Vorapaxar Safe in NSTE-ACS But Bleeding Risk Merits 6-Month Delay Before Noncardiac Surgery

CHICAGO, IL—In patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) who undergo noncardiac surgery, the novel antiplatelet agent vorapaxar is as safe as placebo through 30 days, according to a subanalysis of the TRACER trial presented on November 17, 2014, at the American Heart Association Scientific Sessions. But such surgeries should be delayed for at least 30 days to prevent ischemic events and 180 days to prevent bleeding.

Sean van Diepen, MD, MSc, of the University of Alberta Hospital (Edmonton, Canada), studied the 2,202 NSTE-ACS patients enrolled in the multicenter TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial who underwent noncardiac surgery within a median of 1.5 years after randomization to vorapaxar (Zontivity, Merck; loading dose of 40 mg, daily maintenance dose of 2.5 mg thereafter; n = 1,171) given at least 1 hour before any revascularization or placebo (n = 1,031).  

Vorapaxar is a novel oral platelet protease-activated receptor (PAR)-1 antagonist that has been shown to potently inhibit thrombin-induced platelet aggregation. In 2011, TRACER was terminated early by the trial’s Data and Safety Monitoring Board, which cited an increase in intracranial hemorrhage among patients with a history of stroke who were receiving the drug.

Most Vorapaxar Patients Continued Drug Perioperatively  

While about half of noncardiac surgeries occurred within 6 months of randomization (18.5% within 30 days), about a quarter were reported after more than 1 year. Most patients were on preoperative aspirin (97.2%) and thienopyridines (87.7%), and 78% of patients continued the study drug perioperatively. Average patient age was 64, and slightly more than two-thirds were treated with DES. Patient characteristics in the subanalysis were well balanced between the placebo and study drug groups, with the exception of greater thienopyridine use before NSTE-ACS in the vorapaxar arm.

At 30 days after noncardiac surgery, clinical outcomes were similar between the study groups. Rates of the primary ischemic endpoint (CV death, MI, stent thrombosis, and urgent revascularization) were comparable between patients assigned to receive vorapaxar (3.4%) and those given placebo (3.9%). Noncardiac surgery-related bleeding (defined as GUSTO or TIMI bleeding adjudicated as causally related to the surgery; primary safety endpoint) trended higher with vorapaxar (3.9%) than with placebo (3.4%). Results remained nonsignificant in on-treatment sensitivity analysis and after 30 days.  

When results were broken down according to the timing of noncardiac surgery (using < 30 days as the reference), there was no interaction between study treatment and the primary endpoint, noncardiac surgery-related bleeding, GUSTO bleeding, or TIMI clinically significant bleeding. Noncardiac surgery-related bleeding was numerically higher in those who had their surgeries between 30 and 180 days and 180 days and 1 year, but there was no difference beyond that.

Patients who did not have noncardiac surgery after NSTE-ACS fared better than surgery patients in terms of the primary endpoint, GUSTO severe/moderate bleeding, TIMI clinically significant bleeding, and TIMI major/minor bleeding. With noncardiac surgery as a time-dependent covariant, those who underwent surgeries were 5 times more likely than those who did not to experience GUSTO moderate/severe bleeding (adjusted HR 5.63; 95% CI 3.98-7.97; P < .001).  

The study was “coded for the incidence and timing of study drug interruptions, but it did not provide detailed information on the perioperative management of other cardiac medications,” Dr. van Diepen said. “The analysis was neither randomized nor prespecified, and the results should be considered hypothesis generating.”

Even so, the results tell us that both that “vorapaxar appears to be safe in [noncardiac surgery,]”  he added, noting that the procedures “after NSTE-ACS should be delayed at least 30 days to minimize the risk of ischemic events and at least 180 days to minimize bleeding events when clinically appropriate.” 

Wait Before Elective Surgeries Could Potentially Be Longer  

In response to an audience member who questioned how he manages to convince surgeons to operate on patients receiving vorpaxar, Dr. van Diepen said that he is not sure he could ever be truly persuasive. “The study recommended continuation of the drug through the perioperative period,” because vorapaxar’s half-life is anywhere from 200 to 300 hours, he explained. “You're looking at having all the biologic benefit of the drug… at 4 weeks.”

Session moderator Bina Ahmed, MD, of the University of New Mexico (Albuquerque, NM), called for a breakdown of surgeries by urgency. “You might want to wait beyond a year [for truly elective surgery] because it seems the risk is very high with all three agents on board. It's high enough with 2 agents on board,” she commented.  

Dr. van Diepen said that, while his group did not categorize the surgeries this way, “there was no signal in any direction toward an increased frequency in outcomes between placebo and vorapaxar in any of the surgical subgroups [they did classify].”

Source:

van Diepen S. Efficacy and safety of vorapaxar in NSTE-ACS patients undergoing non-cardiac surgery. Presented at: American Heart Association Scientific Sessions; November 17, 2014; Chicago, IL.

Disclosure:

• Dr. van Diepen reports no relevant conflicts of interest.

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