A large new Cleveland Clinic study has found no link between small molecule medications like tofacitinib or upadicitinib and major adverse cardiovascular events (MACE) in patients with inflammatory bowel disease (IBD), contradicting previous concerns about this class of drugs. Even more surprisingly, researchers found that biologic therapies for IBD were associated less with cardiovascular events.
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“The findings add to the evidence that it may be the underlying inflammation itself that leads to increased rates of cardiovascular events for patients with IBD and not the medications,” says Miguel Regueiro, MD, the Chief of the Digestive Disease Institute at Cleveland Clinic, and senior author on the paper. He added that the large size of the study should give physicians confidence that they can safely use tofacitinib, upadicitinib and ozanimod small molecules treatment for conditions like ulcerative colitis — and that biologics may have a protective effect.
“Our study looks at a large group of patients with all kinds of underlying risk factors, and the fact that we’re not seeing any signal increase is reassuring to me,” Dr. Regueiro says. “I always hesitate to use the word ‘definitive’ in medicine, but I think that growing evidence makes me feel much more comfortable that, to date, the risk of cardiovascular events and clots with these agents has not been established.”
The study, “Biologic and Small Molecule Therapies Are Not Associated With Increased Major Adverse Cardiovascular Events (MACE) in IBD: A Propensity Matched Cohort Study,” was presented in the Presidential Plenary Session at the annual meeting of the American College of Gastroenterology in October.
Patients with IBD historically have higher rates of major cardiovascular events like venous thromboembolism, deep venous thrombosis, pulmonary embolism and stroke. Still, it was unclear whether that increased risk was due to underlying inflammation or other factors.
But when an earlier study found higher rates of blood clots and cardiovascular events in rheumatoid arthritis patients who took tofacitinib, a Janus kinase inhibitor, it raised concerns about the drug.
“Overnight, the FDA changed the labeled use for tofacitinib for any condition — including rheumatoid arthritis, Crohn’s disease, ulcerative colitis — and said that the patient has to be on a Tumor Necrosis Factor (TNF) inhibitor first,” Dr. Regueiro says.
No similar concerns had been raised about biologics, but Dr. Regueiro’s team decided to take a broad look at the therapies used to treat IBD, and assess their association with cardiovascular risk, using a large data set of real-world patients, the TrinNetX multi-institutional database.
Researchers identified 3,194 Crohn’s and ulcerative colitis patients who received oral small molecule therapies, including tofacitinib, upadacitinib and ozanimod, and compared them with the same number of patients who did not receive these medications. They found no significant difference in cardiovascular outcomes between these groups, including coronary artery disease, myocardial infarction, stroke, and venous thromboembolism (either DVT or PE).
They then compared 67,607 patients who received biologics including infliximab, adalimumab, golimumab, certolizumab, vedolizumab, vedolizumab, natalizumab, or ustekinumab, with the same number of patients who did not. The biologics group had lower rates of adverse cardiovascular outcomes across the board. These included coronary artery disease (4.75% with biologics vs. 6.71% without), myocardial infarction (1.33% vs. 1.98%), stroke (1.46% vs 2.04%) and venous thromboembolism (4.44% vs 5.2%).
“I was surprised to see with the biologics such a significant decrease,” Dr. Regueiro says. “But that also makes us think that healing and improving inflammation may lead to better outcomes regarding blood clots and cardiovascular events.”
While novel in its size, Dr. Reguiero notes that his team’s study was not the first to raise doubts about the supposed link between tofacitinib and cardiovascular risk. A postmarketing study and long-term follow-up study have also previously found no significant increase in cardiovascular events.
“I think those who treat IBD feel that the small molecules, tofacitinib and upadicitinib, should be allowable as first-line treatment for IBD, without having to use a TNF inhibitor first,” he says.
Dr. Regueiro plans to repeat the study in several years when the data set is larger. “If that still doesn’t show anything, then I would say it’s definitive,” he says.