WASHINGTON – The lipid changes induced by tocilizumab do not translate into an increased risk of heart attack or stroke in patients with rheumatoid arthritis, a 5-year postmarketing study has determined.
Patients taking the drug experienced quick and dramatic increases in low-density lipoprotein cholesterol: 12% in just 4 weeks. But when compared against patients taking etanercept, they showed no significant increases in stroke, heart attack, heart failure hospitalization, or cardiac death, Jon Giles, MD, said at the annual meeting of the American College of Rheumatology.ENTRACTE study already had cardiovascular risk factors such as hypertension, smoking, and diabetes, Dr. Giles of Columbia University, New York, said in an interview.
“This has been a lingering question,” he said. “These data are very reassuring. Practitioners can feel comfortable that they’re not inducing harm with this drug in patients with high cardiovascular risk. Now when we’re evaluating RA patients for the best drug, we can make a choice based on other parameters ... how the patient wants to take the drug, for example, or other safety indicators. This study takes away one element of uncertainty.”
Tocilizumab’s profound effects on lipids have been confirmed in all of its pivotal trials, with average across-the-board increases of 17%-25% in total cholesterol, low-and high-density cholesterol, and triglycerides. ENTRACTE is the first trial, however, to compare its cardiovascular safety profile to that of another RA medication.
The study comprised 3,080 patients with active, seropositive RA from 353 centers across 31 countries. The mean age of the patients was 61 years. All patients had at least one cardiovascular risk factor, including current smoking (30%), hypertension (71%), or diabetes (18%). About a quarter were already taking a statin, and about 5% had a history of heart attack, stroke, or coronary revascularization.
They were randomized to open-label tocilizumab 8 mg/kg infused every 4 weeks or etanercept 50 mg injected weekly. The mean follow-up reported was 3.5 years, but some patients had full 5-year data. “This was plenty of time to see early atherothrombotic complications if they were going to develop,” Dr. Giles said.
The primary endpoint was a composite of major cardiovascular outcomes including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included individual components of the primary endpoint, as well as all-cause mortality, heart failure hospitalization, fatal and nonfatal myocardial infarction and stroke, and lipid levels.
By week 4, LDL-cholesterol levels had risen by almost 12% in the tocilizumab group. This moderated somewhat, but stayed elevated, reaching 9% above baseline by week 144. In contrast, LDL-cholesterol in the etanercept group was virtually unchanged throughout the study.
In the intent-to-treat analysis, there were 161 occurrences of the composite outcome: 83 in the tocilizumab group and 78 in the etanercept group (hazard ratio, 1.05). This was not a significant difference. The event rate was 1.70 per 100 person-years in the etanercept group and 1.82 in the tocilizumab group – also not significantly different.
The individual secondary endpoints were almost identical in each group: cardiovascular death, 35 with etanercept vs. 36 with tocilizumab; nonfatal MI, 31 vs. 28; nonfatal stroke, 15 vs. 24; and all-cause mortality, 64 in each group. A multivariate regression analysis showed no significantly increased risks associated with tocilizumab in any of the secondary endpoints. The rates and types of adverse events were also similar.
Because this was a safety study, the investigators were interested in the uncertainty in their estimate of risk, Dr. Giles said in an interview.
“The study was designed to exclude at most an 80% increase in cardiovascular events for the patients treated with tocilizumab, compared with etanercept. What we determined was that we could exclude with 95% certainty that if a much larger sample of similar patients was studied, the risk of such events in the tocilizumab group would not exceed a 43% higher rate at the extreme. Notably, the degree of uncertainty included the possibility that the event rate could be lower in the tocilizumab group, compared with those treated with etanercept.”
Dr. Giles reported receiving consulting fees from Genentech, which markets tocilizumab. All other authors also disclosed financial relationships with Genentech or its parent company, Roche. Four authors were employees of Roche/Genentech.
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