there was a trend toward a decrease in the risk of death attributed to worsening heart failure (risk ratio, 0.88; 95 percent confidence interval, 0.77 to 1.01; P=0.06). There were 6 percent fewer hospitalizations overall in that group than in the placebo group, and fewer patients were hospitalized for worsening heart failure (26.8 percent vs. 34.7 percent; risk ratio, 0.72; 95 percent confidence interval, 0.66 to 0.79; P<0.001). In the ancillary trial, the findings regarding the primary combined outcome of death or hospitalization due to worsening heart failure were consistent with the results of the main trial.
CONCLUSIONS: Digoxin did not reduce overall mortality, but it reduced the rate of hospitalization both overall and for worsening heart failure. These findings define more precisely the role of digoxin in the management of chronic heart failure.

PMID 9036306  N Engl J Med. 1997 Feb 20;336(8):525-33. doi: 10.1056/N・・・
著者: Effects of Pimobendan on Chronic Heart Failure Study (EPOCH Study)
雑誌名: Circ J. 2002 Feb;66(2):149-57.
Abstract/Text The long-term beneficial effects of pimobendan in the treatment of chronic heart failure (CHF) have not been established, so the present trial compared pimobendan (1.25 or 2.5mg twice daily) vs placebo in 306 patients with stable New York Heart Association class IIm or III CHF, and a radionuclide or echocardiographic left ventricular ejection fraction (LVEF) < or =45% despite optimal treatment with conventional therapy, for up to 52 weeks in a double-blind protocol. At the end of the 52 weeks of treatment, combined adverse cardiac events had occurred in 19 patients in the pimobendan group (15.9%) vs 33 patients in the placebo group (26.3%). The cumulative incidence of combined adverse cardiac events was 45% lower (95% confidence interval of hazard ratio: 0.31-0.97, log-rank test: p=0.035) in the pimobendan group than in the placebo group. Death and hospitalization for cardiac causes occurred in 12 patients in the pimobendan group (10.1%), vs 19 patients in the placebo group (15.3%), but without significant difference. Treatment with pimobendan also increased the mean Specific Activity Scale score from 4.39+/-0.12 at baseline to 4.68+/-0.15 at 52 weeks (p<0.05). In conclusion, long-term treatment with pimobendan significantly lowered morbidity and improved the physical activity of patients with mild to moderate CHF.

PMID 11999639  Circ J. 2002 Feb;66(2):149-57.
著者: M Packer, J R Carver, R J Rodeheffer, R J Ivanhoe, R DiBianco, S M Zeldis, G H Hendrix, W J Bommer, U Elkayam, M L Kukin
雑誌名: N Engl J Med. 1991 Nov 21;325(21):1468-75. doi: 10.1056/NEJM199111213252103.
Abstract/Text BACKGROUND: Milrinone, a phosphodiesterase inhibitor, enhances cardiac contractility by increasing intracellular levels of cyclic AMP, but the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined.
METHODS: We randomly assigned 1,088 patients with severe chronic heart failure (New York Heart Association class III or IV) and advanced left ventricular dysfunction to double-blind treatment with (40 mg of oral milrinone daily (561 patients) or placebo (527 patients). In addition, all patients received conventional therapy with digoxin, diuretics, and a converting-enzyme inhibitor throughout the trial. The median period of follow-up was 6.1 months (range, 1 day to 20 months).
RESULTS: As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes (95 percent confidence interval, 1 to 61 percent; P = 0.038) and a 34 percent increase in cardiovascular mortality (95 percent confidence interval, 6 to 69 percent; P = 0.016). The adverse effect of milrinone was greatest in patients with the most severe symptoms (New York Heart Association class IV), who had a 53 percent increase in mortality (95 percent confidence interval, 13 to 107 percent; P = 0.006). Milrinone did not have a beneficial effect on the survival of any subgroup. Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P = 0.006) and syncope (P = 0.002), more often than the patients given placebo.
CONCLUSIONS: Our findings indicate that despite its beneficial hemodynamic actions, long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure. The mechanism by which the drug exerts its deleterious effects is unknown.

