PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis

Abstract

Objective To compare the impact of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on cardiovascular outcomes in adults taking maximally tolerated statin therapy or who are statin intolerant. Design Network meta-analysis. Data sources Medline, EMBASE, and Cochrane Library up to 31 December 2020. Eligibility criteria for selecting studies Randomised controlled trials of ezetimibe and PCSK9 inhibitors with ≥500 patients and follow-up of ≥6 months. Main outcome measures We performed frequentist fixed-effects network meta-analysis and GRADE (grading of recommendations, assessment, development, and evaluation) to assess certainty of evidence. Results included relative risks (RR) and absolute risks per 1000 patients treated for five years for non-fatal myocardial infarction (MI), non-fatal stroke, all-cause mortality, and cardiovascular mortality. We estimated absolute risk differences assuming constant RR (estimated from network meta-analysis) across different baseline therapies and cardiovascular risk thresholds; the PREDICT risk calculator estimated cardiovascular risk in primary and secondary prevention. Patients were categorised at low to very high cardiovascular risk. A guideline panel and systematic review authors established the minimal important differences (MID) of 12 per 1000 for MI and 10 per 1000 for stroke. Results We identified 14 trials assessing ezetimibe and PCSK9 inhibitors among 83 660 adults using statins. Adding ezetimibe to statins reduced MI (RR 0.87 (95% confidence interval 0.80 to 0.94)) and stroke (RR 0.82 (0.71 to 0.96)) but not all-cause mortality (RR 0.99 (0.92 to 1.06)) or cardiovascular mortality (RR 0.97 (0.87 to 1.09)). Similarly, adding PCSK9 inhibitor to statins reduced MI (0.81 (0.76 to 0.87)) and stroke (0.74 (0.64 to 0.85)) but not all-cause (0.95 (0.87 to 1.03)) or cardiovascular mortality (0.95 (0.87 to 1.03)). Among adults with very high cardiovascular risk, adding PCSK9 inhibitor was likely to reduce MI (16 per 1000) and stroke (21 per 1000) (moderate to high certainty); whereas adding ezetimibe was likely to reduce stroke (14 per 1000), but the reduction of MI (11 per 1000) (moderate certainty) did not reach MID. Adding ezetimibe to PCSK9 inhibitor and statin may reduce stroke (11 per 1000), but the reduction of MI (9 per 1000) (low certainty) did not reach MID. Adding PCSK9 inhibitors to statins and ezetimibe may reduce MI (14 per 1000) and stroke (17 per 1000) (low certainty). Among adults with high cardiovascular risk, adding PCSK9 inhibitor probably reduced MI (12 per 1000) and stroke (16 per 1000) (moderate certainty); adding ezetimibe probably reduced stroke (11 per 1000), but the reduction in MI did not achieve MID (8 per 1000) (moderate certainty). Adding ezetimibe to PCSK9 inhibitor and statins did not reduce outcomes beyond MID, while adding PCSK9 inhibitor to ezetimibe and statins may reduce stroke (13 per 1000). These effects were consistent in statin-intolerant patients. Among moderate and low cardiovascular risk groups, adding PCSK9 inhibitor or ezetimibe to statins yielded little or no benefit for MI and stroke. Conclusions Ezetimibe or PCSK9 inhibitors may reduce non-fatal MI and stroke in adults at very high or high cardiovascular risk who are receiving maximally tolerated statin therapy or are statin-intolerant, but not in those with moderate and low cardiovascular risk.

PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified recommendations

“…The panel decided that patients and clinicians should consider new lipid-lowering drugs (either a PCSK9 inhibitor or ezetimibe) after statins. The panel proposed a systematic review and network meta-analysis of randomised controlled trials on the comparative effectiveness of PCSK9 inhibitors or ezetimibe versus no PCSK9 inhibitors or ezetimibe on cardiovascular benefits 13. Only trials following patients for ≥6 months and including ≥500 patients were included.…”

“…The systematic review with network meta-analysis included 14 RCTs (93% were industry funded) including 83 660 individuals with or without established cardiovascular diseases. Table 1 shows the characteristics of patients and studies, also available in the systematic review 13…”

BMJ Rapid Recommendations on use of proprotein convertase subtilisin/kexin 9 inhibitors and ezetimibe to reduce cardiovascular risk

“…The panel selected four separate outcomes, rather than a composite: non-fatal MI, non-fatal stroke, all-cause mortality and cardiovascular mortality. Two separate reviews addressed adverse outcomes 1 6. The panellists used assumptions supported by previous studies reporting the expected general distributions for different events.…”

“…The new BMJ Rapid Recommendations addressed the following question: should we add another lipid-lowering drug in adults with low-density lipoprotein-cholesterol (LDL-C) over 1.8 mmol/L using a maximal dose of statins or intolerant to statins?1 Why is this question important? Both proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe have been shown to reduce LDL-C by approximately 60% and approximately 20%, respectively, and correspondingly may reduce major adverse cardiovascular events (MACE), including all-cause death, cardiovascular death, myocardial infarction (MI) and stroke.…”

Improving Cardiovascular Outcomes: The Era of Personalized Therapy in Atherosclerosis

“…The identification of new risk factors, and their associations with atherosclerosis progression or triggering adverse cardiovascular events, led to the introduction of novel, more effective treatment agents [ 13 , 14 ]. Introduction of hypercholesterolemia management with statins, and more recently with protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and/or diabetes treatments with new noninsulin glucose-lowering drugs, and many others are effective in a reduction of cardiovascular morbidity and mortality [ 13 , 14 ]. In consequence, improved management strategies and decision-making algorithms are continuously introduced.…”