PCSK9 Monoclonal Antibodies for Primary and Secondary Prevention of CVD

Study Population: 24 studies with 60,997 participants at high risk of cardiovascular disease (CVD; previous history of CVD or high low-density lipoprotein [LDL] cholesterol despite treatment)

Efficacy End Points: CVD, all-cause mortality, myocardial infarction (MI), cerebrovascular accident (CVA)

Harm End Points: secondary outcome: adverse effects (eg, influenza, type 2 diabetes, cancer, hypertension)

Narrative: CVD is a leading cause of morbidity and mortality despite lifestyle and pharmacotherapy treatments that effectively lower lipid levels. Some patients are unable to tolerate or do not respond to existing lipid-lowering therapies. Proprotein convertase subtilisin/kexin type 9 (PCSK9) medications increase the removal and elimination of LDL cholesterol, effectively lowering LDL cholesterol levels and theoretically reducing CVD risk. However, their effects on mortality, MI, and CVAs are not well defined, and their safety profile is uncertain.¹

The Cochrane review discussed here includes 24 outpatient trials comparing PCSK9 inhibitors (alirocumab [Praluent] or evolocumab [Repatha]) with either placebo or proven agents (statins, ezetimibe).² All trials except one were industry sponsored, 12 compared alirocumab with placebo, and six compared alirocumab with statins or ezetimibe. Three compared evolocumab with placebo, and three compared evolocumab with statins or ezetimibe.

In trials where PCSK9 medications were compared with placebo, participants in both groups were taking statins and other lipid-lowering agents (eg, ezetimibe); many also received lifestyle counseling before the trial began and continued the interventions through the trial. In these trials, PCSK9 inhibitors were therefore being tested as adjunctive therapy, not stand-alone lipid-lowering therapy.

Most participants were male (71%) with an established history of CVD (93% had prior coronary artery disease or CVA). Approximately 33% had type 2 diabetes.² Placebo-comparison follow-up periods ranged from 6 to 36 months; the ezetimibe plus statin follow-up periods ranged from 6 to 12 months.

Compared with placebo, high-certainty evidence showed alirocumab decreased the risk of CVD events (odds ratio [OR] = 0.87; 95% CI, 0.80–0.94; absolute risk difference [ARD] = 1.5%; number needed to treat [NNT] = 67; 10 studies; n = 23,868), all-cause mortality (OR = 0.83; 95% CI, 0.72–0.96; ARD = 0.6%; NNT = 167; 12 studies; n = 24,797), MI (OR = 0.86; 95% CI, 0.79–0.94; ARD = 1.5%; NNT = 67; nine studies; n = 23,352), and CVA (OR = 0.73; 95% CI, 0.58–0.91; ARD = 0.4%; NNT = 250; eight studies; n = 22,835).