Oral Surveillance Study Alters Practice at VA Save

Safety risks found in a postmarketing trial with the Janus-associated kinase (JAK) inhibitor tofacitinib (Xeljanz) appear to have influenced prescribing patterns across the class for rheumatoid arthritis (RA) patients in the Veterans Affairs (VA) health system, researchers found.

Following publication of the ORAL Surveillance data in January 2021, older RA patients in the VA system and those with substantial cardiovascular risk factors were more likely to discontinue JAK inhibitors, compared with the previous 22 months, according to Joshua F. Baker, MD, MSCE, of the University of Pennsylvania in Philadelphia, and colleagues.

Such patients also got fewer new tofacitinib prescriptions, the group reported in Arthritis Care & Research.

ORAL Surveillance was conducted by tofacitinib's manufacturer, Pfizer, under orders from the FDA after some data from its registration trials and postmarketing reports had suggested that the drug increased risks for certain cancers and major cardiovascular events. The active-comparator trial enrolled more than 4,600 RA patients, assigning them 1:1 to tofacitinib or a tumor necrosis factor (TNF) inhibitor.

Major findings were that patients given tofacitinib incurred about 50% more new malignancies than did the TNF inhibitor group; cardiovascular events were also about one-third more common with the JAK inhibitor. Moreover, the study showed that the risk increase was especially prominent in older patients and those with preexisting conditions. These results prompted the FDA to require sterner boxed warnings about cardiovascular and cancer risk for all JAK inhibitors.

In September, Baker's group published an analysis of VA data showing that overall JAK inhibitor use had dropped in the wake of the ORAL Surveillance data. But the researchers also wanted to know whether this shift in prescribing affected all patient subgroups or only those seen most at risk. That was the focus of their new study.

Baker and colleagues examined tofacitinib prescriptions for RA in the VA system from April 2019 to September 2022, i.e., 664 days prior to and after the January 2021 announcement of ORAL Surveillance data.

A total of 2,111 patients started on new courses of tofacitinib in the earlier period versus 1,664 after the announcement. Mean age of these new initiators also declined, from 64.1 to 63.0.

"There were also decreases in the proportion with cardiovascular comorbidities including hypertension, hyperlipidemia, heart failure, coronary artery disease, vascular disease and cerebrovascular disease, skin cancer, and lymphoproliferative disorders (all P<0.05)," the researchers wrote. These declines were mostly in the range of 4-5 percentage points, except for coronary artery disease, for which the decrease was about 8 points (from prevalence of 33% to 25%).

Some of these patterns were reversed for TNF inhibitor prescriptions. Mean age of new users of these drugs increased, as did the prevalence of diabetes, prostate cancer, and lymphoproliferative disorders.

Discontinuation rates also were higher, by 18% (P<0.001), for tofacitinib versus TNF inhibitors after the ORAL Surveillance data came out. This difference was doubled to tripled for patients with various cardiovascular conditions.

Limitations of the study included its conduct among VA patients, whose demographics differ markedly from the general population and who face fewer issues with insurance coverage. Also, it's possible that the VA's electronic records system may have played a role in physicians' decisions. And the study period spanned the appearance of COVID-19, which might have altered practice patterns as the pandemic evolved.

Source Reference:Song S, et al "Changes in characteristics of patients initiating and discontinuing advanced therapies for rheumatoid arthritis following the release of safety data" Arthritis Care Res 2023; DOI: 10.1002/acr.25268.