Background Patients (pts) with RA have increased risk of myocardial infarction (MI) and stroke that cannot be completely explained by traditional cardiovascular (CV) risk factors. Tofacitinib is an oral JAK inhibitor for the treatment of RA. Treatment with tofacitinib may increase total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c) and high-density lipoprotein-cholesterol (HDL-c), without affecting TC/HDL-c ratio.
Objectives To evaluate major adverse CV event (MACE) risk factors in tofacitinib-treated pts with RA in the clinical development programme.
Methods Data were pooled from pts with moderately to severely active RA receiving ≥1 tofacitinib dose in 6 Phase 3 and 2 long-term extension (LTE) studies (1 LTE study ongoing, data cut-off: April 2015). MACE was any MI, stroke or CV death (coronary, cerebrovascular, cardiac). Cox regression models evaluated associations between baseline (BL) values and time (BL to first tofacitinib dose) to first MACE. Changes (BL to Week [wk] 24) in MACE predictors and time to future MACE (first occurrence after 24 wks) were evaluated after adjusting for age, BL values and time-varying tofacitinib dose. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated.
Results 52 MACE cases occurred over 12,873 pt-years (py) of exposure in 4076 pts (incidence rate: 0.4 pts with events/100 py). At BL, compared with pts without MACE, pts with MACE were older (mean age 60.2 vs 52.7 years) with a higher mean BMI (29.2 vs 27.0 kg/m2) and longer mean RA disease duration (10.1 vs 7.7 years), and were more likely to have a history of diabetes (15.4% vs 7.6%) and hypertension (57.7% vs 33.7%). Pts with MACE had higher mean TC (208.2 vs 198.3 mg/dL), LDL-c (123.3 vs 114.0 mg/dL), TC/HDL-c ratio (4.0 vs 3.5) and triglycerides (152.1 vs 125.3 mg/dL) at BL, and lower HDL-c (55.3 vs 59.4 mg/dL) vs pts without MACE. In univariate analyses, traditional CV risk factors and corticosteroid and statin use at BL were associated with MACE risk (Table). BL disease activity and inflammation measures were not associated with MACE risk (Table). In multivariate analysis, BL age, hypertension and the TC/HDL-c ratio were significantly associated with MACE risk. Increases in HDL-c (p<0.001) and decreases in TC/HDL-c ratio (p<0.05) after 24 wks of tofacitinib therapy were significantly associated with decreased risk of future MACE (Figure). Increases in erythrocyte sedimentation rate (ESR; p=0.09) may be associated with increased future MACE risk. Changes in TC, LDL-c or other disease activity measures were not associated with future MACE risk.
Conclusions In pooled analyses of tofacitinib-treated pts (age and BL value adjusted), increases in LDL-c and TC after 24 wks of tofacitinib therapy were not associated with future MACE risk. Increases in HDL-c and decreases in the TC/HDL-c ratio after 24 wks of tofacitinib therapy were associated with reduced future MACE risk. Increases in ESR after 24 wks may be associated with increased future MACE risk. More data are needed to confirm these findings.
Acknowledgements Previously presented at ACR 2016 and reproduced with permission. This study was sponsored by Pfizer Inc. Editorial support was provided by C Viegelmann of CMC and was funded by Pfizer Inc.
Disclosure of Interest C. Charles-Schoeman Grant/research support from: AbbVie, Bristol-Myers Squibb, Pfizer Inc, Consultant for: Amgen, Pfizer Inc, Regeneron-Sanofi, H. Valdez Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Soma Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Hwang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Boy Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, I. McInnes Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Pfizer Inc, Roche