Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta-Analysis of 35 Randomized Controlled Trials

Aris Karatasakis, Barbara A Danek, Judit Karacsonyi, Bavana V Rangan, Michele K Roesle, Thomas Knickelbine, Michael D Miedema, Houman Khalili, Zahid Ahmad, Shuaib Abdullah, Subhash Banerjee, Emmanouil S Brilakis, Aris Karatasakis, Barbara A Danek, Judit Karacsonyi, Bavana V Rangan, Michele K Roesle, Thomas Knickelbine, Michael D Miedema, Houman Khalili, Zahid Ahmad, Shuaib Abdullah, Subhash Banerjee, Emmanouil S Brilakis

Abstract

Background: We sought to examine the efficacy and safety of 2 PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab.

Methods and results: We performed a systematic review and meta-analysis of randomized controlled trials comparing treatment with and without PCSK9 inhibitors; 35 randomized controlled trials comprising 45 539 patients (mean follow-up: 85.5 weeks) were included. Mean age was 61.0±2.8 years, and mean baseline low-density lipoprotein cholesterol was 106±22 mg/dL. Compared with no PCSK9 inhibitor therapy, treatment with a PCSK9 inhibitor was associated with a lower rate of myocardial infarction (2.3% versus 3.6%; odds ratio [OR]: 0.72 [95% confidence interval (CI), 0.64-0.81]; P<0.001), stroke (1.0% versus 1.4%; OR: 0.80 [95% CI, 0.67-0.96]; P=0.02), and coronary revascularization (4.2% versus 5.8%; OR: 0.78 [95% CI, 0.71-0.86]; P<0.001). Overall, no significant change was observed in all-cause mortality (OR: 0.71 [95% CI, 0.47-1.09]; P=0.12) or cardiovascular mortality (OR: 1.01 [95% CI, 0.85-1.19]; P=0.95). A significant association was observed between higher baseline low-density lipoprotein cholesterol and benefit in all-cause mortality (P=0.038). No significant change was observed in neurocognitive adverse events (OR: 1.12 [95% CI, 0.88-1.42]; P=0.37), myalgia (OR: 0.95 [95% CI, 0.75-1.20]; P=0.65), new onset or worsening of preexisting diabetes mellitus (OR: 1.05 [95% CI, 0.95-1.17]; P=0.32), and increase in levels of creatine kinase (OR: 0.84 [95% CI, 0.70-1.01]; P=0.06) or alanine or aspartate aminotransferase (OR: 0.96 [95% CI, 0.82-1.12]; P=0.61).

Conclusions: Treatment with a PCSK9 inhibitor is well tolerated and improves cardiovascular outcomes. Although no overall benefit was noted in all-cause or cardiovascular mortality, such benefit may be achievable in patients with higher baseline low-density lipoprotein cholesterol.

Keywords: PCSK9; alirocumab; evolocumab; hyperlipidemia; outcome.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1
Figure 1
Timeline of randomized controlled trials of alirocumab and evolocumab. FDA indicates US Food and Drug Administration; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia.
Figure 2
Figure 2
All‐cause mortality. Forrest plot showing the odds ratio for all‐cause mortality with PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors (PCSK9i) compared with no PCSK9i. The pooled odds ratio was calculated with random effects according to the Mantel‐Haenszel (M‐H) method. Marker size is proportional to the study weight. CI indicates confidence interval.
Figure 3
Figure 3
Study‐level metaregression analysis with random effects showing the relationship between baseline low‐density lipoprotein cholesterol (LDL‐C) and all‐cause mortality. Circle size is proportional to the study weight; 95% confidence intervals shown in blue.
Figure 4
Figure 4
Cardiovascular mortality. Forrest plot showing the odds ratio for cardiovascular mortality with PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors (PCSK9i) compared with no PCSK9i. The pooled odds ratio was calculated with random effects according to the Mantel‐Haenszel (M‐H) method. Marker size is proportional to the study weight. CI indicates confidence interval.
Figure 5
Figure 5
Myocardial infarction. Forrest plot showing the odds ratio for myocardial infarction with PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors (PCSK9i) compared with no PCSK9i. The pooled odds ratio was calculated with random effects according to the Mantel‐Haenszel (M‐H) method. Marker size is proportional to the study weight. CI indicates confidence interval.
Figure 6
Figure 6
Stroke. Forrest plot showing the odds ratio for stroke with PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors (PCSK9i) compared with no PCSK9i. The pooled odds ratio was calculated with random effects according to the Mantel‐Haenszel (M‐H) method. Marker size is proportional to the study weight. CI indicates confidence interval.
Figure 7
Figure 7
Coronary revascularization. Forrest plot showing the odds ratio for coronary revascularization with PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors (PCSK9i) compared with no PCSK9i. The pooled odds ratio was calculated with random effects according to the Mantel‐Haenszel (M‐H) method. Marker size is proportional to the study weight. CI indicates confidence interval.
Figure 8
Figure 8
Neurocognitive adverse events. Forrest plot showing the odds ratio for neurocognitive adverse events with PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors (PCSK9i) compared with no PCSK9i. The pooled odds ratio was calculated with random effects according to the Mantel‐Haenszel (M‐H) method. Marker size is proportional to the study weight. CI indicates confidence interval.

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