Vorapaxar may reduce acute limb ischemia, peripheral revascularization in patients with PAD

SAN DIEGO — New analyses of the TRA 2P-TIMI 50 trial showed that vorapaxar use was associated with reductions in acute limb ischemia, peripheral revascularization and recurrent major CV events in certain patients with peripheral arterial disease.

Antonio Gutierrez, MD, from Brigham and Women’s Hospital, and colleagues investigated the incidence of acute limb ischemia in 3,787 participants with symptomatic PAD who participated in the TRA 2P-TIMI 50 trial.

According to results reported at the American College of Cardiology Scientific Sessions, there were 109 acute limb ischemia events during follow-up (placebo rate, 3.9% at 3 years; 1.3% annualized). Most acute limb ischemia events were due to acute surgical graft thrombosis (54%) or in situ thrombosis in a native vessel (27%), followed by thromboembolism (9%), stent thrombosis (8%) and vascular disruption (2%). Forty-three percent of patients underwent surgical revascularization, 30% underwent endovascular intervention and 17% required amputation. Overall, vorapaxar (Zontivity, Merck) reduced the relative risk for acute limb ischemia by 42% (HR = 0.58; P = .006).

In another analysis, Ian Gilchrist, MD, from Penn State Hershey Heart and Vascular Institute, and colleagues assessed the reasons for and types of peripheral artery revascularization in 5,845 patients with PAD who participated in TRA 2P-TIMI 50.

During a median follow-up of 2.5 years, 934 peripheral vascularization procedures occurred, including indications for claudication (60%), chronic critical limb ischemia (22%) and acute limb ischemia (13%). The researchers reported a significant reduction in peripheral revascularization for claudication (HR = 0.84; 95% CI, 0.71-0.99; P = .04) and surgical peripheral revascularization (HR = 0.59; 95% CI, 0.47-0.74; P ≤ .001) with vorapaxar.

“There was a significant reduction in peripheral revascularization for claudication and trends for a reduced rate of peripheral revascularization for critical limb ischemia and acute limb ischemia implicating a favorable effect of vorapaxar on mechanisms contributing to worsening atherothrombosis in patients with established PAD,” they wrote in the abstract.

Researchers for a third study assessed the efficacy and safety of vorapaxar in patients with severe CAD who underwent CABG before enrollment in TRA 2P-TIMI 50 (n = 2,942) and those who underwent new CABG during the trial (n = 319).

Ethan Kosova, MD, from Brigham and Women’s Hospital, and colleagues reported that patients with prior CABG had an increased risk for CVD, MI or stroke compared with patients without prior CABG (13.7% vs. 7.8%; P < .001). Vorapaxar was associated with reduced risk for CVD, MI or stroke among patients with prior CABG (HR = 0.71; 95% CI, 0.58-0.88; number needed to treat, 27). Among patients who required new CABG during the trial, those assigned vorapaxar had greater risk for GUSTO moderate/severe bleeding compared with those assigned placebo (6.8% vs. 3.7%; HR = 1.87; 95% CI, 1.28-2.71), and greater risk for TIMI CABG major bleeding within 30 days of surgery (6% vs. 4.2%, respectively; HR = 1.43; 95% CI, 0.53-3.84). The researchers noted that the bleeding risk “appeared similar to that seen in the overall trial population.”

Marc P. Bonaca

“As treating physicians, we are always concerned about our patients with PAD because of their risk for both systemic CV events as well as limb vascular events including acute limb ischemia and disease progression leading to peripheral revascularizations. Because there are limited options available to reduce the risk of limb vascular events, these exploratory subgroup analyses raise important hypotheses regarding the role of [vorapaxar] in the management of PAD,” Marc P. Bonaca, MD, MPH, investigator for the TIMI Study Group and associate physician at Brigham and Women’s Hospital and Harvard Medical School, said in a press release.

Previously reported results from the overall TRA 2P-TIMI 50 trial demonstrated reduced incidence of the primary endpoint of CV death, MI, stroke and urgent coronary revascularization with vorapaxar plus aspirin or clopidogrel as compared with placebo in patients with a history of spontaneous MI, ischemic stroke or documented PAD. The FDA approved vorapaxar in May 2014. – by Stephanie Viguers

References:

Gilchrist I, et al. Abstract 1131M-03.

Gutierrez A, et al. Abstract 1131M-11.

Kosova E. et al. Abstract 905-04. All presented at: American College of Cardiology Scientific Sessions; March 13-16, 2015; San Diego.

Disclosures: Gilchrist, Gutierrez and Kosova report no relevant financial disclosures. Bonaca reports receiving consultant fees/honoraria and research/research grants from Merck and Co.