Vorapaxar Stumbles in ACS, Ups Bleeding Risk: TRACER

November 13, 2011

November 13, 2011 (Orlando, Florida) — A novel oral antithrombotic agent, given to high-risk patients with non-ST-elevation ACS who were mostly already on dual-agent antiplatelet therapy, failed to hit that coveted treatment sweet-spot--reduced ischemic risk without more bleeding--in an huge international trial reported here today at the American Heart Association (AHA) 2011 Scientific Sessions[1].

In the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial with >12 000 patients, adding the investigational vorapaxar (Merck) to standard therapy significantly raised the risk of major bleeding complications, including intracranial hemorrhage (ICH), over two years.

That wasn't a complete surprise, as TRACER had been halted earlier this year after--as announced by Merck--an interim safety analysis saw a jump in ICH among vorapaxar patients with a history of stroke.

Vorapaxar is a protease-activated receptor 1 (PAR-1) antagonist that blocks thrombin-induced platelet activation and therefore inhibits platelets by a mechanism entirely different from those of other available antiplatelets, notably aspirin, clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis), and prasugrel (Effient, Lilly/Daiichi-Sanyo).

But it was too much of what was thought to be a good thing. "The magnitude of the increase [in bleeding] was not expected on the basis of preclinical and phase 2 data" for PAR-1 blockade, which suggested no risk increase when added to aspirin and clopidogrel, TRACER investigators write in the New England Journal of Medicine, where their report was published online, with first author Dr Pierluigi Tricoci (Duke University, Durham, NC),to coincide with its scheduled presentation here at the AHA sessions.

However, they continue, "The results from our study are consistent with previous evidence indicating that more potent antithrombotic therapy incrementally increases the risk of bleeding."

With today's presentation come the trial's clinical-outcomes data, which show no significant advantage to vorapaxar for the primary end point of cardiovascular death, MI, stroke, hospitalization for ischemia, or urgent revascularization. There was, however, a nonsignificant tilt toward a benefit from the new agent, a reduction in CV death/MI/stroke (p=0.072). Still, in their paper, Tricoci et al write that since vorapaxar didn't show benefit for the primary end point, "superiority with respect to the key secondary end point cannot be declared."

Still, "on the efficacy side there are some promising signals," Dr Kenneth W Mahaffey (Duke University), who is slated to present TRACER here, told heartwire . The trial, he said, "supports an effect of vorapaxar on atherothrombotic events, including an absolute 1.4% reduction in myocardial infarction [p=0.021], as well as a trend toward reduction in ischemic strokes."

TRACER randomized 12 944 patients with non-ST-elevation ACS in 37 countries throughout the world to receive vorapaxar or placebo; their symptom onset had to be within 24 hours of presentation and they had to have either elevated troponins/CK-MB or new ST-segment changes and at least one other high-risk marker such as prior MI or revascularization, peripheral vascular disease, or diabetes. Vorapaxar was given as a 40-mg loading dose followed by 2.5 mg/day.

The two randomization groups were well matched for demographics and geography, prevalence of diabetes, MI history, symptom-onset to randomization, and prevalence and technical aspects of revascularization. More than 90% in both groups were positive for troponin or CK-MB.

Over two years, vorapaxar was associated with significantly increased GUSTO moderate or severe bleeding (GUSTO severe bleeding went up by 35%; p<0.001), as well as bleeding that was "clinically significant" by TIMI criteria (the risk of TIMI major bleeding went up by 53%; p<0.001)

Bleeding Outcomes at 2 Years in TRACER (As-Treated Population)

End points Vorapaxar, n=6446 (%) Placebo, n=6441 (%) HR (95 CI) p
GUSTO criteria, moderate or severe 7.2 5.2 1.35 (1.16–1.58) <0.001
TIMI criteria, clinically significant 20.2 14.6 1.43 (1.31–1.57) <0.001
Hemorrhagic stroke 1.07 0.24 3.39 (1.78–6.45) <0.001

For the composite primary end point, the trend hinting at vorapaxar benefit was driven by a significant 12% reduction in risk of MI (p=0.021); there was no significant difference in rates for the other components of the primary end point.

Efficacy Outcomes at 2 Years in TRACER

End points Vorapaxar, n=6473 (%) Placebo, n=6471 (%) HR (95 CI) p
Primarya 18.5 19.9 0.92 (0.85–1.01) 0.072
"Key" secondaryb 14.7 16.4 0.89 (0.81–0.98) 0.018
MI 11.1 12.5 0.88 (0.79–0.98) 0.021
Stent thrombosisc 1.7 1.5 1.12 (0.78–1.62) 0.54

a. CV death, MI, stroke, hospitalization for ischemia, urgent revascularization

b. CV death, MI, stroke

c. Definite or probable by ARC criteria

In a morning press conference, Dr Keith Fox (Edinburgh Centre for Cardiovascular Sciences, Scotland), who was not involved in the study, highlighted key findings. "The critically important issues are that there is an absolute excess at two years of two moderate or severe bleeds, almost one additional intracranial hemorrhage, and about five TIMI clinically relevant bleeds for every 100 patients treated," he said. "Offset against this, there is no evidence of an impact on the primary end point. There was an encouraging trend for MI, but that cannot be individually held to because of the fact that it is a subsidiary analysis."

Fox continued: "The potential remains to reduce thrombotic events after ACS, but unfortunately, TRACER has missed the sweet spot between efficacy and safety."

Of note in a subgroup analysis, there was a "modest" significant interaction between vorapaxar and being on thienopyridine therapy at baseline, "which suggests that patients assigned vorapaxar who are not on a thienopyridine have a lower hazard for bleeding," Mahaffey said in an interview. In the same subgroup, he noted, there was "an [efficacy] trend toward more of a benefit with vorapaxar patients who were not on a thienopyridine." He said those observations will be explored in more detailed analyses later and that it's too early to tell whether vorapaxar might be both effective and safe were it to be given in addition to only one standard antiplatelet.

Insights about that could come from another vorapaxar phase 3 study, the ongoing Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P TIMI-50), which is studying the drug as chronic therapy in the setting of CV disease and peripheral artery disease, observed Mahaffey, who said he is on its steering committee. A component that entered patients with prior stroke was halted early, leaving the two others to continue, for the same reason TRACER was entirely shut down. In TIMI 50, he said, "we expect that there may be a higher proportion of patients than in TRACER who are not on thienopyridines."

TRACER coinvestigator Dr Robert Harrington (Duke University), who presented the results to the press earlier in the day, said that the 2°P results are expected in 2012. "I think that the information from that trial will provide a lot of insights and context to help us understand the TRACER results," he said.

TRACER was funded by Merck. Tricoci discloses grant and travel support paid to his institution from Merck. Mahaffey discloses receiving consulting fees from Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Ortho/McNeill, Sanofi-Aventis, Schering-Plough, Pfizer, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Novartis, and Polymedix; and grants from AstraZeneca, Bayer, Boehringer Ingleheim, Bristol Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Novartis, Portola, Pozen, Regado, Schering-Plough, the Medicines Company, Daiichi Sankyo, GlaxoSmithKline, Momenta Pharmaceuticals, and Sanofi-Aventis. Disclosures for the coauthors are available at https://www.nejm.com .