Patients with refractory rheumatoid arthritis who switched to tocilizumab showed no increased cardiovascular risk when compared with those who switched to a tumor necrosis factor inhibitor in a large cohort study.
Rheumatoid arthritis is known to approximately double the risk of cardiovascular morbidity and mortality partly because of its associated chronic systemic inflammation. Several small trials and observational studies have reported that tocilizumab, an interleukin-6 receptor antagonist typically used as a second-line treatment for RA, elevates serum lipids, including LDL cholesterol. These serum lipid elevations caused by tocilizumab have brought concerns that the drug may further heighten CV risk in people with RA, said Seoyoung C. Kim, MD, ScD, of the division of pharmacoepidemiology and pharmacoeconomics and the division of rheumatology, immunology, and allergy at Brigham and Women’s Hospital, Boston, and her associates.To examine this issue, the investigators analyzed information regarding CV mortality in three large health care claims databases covering all 50 states. They focused on 28,028 adults with RA who switched from taking at least one biologic agent or targeted synthetic disease-modifying antirheumatic drug to either tocilizumab (9,218 patients) or a tumor necrosis factor (TNF) inhibitor (18,810 patients). These patients were followed for a mean of 1 year.
To minimize the effect of confounding by the severity of RA and the baseline CV risk, the researchers adjusted the data to account for more than 90 variables related to CV events and to RA severity.
The primary outcome — a composite of MI and stroke — occurred in 125 patients, 36 taking tocilizumab and 89 taking TNF inhibitors. The rate of this composite outcome was 0.52 per 100 person-years with tocilizumab and 0.59 per 100 person-years for TNF inhibitors, a nonsignificant difference, Dr. Kim and her associates reported (Arthritis Rheumatol. 2017 Feb 28. doi: 10.1002/art.40084).
There also were no significant differences between the two study groups in secondary endpoints, including rates of coronary revascularization, acute coronary syndrome, heart failure, and all-cause mortality. In addition, all subgroup analyses confirmed that tocilizumab did not raise CV risk, regardless of patient age (younger than or older than 60 years), the presence of cardiovascular disease at baseline, the presence of diabetes, the use of methotrexate, the use of oral steroids, or the use of statins.
These “reassuring” findings show that even though tocilizumab appears to raise LDL levels, “such increases do not appear to be associated with an increased risk of clinical CV events,” the investigators said.
The results confirm those reported at the 2016 American College of Rheumatology annual meeting for the 5-year, randomized, postmarketing ENTRACTE trial in which the lipid changes induced by tocilizumab did not translate into an increased risk of heart attack or stroke in RA patients.
This cohort study was sponsored by Genentech, which markets tocilizumab (Actemra). Dr. Kim reported ties to Genentech, Lilly, Pfizer, Bristol-Myers Squibb, and AstraZeneca. Her associates reported ties to Genentech, Lilly, Pfizer, AstraZeneca, Amgen, Corrona, Whiscon, Aetion, and Boehringer Ingelheim. Three of the seven authors were employees of Genentech.