2013年美国心脏病学会/美国心脏协会血液胆固醇治疗指南发现,几乎没有证据支持使用非他汀类药物调脂药物来减少动脉粥样硬化性心血管疾病(ASCVD)事件。自这些指南发布以来,已经发表了多项评估非他汀类药物调脂药物的随机对照试验.
我们进行了系统评价,以评估在已知ASCVD患者或ASCVD高危患者中,与单独使用他汀类药物相比,其他调脂治疗的获益和/或损害程度。我们纳入了来自随机对照试验的数据,样本量>1000名患者,并设计用于随访>1年。我们进行了全面的文献检索,并确定了10项随机对照试验进行密集综述,包括评估ezetimibe的试验,烟酸,胆固醇酯转移蛋白抑制剂,和PCSK9抑制剂。本综述的预设主要结局是致命心血管事件的复合,非致死性心肌梗死,和非致命性中风.
非他汀类药物调脂疗法的心血管益处因药物类别而异。有证据表明,依泽替米贝和2种PSCK9抑制剂降低了ASCVD的发病率。据报道,1种PCSK9抑制剂降低了ASCVD死亡率。Ezetimibe/辛伐他汀与辛伐他汀在IMPROVE-IT(改善降低结果:Vytorin疗效国际试验)中的使用在7年内将主要结果降低了1.8%(风险比:0.90;95%CI:0.84-0.96],需要治疗的7年人数:56)。FOURIER研究中的PSCK9抑制剂evolocumab(在高风险受试者中进行PCSK9抑制的进一步心血管结果研究)在2.2年内将主要结果降低了1.5%(风险比:0.80;95%CI:0.73-0.88;2.2=治疗所需的年数:67)。在ODYSSEY结局(在使用Alirocumab治疗期间急性冠脉综合征后心血管结局的评估)中,alirocumab在2.8年内将主要结局降低了1.6%(风险比:0.86;95%CI:0.79-0.93;需要治疗的2.8年数量:63).对于依泽替米贝和PSCK9抑制剂,肌肉骨骼的比率,神经认知,胃肠,或其他不良事件风险在治疗组和对照组之间没有差异.对于已经接受背景他汀类药物治疗的ASCVD高危患者,胆固醇酯转运蛋白抑制剂可改善ASCVD风险或不良事件的证据极少.没有证据表明在他汀类药物治疗中添加烟酸有益。10项随机对照试验结果的直接比较受到样本量显著差异的限制,随访时间,并报告了主要结果。
在对他汀类药物中添加非他汀类药物调脂治疗以降低ASCVD风险的证据的系统评价中,我们发现依泽替米贝和PCSK9抑制剂获益的证据,但烟酸或胆固醇酯转移蛋白抑制剂无效.
The 2013 American College of Cardiology/American Heart Association guidelines for the treatment of blood cholesterol found little evidence to support the use of nonstatin lipid-modifying medications to reduce atherosclerotic cardiovascular disease (ASCVD) events. Since publication of these guidelines, multiple randomized controlled trials evaluating nonstatin lipid-modifying medications have been published.
We performed a systematic review to assess the magnitude of benefit and/or harm from additional lipid-modifying therapies compared with statins alone in individuals with known ASCVD or at high risk of ASCVD. We included data from randomized controlled trials with a sample size of >1 000 patients and designed for follow-up >1 year. We performed a comprehensive literature search and identified 10 randomized controlled trials for intensive review, including trials evaluating ezetimibe, niacin, cholesterol-ester transfer protein inhibitors, and PCSK9 inhibitors. The prespecified primary outcome for this review was a composite of fatal cardiovascular events, nonfatal myocardial infarction, and nonfatal stroke.
The cardiovascular benefit of nonstatin lipid-modifying therapies varied significantly according to the class of medication. There was evidence for reduced ASCVD morbidity with ezetimibe and 2 PSCK9 inhibitors. Reduced ASCVD mortality rate was reported for 1 PCSK9 inhibitor. The use of ezetimibe/simvastatin versus simvastatin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) reduced the primary outcome by 1.8% over 7 years (hazard ratio: 0.90; 95% CI: 0.84-0.96], 7-year number needed to treat: 56). The PSCK9 inhibitor evolocumab in the FOURIER study (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) decreased the primary outcome by 1.5% over 2.2 years (hazard ratio: 0.80; 95% CI: 0.73-0.88; 2.2=year number needed to treat: 67). In ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), alirocumab reduced the primary outcome by 1.6% over 2.8 years (hazard ratio: 0.86; 95% CI: 0.79-0.93; 2.8-year number needed to treat: 63). For ezetimibe and the PSCK9 inhibitors, rates of musculoskeletal, neurocognitive, gastrointestinal, or other adverse event risks did not differ between the treatment and control groups. For patients at high risk of ASCVD already on background statin therapy, there was minimal evidence for improved ASCVD risk or adverse events with cholesterol-ester transfer protein inhibitors. There was no evidence of benefit for the addition of niacin to statin therapy. Direct comparisons of the results of the 10 randomized controlled trials were limited by significant differences in sample size, duration of follow-up, and reported primary outcomes.
In a systematic review of the evidence for adding nonstatin lipid-modifying therapies to statins to reduce ASCVD risk, we found evidence of benefit for ezetimibe and PCSK9 inhibitors but not for niacin or cholesterol-ester transfer protein inhibitors.