The Risk of Venous Thromboembolic Events in Patients with RA Aged ≥ 50 Years with ≥ 1 Cardiovascular Risk Factor: Results from a Phase 3b/4 Randomized Safety Study of Tofacitinib vs TNF Inhibitors
Abstract: 1941
Authors: Christina Charles-Schoeman et al.
Risk Factors for Major Adverse Cardiovascular Events in Patients Aged ≥ 50 Years with RA and ≥ 1 Additional Cardiovascular Risk Factor: Results from a Phase 3b/4 Randomized Safety Study of Tofacitinib vs TNF Inhibitors
Abstract: 0958
Authors: Christina Charles-Schoeman et al.
Key content:
The Open Surveillance study was a phase IIIb/IV randomised, open-label, safety endpoint-driven study, which has enrolled 4362 patients with moderate to severe RA, who had failed at least methotrexate (MTX) and had cardiovascular risk factors: Participants were randomized to either Tofacitinib (Tofa) 5 mg BID + MTX, or Tofa 10 mg BID + MTX, or an TNF inhibitors (TNFi: adalimumab or etanercept) + MTX.
A total of 135 major cardiovascular events occurred during the 5 years of the study: 37 on TNFi (reference arm), 47 on Tofa 5 mg (HR 1.24 (0.81–1.91)), and 51 on Tofa 10 mg (HR 1.43 (0.94–2.18)). The number needed to harm (NNH) for Tofa 5 mg compared to a TNFi was 560 patients. No increased risk was seen in the subgroup of patients who were younger (< 65 years) and/or non- or never smokers.
A total of 164 malignancies occurred during the 5 years of the study: 42 on TNFi (reference arm), 62 on Tofa 5 mg and 60 on Tofa 10 mg, with an HR for Tofa (any dosage) of 1.48 (1.04–2.09). The NNH for Tofa 5 mg compared to a TNFi was 276 patients. No increased risk was seen in a subgroup of younger non-smoking patients.
Relevance:
While most these results have already been communicated by Pfizer, this was the first official presentation of the primary outcomes of the Oral Surveillance study. The unexpected increased risk of venous thromboembolic events had already lead to the withdrawal of the higher dose of Tofa in 2019 in Switzerland. Now the increase of cardiovascular events and cancers has led to further narrowing of the indication of Tofa. Interestingly, none of the observational studies has found similar results (i.e. abstract N° 1939), which begs the question whether these results are due to an authentic causal association, or whether the open label design of the Oral Safety study could have led to some biases (compliance issues, differential co-medication use …) that would explain these results. Another open question is whether this is a class effect or an effect linked specifically to Tofa. Rheumatologist are impatiently awaiting the results from a similar safety study with baricitinib, which should give us some answers to these questions. Meanwhile, rheumatologists need to discuss these issues openly and transparently with their patients.
