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The Antiplatelet Debate: Pretreatment and Its Role in Clinical Practice
Sparked by results from several studies, the interventional cardiology community has been debating whether pretreating patients with MI expected to undergo PCI with antiplatelet therapy is a good idea.
In reality, according to experts interviewed by Cardiology Today’s Intervention, the decision is an individual one, not a formulaic one, driven by, among other things, what sort of MI the patient experienced, how high risk the patient is and what agents are available.
Pretreatment on Recurrent Ischemic Events
The idea behind pretreatment, said Gregg W. Stone, MD, professor of medicine at Columbia University College of Physicians and Surgeons and co-director of the medical research and education division at the Cardiovascular Research Foundation, New York, is that “you can restore TIMI 3 flow, before you even get to the cath lab, [to] prevent periprocedural events, particularly cath lab-related events, and reduce recurrent ischemic events such as stent thrombosis or reinfarction. The risk, presumably, would be increased bleeding.”
Pretreatment may be needed because the medications — clopidogrel, prasugrel (Effient, Daiichi Sankyo/Eli Lilly) and ticagrelor (Brilinta, AstraZeneca) — must be administered orally, said George D. Dangas, MD, PhD, professor of medicine at the Icahn School of Medicine at Mount Sinai and director of cardiovascular innovation at the Zena and Michael A. Weiner Cardiovascular Institute of The Mount Sinai Hospital, New York. “They need some time to get to the full activity, so if you load them beforehand, they have time for absorption and metabolism,” he said.
George D.
Dangas
However, pretreatment appears more likely to benefit patients with STEMI than patients with non-STEMI or stable CAD, experts said. For example, the ACCOAST trial and the subsequent ACCOAST-PCI substudy, which was presented at EuroPCR in May and was a retrospective selection of patients from ACCOAST once the coronary angiogram and PCI were performed, showed no benefit for pretreatment of non-STEMI with prasugrel.
“You’re going to intuitively enhance your platelet activity in patients with higher risk and minimize it in patients with risk for bleeding,” Dangas said. “In this regard, you want to prioritize the high-risk patients, such as those with STEMI and those at high risk with non-STEMI, for pretreatment. As the risk drops, the benefit of pretreatment is to be questioned.”
Quick Decisions
Because of the high prothrombotic status of patients with acute MI, a decision on pretreatment should be made quickly, perhaps even as early as first medical contact, Petr Kala, MD, PhD, head of cath lab at Masaryk University and University Hospital Brno, Czech Republic, said.
“Based on the higher risk for bleeding after dual antiplatelet therapy, particularly after novel molecules like prasugrel and ticagrelor, the diagnosis of acute MI has to be confirmed without any serious doubts,” Kala said. “[In contrast to] STEMI, where preloading before primary PCI is beneficial and the discussion is potentially only about the best drug, non-STEMI patients represent a very different entity — they are at a higher age and have more comorbidities and a higher frequency of multivessel CAD. In my personal view, if the patient with non-STEMI would undergo urgent coronary angioplasty within the first 4 hours, it would be reasonable to postpone [DAPT] until [the procedure’s end] result.”
Pretreatment is often appropriate in patients with STEMI because the benefits of improvement of perfusion usually outweigh the risk for bleeding, Gilles Montalescot, MD, PhD, professor at the Institut de Cardiologie, Hôpital la Pitié-Salpêtrière, Paris, said. “It makes sense for STEMI because stenting is performed in more than 90% of those patients compared with 30% to 40% in stable patients and 60% in non-STEMI patients, for whom ACCOAST did not support pretreatment.”
Gilles
Montalescot
Montalescot and fellow researchers of the ATLANTIC study are investigating whether there is a difference in outcomes for pre-hospital administration of ticagrelor vs. in-hospital administration of the drug in STEMI patients planned for PCI. The primary endpoints are TIMI flow grade 3 of MI culprit vessel at initial angiography and ST-segment resolution between baseline and PCI >70%. The 1,874-patient study was completed in November, and the results are planned for the European Society of Cardiology Congress, which begins in late August.
Stone, who is also a member of Cardiology Today’s Intervention Editorial Board, noted that his institution generally favors pretreatment for anyone undergoing primary PCI.
“These are the patients who have the greatest amount of platelet activation to begin with,” he said. “They’ve already got a ruptured plaque with a formation of a platelet thrombus; the largest amount of thrombus burden; and the lowest likelihood of restoring effective myocardial reperfusion in the cath lab. It makes mechanistic sense to have a maximum amount of platelet inhibition on board.”
Although it is also possible to use glycoprotein IIb/IIIa inhibitors for that purpose, “those agents cause substantially more bleeding and thrombocytopenia than do the [adenosine diphosphate receptor] antagonists,” he added.
The ACCOAST results may not necessarily close the book on pretreatment in patients with non-STEMI, Stone said.
