ORAL Surveillance
Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis
On this page
Overview
In older adults with RA and cardiovascular risk, tofacitinib did not meet noninferiority versus TNF inhibitors for MACE or cancer.
Clinical takeaway
Do not treat tofacitinib as interchangeable with a TNF inhibitor for safety in older RA patients with cardiovascular risk. Combined doses failed noninferiority for both coprimaries. Cancer incidence was higher (HR 1.48, 95% CI 1.04-2.09); the MACE interval included no effect (HR 1.33, 95% CI 0.91-1.94).
Key result
Combined tofacitinib versus a TNF inhibitor: HR 1.33 (95% CI 0.91-1.94) for MACE and HR 1.48 (95% CI 1.04-2.09) for cancers; noninferiority was not shown.
Practice impact
In RA with cardiovascular risk, do not assume tofacitinib is noninferior to a TNF inhibitor for MACE or cancer.
Evidence
Study design
Randomized, open-label, noninferiority, postauthorization, safety end-point trial. Noninferiority required the upper bound of the two-sided 95% CI for the hazard ratio to be less than 1.8 for combined tofacitinib doses versus a TNF inhibitor.
Enrollment
4,362
Follow-up
Median follow-up of 4.0 years.
Geography
Not listed
Clinical question
Is tofacitinib noninferior to a TNF inhibitor for adjudicated MACE and cancers (excluding nonmelanoma skin cancer) in older patients with RA and cardiovascular risk?
Population
- Patients with active rheumatoid arthritis despite methotrexate who were 50 years of age or older and had at least one additional cardiovascular risk factor.
- 1455 patients received tofacitinib 5 mg twice daily, 1456 received 10 mg twice daily, and 1451 received a TNF inhibitor (4362 treated).
Intervention
Tofacitinib 5 mg or 10 mg twice daily (combined tofacitinib doses for the noninferiority comparison).
Comparator
A TNF inhibitor.
Primary outcome
Coprimary end points of adjudicated major adverse cardiovascular events (MACE) and cancers, excluding nonmelanoma skin cancer.
The noninferiority criteria were not met. The MACE confidence interval included no effect (HR 1.33, 95% CI 0.91-1.94) but crossed the 1.8 noninferiority margin. The cancer interval excluded no effect (HR 1.48, 95% CI 1.04-2.09) and also failed noninferiority.
Hazard ratio / MACE 95% CI 0.91-1.94; cancers 95% CI 1.04-2.09
Key results
- During a median follow-up of 4.0 years, MACE occurred in 98 patients (3.4%) with combined tofacitinib doses versus 37 (2.5%) with a TNF inhibitor (HR 1.33, 95% CI 0.91-1.94).
- Cancers excluding nonmelanoma skin cancer occurred in 122 patients (4.2%) with combined tofacitinib versus 42 (2.9%) with a TNF inhibitor (HR 1.48, 95% CI 1.04-2.09).
- The noninferiority of tofacitinib was not shown for either coprimary end point (upper 95% CI bounds 1.94 and 2.09, both above the 1.8 margin).
- Efficacy was similar in all three groups, with improvements from month 2 that were sustained through trial completion. This is a secondary efficacy observation, not the safety primary.
Harms
- Incidences of adjudicated opportunistic infections (including herpes zoster and tuberculosis), all herpes zoster (nonserious and serious), and adjudicated nonmelanoma skin cancer were higher with tofacitinib than with a TNF inhibitor.
- The MACE point estimate was higher with tofacitinib, but that 95% CI included no effect.
Clinical Use
Practice impact
- In patients 50 or older with RA, methotrexate failure, and extra cardiovascular risk, do not assume tofacitinib is noninferior to a TNF inhibitor for MACE or cancer.
Applicability
- Most applicable to a cardiovascular risk-enriched RA population: age 50 or older, active disease despite methotrexate, and at least one additional cardiovascular risk factor.
Limitations
- Treatment assignment was open-label.
- Enrollment is the treated N (4362); a separate randomized N is not reported.
- The noninferiority comparison pooled 5 mg and 10 mg twice-daily tofacitinib against an unspecified TNF inhibitor.
Common misinterpretations
- Failed noninferiority is not the same as proven MACE harm; the MACE 95% CI included 1.0.
- This is not an efficacy-failure trial; disease control was similar across groups.
- Results apply to a cardiovascular risk-enriched population, not all patients with RA.
Citation
Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022;386(4):316-326. doi:10.1056/NEJMoa2109927
In this trial comparing the combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk-enriched population, risks of MACE and cancers were higher with tofacitinib and did not meet noninferiority criteria.
- PMID
- 35081280