Meta-analysis of PCSK9 inhibition in treatment of dyslipidaemia shows mortality benefit
Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis
Literature - Navarese EP et al., Ann Intern Med 2015
Navarese EP, Kołodziejczak M, Schulze V, et al.
Ann Intern Med. Published online 28 April 2015 doi:10.7326/M14-2957
Background
Intensive statin treatment is known to delay atherosclerotic plaque development and lower the risk of cardiovascular (CV) complications, but a considerable proportion of statin-treated patients does not achieve recommended target LDL-c levels, or they discontinue treatment owing to drug-related side-effects [1-3].
Inhibiting the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9) with monoclonal antibodies has been shown in randomised controlled trials (RCTs) to yield marked reductions in LDL-c levels [4-6]. Inhibition of PCSK9 via antibody binding prevents degradation of the LDL receptor, with a consequential increase in LDL-c clearing. Three PCSK9 inhibitors are in development and currently undergoing regulatory review: evolocumab, alirocumab and bococizumab.
This is a systematic review and meta-analysis (following Cochrane guidelines) of RCTs that evaluated the efficacy and safety of treatment with PCSK9 antibodies, with a focus on their effect on clinical outcomes. Anti-PCSK9 treatment was compared with either placebo or ezetimibe, in patients who did not meet LDL-c targets on statins or not tolerating statins. 24 studies comprising 10159 patients with hypercholesterolaemia were included in the analysis, of which 8 trials were phase 2, and 16 were phase 3 trials. 17 trials had follow-up shorter than 6 months, 2 studies were 6-12 months, and 4 were longer than 1 year, with the longest follow-up being 104 weeks. The OSLER trial was not included, since this study enrolled patients derived from previous RCTs.
Main results
- Overall, use of PCSK9 antibodies was associated with a significant reduction in all-cause mortality: 0.31% (19/1687) in anti-PCSK9-treated vs. 0.53% (21/3971) no anti-PCSK9 patients (OR: 0.45, 95%CI: 0.23-0.86, P=0.015). No inconsistency was detected across trials (I2=0%). An analysis adjusted for follow-up showed the consistency of the result (OR: 0.48, 95%CI: 0.27-0.85, P=0.010).
- A statistically non-significant reduction in CV mortality was seen with use of PCSK9 antibodies: 0.19% (12/6187) vs. 0.33% (13/3972) in patients with no anti-PCSK9 treatment (OR: 0.50, 95%CI: 0.23-1.10, P=0.084) (I2=0%). Adjusting for follow-up yielded consistent results (OR: 0.49, 95%CI: 0.23-1.07, P=0.070).
- PCSK9-inhibition resulted in a statistically significant reduction of the secondary safety end point myocardial infarction as compared with no anti-PCSK9 treatment (OR: 0.49, 95%CI: 0.26-0.93, P=0.030), but not unstable angina (OR: 0.61, 95%CI: 0.06-6.14, P=0.676).
- Fewer patients with anti-PCSK9 treatment had increased creatine kinase levels (1.96% ) than those not on PCSK9 antibodies (2.31%, OR: 0.72, 95%CI: 0.54-0.96, P=0.026).
- The overall incidence of serious adverse events was similar in anti-PCSK9 treated and in those not treated with anti-PCSK9 antibodies (OR: 1.01, 95%CI: 0.87-1.18, P=0.879), and average discontinuation rates were not higher in patients on PCSK9-inhibition than among patients receiving placebo or ezetimibe.
- Efficacy end point results showed an overall reduction of 47,49% (95%CI: -69.64% to -25.35%, P<0.001) in LDL-c with PCSK9-inhibition, with a larger reduction when compared to placebo (-58.77%) than compared with ezetimibe (-36.17%).
In 14 studies (4378 patients) assessing the effect of PCSK9-inhibition on HDL-c, an increase of 6.30% (95%CI: 5.58% - 7.02%, P<0.001) was seen as compared with no treatment with PCSK9 antibodies.
PCSK9 antibodies gave a 31.49% (95%CI: -46.35% to -16.64%, P<0.001) reduction in total cholesterol as compared with no anti-PCSK9 treatment (10 studies, 5357 patients).
A reduction of 26.45% (95%CI: -30.19% to -22.71%, P<0.001) in lipoprotein(a) was seen with anti-PCSK9 treatment, as compared with no anti-PCSK9 treatment.
Conclusion
This meta-analysis shows that use of antibodies directed at PCSK9, compared with no anti-PCSK9 treatment, is associated with lower risk of all-cause mortality and myocardial infarction. Additionally, lower increase of serum creatine kinase levels is seen, and a marked reduction in atherogenic lipid fractions. Serious adverse events are not more often seen with than without PCSK9 inhibition. Thus, anti-PCSK9 monoclonal antibodies seems to be a safe and effective therapy of dyslipidaemia.
This large-scale report is the first analysis of the novel PCSK9 antibodies that shows an all-cause mortality benefit. Although preliminary, these data are encouraging, also because a similar reduction in the odds of CV mortality was seen.
Editorial comment [7]
The authors regard the reduction in all-cause mortality rates, CV mortality and myocardial infarctions as the most remarkable finding of the meta-analysis, but warn that these encouraging results should be interpreted with caution. “Included trials were of small or moderate size and mostly had shortfollow-up periods. The total number of events was small (for example, the results for all-cause mortality were based on only 40 events), several studies did not report any events at all, and quantitative pooling of rare events remains a challenging task. Moreover, the trials that were summarized were not specifically designed or powered to assess and detect differences in clinical
outcomes or rare adverse events.”
Trials with long follow-up periods together with real-world experience is furthermore needed to learn more about the long-term adverse effects of sustained PCSK9 inhibition. The current meta-analysis provides important preliminary information on clinical outcomes, as the U.S. Food and Drug Administration considers approval of PCSK9 inhibitors for clinical use. These findings need to be confirmed in long-term, ongoing trials with prespecified CVD end points, that monitor adverse events, to help establish the role of these novel agents in CVD risk management.
Find this article online at Annals of Internal Medicine
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