Vorapaxar Effective for Secondary Prevention in Diabetic Patients With Prior MI

Patients with diabetes who have had an MI are at particularly increased risk for recurrent ischemic events, but a new study published online February 13, 2015, ahead of print in Circulation suggests that the addition of the novel antiplatelet agent vorapaxar provides effective long-term secondary prevention of cardiovascular events and stroke in this subgroup.

“Our data raise the possibility that vorapaxar [Zontivity; Merck Sharp & Dohme], which inhibits platelets via a pathway separate from that of aspirin and P2Y12 inhibitors… offers a particular advantage for patients with [diabetes],” write David A. Morrow, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), and colleagues. Vorapaxar inhibits PAR-1, the predominant receptor for thrombin on the surface of platelets. 

The TRA 2°P-TIMI 50 study included 26,449 patients with stable atherosclerosis who were randomized to receive standard care, including aspirin, and either vorapaxar (2.5 mg daily) or placebo at 1,032 sites in 32 different countries. It demonstrated a reduction in the composite of cardiovascular death, MI, or stroke at 3 years with vorapaxar vs placebo.

For the new analysis, Dr. Morrow and colleagues looked at the subset of patients from the trial who had diabetes (median age 61 years; 73.6% male) but no prior stroke or TIA and who were randomized to standard therapy plus vorapaxar (n = 1,809) or placebo (n = 1,814).

Compared with patients without diabetes, diabetic patients were older, more often female, and were more likely to have hypertension, PAD, renal dysfunction, and obesity. The majority of patients (84%) were on insulin or noninsulin therapies for hyperglycemia.

Sharp Reduction in Combined Death, MI, or Stroke

Among patients assigned to placebo, those with diabetes had nearly twice the incidence of cardiovascular death, MI, or stroke (primary endpoint) compared with nondiabetic patients (14.3% vs 7.6%; P < .001). After adjusting for potential confounders, diabetes continued to contribute a higher risk of the primary endpoint (adjusted HR 1.47; 95% CI 1.24-1.75). Furthermore, compared with nondiabetic patients, those with diabetes also had increased risk of the individual endpoints of cardiovascular death and recurrent MI, with a trend toward greater stroke risk (2.5% vs 1.1%; P = .051). Diabetes did not increase the risk of GUSTO moderate/severe bleeding.

Within the diabetic subgroup, addition of vorapaxar to standard care reduced both the primary endpoint and its individual components (table 1)—excluding cardiovascular death—with a number needed to treat of 29 (vs 74 in patients without diabetes) to avoid 1 major cardiovascular event.

The reductions in risk with vorapaxar were similar regardless of whether patients did or did not take insulin.

Vorapaxar increased the risk of GUSTO moderate/severe bleeding compared with placebo in diabetic patients (4.4% vs 2.6%; HR 1.60; 95% CI 1.07-2.40), which mirrored the increase seen in the nondiabetic population. However, an evaluation of net clinical outcome integrating the endpoints of cardiovascular death, MI, stroke, recurrent ischemia leading to revascularization, and GUSTO moderate/severe bleeding showed an overall improvement with vorapaxar in the diabetic subset (HR 0.79; 95% CI 0.67-0.93).

Additionally, compared with nondiabetic patients, those with diabetes had greater relative reductions in hospitalization for unstable angina (P = .02 for interaction) and coronary revascularizations (P = .008 for interaction) with vorapaxar vs standard care alone.

Antiplatelet Effects Speculative

“Although exploratory in nature, this observation that more potent antithrombotic therapy with vorapaxar provided a more pronounced reduction in ischemic events is consistent with what is known about the platelet pathobiology as well as prior studies of antithrombotic agents in patients with [diabetes],” Dr. Morrow and colleagues write. “In light of these findings, when weighing the risk of bleeding with the antithrombotic benefits of vorapaxar, patients with [diabetes] appear to be particularly appropriate candidates for consideration for treatment with this new therapy.”

In an accompanying editorial, Shinichi Goto, MD, and Shinya Goto, MD, PhD, of Tokai University School of Medicine (Kanagawa, Japan), say the study supports the idea that the effects of standard therapy may be impaired in diabetic patients, leading to higher cardiovascular event rates.

“Further quantitative understanding of the mechanism and role of platelet cells and the effects of currently available antiplatelet agents for the onset and prevention of thrombotic CV events in [diabetic] patients are awaited,” they observe.

Sources:
1. Cavender MA, Scirica BM, Bonaca MP, et al. Vorapaxar in patients with diabetes and prior MI: findings from the TRA 2°P-TIMI 50 trial. Circulation. 2015;Epub ahead of print.
2. Goto S, Goto S. The way to select a suitable patient population for thrombin receptor antagonist from the large clinical trial database of the TRA-2P-TIMI50 trial. Circulation. 2015;Epub ahead of print.

Disclosures:

• The TRA 2°P-TIMI 50 trial was sponsored by Merck Sharp & Dohme.
• Dr. Morrow reports consulting fees from BG Medicine, Eli Lilly, Gilead, Instrumentation Laboratory, Konica Minolta, Merck, Novartis, Roche Diagnostics, and Servier.
• Dr. Shinya Goto reports consulting fees and honoraria from multiple pharmaceutical companies.

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