WAIKOLOA, HAWAII – The anti-interleukin-12/23 biologic agents ustekinumab and briakinumab were associated with a statistically significant 4.23-fold increased risk of major adverse cardiac events in the latest meta-analysis of placebo-controlled clinical trials conducted in patients with chronic plaque psoriasis.
"What are the implications? It’s probably a class effect. That’s the way I practice. I think there is a slightly increased risk of myocardial infarction in our anti-IL-12/23-treated patients. So I think you should consider all of your options when selecting a biologic therapy. We know that our psoriasis patients typically have multiple cardiac risk factors, and that TNF antagonists are cardioprotective," Dr. Craig L. Leonardi said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.
Dr. Craig Leonardi
The latest industry-independent meta-analysis (J. Eur. Acad. Dermatol. Venereol. 2013;27:622-7), led by dermatologists at Dessau (Germany) Medical Center, examined the same nine phase-II and phase-III placebo-controlled randomized trials scrutinized in an earlier meta-analysis, also industry independent, carried out by Dr. Leonardi and coinvestigators (JAMA 2011;306:864-71).
The earlier meta-analysis identified 10 major adverse cardiovascular events (MACE) in 3,179 IL-12/23-treated subjects and none among 1,474 placebo-treated controls. This signal was deemed not statistically significant, although Dr. Leonardi and coworkers noted that their meta-analysis may have been underpowered to detect a small increase in risk.
Given that the two meta-analyses relied upon essentially the same data, how did they reach such different conclusions? It’s all in the statistical methods. Without getting geeky about the statistical fine points, Dr. Leonardi noted that his group used the Mantel-Haenszel fixed-effects model, while the Dessau group employed the Peto method, which their statisticians deemed more appropriate on the basis of its previously established superior performance in detecting rare events.
The Peto method is named for Sir Richard Peto, a renowned University of Oxford epidemiologist knighted for his statistical contributions.
Dr. Leonardi, a dermatologist in private practice in St. Louis and a clinical professor of dermatology at Saint Louis University, wasn’t about to quibble about statistics. Taken together, he said, the story conveyed by the two meta-analyses is one of a small but real increase in the absolute risk of MACE in psoriasis patients exposed to anti-IL-12/23 biologics. Based upon this evidence, when he starts a psoriasis patient on ustekinumab (Stelara), he now generally does so at the lower 45-mg dose regardless of the patient’s weight, even though the 90-mg dose is approved for use in patients weighing more than 100 kg.
"And I’m placing my patients on aspirin at 81 mg/day while we await further data," he added.
He anticipates that clinically meaningful data will eventually come from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) study, an ongoing observational registry that has enrolled nearly 12,000 psoriasis patients for a planned follow-up period of at least 8 years at 266 investigative sites in 15 countries. The Janssen-funded registry includes roughly 3,800 patients on ustekinumab, lesser numbers on the other biologics, as well as a large group on phototherapy and no biologics.
Dr. Leonardi presented an early interim analysis in which the rate of MACE in the ustekinumab group was 0.28 per 100 patient-years. This was numerically slightly lower than but still comparable to the rates observed with infliximab and other biologics, and half the rate in patients on no biologics. He stressed, however, that these are unadjusted rates. Planned formal comparisons will require longer follow-up periods, more MACE, and multivariate analysis to control for baseline differences in comorbid conditions and cardiovascular risk factors. The no-biologics group, for example, was significantly older than patients on biologic agents, because once patients become Medicare eligible it is quite difficult to get a prescription for a biologic. And of course cardiovascular risk climbs with advancing age.
Dr. Leonardi is a PSOLAR coinvestigator, and a big fan of the project’s potential.
"Don’t wait for an NIH-sponsored disease-specific registry. The fact is the government is not going to fund it, so we have to do the best we can with the tools we have. PSOLAR is the largest psoriasis registry in the world. It will allow us to answer questions about the emergence of comorbid diseases like psoriatic arthritis and cardiovascular disease, and treatment-specific questions like rates of infection, cancer, and MACE, as well as unanticipated issues nobody knew about," he said.
Dr. Leonardi disclosed ties with Janssen and nearly two dozen other pharmaceutical companies.
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