ACS at AHA: Experts Speculate on Vorapaxar and Rivaroxaban

November 08, 2011

November 8, 2011 (Orlando, Florida)Results of two large-scale trials of novel antithrombotic drugs in ACS patients will be announced this Sunday at the American Heart Association 2011 Scientific Sessions. These are the TRACER trial of vorapaxar, the first-ever platelet protease-activated receptor 1 (PAR-1) blocker to be tested in a phase 3 trial for ACS, and the ATLAS trial of the new oral factor Xa inhibitor anticoagulant rivaroxaban (Xarelto, Bayer/Johnson & Johnson).

Both trials have been the subject of preliminary announcements, one hinting that rivaroxaban may have shown some success in ATLAS, while the opposite appears to be the case in TRACER, which was stopped prematurely earlier this year. At the same time as the TRACER announcement, the manufacturer reported that vorapaxar had been associated with an increase in intracranial hemorrhage in patients with a history of stroke in both of its phase 3 trials.

heartwire asked several experts in the field who were not involved in these particular studies what they would be looking for in the final results and whether they thought there could be a future for either of these drugs in the now-quite-crowded ACS market.

Vorapaxar Bleeds

The PAR-1 receptor, which vorapaxar blocks, is the site at which thrombin binds to the platelet, a key step in the thrombotic process, and vorapaxar is thus being investigated in both ACS patients in TRACER and in a more general secondary-prevention setting in the TRA-2P TIMI-50 trial. In 2007, investigators hailed phase 2 results with vorapaxar, saying they may have "stumbled upon" a drug that reduced ischemic events without increasing bleeding, an achievement that has so far been elusive. But hopes were seriously dashed earlier this year when the intracranial-hemorrhage announcement was made. When the TRACER trial was stopped, it was reported that it had accumulated the predefined number of primary and secondary end points necessary to assess whether the drug was effective or not.

Commenting for heartwire , Dr Dominick Angiolillo (University of Florida College of Medicine, Jacksonville) says because of their different mechanism of action, PAR-1 blockers might be able to block platelets more effectively, "but the finding of increased intracranial hemorrhage has shown us that we can be too aggressive in some patients." Noting that prasugrel (Effient, Lilly) had also shown similar problems in patients with prior stroke, Angiolillo added that patients with known cerebrovascular disease appear to be at an increased risk of bleeding.

All the experts said they were skeptical of initial claims that vorapaxar could separate the anti-ischemic benefit from the bleeding risk. Angiolillo pointed out that although the phase 2 results did not show an overall increase in bleeding, there did appear to be a dose-related effect on bleeding. "Perhaps the view at the time was a bit too good to be true," he suggested.

Dr William Boden (University at Buffalo School of Medicine, NY) concurs with this. "I think we can deduce that vorapaxar has not lived up to initial claims that it could be the safest antiplatelet drug ever. We have to concede that there is no such thing as a free lunch."

Dr Peter Berger (Geisinger Medical Center, Danville, PA) says he never believed the idea of reduced ischemic events without an increase in bleeding was real. "I would have bet a lot of money that this was not a true finding," he told heartwire .

Boden says he has no inside information on TRACER or ATLAS, but he is not expecting "anything spectacular" from either of these trials, noting that the other oral anticoagulants similar to rivaroxaban have shown bleeding issues when used on top of dual antiplatelet therapy in ACS.

Ticagrelor: A Hard Act to Follow

For ATLAS, all that's known so far about the trial is based on a Bayer press release from late September, saying that rivaroxaban plus standard therapy met its primary efficacy end point, "showing a statistically significant reduction in the rate of events for the primary composite end point of cardiovascular death, myocardial infarction, and stroke in patients with ACS, compared with standard therapy plus placebo." In terms of the primary safety end point, defined as TIMI major bleeding events not associated with CABG, "there was a statistically significant increase in such events in patients receiving rivaroxaban vs placebo," the release read. No numbers in either direction were provided. Of note, ACS studies of other drugs in this class have not met with success.

Experts questioned about their predictions for both rivaroxaban and vorapaxar voiced the opinion that new drugs in the ACS field had a tough act to follow in ticagrelor (Brilinta, AstraZeneca).

Boden said: "I think it will be very difficult for any new antithrombotic drug to outperform ticagrelor in ACS, which has shown a reduction in mortality vs aspirin plus clopidogrel [Plavix, Bristol-Myers Squibb/Sanofi-Aventis] (in PLATO). It's just getting onto formularies now, and there is huge enthusiasm for it." He pointed out that even if one of the new drugs showed results as good as ticagrelor, it would still take a year for them to get to the market, by which time ticagrelor would have taken hold. "Then you have clopidogrel coming off patent early in 2012, which will put further pressure on new drugs for ACS. Hospitals will make choices over which one to have on their formulary, and I think they will go for generic clopidogrel and/or branded ticagrelor, I think prasugrel will get squeezed out, and I can't see that there will be much room for any more ACS drugs."

Dr Paul Gurbel (Sinai Hospital of Baltimore, Maryland) agrees: "Any new therapy will be challenged to beat what ticagrelor has shown. The reduction in mortality over clopidogrel in PLATO is a huge benefit, and it has been achieved by using only two drugs--ticagrelor plus aspirin. These new drugs being tested are being added to clopidogrel plus aspirin, and why would you give three drugs if you can achieve the same or better results with two?"

But Berger is slightly more optimistic. "I personally do not believe that we will find a drug that reduces thrombotic complications without increasing bleeding, but I am hopeful that we can find drugs that can improve clinical outcomes when added to dual antiplatelet therapy in ACS patients," he added.

He says that finding the optimum dose is the key factor for success in this regard. "There are few drugs in medicine for which we can be certain that we have found the best dose. But when balancing ischemic events and bleeding risk, the dose is crucial, and the doses that are studied in phase 3 trials are often selected based on too little information from undersized dose-finding studies that produce ambiguous results or on insufficient data."

Expanding on this view, Gurbel pointed out that the phase 2 trial with vorapaxar was too short and too small to give meaningful information. "You cannot really assess the risks of intracranial hemorrhage in 600 patients followed for just 60 days. This is always the case with phase 2 trials, but the issue was bigger with vorapaxar because it was the first of a new class. There are just so many unknowns. I personally wouldn't have leaped into phase 3 so quickly just based on this one study. That was an enormous leap of faith."

Subgroup Analysis Will Be Interesting

Finally, while these new drugs may have a challenging road ahead in the ACS market, results of these studies will probably give much new information relevant to specific patient groups, possible other indications, and similar compounds in earlier development.

Angiolillo commented: "I will be looking to see if there are some specific populations for whom the new drugs may be associated with particular benefit or danger. I think the best net clinical benefit could be when the new compounds are used with aspirin alone rather than on top of dual antiplatelet therapy."

Gurbel is on the steering committee of the TRA-2P TIMI-50 trial of vorapaxar and is an advisor for rivaroxaban. Angiolillo is involved in the TRA-2P TIMI-50 study. Berger briefly participated in TRACER and was site primary investigator for the ROCKET AF trial of rivaroxaban.


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