PMID 1944425  N Engl J Med. 1991 Nov 21;325(21):1468-75. doi: 10.1056・・・
著者: J N Cohn, S O Goldstein, B H Greenberg, B H Lorell, R C Bourge, B E Jaski, S O Gottlieb, F McGrew, D L DeMets, B G White
雑誌名: N Engl J Med. 1998 Dec 17;339(25):1810-6. doi: 10.1056/NEJM199812173392503.
Abstract/Text BACKGROUND: Vesnarinone, an inotropic drug, was shown in a short-term placebo-controlled trial to improve survival markedly in patients with severe heart failure when given at a dose of 60 mg per day, but there was a trend toward an adverse effect on survival when the dose was 120 mg per day. In a longer-term study, we evaluated the effects of daily doses of 60 mg or 30 mg of vesnarinone, as compared with placebo, on mortality and morbidity.
METHODS: We enrolled 3833 patients who had symptoms of New York Heart Association class III or IV heart failure and a left ventricular ejection fraction of 30 percent or less despite optimal treatment. The mean follow-up was 286 days.
RESULTS: There were significantly fewer deaths in the placebo group (242 deaths, or 18.9 percent) than in the 60-mg vesnarinone group (292 deaths, or 22.9 percent) and longer survival (P=0.02). The increase in mortality with vesnarinone was attributed to an increase in sudden death, presumed to be due to arrhythmia. The quality of life had improved significantly more in the 60-mg vesnarinone group than in the placebo group at 8 weeks (P<0.001) and 16 weeks (P=0.003) after randomization. Trends in mortality and in measures of the quality of life in the 30-mg vesnarinone group were similar to those in the 60-mg group but not significantly different from those in the placebo group. Agranulocytosis occurred in 1.2 percent of the patients given 60 mg of vesnarinone per day and 0.2 percent of those given 30 mg of vesnarinone.
CONCLUSIONS: Vesnarinone is associated with a dose-dependent increase in mortality among patients with severe heart failure, an increase that is probably related to an increase in deaths due to arrhythmia. A short-term benefit in terms of the quality of life raises issues about the appropriate therapeutic goal in treating heart failure.

PMID 9854116  N Engl J Med. 1998 Dec 17;339(25):1810-6. doi: 10.1056/・・・
著者: Justin A Ezekowitz, Paul W Armstrong, Finlay A McAlister
雑誌名: Ann Intern Med. 2003 Mar 18;138(6):445-52.
Abstract/Text BACKGROUND: Sudden cardiac death is common in persons with cardiovascular disease.
PURPOSE: To assess the efficacy of implantable cardioverter defibrillators (ICDs) in persons at increased risk for sudden cardiac death.
DATA SOURCES: MEDLINE (1980-2002), EMBASE (1980-2002), Cochrane Controlled Clinical Trial Registry (2002, Volume 3), other databases, and conference proceedings. Primary study authors and device manufacturers were contacted, and bibliographies of relevant papers were hand searched.
STUDY SELECTION: Randomized, controlled clinical trials evaluating ICDs versus usual care were selected.
DATA EXTRACTION: Two reviewers extracted data independently.
DATA SYNTHESIS: Eight trials were included in the final analysis (4909 patients, 1154 deaths). Compared with usual care (most commonly amiodarone therapy), ICDs significantly reduced sudden cardiac death (relative risk [RR], 0.43 [95% CI, 0.35 to 0.53]) and all-cause mortality (RR, 0.74 [CI, 0.67 to 0.82]). The included trials were divided a priori into two categories: secondary prevention (involving patients resuscitated after cardiac arrest or unstable ventricular tachycardia or ventricular fibrillation [ n = 1963]) and primary prevention (involving patients at increased risk for sudden cardiac death but without documented cardiac arrest, ventricular fibrillation, or ventricular tachycardia [ n = 2946]). Regardless of baseline risk, ICDs were equally efficacious in preventing sudden cardiac death in both types of trials (RR, 0.50 [CI, 0.38 to 0.66] for secondary prevention vs. 0.37 [CI, 0.27 to 0.50] for primary prevention). However, the magnitude of benefit in total mortality varied within the primary prevention trials depending on baseline risk for sudden cardiac death.
CONCLUSIONS: Implantable cardioverter defibrillators prevent sudden cardiac death regardless of baseline risk. However, their impact on total mortality is sensitive to baseline risk for arrhythmic death. Decisions about resource allocation for ICDs depend on accurate stratification of patients according to risk.

