Interventional Cardiology and Cardiovascular Medicine Research, Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, Virginia.
Systematic Investigation and Research on Interventions and Outcomes (SIRIO) MEDICINE Cardiovascular Research Network.
JAMA. 2018 Apr 17;319(15):1566-1579. doi: 10.1001/jama.2018.2525.
Effects on specific fatal and nonfatal end points appear to vary for low-density lipoprotein cholesterol (LDL-C)-lowering drug trials.
To evaluate whether baseline LDL-C level is associated with total and cardiovascular mortality risk reductions.
Electronic databases (Cochrane, MEDLINE, EMBASE, TCTMD, ClinicalTrials.gov, major congress proceedings) were searched through February 2, 2018, to identify randomized clinical trials of statins, ezetimibe, and PCSK9-inhibiting monoclonal antibodies.
Two investigators abstracted data and appraised risks of bias. Intervention groups were categorized as "more intensive" (more potent pharmacologic intervention) or "less intensive" (less potent, placebo, or control group).
The coprimary end points were total mortality and cardiovascular mortality. Random-effects meta-regression and meta-analyses evaluated associations between baseline LDL-C level and reductions in mortality end points and secondary end points including major adverse cardiac events (MACE).
In 34 trials, 136 299 patients received more intensive and 133 989 received less intensive LDL-C lowering. All-cause mortality was lower for more vs less intensive therapy (7.08% vs 7.70%; rate ratio [RR], 0.92 [95% CI, 0.88 to 0.96]), but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with greater reductions in all-cause mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.91 [95% CI, 0.86 to 0.96]; P = .001; absolute risk difference [ARD], -1.05 incident cases per 1000 person-years [95% CI, -1.59 to -0.51]), but only when baseline LDL-C levels were 100 mg/dL or greater (P < .001 for interaction) in a meta-analysis. Cardiovascular mortality was lower for more vs less intensive therapy (3.48% vs 4.07%; RR, 0.84 [95% CI, 0.79 to 0.89]) but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with a greater reduction in cardiovascular mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.86 [95% CI, 0.80 to 0.94]; P < .001; ARD, -1.0 incident cases per 1000 person-years [95% CI, -1.51 to -0.45]), but only when baseline LDL-C levels were 100 mg/dL or greater (P < .001 for interaction) in a meta-analysis. Trials with baseline LDL-C levels of 160 mg/dL or greater had the greatest reduction in all-cause mortality (RR, 0.72 [95% CI, 0.62 to 0.84]; P < .001; 4.3 fewer deaths per 1000 person-years) in a meta-analysis. More intensive LDL-C lowering was also associated with progressively greater risk reductions with higher baseline LDL-C level for myocardial infarction, revascularization, and MACE.
In these meta-analyses and meta-regressions, more intensive compared with less intensive LDL-C lowering was associated with a greater reduction in risk of total and cardiovascular mortality in trials of patients with higher baseline LDL-C levels. This association was not present when baseline LDL-C level was less than 100 mg/dL, suggesting that the greatest benefit from LDL-C-lowering therapy may occur for patients with higher baseline LDL-C levels.
降低 LDL-C 的药物试验似乎对特定的致命和非致命终点的效果有所不同。
评估基线 LDL-C 水平与全因死亡率和心血管死亡率降低风险之间的关系。
通过 Cochrane、MEDLINE、EMBASE、TCTMD、ClinicalTrials.gov、主要会议记录等电子数据库，检索至 2018 年 2 月 2 日，以确定他汀类药物、依折麦布和 PCSK9 抑制单克隆抗体的随机临床试验。
两名研究人员提取数据并评估了偏倚风险。干预组分为“更强化”（更强效的药物干预）或“较不强化”（弱效、安慰剂或对照组）。
主要终点是全因死亡率和心血管死亡率。随机效应荟萃回归和荟萃分析评估了基线 LDL-C 水平与死亡率终点以及包括主要不良心脏事件（MACE）在内的次要终点降低之间的关联。
在 34 项试验中，136299 名患者接受了更强化的 LDL-C 降低治疗，133989 名患者接受了较不强化的 LDL-C 降低治疗。与较不强化治疗相比，更强化治疗的全因死亡率更低（7.08%比 7.70%；RR，0.92[95%CI，0.88 至 0.96]），但因基线 LDL-C 水平而异。荟萃回归显示，随着基线 LDL-C 水平的升高，更强化的 LDL-C 降低与全因死亡率的降低幅度更大相关（每增加 40mg/dL 基线 LDL-C，RR 降低 0.91[95%CI，0.86 至 0.96]；P=0.001；绝对风险差异[ARD]，每 1000 人年减少 1.05 例[95%CI，-1.59 至-0.51]），但仅当基线 LDL-C 水平为 100mg/dL 或更高（P<0.001 用于交互作用）时，荟萃分析才有意义。与较不强化治疗相比，更强化治疗的心血管死亡率更低（3.48%比 4.07%；RR，0.84[95%CI，0.79 至 0.89]），但因基线 LDL-C 水平而异。荟萃回归显示，随着基线 LDL-C 水平的升高，更强化的 LDL-C 降低与心血管死亡率的降低幅度更大相关（每增加 40mg/dL 基线 LDL-C，RR 降低 0.86[95%CI，0.80 至 0.94]；P<0.001；ARD，每 1000 人年减少 1.0 例[95%CI，-1.51 至-0.45]），但仅当基线 LDL-C 水平为 100mg/dL 或更高（P<0.001 用于交互作用）时，荟萃分析才有意义。在基线 LDL-C 水平为 160mg/dL 或更高的试验中，全因死亡率的降低幅度最大（RR，0.72[95%CI，0.62 至 0.84]；P<0.001；每 1000 人年减少 4.3 例死亡），荟萃分析也显示出更高的风险降低。随着基线 LDL-C 水平的升高，与更强化的 LDL-C 降低相比，心肌梗死、血运重建和 MACE 的风险降低幅度也逐渐增大。
在这些荟萃分析和荟萃回归中，与较不强化的 LDL-C 降低相比，基线 LDL-C 水平较高的患者接受更强化的 LDL-C 降低治疗与全因死亡率和心血管死亡率降低的风险降低幅度更大相关。当基线 LDL-C 水平低于 100mg/dL 时，这种关联并不存在，这表明 LDL-C 降低治疗的最大益处可能发生在基线 LDL-C 水平较高的患者中。
