JAKi VTE Risk: Does Aspirin, NSAID, or DOAC Use Matter? Save

Hi, this is Chiha Lee from Michigan reporting for RheumNow in London for EULAR 2026. I wanted to discuss poster number 0068, and this looks at the role of low-dose aspirin and NSAIDs and DOACs in the risk of venous thromboembolism or VTE for this presentation among patients with RA treated with JAK inhibitors or biologics.

So like many of you, I have patients who are increasingly taking JAK inhibitors because they're very effective. But we have a really pressing clinical question in rheumatology: is it safe? Because we are increasingly understanding that JAK inhibitors are associated with increased risk of VTE.

So recently there was a paper from — actually the authors of this poster — from Karolinska Institute that showed in laboratory findings that aspirin seemed to reduce the risk of VTE. And so their question then was, what about in the real world, in the clinical setting — is aspirin protective for patients who are taking JAK inhibitors?

So in terms of the study setup, this was really sophisticated and I thought it was very well designed. The objective, as I said, was to look at not just aspirin — even though that was their first premise from the lab findings — but direct oral anticoagulants or DOACs and NSAIDs at the time of biologic or targeted synthetic DMARD initiation. And they did it in this way so they could compare those who are starting JAK inhibitors to those who are starting TNFs and non-TNF biologics, and to look at the outcome: does it modify the VTE risk?

So the researchers were — as I mentioned, oh, maybe I said Norway, that is my bad. This is from Sweden; if I did that, please forgive me — from the Karolinska Institute. And they used their Swedish Rheumatology Quality Register linked to national healthcare data and drug dispensing registers. So that really allowed them to capture drug initiation, comorbidities, and other important covariants for such real-world pharmacologic studies.

The study time period was from 2017 to 2024, and they really made an effort to identify those who are truly initiating biologic or targeted synthetic DMARDs. They actually included over 26,000 patients with a median age of 61. It's really meaningful that they have older adults who are more prone and at risk of adverse outcomes of these drugs and with our rheumatic diseases. Of course, three-quarters or 76% were women.

So the exposure was defined as being on aspirin, a DOAC, or an NSAID within 30 days before treatment start with a biologic or targeted synthetic DMARD. They really wanted these patients to have some exposure to these hypothetically protective drugs before drug initiation. And they were followed until the first VTE event, or until treatment discontinuation with the index bTSDMARD plus a 90-day lag period to allow for additional drug exposure effects, or the end of the study period. Of course, because the outcome of interest was VTE, anybody who had an event one year prior to the drug start were excluded. Their analysis was a Cox proportional hazards model estimating VTE risk by treatment group and concomitant medication status.

So the setup is a little bit confusing, but I will do my best to verbally walk you through that. The reference group for comparison was the TNF group without concomitant drug use for protection.

So let's start with the primary question of aspirin. Among JAK inhibitors, VTE incidence was 12 per 1,000 for those who are on aspirin compared to 8 per 1,000 for those who are not on aspirin. So this makes it sound like aspirin might be making VTE worse. But the adjusted hazard ratio was only 1.02 — essentially no difference, because the confidence interval crossed one.

The key comparison I think is more interesting is when it's made against TNF users. So in that case, JAK users had an elevated VTE risk whether or not they had aspirin. The hazard ratio here after all adjustment was 1.8 without aspirin relative to TNF inhibitors, or a hazard ratio of 2.05 among JAK inhibitors with aspirin relative to TNF inhibitors. So in either case, it's not reassuring, right? Whether you have aspirin or not, JAK inhibitor users are at elevated risk of VTE. And we've actually seen a number of studies at EULAR reconfirming this — and again, hence the motivation for this study.

For the DOACs, the VTE rates were markedly higher — like for JAK inhibitor users it was 40 out of 1,000, and also 8 out of 1,000 depending on whether you are on DOACs or not with JAK inhibitors. One thing to remember, however, is that this is likely confounding by indication, because even though patients who had a VTE were excluded, those who are on DOACs are likely to have some risk factor of elevated clotting risk that put them on this in the first place. So even though the absolute incidence rates are higher, I think we need to interpret that with caution.

Now when you compare these groups again to those who are TNF users without any other DOAC, the hazard
ratio of VTE for JAK inhibitor users with the DOAC was 1.43 and for those who are JAK inhibitor users with the DOAC relative to TNF without anything was 1.85. So again being on a DOAC in this population for JAK inhibitor users it did not eliminate the VTE risk. Something peculiar though that the researchers found was that NSAIDs — so with the NSAID group among the JAK inhibitor users the hazard ratio of VTE with NSAIDs versus without was 0.8. So if anything was showing some kind of a protective effect, but I think this is more of a numeric reduction because the confidence interval again crossed one. So it was not a statistically significant finding. So this may be potentially hypothesis generating but again I think there's also a healthy user effect because those who are healthy are probably likely to be on NSAIDs. And the other thing I'm not aware of is that in the US we use NSAIDs over the counter a lot and I don't know what that looks like for the Swedish population and whether that may have played into the selection process.

So with some of these limitations, the authors themselves are very candid about the central limitations of the study and it's a significant run and as I mentioned before, it's really about the confounding by indication — like low-dose aspirin and DOACs are prescribed preferentially to patients at elevated risk of cardiovascular disease or thrombotic risk, which means when the comparison groups are not exactly exchangeable at baseline or comparable, any protective effects of aspirin could be entirely masked by higher background risk and such on the NSAID. As I mentioned, I think it's mostly that it's the healthy individuals who are getting it which may inflate what appears to be a protective effect. And the other central limitation to note is that these drug exposures were only defined at treatment initiation with the biologic or targeted synthetic drug. So it was not a time-varying covariate. So if there were any changes in aspirin or DOAC use itself or in the dosage during the follow-up, that was not captured. There could additionally be unmeasured confounders — as I mentioned, any over-the-counter use in either group, and also those who may not be getting their drugs paid through their national healthcare system and therefore not captured in their databases as well. And even though overall they had very large numbers for the entire group, some groups were smaller, whereas a subgroup analysis may not have the necessary power.

So what does this mean for us as rheumatologists in practice? I think what it means is that we should not be prescribing low-dose aspirin to our JAK inhibitor users for the purpose of reducing VTE risk, because thus far there's no evidence that it works and if anything it carries a risk of bleeding, especially if the JAK inhibitor users are older as well. So although the in vitro data were very interesting regarding the potential for aspirin in reducing the risk of VTE, this real-world study is showing that that translational step has not materialized yet. And one thing to keep in mind is that there again is a confirmatory finding from this and other studies that there is an elevated risk of VTE in those who use JAK inhibitors relative to TNFi. So it's really important that we pre-screen these patients and have conversations about it and have shared decision-making when it comes to prescribing, and have support available for these patients.

For future direction I think it'd be really interesting, as I said, to perhaps redo the study or in a smaller set looking at it as a time-varying exposure, to be a little bit more rigorous — even though it's a very well-designed study — and whether prospectively this was with low dose, whether high dose, or other random allocation instead of retrospectively looking back, to kind of remove that confounding by indication would be more informative.

So the bottom line from this poster, abstract 0068, is that in the real world low-dose aspirin does not appear to protect JAK inhibitor-treated RA patients from VTE. And so we will hopefully be on the lookout for more additional data or guidance about how best to manage the risk of VTE in our patients, because increasingly it's getting approved and used for many indications. Thank you for listening. This is Jali reporting for RheumNow in London for EULAR 2025.