Review: In dyslipidemia or atherosclerotic CVD, alirocumab and evolocumab vs control each reduce MI and stroke

Abstract

Question In adults with dyslipidemia or atherosclerotic cardiovascular disease (ASCVD), what are the efficacy and safety of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors? Review scope Included studies compared US Food and Drug Administrationapproved PCSK9 inhibitors (alirocumab and evolocumab) with placebo or another lipid-lowering drug in adults with dyslipidemia or atherosclerotic CVD. Primary efficacy outcomes were all-cause and cardiovascular (CV) mortality, myocardial infarction (MI), and stroke. Primary safety outcomes were study drug discontinuation, neurocognitive adverse events, elevated liver enzymes, and rhabdomyolysis. PROSPERO CRD42018090768. Review methods MEDLINE, CENTRAL, ClinicalTrials.gov, and international conference abstracts were searched to March 2018 for phase 2 or 3 randomized controlled trials (RCTs). 39 RCTs (n =66478, mean age 61 y, 54% men) met inclusion criteria. 22 (n =27097) evaluated alirocumab and 17 (n =39381) evolocumab, each combined with maximally tolerated statin therapy or another lipid-lowering therapy. Follow-up or treatment duration was 8 to 208 weeks (alirocumab, median 24 wk; evolocumab, median 12 wk). 31 RCTs included a placebo control; other control groups received ezetimibe, double-dose statins, or usual care. {19 trials had adequate allocation concealment, 36 blinded patients and physicians, 39 blinded outcome assessors, and 32 had adequate completeness of data}*. Main results The main results are in the Table. Conclusion In adults with dyslipidemia or atherosclerotic CVD, alirocumab and evolocumab each reduce myocardial infarction and stroke compared with placebo or another treatment. PCSK9 inhibitors (alirocumab or evolocumab) vs control (placebo or another treatment) in adults with dyslipidemia or atherosclerotic CV disease Outcomes Number of trials (n) Events/100 patient-y At a mean weighted follow-up of 2.3 y PCSK9 inhibitors Control RRR (95% CI) NNT (CI) All-cause mortality 39 (66478) 1.03 1.15 11% (4 to 25) NS CV mortality 37 (64707) 0.66 0.73 6% (6 to 16) NS Myocardial infarction 25 (61784) 1.49 1.93 20% (14 to 26) 103 (79 to 147) Ischemic stroke 23 (60328) 0.44 0.58 22% (11 to 33) 306 (204 to 611) Elevated liver enzymes 34 (63807) 0.73 0.73 6% (6 to 16) NS Rhabdomyolysis 12 (23526) 0.14 0.14 10% (31 to 38) NS RRI (CI) NNH (CI) Study drug discontinuation 36 (60908) 1.26 1.07 4% (5 to 15) NS Neurocognitive adverse events 24 (62480) 0.57 0.55 1% (16 to 21) NS CV = cardiovascular; NS = not significant; PCSK9 = proprotein convertase subtilisin/kexin type 9; other abbreviations defined in Glossary. RRR, RRI, NNT, and CI calculated from control event rates and risk ratios in article using a random-effects model. Interactions between type of drug (alirocumab or evolocumab) and treatment effect were not significant unless noted otherwise. P interaction =0.03 for drug type and treatment effect: alirocumab vs control, risk ratio 0.83 (CI 0.72 to 0.95); evolocumab vs control, risk ratio 1.03 (CI 0.90 to 1.17). Commentary In a well-done meta-analysis, Guedeney and colleagues showed that PCSK9 inhibitors, with or without concomitant statin therapy, achieved impressive relative risk reductions in MI (20%), ischemic stroke (22%), and coronary revascularization (17%) over a mean weighted follow-up of 2.3 years; the decrease in low-density lipoprotein cholesterol (LDL-C) levels was 76 mg/dL (2.0 mmol/L). Results were similar to a meta-analysis of cholesterol-lowering treatments, including early statin trials, which found a 24% 2-year reduction in ischemic heart disease death and nonfatal MI, standardized to a 1-mmol/L (39-mg/dL) LDL-C decrease (1). The first statin trial (4S) to show a CV mortality relative risk (RR) reduction (42%), with a 35% reduction in LDL-C levels, had a median follow-up of 5.4 years and a number-needed-to-treat (NNT) of 15 to prevent 1 additional major coronary event (2). In Guedeney and colleagues review, alirocumab studies (mean weighted follow-up 3.1 y) trended toward reducing CV mortality (RR 0.86, 95% CI 0.73 to 1.02), whereas evolocumab studies (mean weighted follow-up 1.7 y) did not (RR 1.04, CI 0.87 to 1.23, P interaction =0.13), emphasizing the importance of treatment duration in comparing clinical outcomes in 2 agents with similar LDL-C-lowering potency. The high NNT to prevent 1 additional MI (NNT 103) or stroke (NNT 306) with PCSK9 inhibitors may be due to a lower-risk population in, or the shorter duration of, these studies. Whether longer-term prevention with PCSK9 inhibitors will be cost-effective for preventing clinical events remains to be shown. The 2 PCSK9 inhibitors were associated with short-lived injection site inflammation but not neurocognitive dysfunction or side effects associated with statins: rhabdomyolysis, liver enzyme elevations, or new-onset diabetes mellitus. In the USA, the drugs are much more expensive than generic statins or ezetimibe. The GLAGOV trial evaluated evolocumab and statins in 846 patients with coronary disease and used intravascular ultrasonography to measure 18-month growth patterns in a nonobstructive coronary plaque based on attained LDL-C levels from 30 to 110 mg/dL (3). Figure 4 in the published article (3) may help motivate patients to continue lipid-lowering medications because the patterns support previous studies showing that the average coronary plaque stops growing at LDL-C levels of 80 mg/dL (2.1 mmol/L) and all plaques shrink at LDL-C <60 mg/dL (1.6 mmol/L).