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

Caitriona Ryan, MB, BAO, BCh; Craig L. Leonardi, MD; James G. Krueger, MD, PhD; Alexa B. Kimball, MD, MPH; Bruce E. Strober, MD, PhD; Kenneth B. Gordon, MD; Richard G. Langley, MD; James A. de Lemos, MD; Yahya Daoud, MA; Derek Blankenship, PhD; Salahuddin Kazi, MD; Daniel H. Kaplan, MD, PhD; Vincent E. Friedewald, MD; Alan Menter, MD
JAMA. 2011;306(8):864-871. doi:10.1001/jama.2011.1211.
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Context Ustekinumab and briakinumab, monoclonal antibodies to the shared p40 subunit of interleukin (IL)-12 and IL-23, have shown efficacy in treating chronic plaque psoriasis (CPP). Preliminary reports of major adverse cardiovascular events (MACEs) in psoriasis patients receiving anti–IL-12/23 agents have prompted concern.

Objective To evaluate a possible association between biologic therapies for CPP and MACEs via meta-analysis.

Data Sources Randomized controlled trials (RCTs) of anti–IL-12/23 (ustekinumab and briakinumab) agents and anti–tumor necrosis factor α (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.

Study Selection Randomized, placebo-controlled, double-blind, monotherapy studies (with safety outcome data for MACE) of IL-12/23 antibodies and anti–TNF-α agents in adults. Studies of psoriatic arthritis were excluded.

Data Extraction Two investigators independently searched data while 6 investigators reviewed the abstracted data.

Results A total of 22 RCTs comprising 10 183 patients met the predefined inclusion criteria. The primary outcome measure was MACE, a composite end point of myocardial infarction, cerebrovascular accident, or cardiovascular death during the placebo-controlled phase of treatment in patients receiving at least 1 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 3179 patients receiving anti–IL-12/23 therapies experienced MACEs compared with zero events in 1474 patients receiving placebo (Mantel-Haenszel risk difference, 0.012 events/person-year; 95% confidence interval [CI], −0.001 to 0.026; P =.12). In the anti–TNF-α trials, only 1 of 3858 patients receiving anti–TNF-α agents experienced a MACE compared with 1 of 1812 patients receiving placebo (Mantel-Haenszel risk difference, −0.0005 events/person-year; 95% CI, −0.010 to 0.009; P = .94).

Conclusions Compared with placebo, there was no significant difference in the rate of MACEs observed in patients receiving anti–IL-12/IL-23 antibodies or anti–TNF-α treatments. This study may have been underpowered to identify a significant difference.

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Figure 1. PRISMA Flowchart of Studies Included in Meta-analysis
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aA sensitivity analysis excluding these 3 studies was also performed. PRISMA indicates Preferred Reporting Items for Systematic Reviews and Meta-analyses.

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Figure 2. Risk Difference of MACEs in Patients Treated With Anti–IL-12/23 Agents Compared With Placebo in RCTs
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Mantel-Haenszel fixed-effects method used to calculate risk difference, person-years of events. MACE indicates major adverse cardiovascular event; IL, interleukin; RCTs randomized controlled trials; CI, confidence interval.

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Figure 3. Risk Difference of MACEs in Patients Treated With Anti–TNF-α Agents Compared With Placebo in RCTs
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Mantel-Haenszel fixed-effects method used to calculate risk difference, person-years of events. CI indicates confidence interval; MACE, major adverse cardiovascular event; RCTs, randomized controlled trials; TNF, tumor necrosis factor.

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