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New ORAL Surveillance data examines CV outcomes in patients without history of atherosclerotic cardiovascular disease.

A new subgroup analysis from the ORAL Surveillance data suggests that patients with no history of atherosclerotic cardiovascular disease are not at increased risk of major adverse cardiovascular events (MACE) when taking JAK inhibitors, despite having cardiovascular risk factors.

Among the original analyses, which led to an FDA JAKi black box warning, it was reported that the incidence of MACE was numerically higher with tofacitinib than TNFi (the numbers were small, and 95% confidence intervals included 1).

The incidence of myocardial infarction (MI) was numerically higher for tofacitinib than TNFi, and that was mostly due to non-fatal MI (HR>2 in both 10mg and 5mg groups). The incidence of stroke was similar across the treatment groups.

In the current analyses, published in Annals of the Rheumatic Diseases, researchers compared MACE risk when taking TNFi vs tofacitinib in patients with or without a history of atherosclerotic cardiovascular disease (ASCVD). ASCVD included coronary artery disease, cerebrovascular disease and peripheral artery disease.

The FDA-mandated post-authorisation ORAL Surveillance safety study, which began in 2014, included almost 4,500 RA patients. They were allocated 1:1:1 to 10mg tofacitinib bid, 5mg tofacitinib bid or TNFi (adalimumab or etanercept). Patients were at least 50 years old and were required to have at least one cardiovascular risk factor, and all were treated with background methotrexate.

A total of 640 patients (almost 15%) of the total cohort had a history of ASCVD, evenly distributed among the three treatment groups (i.e. 5mg tofacitinib BID, 10mg tofacitinib BID and TNFi). Compared with those with no ASCVD history, they were more likely to be aged 65 years or older, male, past smokers and have a history of diabetes, hypertension or hyperlipidaemia.

Among patients with a history of ASCVD, those taking tofacitinib were around twice as likely to report MACE as those in the TNFi group, although numbers were small. For the tofacitinib 5mg BID group the HR was 1.96 (95% CI 0.87-4.40), while the HR for combined tofacitinib was 1.98 (0.95-4.14).

For patients with no history of ASCVD, MACE risk was similar for the tofacitinib 5mg BID group vs TNFi (HR 1.03, CI 0.62-1.73) and slightly raised in the combined tofacitinib group (HR 1.14, CI 0.73-1.78), although again, these were based on small numbers.

There were trends to increased risk for patients with a history of ASCVD taking tofacitinib and experiencing stroke and MI, and likewise for patients without a history of ASCVD taking tofacitinib and MI. But the authors stated the results should be interpreted with caution due to the low number of events.

The authors noted that the findings aligned with some from the STAR-RA observational study, which was based on a real-world cohort.

While STAR-RA reported no increased risk of CV outcomes overall, there was a similar increased risk associated with taking tofacitinib among patients who would have met inclusion and exclusion criteria for ORAL surveillance. Likewise, there was an increased risk of CV outcomes among patients in the STAR-RA cohort with pre-existing CV disease.

The authors pointed to a need for more data on various RA treatments and the risk of MACE in patients with CV risk factors but no history of ASCVD.

“Our post hoc analysis of ORAL Surveillance showed that increased risk of MACE with tofacitinib 5mg and 10mg two times per day versus TNFi was found in patients with a history of ASCVD,” concluded the authors.

“Among patients without a history of ASCVD, who all had prevalent CV risk factors, risk of MACE did not appear to be different comparing tofacitinib 5mg two times per day and TNFi.”

They cautioned, however, that because the analysis was exploratory in nature and had low statistical power, “we cannot exclude any differential MACE risk for tofacitinib 5mg two times per day versus TNFi among patients without [a history of] ASCVD, but any absolute risk excess is likely low.”

Ann Rheum Dis 2022, online 22 September

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