Background

The objective of this study was to investigate whether baseline low-density lipoprotein cholesterol (LDL-C) levels influence total and cardiovascular mortality reduction associated with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor therapy.

Methods

In this meta-analysis, 9 randomized controlled trials were selected using Medline, Embase, and CENTRAL until November 2018. Analyses were stratified by mean baseline LDL-C (<100 mg/dL and ≥ 100 mg/dL). Stepwise prespecified sensitivity analyses were performed after excluding the SPIRE trials and by regrouping ODYSSEY OUTCOME mortality data according to the baseline LDL-C (< and ≥100 mg/dL).

Results

In 83,321 patients, PCSK9 inhibitor therapy was not associated with a reduction in the risk of all-cause mortality (relative risk [RR], 0.94, 95% confidence interval [CI], 0.81–1.09, P = .41). These results remained consistent after excluding the SPIRE trials (RR, 0.89, 95% CI, 0.75–1.05, P = .18). However, the RR varied by baseline LDL-C, with significant RR reduction only in patients with LDL-C ≥ 100 mg/dL (RR, 0.39, 95% CI, 0.20–0.76) (P-interaction = .01). Meta-regression showed RR of 0.97 for all-cause mortality per 1 mg/dL higher baseline LDL-C (95% CI, 0.94–0.99). PCSK9 inhibitor therapy showed no significant effect on cardiovascular mortality, with no effect when excluding the SPIRE trials. However, after regrouping ODYSSEY OUTCOME estimates, there was a significant reduction in cardiovascular mortality restricted to patients with LDL-C ≥ 100 mg/dL (RR, 0.67, 95% CI, 0.51–0.87) (P-interaction = .006).

Conclusion

PCSK9 inhibitor therapy on a background statin treatment may reduce the risk of total and cardiovascular mortality in patients with baseline LDL-C ≥ 100 mg/dL. These results support current guidelines reserving PCSK9 inhibitors for high-risk patients with residually high LDL-C.

中文翻译：

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使用原蛋白转化酶枯草杆菌蛋白酶-kexin 9型抑制剂的患者基线LDL-C与总死亡率和心血管死亡率的关联：系统评价和荟萃分析。

背景

这项研究的目的是调查基线低密度脂蛋白胆固醇（LDL-C）水平是否影响与9型前蛋白转化酶枯草杆菌蛋白酶-kexin（PCSK9）抑制剂疗法相关的总死亡率和心血管死亡率的降低。

方法

在这项荟萃分析中，选择了使用Medline，Embase和CENTRAL进行的9项随机对照试验，直至2018年11月。分析按平均基线LDL-C（<100 mg / dL和≥100 mg / dL）进行分层。在排除SPIRE试验并根据基线LDL-C（<和≥100mg / dL）重新分组ODYSSEY OUTDEE死亡率数据后，进行了预先指定的逐步敏感性分析。

结果

在83,321例患者中，PCSK9抑制剂治疗与降低全因死亡率的风险无关（相对风险[RR]为0.94，95％置信区间[CI]为0.81-1.09，P  = 0.41 ）。在排除SPIRE试验后，这些结果保持一致（RR，0.89，95％CI，0.75-1.05，P  = .18）。然而，RR随基线LDL-C的不同而变化，仅在LDL-C≥100 mg / dL的患者中RR显着降低（RR，0.39、95％CI，0.20–0.76）（P-interaction = .01）。Meta回归显示，每升高1 mg / dL基线LDL-C，全因死亡率的RR为0.97（95％CI，0.94-0.99）。PCSK9抑制剂疗法对心血管死亡率无明显影响，但排除SPIRE试验则无效果。但是，在对ODYSSEY结果评估重新分组后，LDL-C≥100 mg / dL的患者的心血管死亡率显着降低（RR，0.67、95％CI，0.51-0.87）（P相互作用= .006）。

结论

基线他汀类药物治疗的PCSK9抑制剂疗法可降低基线LDL-C≥100 mg / dL的患者总死亡率和心血管死亡的风险。这些结果支持了目前保留PCSK9抑制剂用于残留高LDL-C的高危患者的指南。