據估計，全球每年有一千八百萬人死於心血管疾病，其中80%發生於中低收入國家。因此，價廉物美的老藥大有用武之地。一項全球多中心試驗（TIPS-3）評估了他汀、降壓藥和阿司匹林傳統老藥組成的複方藥對於心血管疾病風險上升但尚未發生心血管疾病的參與者的一級預防效果。其結果顯示，雖然聯合用藥效果低於預期，但仍比安慰劑降低31%心血管事件發生率。
心肌肌球蛋白激活劑能直接增強心臟收縮功能，因而有望治療射血分數降低的心力衰竭。作為心肌肌球蛋白靶點的首創藥，omecamtiv mecarbil備受業界矚目。3期臨床試驗GALACTIC-HF顯示，omecamtiv mecarbil降低了由心力衰竭事件或心血管原因死亡組成的複合結局發生率。然而與安慰劑相比，其風險僅降低8%（風險比，0.92；P=0.03）。據醫藥行業分析網站fiercebiotech報導，一些行業分析師認為該結果「令人失望」。
複方藥聯合或不聯合阿司匹林用於無心血管疾病者
Polypill with or without Aspirin in Persons without Cardiovascular Disease
Yusuf S, Joseph P, Dans A, et al.
DOI: 10.1056/NEJMoa2028220
背景
有人提議應用含他汀類藥物、多種降壓藥和阿司匹林的複方藥降低心血管疾病風險。A polypill comprising statins, multiple blood-pressure–lowering drugs, and aspirin has been proposed to reduce the risk of cardiovascular disease.方法
我們採用2×2×2析因設計，將INTERHEART風險評分（INTERHEART Risk Score）升高的無心血管疾病參與者隨機分組，分別每日接受複方藥（含40 mg辛伐他汀、100 mg阿替洛爾、25 mg氫氯噻嗪和10 mg雷米普利）或安慰劑，每日接受阿司匹林（75 mg）或安慰劑，以及每月接受維生素D或安慰劑。本文報告了單獨應用複方藥或應用匹配安慰劑的比較，單獨應用阿司匹林與應用匹配安慰劑的比較，以及應用複方藥聯合阿司匹林與應用兩種安慰劑的比較。對於單獨應用複方藥與應用複方藥+阿司匹林之間的比較，主要結局是因心血管原因死亡、心肌梗死、卒中、復甦成功的心臟停搏、心力衰竭或血運重建。對於阿司匹林的比較，主要結局是因心血管原因死亡、心肌梗死或卒中。本試驗還評估了安全性。Using a 2-by-2-by-2 factorial design, we randomly assigned participants without cardiovascular disease who had an elevated INTERHEART Risk Score to receive a polypill (containing 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril) or placebo daily, aspirin (75 mg) or placebo daily, and vitamin D or placebo monthly. We report here the outcomes for the polypill alone as compared with matching placebo, for aspirin alone as compared with matching placebo, and for the polypill plus aspirin as compared with double placebo. For the polypill-alone and polypill-plus-aspirin comparisons, the primary outcome was death from cardiovascular causes, myocardial infarction, stroke, resuscitated cardiac arrest, heart failure, or revascularization. For the aspirin comparison, the primary outcome was death from cardiovascular causes, myocardial infarction, or stroke. Safety was also assessed.結果
共計5713名參與者接受了隨機分組，平均隨訪時間為4.6年。與安慰劑相比，複方藥和聯合治療使低密度脂蛋白膽固醇水平降低了約19 mg/dL，使收縮壓降低了約5.8 mmHg。複方藥組126名參與者（4.4%）和安慰劑組157名參與者（5.5%）發生了用於複方藥比較的主要結局（風險比，0.79；95%置信區間[CI]，0.63~1.00）。阿司匹林組116名參與者（4.1%）和安慰劑組134名參與者（4.7%）發生了用於阿司匹林比較的主要結局（風險比，0.86；95% CI，0.67~1.10）。聯合治療組59名參與者（4.1%）和雙安慰劑組83名參與者（5.8%）發生了用於複方藥+阿司匹林比較的主要結局（風險比，0.69；95% CI，0.50~0.97）。複方藥組的低血壓或眩暈發生率高於相應安慰劑組。
Result
A total of 5713 participants underwent randomization, and the mean follow-up was 4.6 years. The low-density lipoprotein cholesterol level was lower by approximately 19 mg per deciliter and systolic blood pressure was lower by approximately 5.8 mm Hg with the polypill and with combination therapy than with placebo. The primary outcome for the polypill comparison occurred in 126 participants (4.4%) in the polypill group and in 157 (5.5%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.63 to 1.00). The primary outcome for the aspirin comparison occurred in 116 participants (4.1%) in the aspirin group and in 134 (4.7%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.67 to 1.10). The primary outcome for the polypill-plus-aspirin comparison occurred in 59 participants (4.1%) in the combined-treatment group and in 83 (5.8%) in the double-placebo group (hazard ratio, 0.69; CI, 0.50 to 0.97). The incidence of hypotension or dizziness was higher in groups that received the polypill than in their respective placebo groups.