PMID 12639076  Ann Intern Med. 2003 Mar 18;138(6):445-52.
著者: Akshay S Desai, James C Fang, William H Maisel, Kenneth L Baughman
雑誌名: JAMA. 2004 Dec 15;292(23):2874-9. doi: 10.1001/jama.292.23.2874.
Abstract/Text CONTEXT: Implantable cardioverter defibrillator (ICD) therapy is effective in primary and secondary prevention of sudden cardiac death among patients with prior myocardial infarction and depressed ejection fraction. However, conclusive evidence of survival benefit in patients with nonischemic cardiomyopathy (NICM) is still lacking.
OBJECTIVE: To determine whether ICD therapy reduces all-cause mortality in patients with NICM.
DATA SOURCES: MEDLINE (1966-2004), EMBASE (1991-2004), the Cochrane Central Register of Controlled Trials (through first quarter, 2004), reports presented at scientific meetings (2003-2004), and bibliographic review of secondary sources. Search terms included defibrillator, randomized controlled trials, clinical trials, and sudden death.
STUDY SELECTION: Eligible studies were prospective randomized controlled trials of ICD or combined cardiac resynchronization therapy and defibrillator (CRT-D) vs medical therapy enrolling at least some individuals with NICM and reporting all-cause mortality as an outcome. Of 675 potentially relevant articles screened initially, 8 reports of randomized trials enrolling a total of 2146 patients with NICM were included.
DATA EXTRACTION: Included studies were reviewed to determine the number of patients randomized, mean duration of follow-up, primary end point, mortality of ICD cohort, and mortality of control cohort.
DATA SYNTHESIS: Five primary prevention trials enrolling 1854 patients with NICM were identified; pooled analysis suggested a significant reduction in total mortality among patients randomized to ICD or CRT-D vs medical therapy (risk ratio [RR], 0.69; 95% confidence interval [CI], 0.55-0.87; P = .002). Mortality reduction remained significant even after elimination of CRT-D trials. Two of the 3 secondary prevention trials presented subgroup estimates for ICD efficacy in NICM. Pooled analysis of these secondary prevention trials (n = 256 patients with NICM) indicated an equivalent but nonsignificant mortality reduction with ICD therapy (RR, 0.69; 95% CI, 0.39-1.24; P = .22). Analysis of all 7 trials combined demonstrated a statistically significant 31% overall reduction in mortality with ICD therapy (RR, 0.69; 95% CI, 0.56-0.86; P = .002).
CONCLUSION: ICD therapy appears to significantly reduce mortality in selected patients with NICM.

PMID 15598919  JAMA. 2004 Dec 15;292(23):2874-9. doi: 10.1001/jama.292・・・
著者: James B Young, William T Abraham, Andrew L Smith, Angel R Leon, Randy Lieberman, Bruce Wilkoff, Robert C Canby, John S Schroeder, L Bing Liem, Shelley Hall, Kevin Wheelan, Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD) Trial Investigators
雑誌名: JAMA. 2003 May 28;289(20):2685-94. doi: 10.1001/jama.289.20.2685.
Abstract/Text CONTEXT: Cardiac resynchronization therapy (CRT) through biventricular pacing is an effective treatment for heart failure (HF) with a wide QRS; however, the outcomes of patients requiring CRT and implantable cardioverter defibrillator (ICD) therapy are unknown.
OBJECTIVE: To examine the efficacy and safety of combined CRT and ICD therapy in patients with New York Heart Association (NYHA) class III or IV congestive HF despite appropriate medical management.
DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, parallel-controlled trial conducted from October 1, 1999, to August 31, 2001, of 369 patients with left ventricular ejection fraction of 35% or less, QRS duration of 130 ms, at high risk of life-threatening ventricular arrhythmias, and in NYHA class III (n = 328) or IV (n = 41) despite optimized medical treatment.
INTERVENTIONS: Of 369 randomized patients who received devices with combined CRT and ICD capabilities, 182 were controls (ICD activated, CRT off) and 187 were in the CRT group (ICD activated, CRT on).
MAIN OUTCOME MEASURES: The primary double-blind study end points were changes between baseline and 6 months in quality of life, functional class, and distance covered during a 6-minute walk. Additional outcome measures included changes in exercise capacity, plasma neurohormones, left ventricular function, and overall HF status. Survival, incidence of ventricular arrhythmias, and rates of hospitalization were also compared.
RESULTS: At 6 months, patients assigned to CRT had a greater improvement in median (95% confidence interval) quality of life score (-17.5 [-21 to -14] vs -11.0 [-16 to -7], P =.02) and functional class (-1 [-1 to -1] vs 0 [-1 to 0], P =.007) than controls but were no different in the change in distance walked in 6 minutes (55 m [44-79] vs 53 m [43-75], P =.36). Peak oxygen consumption increased by 1.1 mL/kg per minute (0.7-1.6) in the CRT group vs 0.1 mL/kg per minute (-0.1 to 0.8) in controls (P =.04), although treadmill exercise duration increased by 56 seconds (30-79) in the CRT group and decreased by 11 seconds (-55 to 12) in controls (P<.001). No significant differences were observed in changes in left ventricular size or function, overall HF status, survival, and rates of hospitalization. No proarrhythmia was observed and arrhythmia termination capabilities were not impaired.
CONCLUSIONS: Cardiac resynchronization improved quality of life, functional status, and exercise capacity in patients with moderate to severe HF, a wide QRS interval, and life-threatening arrhythmias. These improvements occurred in the context of underlying appropriate medical management without proarrhythmia or compromised ICD function.

