Nonsignificant CV Risk with Actemra vs Enbrel Save

WASHINGTON -- Rheumatoid arthritis is a recognized risk factor for heart attacks and stroke, but a study comparing two leading biologics found only a non-significant increase in relative risk for patients treated with toclizimab (Actemra) vs etanercept (Enbrel), researchers reported here.

Per the intention-to-treat analysis, there were 83 major adverse cardiovascular events (MACE) -- consisting of cardiac death, non-fatal myocardial infarction, and non-fatal stroke -- in the tocilizumab arm versus 78 in the etanercept arm (HR 1.05, 95% CI 0.77, 1.43), according to Jon Giles, MD, MPH, of Columbia University in New York City, and colleagues.

That small event rate may be the Achilles heel of the study, which enrolled more than 1,500 patients in each arm and followed them for a little more than 3 years.

Finding cardiovascular risk is often compared with seeking a needle in a haystack: studies require huge populations followed over long periods. For example, the recently reported PRECISION study enrolled more than 24,000 RA and osteoarthritis patients and followed them for more than a decade to test the study of NSAIDs.

The overall rate of MACE, serious infections, and medically confirmed gastrointestinal perforations was higher among tocilizumab patients versus etanercept patients, they reported in a presentation at the American College of Rheumatology annual meeting.

Also, LDL cholesterol increased significantly in the tocilizumab arm compared with the etanercept arm, they stated.
RA treatment with tocilizumab is associated with clinical efficacy and "marked reduction" in systemic inflammatory markers tied to atherogenesis and atherothrombosis, the researchers explained. But treatment-associated increases in LDL cholesterol have "called into question the net cardiovascular risk-benefit ratio of TCZ in RA," the authors pointed out.

No randomized trials had been conducted to evaluate comparative CVD safety in tocilizumab, "particularly with CVD outcomes as the primary endpoints," they stated.

Giles' group conducted a randomized, open-label, parallel-group, multicenter outcomes study in adult patients with moderate-to-severe RA. MACE was the primary endpoint. Secondary endpoints included all-cause mortality and lipid levels.

The patient population consisted of 3,080 people, 96% of whom completed the study with full assessment of CVD events, across 353 sites in 31 countries. Patients were tracked for a maximum of 5 years, and average follow-up time was 3.2 years.

Baseline characteristics were mean age 61, 22% male, 29% current smokers, 71% with hypertension, 18% with diabetes, and mean C-reactive protein (CRP) of 19.3 mg/L. Current statin use was the same in both groups (22%), and the same percentage of patients in both groups (69%) were also taking methotrexate.The tocilizumab dose was 8 mg/kg (Q4W IV) while the etanercept dose was 50 mg (QW SC).

Patients had to have ≥1 CVD risk factor, extra-articular RA manifestations, or history of a CVD event. Primary analysis sought to measure time from randomization to the first occurrence of a MACE (patients were not censored at the time of treatment switch). Hazard ratios were derived from Cox proportional hazards model stratified by previous anti-TNF exposure and history of CVD events. Researchers tallied 6-month and overall incidence rates for both study arms.
The study was powered to rule out at least 80% relative hazard of MACE for tocilizumab versus etanercept.
For the incidence rates of MACE between groups (tocilizumab versus etanercept), including multiple events per patient over time, the group reported that:

• Total exposure (patient-years): 4,900 versus 4891.4
• Number of events observed: 89 versus 83
• Event rate per 100 patient-years: 1.82 (95% CI 1.46, 2.24) versus 1.70 (95% CI 1.35, 2.10)

For the secondary endpoint of all-cause mortality, the number of events in both groups was 63 (HR 0.99, 95% CI 0.70, 1.41). For LDL-cholesterol levels, the percentage change from baseline (112 mg/dL for both arms ) was +11.8 at week 4 and -0.9% at week 144 for tocilizumab. For etanercept, it was +0.7 at week 4 and +9.2 at week 144.

Finally, the overall adverse event rate was higher with tocilizumab (95% CI 272.8, 282.7) versus etanercept (95% CI 179.1, 187.1):

• Number of events: 11,785 versus 8,004
• Rate/100 patient-years: 278 versus 183

"The CVD safety of TCZ relative to ETA should be interpreted in the context of its non-CVD safety and clinical efficacy," they concluded.

Study limitations included a potential reporting bias, especially for non-adjudicated events; and a "relatively" small sample for a CVD outcomes study as overall numbers of CVD events were low, the authors noted. Also, the results may not be generalizable to the general RA population because most study patients were at high risk for CVD events, they added.