Tofacitinib Safety and Effectiveness in Canadian Patients with Rheumatoid Arthritis by Cardiovascular Risk Enrichment: Subanalysis of the CANTORAL Study

Abstract

Introduction: ORAL Surveillance, a post-authorisation safety study of patients with rheumatoid arthritis (RA) enriched for cardiovascular (CV) risk, demonstrated increased risk of major adverse CV events (MACE) and malignancies (excluding non-melanoma skin cancer [NMSC]) for tofacitinib versus tumour necrosis factor inhibitors (TNFi). This analysis of a real-world Canadian observational study evaluated tofacitinib safety/effectiveness in patients meeting or not meeting CV risk criteria.

Methods: CANTORAL included patients with moderate-to-severe RA initiating tofacitinib (10/2017-07/2020; N = 504). Interim data (data-cut: 07/2021) were stratified as CV risk-enriched (CV+ ; patients ≥ 50 years with ≥ 1 additional CV risk factor) or not CV risk-enriched (CV-; ≥ 50 years without additional CV risk factors and 18-49 years with/without CV risk factors). Safety and persistence were evaluated to month (M) 36. Effectiveness outcomes to M18 included Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA)/remission (CANTORAL co-primary endpoints) and Disease Activity Score in 28 joints, C-reactive protein (DAS28-4[CRP]) < 3.2/ < 2.6.

Results: Overall, 272/232 patients were included in CV+ /CV- cohorts (full analysis set) (435/356 patient-years [safety analysis set]). Incidence rates (events/100 patient-years) in CV+ /CV- cohorts were 138.5/112.5 for treatment-emergent adverse events (AEs); 17.0/5.6 for serious AEs; 1.2/0.3 for deaths; 5.5/1.7 for serious infections; 1.4/1.1 for herpes zoster; 1.6/0.0 for MACE; 2.1/0.3 for malignancies (excluding NMSC); 0.7/0.6 for NMSC; 0.5/0.0 for venous thromboembolic events. Persistence was generally comparable between cohorts. In CV+ /CV- cohorts, at M6, CDAI LDA and remission rates were 51.5%/54.6% and 12.0%/19.6%; DAS28-4(CRP) < 3.2/ < 2.6 rates were 44.0%/39.3% and 31.5%/28.8%, respectively; effectiveness was generally maintained to M18.

Conclusions: In concordance with studies of background risk, AEs were more common in patients with CV risk enrichment, particularly those aged ≥ 65 years. Tofacitinib effectiveness/persistence were generally similar regardless of CV risk enrichment. These findings support individualised treatment benefit-risk assessment, including CV assessment/management, to optimise RA outcomes.

Keywords: Antirheumatic agents; Cardiovascular diseases; JAK inhibitors; Rheumatoid arthritis; Therapeutics; Tofacitinib.

Fig. 1

CANTORAL study design and CV risk stratification criteria. ^aInitiation of treatment with tofacitinib was within 28 days from study enrolment. Baseline assessment did not take place for patients who initiated treatment with tofacitinib at the baseline/enrolment visit. ^bCV risk stratification was performed post hoc. ^cMay include revascularisation procedure, coronary artery bypass grafting, myocardial infarction, cardiac arrest, unstable angina or acute coronary syndrome. ^dMay include nodules, Sjögren’s syndrome, anaemia of chronic disease or pulmonary manifestation. BL baseline, CV cardiovascular, M month, RA rheumatoid arthritis, W week

Fig. 2

Kaplan–Meier time to study discontinuation: a all-cause; b due to AE (including intolerance); c due to lack or loss of efficacy in patients who were (CV+) or were not (CV−) CV risk-enriched. ^aDefined as time from treatment initiation until premature study discontinuation or last available assessment date. AE adverse event, CI confidence interval, CV cardiovascular, n number of patients with event, N number of evaluable patients, NE non-estimable

Fig. 3

Proportion of patients with CV risk enrichment (CV+) and those who were not CV risk-enriched (CV−) achieving a CDAI-defined LDA and remission; b DAS28-4(ESR)-defined LDA and remission; c DAS28-4(CRP) < 3.2 or DAS28-4(CRP) < 2.6^a and d estimated change from baseline in HAQ-DI. Denominators for the response rates were the number of patients available at that visit. ^aLDA and remission values for DAS28-4(CRP) (< 3.2 and < 2.6, respectively) have not been validated [21], but are commonly used in rheumatology [22]. The dotted line at month 6 indicates the time point for assessment of the co-primary endpoints (achievement of CDAI LDA and remission). Black arrow (panel d) indicates the direction of improvement [23]. Δ change from baseline, CDAI Clinical Disease Activity Index, CI confidence interval, DAS28-4(CRP) Disease Activity Score in 28 joints, C-reactive protein, DAS28-4(ESR) Disease Activity Score in 28 joints, erythrocyte sedimentation rate, HAQ-DI Health Assessment Questionnaire-Disability Index, LDA low disease activity, LS least squares, n number of patients meeting response criteria, N number of patients with available data at each visit