Treatment of rheumatoid arthritis with the interleukin-6 receptor antagonist tocilizumab (Actemra) was not associated with an increased risk of cardiovascular disease (CVD) when compared with other biologics, including tumor necrosis factor (TNF) and non-TNF agents, a large cohort study found.
An analysis of Medicare claims data found nonsignificant differences in risk for a composite CVD endpoint for two of three commonly used TNF inhibitors compared with tocilizumab, with adjusted hazard ratios of 1.10 (95% CI 0.80-1.51) for etanercept (Enbrel), 1.33 (95% CI 0.99-1.80) for adalimumab (Humira), and 1.61 (95% CI 1.22-2.12) for infliximab (Remicade), according to Jeffrey R. Curtis, MD, and colleagues from the University of Alabama at Birmingham.
And for non-TNF biologics, the hazard ratios were 1.01 (95% CI 0.79-1.28) for abatacept (Orencia) and 1.16 (95% CI 0.89-1.53) for rituximab (Rituxan), the researchers reported online in Arthritis Care & Research
CVD remains a major cause of death in rheumatoid arthritis, with increased disease activity associated with high levels of inflammatory cytokines and other markers that have been linked with atherosclerosis. Biologic therapies reduce these markers, suggesting that these treatments may help lower the risk of CVD events.
In early studies tocilizumab demonstrated efficacy as a treatment for rheumatoid arthritis, but was found to have negative effects on lipid profiles, which might exert an adverse influence on CVD, the researchers explained. For instance, in one study, greater increases by week 8 of treatment were seen among tocilizumab-treated patients compared with adalimumab-treated patients in low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, and total cholesterol:HDL ratio.
However, most of the studies showing lipid changes with tocilizumab had limitations such as small sample sizes and lack of adjustment for confounding factors such as disease activity.
Therefore, to provide a fuller analysis of the potential CVD risks with tocilizumab, the researchers undertook a retrospective study of Medicare and MarketScan claims data for patients with rheumatoid arthritis from 2006 to 2015. The composite CVD outcome included myocardial infarction, stroke, and fatal CVD.
Adjustment for disease activity was done with the Multi-Biomarker Disease Activity (MBDA) laboratory test, which dichotomizes disease activity as low or moderate-to-high. Additional adjustments addressed demographics, comorbidities, healthcare utilization, medication use, and smoking.
The analysis included 88,463 patients with rheumatoid arthritis and 117,493 biologic initiations. Mean age was 64.7 among Medicare patients and 52.2 among patients with data in MarketScan. More than 80% were women, and mean follow-up time was about 1 year.
Tocilizumab initiators were more likely than anti-TNF users to have a history of CVD, atrial fibrillation, and heart failure. This group also more often used steroids, were admitted to the hospital, and had more visits to physicians.
Among Medicare patients, the unadjusted incidence rates ranged from 11.8 (95% CI 9.7-14.4) per 1,000 person-years for etanercept to 17.3 (95% CI 15.2-19.7) per 1,000 for infliximab. The crude incidence rate for tocilizumab was 12.9 (95% CI 10.7-15.7) per 1,000.
The unadjusted incidence rate for the pooled TNF inhibitors was 15 (95% CI 13.9-16.3) per 1,000, while the adjusted incidence rate for pooled TNF inhibitors was 1.27 (95% CI 1.02-1.59) compared with tocilizumab.
For stroke, again the lowest rate was seen for etanercept, at 5.3 (95% CI 4-7.1) per 1,000 and the highest for infliximab, at 7.6 (95% CI 6.3-9.2), with tocilizumab being 6.2 (95% CI 4.7-8.2). The lowest rates for fatal CVD were seen for both etanercept (1.8, 95% CI 1.1-3) and tocilizumab (1.8, 95% CI 1.1-3.1), while the highest rate was for rituximab (3.6, 95% CI 2.4-5.4).
Among MarketScan patients, who were 10 years younger than the Medicare group, the unadjusted incidence rates were about half what was seen in the older patients, but the adjusted hazard ratios were similar to the Medicare outcomes.
In the analysis that adjusted for MBDA results, patients receiving tocilizumab or rituximab were more likely than anti-TNF users to be in the high disease activity category. With this disease activity adjustment, the hazard ratio for the composite endpoint comparing etanercept with tocilizumab was similar to that in the main analysis (HR 1.11).
In a subgroup analysis, patients with a history of other CVD had much higher incidence rates for the composite endpoint than those without such a history. For instance, the incidence rates for those without a CVD history were 11.1 (95% CI 8.8-14) per 1,000 for those receiving tocilizumab and 12.8 (95% CI 11.7-14.1) per 1,000 for the pooled anti-TNF group. The corresponding rates for those with a CVD history were 19.8 (95% CI 14.1-27.8) and 24.2 (95% CI 20.9-27.9), respectively.
"In this cohort study of rheumatoid arthritis patients who initiated biologic [disease-modifying antirheumatic drugs], we observed comparable risks for composite CVD associated with tocilizumab versus most other biologic therapies, irrespective of patients' history of CVD risk factors," the authors stated, concluding that the earlier concern raised about cardiovascular risk with lipid changes "was not borne out by our analysis."
A limitation of the study, the team noted, was the reliance on administrative data.
The authors reported financial relationships with Amgen, AbbVie, Bristol-Myers Squibb, Corrona, Janssen, Eli Lilly, Myriad, Pfizer, Roche, Novartis, and UCB.
- Reviewed by Dori F. Zaleznik, MD Associate Clinical Professor of Medicine (Retired), Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner
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Arthritis Care & Research
Source Reference: Xie F, et al “Tocilizumab and the risk for cardiovascular disease: A direct comparison among biologic disease-modifying antirheumatic drugs for rheumatoid arthritis patients” Arthritis Care Res 2018; DOI: 10.1002/acr.23737.
Read the original article on Medpage Today: No Increased CVD Risk With IL-6 Blocker in RA