Rate of major cardiovascular events in RA higher for tofacitinib vs. TNF inhibitors
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Tofacitinib is associated with a numerically higher incidence of major adverse cardiac events, versus TNF inhibitors, in patients with rheumatoid arthritis at an increased cardiac risk, according to data presented at ACR Convergence 2021.
Overall, baseline smoking, aspirin use, male sex and being 65 year or older are the most significant independent risk factors for major adverse cardiac events in patients with RA, the researchers added.
“Today we are talking about the ORAL Surveillance study, which is a randomized, open-label, non-inferiority, Phase 3b/4 safety study that assessed the relative risk of major adverse cardiovascular events, or MACE, and malignancies with tofacitinib 5 mg or 10 mg BID versus TNF inhibition in patients with active, moderate to severe RA despite methotrexate treatment,” Christina Charles-Schoeman, MD, MS, of the University of California, Los Angeles, told attendees at the virtual meeting.
“All patients had an increased risk of MACE; they were greater than or equal to 50 years of age and had at least one additional cardiovascular risk factor,” she added.
To analyze the independent risk factors for major adverse cardiac events in the ORAL Surveillance study, Charles-Schoeman and colleagues randomized 4,362 participants 1:1:1 to receive either tofacitinib (Xeljanz, Pfizer) 5 mg or 10 mg twice daily, or a TNF inhibitor. In all, 1,455 participants were treated with 5 mg of tofacitinib, 1,456 patients received 10 mg, and 1,451 received a TNF inhibitor — either adalimumab (Humira, AbbVie) 40 mg every 2 weeks or etanercept (Enbrel, Amgen) 50 mg every week.
The researchers examined incidence rates and HRs for the co-primary endpoint, defined as adjudicated major adverse cardiac events as well as myocardial infarction and stroke. Major events were defined as cardiovascular death not due to pulmonary embolism, non-fatal myocardial infarction and non-fatal stroke. In addition, the researchers performed a post-hoc analysis to identify independent overall risk factors for major adverse cardiac events across all treatment groups, based on Cox regression models.
Baseline categorical covariates were initially screened in two univariate Cox analyses and were then selected in the final multivariate Cox model using backward selection. Incidence rates and HRs for major events were then stratified by the four most important risk factors.
According to the researchers, major adverse cardiac events were reported in 47 patients in the 5 mg tofacitinib group, 51 patients in the 10 mg group, and among 37 participants receiving a TNF inhibitor. Incidence rates for major events, myocardial infarction, fatal and non-fatal events, and nonfatal myocardial infarction were numerically higher with both tofacitinib doses, compared with TNF inhibitors. Meanwhile, incidence rates for fatal myocardial infarction, as well as stroke — including fatal and non-fatal events — were similar across all treatment groups.
In addition, HRs for major adverse cardiac events, myocardial infarction and stroke were generally greater than one for tofacitinib, compared with TNF inhibitors. According to the researchers, current smoking, aspirin use, age 65 years or older, and male sex at baseline were the most important independent overall risk factors for major adverse cardiac events.
Among participants with one of these risk factors, incidence rates for major events were numerically higher with both tofacitinib doses, compared with TNF inhibitors. Incidence rates for major events were similar across all treatment groups in patients without these risk factors. However, in general, HRs for major events were greater than one for tofacitinib, versus TNF inhibitors, in participants with or without risk factors.
“In patients with RA at an increased risk of MACE — age greater than or equal to 50 years with at least one additional cardiovascular risk factor — incidence of MACE was numerically higher with tofacitinib versus TNF inhibition,” Charles-Schoeman said. “Across treatment groups, the baseline covariates of current smoking, aspirin use, age greater than or equal to 65 years and male sex were identified as the most significant independent overall risk factors for MACE in the multivariate analysis.”
“Tofacitinib treatment in patients with any of these risk factors was associated with a numerically higher incidence of MACE versus TNFi,” she added. “Across treatment groups, MACE and, in particular myocardial infarction, were largely associated with baseline cardiovascular risk. Overall, these data do emphasize the importance of assessing baseline cardiovascular risk when treating patients with RA.”
Perspective
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When deciding on treatment for my patients with rheumatoid arthritis, I utilize a method of screening them for any contraindications to treatment since rheumatic disease therapies often possess some level of risk, such as side effects or contraindications to certain diseases.
Unfortunately, most patients with rheumatic disease, especially RA and lupus, are at risk for developing cardiovascular disease or already possess a degree of it. It is important that we as rheumatology providers continue to be vigilant when treating our patients and consider implementing a strategic approach to identifying cardiovascular risk factors and changing treatments that may exacerbate pre-existing disease.
It is equally important to educate the patient on ways they can modify risk factors, such as exercise, smoking cessation, healthy diet and weight loss, which will ultimately not only improve their rheumatic disease but decrease the risk of a cardiovascular event.
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Charles-Schoeman C. Abstract 0958. Presented at: ACR Convergence 2021; November 5-9, 2021 (virtual meeting).
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