Background: Results from ORAL Surveillance, a post-authorisation safety study, indicated that patients (pts) with rheumatoid arthritis (RA) aged ≥50 yrs with ≥1 additional cardiovascular (CV) risk factor have an increased risk of major adverse CV events (MACE) with tofacitinib vs tumour necrosis factor inhibitors. ¹

Objectives: To evaluate the impact of baseline (BL) CV risk on MACE in the wider tofacitinib RA clinical programme.

Methods: Data for pts who received ≥1 tofacitinib dose in 21 Phase 1–3b/4 (excluding ORAL Surveillance) and 2 long-term extension tofacitinib RA studies were pooled and analysed post hoc as two cohorts: (1) overall cohort and (2) CV risk-enriched cohort (pts aged ≥50 yrs with ≥1 additional CV risk factor [current smoker, hypertension, HDL-cholesterol <40 mg/dL, diabetes mellitus, history of myocardial infarction (MI) or coronary heart disease (CHD)]). Data were summarised by average tofacitinib 5 or 10 mg twice daily (BID; average total daily dose of <15 or ≥15 mg, respectively). Incidence rates (IRs; pts with first events/100 pt-yrs) for adjudicated MACE were calculated. MACE IRs were stratified by pts’ BL CV risk profile: pts were first categorised by history of coronary artery disease (HxCAD), then pts without a HxCAD were categorised by 10-yr risk of MACE, per the ASCVD-PCE risk calculator ² with a 1.5 multiplier applied. ³

Results: The overall cohort included 7964 pts (average tofacitinib 5 mg BID, n=3969; average tofacitinib 10 mg BID, n=3995); of these, 3125 (39.2%) pts were included in the CV risk-enriched cohort (average tofacitinib 5 mg BID, n=1614; average tofacitinib 10 mg BID, n=1511). In both treatment arms, as expected, higher proportions of pts in the CV risk-enriched cohort had a HxCAD or a high or intermediate 10-yr predicted risk of MACE at BL vs the overall cohort ( Table 1 ). MACE IRs (95% CIs) were lower in the overall cohort (0.38 [0.26, 0.54] and 0.37 [0.27, 0.48] for average tofacitinib 5 and 10 mg BID, respectively) vs the CV risk-enriched cohort (0.72 [0.46, 1.09] and 0.67 [0.46, 0.93], respectively), and were similar between treatment arms. MACE IRs were lower than reported in ORAL Surveillance. ¹ In the overall cohort, adjudicated MACE most commonly occurred in pts with a HxCAD (IR [95% CI] 0.98 [0.02, 5.47] and 1.05 [0.13, 3.78] for average tofacitinib 5 and 10 mg BID, respectively), or in pts with a high 10-yr risk of MACE at BL ( Figure 1 ). A lower predicted 10-yr MACE risk was associated with lower MACE IRs ( Figure 1 ); trends were similar for the CV risk-enriched cohort (data not shown).

Conclusion: In the tofacitinib RA clinical programme, MACE were largely associated with BL CV risk in the overall cohort, consistent with results of ORAL Surveillance, although results should be interpreted with caution due to low pt-yrs of exposure in some pt groups. Noting this limitation, these findings emphasise the importance of assessing and addressing BL CV risk when treating pts with RA.

REFERENCES:

[1]Ytterberg et al. New Engl J Med 2022; 386: 316-326.

[2]American College of Cardiology, American Heart Association. ASCVD risk estimator. https://tools.acc.org/ldl/ascvd_risk_estimator/index.html# !/calulate/estimator/.

[3]Agca et al. Ann Rheum Dis 2017; 76: 17-28.

Acknowledgements: Study sponsored by Pfizer Inc. Medical writing support was provided by Kirsten Woollcott, CMC Connect, and funded by Pfizer Inc.

Disclosure of Interests: Maxime Dougados Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer Inc, Roche and UCB, Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer Inc, Roche and UCB, Christina Charles-Schoeman Consultant of: AbbVie, Gilead Sciences, Pfizer Inc and Sanofi-Regeneron, Grant/research support from: AbbVie, Bristol-Myers Squibb and Pfizer Inc, Zoltán Szekanecz Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Paid instructor for: AbbVie, Eli Lilly, Gedeon Richter, Novartis, Pfizer Inc and Roche, Consultant of: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Grant/research support from: Pfizer Inc, Jon T Giles Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Genentech, Gilead Sciences and UCB, Grant/research support from: Pfizer Inc, Steven R. Ytterberg Consultant of: Corbus Pharmaceuticals, Kezar Life Sciences and Pfizer Inc, Deepak L Bhatt Grant/research support from: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Eli Lilly, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Medtronic, MyoKardia, Novo Nordisk, Owkin, Pfizer Inc, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic and The Medicines Company, Gary G Koch Grant/research support from: AbbVie, Acceleron, Amgen, Arena, AstraZeneca, Cytokinetics, Eli Lilly, Gilead Sciences, GSK, Huya Bioscience International, Johnson & Johnson, Landos Biopharma, Merck, Momentum, Novartis, Otsuka, Pfizer Inc, Sanofi and vTv Therapeutics, Employee of: University of North Carolina at Chapel Hill, Ivana Vranic Shareholder of: Pfizer Inc, Employee of: Pfizer Ltd, Joseph Wu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Cunshan Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Kenneth Kwok Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Sujatha Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Carol A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Arne Yndestad Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Jose L. Rivas Shareholder of: Pfizer Inc, Employee of: Pfizer SLU, Maya H Buch Speakers bureau: AbbVie, Consultant of: AbbVie, Eli Lilly, Gilead Sciences, MSD, Pfizer Inc and Roche, Grant/research support from: Pfizer Inc, Roche and UCB