“The primary endpoint was a complex collection of multiple different adverse endpoints, and it was a negative endpoint,” he said. “However, there was an intriguing trend toward reduction in mortality in the prasugrel group. The endpoints are often dominated by MI; but in patients with non-STEMI, it’s extremely difficult to adjudicate recurrent MIs accurately because the patients have elevated biomarkers. It didn’t have the power to demonstrate positivity.”
However, Stone noted, the bleeding risks seen with prasugrel in ACCOAST should be taken seriously, especially because prasugrel is irreversible. “To use it in a preloading fashion in patients with non-STEMI — where usually about one in 10 are referred to bypass surgery — is not an optimal decision,” he said. “Ticagrelor is a better agent to use in that setting because it’s a reversible agent with a shorter half-life, so if there’s bleeding or a requirement to go to surgery, the drug can be reversed more quickly. That is how ticagrelor was tested in the PLATO trial, and in patients with both STEMI and non-STEMI, preloading with ticagrelor compared with preloading with clopidogrel reduced MI, stent thrombosis, and both CV and all-cause mortality.”
Gregg W.
Stone
A Variety of Considerations
Whether to pretreat and when to initiate it also depends on which drug is chosen or available. “Drug pretreatment is less necessary with the drugs of rapid onset — prasugrel and ticagrelor — than with clopidogrel,” said Montalescot, a member of the Cardiology Today’s Intervention Editorial Board and an investigator for the ACCOAST trial.
Doctors must know how long it takes to metabolize each drug on average, Dangas said. “Each one of the agents has a different metabolism time,” he said. “You want to calculate the peak effect being around the time of PCI. Then you subtract the hours estimated for this to be needed.” He noted that in some cases, the decision must be made at an urgent point-of-care setting, such as an ambulance or ER, where there may only be one available antiplatelet therapy, if that.
Whatever the decision, it should be arrived at via collaboration between the interventional cardiologist and the emergency medical staff to enable a fast, effective and simple triage, Kala said.
That time can vary not only based on the drug, but also the patient, Stone said.
“We have to rely on oral absorption for these agents to become effective,” he said. “That requires a certain amount of time, and in the cases of clopidogrel and prasugrel, we have to allow a certain amount of time for metabolic transformation of the drug to the active metabolite; ticagrelor is active by itself. In patients with MI, there’s delayed absorption of the oral agents, so they take a certain amount of time to work, somewhere between 1 and 6 hours depending on the individual patient. So the earlier you can give the drug, the better.”
There have been no outcome studies comparing prasugrel and ticagrelor directly, so when choosing which agents to use, doctors have to rely on the available research and their own judgments, experts said.
Petr Kala
“In the STEMI population, based on the TRITON-TIMI 38 trial, prasugrel, respecting its contraindications, seems to be the best option, followed by ticagrelor and clopidogrel,” Kala said. “In the non-STEMI population, except for patients indicated to urgent coronary angioplasty within 4 hours, the results of the PLATO trial do prefer ticagrelor over prasugrel and clopidogrel. The safety/efficacy profile of ticagrelor makes this molecule relatively most universal. Clopidogrel is the cheapest option and is definitely better than nothing.”
Stone noted that he and colleagues at Columbia decided that the data at the moment favor ticagrelor for most cases. “At Columbia, we use ticagrelor almost exclusively because the large-scale randomized trial that was done with ticagrelor showed a reduction in mortality and a somewhat more favorable bleeding profile with ticagrelor than with prasugrel,” he said. “Absent a head-to-head randomized trial, that’s not an absolute definitive conclusion, although it’s the data we followed to make that choice.”
Is Cangrelor the Future?
The preloading debate may become less important if cangrelor (The Medicines Company), an investigational IV adenosine diphosphate antagonist, becomes available. In the CHAMPION PHOENIX trial, cangrelor, which achieves approximately 90% of adenosine diphosphate-induced platelet activation at the time of administration, was compared with clopidogrel in patients with STEMI, non-STEMI or stable CAD undergoing PCI.
“Clopidogrel, of course, takes 3 to 6 hours to work, so it was basically a trial of preloading with cangrelor vs. no active agent,” Stone said. “And that trial showed a clear reduction in periprocedural stent thrombosis, MI and other complications with cangrelor, demonstrating definitively that the concept of preloading is appropriate and does improve outcomes. It’s a matter now of which agent to use, given that the IV agent cangrelor is not yet available.” In February, an FDA advisory panel advised against approval of cangrelor, citing concerns about trial design and risk/benefit profile. Three months later, the FDA denied both the PCI and bridge to surgery indications for the drug.
For now, according to Kala, the decision on pretreatment has to be individualized. “A tailored mechanical and pharmacological approach has to be selected to achieve the best results,” he said. “Short-term potent and safe antiplatelet drugs might be beneficial in patients with hemodynamic instability, particularly cardiogenic shock.” – by Erik Swain