The increased risk of cardiovascular events associated with JAK inhibitors seems to predominantly affect patients with a history of atherosclerotic cardiovascular disease, according to findings of a new analysis of data from the ORAL Surveillance trial.
Preliminary findings from the safety study in rheumatoid arthritis patients indicated an increased risk of major adverse cardiovascular events (MACE) with tofacitinib versus TNF inhibitors (hazard ratio=1.33), as reported by the limbic earlier this year.
The latest analysis of data, published in in Annals of the Rheumatic Diseases (link here) has shown that the risk of MACE was significantly increased with tofacitinib 5mg and 10mg two times daily doses versus TNFi, but that this was primarily observed in patients with ASCVD history at baseline.
Risk of MACE did not appear to be increased with tofacitinib 5mg twice daily versus TNFi in patients without a history of atherosclerotic cardiovascular disease (ASCVD), however, “given the exploratory nature of the analysis and the low event rate, we cannot rule out an increased risk of MACE in patients with several CV risk factors … but any absolute risk excess is likely low,” the authors wrote.
In the trial, patients were randomised to receive either tofacitinib 5 mg two times per day (BID, n=1,455); tofacitinib 10 mg two times per day, n=1,456); or TNFi (n=1,451). Median follow-up was 4.0 years, and 71.3% patients completed the trial.
Overall, data showed that hazard ratios (HR) for MACE in patients taking JAKi compared to TNFi, were: 1.24 for tofacitinib 5mg BID; 1.43 for tofacitinib 10 mg BID; and 1.33 for combined tofacitinib doses.
Among patients with a history of ASCVD, they were 1.96, 2.01 and 1.98, while for those without a history of ASCVD but with CV risk factors, HRs were 1.03, 1.25 and 1.14, respectively.
The results show that “increased risk of MACE with tofacitinib 5 mg and 10 mg two times per day versus TNFi was found in patients with a history of ASCVD,” and “emphasise the importance of rheumatologists assessing overall CV risk, including medical history of ASCVD, when considering tofacitinib as a treatment for patients with RA”, the authors concluded.
VTE risk also elevated with JAKi
The findings come alongside those of a separate study which seemed to confirm that RA patients treated with JAKi are at increased risk of VTE compared to taking bDMARDs.
The study, also published in the Annals of the Rheumatic Diseases and based on a Swiss cohort that included 32,737 b/tsDMARD treatment initiations, found that the incidence of VTE in RA patients treated with JAKi was 50%-100% greater than the corresponding incidence in those treated with TNFi.
The authors also noted that this increase was at least numerically confined to PE rather than DVT.
The data showed that the fully adjusted HR for VTE with JAKi versus TNFi was 1.73, with the corresponding HR for PE 3.21 and for DVT 0.83.
Compared to TNFi, the fully adjusted HR for VTE for patients treated with baricitinib was 1.79 and for tofacitinib the HR was 1.66.
The authors concluded that “patients with RA treated with JAKi in clinical practice are at increased risk of VTE compared with those treated with bDMARDs, an increase numerically confined to PE,” and that the findings “underscore the need for VTE risk stratification before initiating JAKi treatment”.
However, they also noted that although the study results “add to the concerns regarding cardiovascular safety of JAKi, these risks must be viewed in light of the cardiovascular risks in patients with active RA for whom alternative treatment options may not exist”.