結論
在心血管風險中等的無心血管疾病參與者中，複方藥+阿司匹林聯合治療與安慰劑相比降低了心血管事件發生率。（由惠康基金會等資助；TIPS-3在ClinicalTrials.gov註冊號為NCT01646437。）
Conclusions
Combined treatment with a polypill plus aspirin led to a lower incidence of cardiovascular events than did placebo among participants without cardiovascular disease who were at intermediate cardiovascular risk. (Funded by the Wellcome Trust and others; TIPS-3 ClinicalTrials.gov number, NCT01646437.)
心肌肌球蛋白激活劑omecamtiv mecarbil治療收縮期心力衰竭
Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure
Teerlink JR, Diaz R, Felker GM, et al.
DOI: 10.1056/NEJMoa2025797
背景
選擇性心肌肌球蛋白激活劑omecamtiv mecarbil已被證明可改善射血分數降低的心力衰竭患者的心功能。其對心血管結局的影響尚不明確。
The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown.方法
我們將8256例射血分數≤35%的有症狀慢性心力衰竭患者（住院患者和門診患者）隨機分組，兩組分別在心力衰竭標準療法的基礎上加用omecamtiv mecarbil（根據藥代動力學決定劑量，每日兩次，每次25 mg、37.5 mg或50 mg）或安慰劑。主要結局是由首次心力衰竭事件（因心力衰竭住院或緊急就診）或心血管原因死亡構成的複合結局。
We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes.
結果
在中位21.8個月期間，omecamtiv mecarbil組4120例患者中的1523例（37.0%）和安慰劑組4112例患者中的1607例（39.1%）發生了主要結局事件（風險比，0.92；95%置信區間[CI]，0.86~0.99；P=0.03）。兩組分別有808例患者（19.6%）和798例患者（19.4%）因心血管原因死亡（風險比，1.01；95% CI，0.92~1.11）。在堪薩斯城心肌病問卷（Kansas City Cardiomyopathy Questionnaire）症狀總分相對於基線的變化方面，兩組無顯著差異。第24周時，在omecamtiv mecarbil組中，中位N末端B型鈉尿肽前體水平相對於基線的變化比安慰劑組小10%；前者的心肌肌鈣蛋白I中位水平比後者高4 ng/L。兩組的心臟缺血和室性心律失常事件發生率相似。
Result
During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P=0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro–B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups.結論
在射血分數降低的心力衰竭患者中，omecamtiv mecarbil組的複合結局（心力衰竭事件或心血管原因死亡）發生率低於安慰劑組。（由安進等資助；GALACTIC-HF在ClinicalTrials.gov註冊號為NCT02929329；在EudraCT註冊號為2016-002299-28。）
Conclusions
Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329. opens in new tab; EudraCT number, 2016-002299-28. )本文由嘉會醫學研究和教育集團（JMRE）與《新英格蘭醫學雜誌》（NEJM）聯手打造的《NEJM醫學前沿》翻譯、編寫或約稿。中譯全文及所含圖表等由NEJM集團獨家授權。如需轉載，請留言或聯繫nejmqianyan@nejmqianyan.cn。未經授權的翻譯是侵權行為，版權方保留追究法律責任的權利。點擊「閱讀原文」 第一時間獲得NEJM英文原文