JAK Inhibitors Show No Excess Cardiovascular Safety Signal in French Nationwide Cohort

Will Pass

October 19, 2022

JAK inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.

The French data, which included almost 16,000 patients with rheumatoid arthritis (RA), revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, France, and colleagues.

These findings arrive 1 year after the US Food and Drug Administration (FDA) imposed class-wide boxed warnings on three JAK inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.

More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.

"In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents," Hoisnard and colleagues write in Annals of the Rheumatic Diseases .

Their retrospective study included 8481 patients who received baricitinib or tofacitinib, and 7354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.

Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs 35 MACEs; weighted hazard ratio [HRw], 1.0; 95% CI, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).

These findings held consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.

Findings From Echo ORAL Surveillance

"I think the baricitinib data are important," Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told Medscape Medical News. "There's no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn't really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial."

Dr Kevin Winthrop

Winthrop, who has been active in JAK inhibitor clinical trials, recently co-authored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.

He and his co-author also called into question the FDA's "better to be safe than sorry" approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.

"There are pros and cons of taking that approach," Winthrop said in an interview. "The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they're similar with regard to malignancy or cardiovascular events, I don't think we know."

Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA's approach. The agent headlines as a "TYK2 inhibitor," but TYK2 is a member of the JAK family.

"I don't know why the FDA decided to treat them differently," Winthrop said.

Boxed Warnings Encourage Caution, Lock Treatment Sequence

Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.

"It forces you to have that discussion with your patient, which may take some time, but it's actually a very good thing," Thakor said in an interview. "Some patients will say, 'Oh my gosh, I don't want to take that drug.' But most patients, considering the level of risk that you're talking about, are actually okay going ahead with the medication."

If these risks aren't discussed, he noted, patient trust may falter.

"They're going to go online, and they're going to be reading about it," Thakor said. "And then they tend to get more spooked. They also may question your advice from then on, if you're not telling them the possible risk."

Reflecting on the present study, Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.

Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don't take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don't alter this picture in daily practice.

"If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor," Thakor said. "If the patient is comfortable with it, then I would feel comfortable going ahead."

The investigators disclosed no outside funding or conflicts of interest. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Thakor disclosed no conflicts of interest.

Ann Rheum Dis. Published online October 5, 2022. Abstract

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