ACC: Patient selection will be key if vorapaxar gets approved
“The results of this trial are very clear and very exciting,” said study's lead investigator David A. Morrow, MD, MPH, senior investigator at the TIMI Study Group, director of the Samuel A. Levine Cardiac Unit at Brigham & Women’s Hospital, during the ACC press conference.
The randomized, double blind, placebo-controlled trial TRA2°P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombosis), trial included 26,449 patients who received antiplatelet therapy for diagnosed atherosclerosis (heart attack, stroke or peripheral artery disease).
The goals of the trial were to evaluate whether vorapaxar would decrease antithrombotic events in atherosclerotic patients.
“There are still more than one million patients in the U.S. that have a heart attack each year,” said Morrow. And, for those who survive, many are placed on antiplatelets to help a future risk of MI. However, it is unknown as to whether adding a platelet blocker to aspirin is beneficial in the long term.
Patients were randomized to receive a once daily 2.5 mg dose of vorapaxar with aspirin (13,225 patients) or placebo (13,224 patients). There was a 9.3 percent CV event rate reported in the vorapaxar plus aspirin group compared with 10.5 percent event rate in the placebo arm.
While the reduction was greatest in MI patients, with an almost 20 percent decline in CV events, Marrow noted that the drug may not be suitable for every patinet with atherosclerosis. “Of the groups we studied, the benefit was compelling to us only in patients with a prior heart attack,” said Morrow.
Cardiovascular death or MI occurred in 7.3 percent in the vorapaxar group vs. 8.2 percent in the placebo group. Rates of bleeding were highest in patients with a previous incidence of stroke, the researchers found.
In January 2011, the study’s data monitoring and safety board advised that stroke patients discontinue study participation due to the heightened rate of intracranial hemorrhage found within the vorapaxar group.
Due to this finding, Morrow said that the drug may not be appropriate for stroke patients and those who have a higher risk of bleeding. Patients in the voraxapar arm had a 4.2 percent bleeding (GUSTO moderate or severe) rate at three years compared with the 2.5 percent in the placebo arm. The rates of intracranial bleeding were 1 percent in the voraxapar arm vs. 0.5 percent in the placebo arm, and the lowest rates were seen in patients who had no previous history of stroke.
Morrow said TRA2°P-TIMI 50 results will advance practice in three areas:
- Results shed light in this new class of antiplatelet blockers (PAR-1 antagonism);
- Improves long-term antiplatelet treatments on top of aspirin and has been shown to reduce the rate of recurrent thrombosis in patients with previous MI; and
- Challenges the notion that all atherosclerosis can be treated the same way. Morrow said that it will be important to consider patient selection to balance the antithrombotic benefits and the risks of potential bleeding.
“Overall, our findings show that voraxapar is not an agent for all patients with atherosclerosis,” he said. “We need to select patients where we think there is a potential benefit. We need to identify patients where those reduction and clotting events outweigh the small risk of bleeding.”
Morrow added that the number needed to treat is: 53 to avoid one CV death, MI or stroke; 333 to avoid one severe bleed; and 500 patients to avoid one intracranial hemorrhage.
But with the increased risk of bleeds found though, some questioned whether the drug is safe enough.
“This is not a drug that I would put in my personal medicine chest,” said Eduardo Marban, MD, of Cedars Sinai Medical Center in New York City, during a panel discussion. “The number to treat is high, the effects are significant but rather small in absolute terms. Risks are not minor and the hazard ratios for minor bleeding are more than 1.4 even though the number of events is too low to reach significance.”
Additionally, David R. Holmes Jr., MD, president of ACC, said, “When we are faced with a patient in front of us we see there is a risk.” He added that the physician must lay out the risks and benefits of the drugs and education patients’ on the potential for harm.
While Holmes added that ultimately the decision for drug approval will be left up to the FDA, he said that making the drug available for widespread use may not be the best idea. “In very selected patients and very selected cerebrovascular centers, this drug offers the potential to improve outcomes with important safety hazards,” Holmes added. “It’s not for everyone.”
Morrow summed that individualizing treatment to the patient is a strategy is used in clinical practice today with the other approved antiplatelet agents on the market.