Risk Factors for Major Adverse Cardiovascular Events in Phase III and Long‐Term Extension Studies of Tofacitinib in Patients With Rheumatoid Arthritis

Abstract

Objective Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). This study was undertaken to evaluate the risk of major adverse cardiovascular events (MACE) in patients with RA receiving tofacitinib. Methods Data were pooled from patients with moderately to severely active RA receiving ≥1 tofacitinib dose in 6 phase III and 2 long‐term extension studies over 7 years. MACE (myocardial infarction, stroke, cardiovascular death) were independently adjudicated. Cox regression models were used to evaluate associations between baseline variables and time to first MACE. Following 24 weeks of tofacitinib, changes in variables and time to future MACE were evaluated after adjusment for age, baseline values, and time‐varying tofacitinib dose. Hazard ratios and 95% confidence intervals were calculated. Results Fifty‐two MACE occurred in 4,076 patients over 12,873 patient‐years of exposure (incidence rate 0.4 patients with events per 100 patient‐years). In univariable analyses of baseline variables, traditional cardiovascular risk factors and glucocorticoid and statin use were associated with MACE risk; disease activity and inflammation measures were not. In subsequent multivariable analyses, baseline age, hypertension, and the total cholesterol to high‐density lipoprotein (HDL) cholesterol ratio remained significantly associated with risk of MACE. After 24 weeks of treatment, an increase in HDL cholesterol and a decrease in the total to HDL cholesterol were associated with decreased MACE risk; changes in total cholesterol, low‐density lipoprotein (LDL) cholesterol, and disease activity measures were not. Increased erythrocyte sedimentation rates trended with increased future MACE risk. Conclusion In this post hoc analysis, after 24 weeks of tofacitinib treatment, increased HDL cholesterol, but not increased LDL cholesterol or total cholesterol, appeared to be associated with lower future MACE risk. Further data are needed to test the cardiovascular safety of tofacitinib.

Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data

“…Study A3921133 is designed to assess differences between tofacitinib doses, maintain patients on the same dose throughout treatment (note patients randomised to tofacitinib 10 mg twice daily had their dose reduced to 5 mg twice daily as per protocol amendment in February 2019), 41 and encourage patients to remain in the study after treatment discontinuation. Given the observed incidence of MACE among RA patients using advanced therapies, [49][50][51][52] an endpoint-driven study such as Study A3921133 was projected to take >10 years if enrolling a nonenriched RA population. Therefore, the study was designed to enrich for cardiovascular risk, and enrolled patients aged ≥50 years and with ≥1 cardiovascular risk factor, with the goal of study completion in <8 years.…”

Letter: thromboembolic and cardiovascular events with tofacitinib in ulcerative colitis—two cases in real world clinical practice

“…Ratios of low‐density lipoprotein (LDL) cholesterol to high‐density lipoprotein cholesterol and total cholesterol did not change over 61 weeks. Data from rheumatoid arthritis patients also described 52 MACEs in 4076 patients over 12 873 patient‐years of exposure to tofacitinib, with an incidence rate of 0.4 cases/100 patient‐years . Increased LDL cholesterol was not associated with future risk of MACEs in this post hoc analysis.…”

Incorporating the erythrocyte sedimentation rate for enhanced accuracy of the global registry of acute coronary event score in patients with ST-segment elevated myocardial infarction

“…[ 37 ] Meanwhile, prior studies indicate that patients with chronic inflammation disorders, such as rheumatoid arthritis, psoriasis, and chronic obstructive pulmonary disease, are vulnerable to a higher risk of MACE. [ 38 – 40 ] Moreover, in this circumstance, increased ESR is associated with an increased prevalence of future MACE risk. Therefore, we assume that the fluctuation in rheology could offer a possible mechanism to mediate the higher prevalence of cardiovascular morbidity and mortality in patients with inflammatory disorders.…”