Vorapaxar: A Novel Antiplatelet
Naveen L. Pereira, MD: My name is Naveen Pereira, Assistant Professor of Cardiology and Pharmacology at the Mayo Clinic. Today on theheart.org we will be discussing adjunctive pharmacotherapy and coronary artery disease, with an emphasis on anticoagulation and antiplatelet drugs, with my colleague Dr. Guri Sandhu, Director of the Cardiac Catheterization Laboratory at Mayo Clinic in Rochester, who specializes in percutaneous coronary intervention (PCI) and structural heart disease intervention. Welcome, Dr. Sandhu.
Gurpreet S. Sandhu, MD, PhD: Thank you, Naveen. We have some medications to discuss today that have both been in the news.
Dr. Pereira: We will get right into the news. We know about all the traditional antiplatelet drugs that we have been using for acute coronary syndromes (ACS) after PCI and stable coronary artery disease. Aspirin, which seems to be the mainstay, irreversibly acetylates the platelets. We also have the P2Y12 inhibitors, specifically clopidogrel, and the newer drugs, ticagrelor and prasugrel. But there is a new kid on the block, and that is vorapaxar (Zontivity™). Vorapaxar is a protease-activated receptor inhibitor.
Can you elaborate on this new antiplatelet agent and its mechanism of action?
Dr. Sandhu: This is an entirely new class of agents. Vorapaxar was recently approved by the US Food and Drug Administration (FDA) for clinical use. This medication works through the protease-activated receptor pathway, and once the coagulation system is activated, thrombin will irreversibly activate this receptor. That sets off the usual G protein-based intracellular activation of the platelets. The hope is that inhibiting this receptor will reduce platelet activation, and this medication has been approved for secondary prevention.
The TRAº2P-TIMI 50 Trial
Dr. Pereira: Vorapaxar has come into the news recently because of the FDA approval, and my understanding is that the approval came after a consensus. There was a vote of 10 to 1 in favor of approving vorapaxar for secondary prevention in coronary artery disease and peripheral arterial disease. The basis of this approval came from the TRAº2P-TIMI 50.[1]
Could you tell us about this trial -- the kind of patients who were involved and the basic findings?
Dr. Sandhu: This was a pretty large trial, with about 26,000 patients, all with stable atherosclerotic disease. There were 3 subgroups. The first subgroup was patients who had had a myocardial infarction (MI) within the past year. The second subgroup was patients with cerebral vascular disease (a transient ischemic attack or a nonhemorrhagic stroke) in the past year. The third subgroup was patients with peripheral arterial disease.
These patients were placed on either a placebo or vorapaxar, and the usual outcomes of major adverse cardiac events (MACE) -- death, stroke, need for urgent revascularization -- and other criteria were looked at.
Dr. Pereira: Were patients allowed to take other medications?
Dr. Sandhu: They were also on their usual medications, and a confounding issue that has been brought up repeatedly was that about 16,000 of the patients were on thienopyridines, primarily clopidogrel, so that may have affected their overall outcomes and results.
Dr. Pereira: More than 60% of these patients were on clopidogrel, so vorapaxar was given in addition to clopidogrel in a large proportion of patients in this trial.
Dr. Sandhu: As the trial unfolded, the data safety monitoring board stopped one arm of the trial (the patients who had a previous ischemic stroke or transient ischemic attack) because of a higher signal of bleeding, both moderate-to-severe and intracerebral bleeding.
Dr. Pereira: Was there a certain weight range? With prasugrel, patients of a certain weight are excluded because of high risk for bleeding. Was the same applicable in this trial?
Dr. Sandhu: Exactly. It is pretty much the same. When this drug was approved, the 2 groups that were excluded from using this drug were patients who weighed less than 60 kg and patients who had experienced a previous cerebral vascular event.
A Drug in Search of a Patient Population
Dr. Pereira: They looked at a composite endpoint of MI, stroke, and coronary revascularization. Can you elaborate on the relative and absolute risk reduction? That is important because the relative risk reduction always sounds impressive, but when you look at the absolute risk reduction, we may not be that impressed.
Dr. Sandhu: The relative risk reduction was 13% with vorapaxar, and the number needed to treat was 53. In terms of absolute risk reduction, it was 1% (from 10% to 9%).
Dr. Pereira: There is some adjunctive benefit, but there may be an increased risk for bleeding. What is the take-home point? Will this change your practice?
Dr. Sandhu: Not immediately, because the biggest concern is the risk for bleeding. There was a 4.2% rate of bleeding with the medication compared with placebo, which was 2.5%. In balance, the risk for bleeding seems to neutralize any obvious benefit across the larger population.
However, this is potentially a medication that could be individualized. As we have more data coming forth, we will probably find the right patient population. At this time, it is still an early-stage medication. We need more evidence before we have any definitive conclusions.
Dr. Pereira: It would be nice not to have had clopidogrel as a confounding factor in terms of antiplatelet agents.
Heated Controversy Over Bivalirudin
Dr. Pereira: Let's move to another interesting topic of anticoagulation. We use unfractionated heparin or low-molecular-weight heparin commonly in ACS. There is a big controversy about whether we should use bivalirudin. The HEAT-PPCI trial[2] addressed this issue. Can you tell us briefly about this trial and give us the key findings?
Dr. Sandhu: The HEAT-PPCI trial was done in the United Kingdom, where they randomly assigned patients with ST-elevation MI (STEMI) to unfractionated heparin vs bivalirudin. They had about 1800 patients, and their findings were a little bit controversial.
Previously, bivalirudin had been shown to reduce the risk for bleeding. In this trial, they showed that there was no difference between unfractionated heparin vs bivalirudin. On the other hand, the risk for stent thrombosis was a little higher with bivalirudin. This created a large amount of controversy and discussion, and the jury is still out on where this is going.
Dr. Pereira: There were no differences in bleeding between unfractionated heparin and bivalirudin? Was there any effect on MACE?
Dr. Sandhu: The effect on MACE seemed to be slightly lower with heparin. Coming back to the bleeding issue, all of the previous studies with bivalirudin had used unfractionated heparin, plus an intravenous glycoprotein inhibitor vs bivalirudin alone. We know for a fact that glycoprotein inhibitors increase the risk for bleeding.
Those are used less commonly today, so that is one issue that has been taken off the table in this comparison. The other issue is that radial access is gaining prominence, and transfemoral access management is better. Bleeding risk across the board is declining, so the difference is potentially less than was seen in the previous studies.
Dr. Pereira: What do we do at Mayo Clinic for patients with STEMI in terms of using heparin vs low-molecular-weight heparin vs bivalirudin?
Dr. Sandhu: At Mayo, our practice for any acute coronary event is to use dual-antiplatelet loading upfront. All patients receive aspirin with either ticagrelor or clopidogrel.
Then in terms of the anticoagulant, our preferred approach is unfractionated heparin with appropriate activated clotting time levels, and we will also selectively use an intravenous glycoprotein IIb/IIIa agent for patients with slow flow and thrombus.
Dr. Pereira: So the HEAT-PPCI trial results substantiate and validate the approach used here.
Dr. Sandhu: They do seem to fit in with what we are doing.
Dr. Pereira: Thanks to Dr. Sandhu for these great insights, and thank you, our viewers. We hope that you will continue to check out future content on Mayo Clinic's page at theheart.org on Medscape.
© 2014
Mayo Clinic
Cite this: PCI and ACS: Where Do Vorapaxar and Bivalirudin Fit In? - Medscape - Jul 30, 2014.
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