Association of ustekinumab and briakinumab with major adverse cardiovascular events An appraisal of meta-analyses and industry sponsored pooled analyses to date

Safety concerns have been raised regarding possible association of major adverse cardiovascular events (MACEs) with use of anti-IL-12/ 23 biologic agents for the treatment of chronic plaque psoriasis (CPP). Ten MACEs have been recorded in actively-treated patients during the placebo-controlled phase of phase II and III studies compared with zero events in placebo-treated patients, along with a total of 53 MACEs (26 ustekinumab, 27 briakinumab) and five cardiovascular deaths (1 ustekinumab, 4 briakinumab) across all phases of these studies. Two industry-independent meta-analyses of randomized, double-blind, placebo-controlled, monotherapy trials calculated risk for MACEs. One detected statistically significant increase in cardiovascular risk using Peto method (p = 0.04), while the other utilized Mantel-Haenszel fixed-effects model with absolute risk differences as effect measure, but did not achieve significance (p = 0.11). Statistical theory reports that Peto method is more suitable for meta-analyses of studies with baseline event rates of 1% or less and randomization ratios ranging from 1: 5 to 1: 1 as is the case in these meta-analyses. Potential of anti-IL-12/ 23 biologic agents to further increase cardiovascular morbidity cannot be excluded and a class effect cannot be denied. Clinicians should screen CPP patients for manageable cardiovascular risk factors before initiating anti-IL-12/ 23 agents along with intensive monitoring of these patients.