PMID 12771115  JAMA. 2003 May 28;289(20):2685-94. doi: 10.1001/jama.28・・・
著者: Arthur J Moss, W Jackson Hall, David S Cannom, Helmut Klein, Mary W Brown, James P Daubert, N A Mark Estes, Elyse Foster, Henry Greenberg, Steven L Higgins, Marc A Pfeffer, Scott D Solomon, David Wilber, Wojciech Zareba, MADIT-CRT Trial Investigators
雑誌名: N Engl J Med. 2009 Oct 1;361(14):1329-38. doi: 10.1056/NEJMoa0906431. Epub 2009 Sep 1.
Abstract/Text BACKGROUND: This trial was designed to determine whether cardiac-resynchronization therapy (CRT) with biventricular pacing would reduce the risk of death or heart-failure events in patients with mild cardiac symptoms, a reduced ejection fraction, and a wide QRS complex.
METHODS: During a 4.5-year period, we enrolled and followed 1820 patients with ischemic or nonischemic cardiomyopathy, an ejection fraction of 30% or less, a QRS duration of 130 msec or more, and New York Heart Association class I or II symptoms. Patients were randomly assigned in a 3:2 ratio to receive CRT plus an implantable cardioverter-defibrillator (ICD) (1089 patients) or an ICD alone (731 patients). The primary end point was death from any cause or a nonfatal heart-failure event (whichever came first). Heart-failure events were diagnosed by physicians who were aware of the treatment assignments, but they were adjudicated by a committee that was unaware of assignments.
RESULTS: During an average follow-up of 2.4 years, the primary end point occurred in 187 of 1089 patients in the CRT-ICD group (17.2%) and 185 of 731 patients in the ICD-only group (25.3%) (hazard ratio in the CRT-ICD group, 0.66; 95% confidence interval [CI], 0.52 to 0.84; P=0.001). The benefit did not differ significantly between patients with ischemic cardiomyopathy and those with nonischemic cardiomyopathy. The superiority of CRT was driven by a 41% reduction in the risk of heart-failure events, a finding that was evident primarily in a prespecified subgroup of patients with a QRS duration of 150 msec or more. CRT was associated with a significant reduction in left ventricular volumes and improvement in the ejection fraction. There was no significant difference between the two groups in the overall risk of death, with a 3% annual mortality rate in each treatment group. Serious adverse events were infrequent in the two groups.
CONCLUSIONS: CRT combined with ICD decreased the risk of heart-failure events in relatively asymptomatic patients with a low ejection fraction and wide QRS complex. (ClinicalTrials.gov number, NCT00180271.)

2009 Massachusetts Medical Society
PMID 19723701  N Engl J Med. 2009 Oct 1;361(14):1329-38. doi: 10.1056/・・・
著者: Anthony S L Tang, George A Wells, Mario Talajic, Malcolm O Arnold, Robert Sheldon, Stuart Connolly, Stefan H Hohnloser, Graham Nichol, David H Birnie, John L Sapp, Raymond Yee, Jeffrey S Healey, Jean L Rouleau, Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators
雑誌名: N Engl J Med. 2010 Dec 16;363(25):2385-95. doi: 10.1056/NEJMoa1009540. Epub 2010 Nov 14.
Abstract/Text BACKGROUND: Cardiac-resynchronization therapy (CRT) benefits patients with left ventricular systolic dysfunction and a wide QRS complex. Most of these patients are candidates for an implantable cardioverter-defibrillator (ICD). We evaluated whether adding CRT to an ICD and optimal medical therapy might reduce mortality and morbidity among such patients.
METHODS: We randomly assigned patients with New York Heart Association (NYHA) class II or III heart failure, a left ventricular ejection fraction of 30% or less, and an intrinsic QRS duration of 120 msec or more or a paced QRS duration of 200 msec or more to receive either an ICD alone or an ICD plus CRT. The primary outcome was death from any cause or hospitalization for heart failure.
RESULTS: We followed 1798 patients for a mean of 40 months. The primary outcome occurred in 297 of 894 patients (33.2%) in the ICD-CRT group and 364 of 904 patients (40.3%) in the ICD group (hazard ratio in the ICD-CRT group, 0.75; 95% confidence interval [CI], 0.64 to 0.87; P<0.001). In the ICD-CRT group, 186 patients died, as compared with 236 in the ICD group (hazard ratio, 0.75; 95% CI, 0.62 to 0.91; P = 0.003), and 174 patients were hospitalized for heart failure, as compared with 236 in the ICD group (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). However, at 30 days after device implantation, adverse events had occurred in 124 patients in the ICD-CRT group, as compared with 58 in the ICD group (P<0.001).
CONCLUSIONS: Among patients with NYHA class II or III heart failure, a wide QRS complex, and left ventricular systolic dysfunction, the addition of CRT to an ICD reduced rates of death and hospitalization for heart failure. This improvement was accompanied by more adverse events. (Funded by the Canadian Institutes of Health Research and Medtronic of Canada; ClinicalTrials.gov number, NCT00251251.).

PMID 21073365  N Engl J Med. 2010 Dec 16;363(25):2385-95. doi: 10.1056・・・

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