Association Between Biologic Therapies for Chronic Plaque Psoriasis and Cardiovascular Events: A Meta-Analysis of Randomized Controlled Trials

Study Questions:

What is the possible association between biologic therapies for chronic plaque psoriasis (CPP) and major adverse cardiovascular events (MACE)?

Methods:

Randomized controlled trials (RCTs) of anti–interleukin (IL)-12/23 (ustekinumab and briakinumab) agents and anti–tumor necrosis factor alpha (TNF-α) agents (adalimumab, etanercept, and infliximab) used in treating CPP were reviewed using the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Ovid MEDLINE from database inception to May 2011. The results of registered nonpublished completed studies were procured through abstract publications or poster presentations. Two investigators independently searched data while six investigators reviewed the abstracted data. Absolute risk differences were used as an effect measure, measuring the excess probability of MACE in those receiving active treatment compared with those receiving placebo.

Results:

A total of 22 RCTs comprising 10,183 patients met the predefined inclusion criteria. The primary outcome measure was MACE, a composite endpoint of myocardial infarction, cerebrovascular accident, or cardiovascular death during the placebo-controlled phase of treatment in patients receiving at least one dose of study agent or placebo. Absolute risk differences were used as an effect measure. There was no evidence of statistical heterogeneity across the studies using the I2 statistic (I2 = 0), allowing for combination of trial results using the Mantel-Haenszel fixed-effects method. During the placebo-controlled phases of the anti–IL-12/23 studies, 10 of 3,179 patients receiving anti–IL-12/23 therapies experienced MACE compared with zero events in 1,474 patients receiving placebo (Mantel-Haenszel risk difference, 0.012 events/person-year; 95% confidence interval [CI], −0.001 to 0.026; p = 0.12). In the anti–TNF-α trials, only 1 of 3,858 patients receiving anti–TNF-α agents experienced a MACE compared with 1 of 1,812 patients receiving placebo (Mantel-Haenszel risk difference, −0.0005 events/person-year; 95% CI, −0.010 to 0.009; p = 0.94).

Conclusions:

The authors concluded that compared with placebo, there was no significant difference in the rate of MACE observed in patients receiving anti–IL-12/23 antibodies or anti–TNF-α treatments.

Perspective:

This meta-analysis did not show a significant increase in the risk of MACE associated with the use of anti–IL-12/23 agents. It should be noted that access to patient-level data for these studies was not granted by any of the study sponsors, which prevented the use of a more statistically robust time-to-event analysis, and the study may also have been underpowered to identify a significant difference in MACE. This analysis highlights the inherent limitations of placebo-controlled clinical trials to reliably interpret the significance of rare events, and clinicians need to carefully weigh the benefits versus the concern of increased cardiovascular events with biological therapies to best serve patients with psoriasis.

Clinical Topics: Novel Agents

Keywords: Antibodies, Monoclonal, Humanized, Myocardial Infarction, Psoriasis, Biological Markers, Interleukin-12, Biological Therapy, Interleukin-23, Tumor Necrosis Factor-alpha


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