Cardiovascular events with PCSK9 inhibitors: an updated meta-analysis of randomised controlled trials

The therapy with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors efficiently reduces plasma cholesterol levels, which has been recently associated with improvement in cardiovascular outcomes. This meta-analysis aimed at investigating the safety and efficacy of treatment with the clinically available anti-PCSK9 monoclonal antibodies (mAbs) in all published randomized clinical trials (RCTs), updating the available results with the recently published ODYSSEY OUTCOMES trial. Data search was carried out using PubMed/MEDLINE and EMBASE (inception - January 2019). Inclusion criteria were: (1) phase 2 or 3 RCTs; (2) comparing anti-PCSK9 mAbs (specifically evolocumab and alirocumab) with placebo; (3) with effects on outcomes reported; (4) with treatment duration longer than 8 weeks. Odds ratios (ORs) with 95% CIs were used as summary statistics. We pooled the estimates by using both the DerSimonian & Laird method (random-effects model). Between-study heterogeneity was tested by Cochrane's Q test and measured with the I2 statistics. Twenty-eight RCTs comprising 62,281 participants (33,204 in the mAb arm, 29,077 in the placebo arm) were included in the meta-analysis. The treatment follow-up ranged from 8 weeks up to 208 weeks. Overall, no significant difference in all-cause mortality was observed between the two groups (OR 0.93 [95% CI, 0.85-1.03]). The treatment with an anti-PCSK9 mAb was associated with a significant reduction of CV events compared with placebo (OR 0.83 [95% CI, 0.78-0.87]), being the FOURIER and ODYSSEY OUTCOMES studies the major contributors. Both myocardial infarction and stroke were significantly reduced following the treatment with an anti-PCSK9 mAb. No significant difference was observed in cardiovascular mortality (OR 0.94 [95% CI, 0.83-1.07]). The incidence of serious adverse events was similar in the two groups (OR: 0.95, [95% CI, 0.91-0.99]). Thus, the pharmacological approach with anti-PCSK9 mAbs significantly and safely improves cardiovascular outcomes. Despite that, the pooled analysis failed to show a significant cardiovascular mortality benefit with anti-PCSK9 mAb treatment, suggesting that specific longer-term studies are warranted to address this issue. We suggest that the observed delay between the rapid effect on plasma cholesterol levels and the emergence of the clinical benefit, observed both in FOURIER and ODYSSEY OUTCOMES trials, might explain this finding.