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In people with immune-mediated inflammatory disease including psoriatic arthritis, janus kinase (JAK) inhibitors increased the risk of venous thromboembolism (VTE) compared with other active treatments. The heightened risk was dependent on duration of exposure.

That's according to a systematic review meta-analysis into the controversial connection, published in .

Previous research found a higher incidence of pulmonary embolism in JAK inhibitors compared with tumor necrosis factor (TNF) inhibitors in people with rheumatoid arthritis. This led to a 2019 "black box" warning from the FDA for VTE at higher doses of tofacitinib. A subsequent study also found heightened VTE and major adverse cardiac event (MACE) risks for people taking 10 milligrams twice daily of tofacitinib.

The meta-analysis included 66 randomized clinical trials, collectively enrolling 38,574 patients. Patients who took JAK inhibitors had a numerically higher rate of VTE than controls (OR 1.65; 95% CI 0.97-2.79); differences were most pronounced after a year or more of follow-up. Versus active comparators, JAK inhibitors revealed similar results, increasing VTE after 12 or more months of follow-up compared with less than 12 months of follow-up (OR 2.38 [95% CI 1.24-4.57] vs 0.30 [95% CI 0.07-1.26], respectively; P=0.01). There was no increased risk of VTE for JAK inhibitors when compared with placebo arms. Results were similar for MACE but not statistically significant (OR 1.19; 95% CI 0.86-1.64).

Michael Garshick, MD, a cardiologist and researcher with NYU Langone Health in New York, served as a co-investigator on the meta-analysis. Garshick recently discussed the review and its findings with the Reading Room. The exchange has been edited for length and clarity.

What motivated you and your team to address this particular question?

Garshick: There's been an ongoing concern about risks related to the relationship between JAK inhibitors and the risk of VTE.

In prior clinical trials of JAK inhibitors, a concern was raised over a numerically higher rate of VTE, including pulmonary embolism, specifically at higher JAK inhibitor dosing in those with rheumatoid arthritis. However, expanded meta-analyses across a variety of JAK inhibitors and a prospective registry analysis over 5 years had not shown this. The FDA warned of a potential relationship between the JAK inhibitors and cardiovascular events.

So because studies suggested there could be a risk of blood clots or embolism or major cardiac events, our team decided to conduct a meta-analysis on the research related to these relationships.

How would you describe your main finding?

Garshick: There was a lot of heterogeneity in the trials, from the kind of JAK inhibitors used to the diseases that were studied. Even so, when we pulled everything together, we still saw a soft relationship between VTE and JAK inhibitors.

We found it predominantly in those who had been in a given trial for a long time, particularly over 12 months.

What did you find related to JAK inhibitors and MACE?

Garshick: We didn't find as much of an association with MACE and JAK inhibitors, but that's in line with what we've seen so far. The FDA warnings indicated that you should be somewhat cautious with higher-risk individuals and extended use of JAK inhibitors.

What are your clinical take-home messages based on these results?

Garshick: I don't think anyone is suggesting that you shouldn't use JAK inhibitors at all. That's way too much of an extreme position based on these data. But using just that extra little bit of caution in high-risk cases is probably a good idea.

In addition, you should be counseling patients on this as well, and understanding what all your options are for treating the underlying condition.

How do you mitigate VTE risk for higher-risk people taking JAK inhibitors?

Garshick: The best thing you can do is control their lipids. You could put them on an antithrombotic agent.

In my own clinic, I counsel my patients that if their rheumatologist thinks they should be taking a JAK inhibitor, then we have to be sure that all the traditional risk factors are low.

IMPLICATIONS FOR PRACTICE:

• The link between JAK inhibitors and increased risk of VTE appears to be soft, but increases predominantly in those taking the medication for longer than 12 months.
• Caution is advised for individuals at higher-risk for VTE and MACE who take JAK inhibitors, particularly over longer periods.
• Controlling lipids and addressing risk factors are key to reducing VTE risk in high-risk patients taking JAK inhibitors.

Read the study here.