ALPHEUS results do not support routine ticagrelor in elective PCI
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Ticagrelor was not superior to clopidogrel for reducing periprocedural myocardial necrosis or myocardial injury within 48 hours of high-risk elective PCI performed in patients with stable coronary disease, according to the ALPHEUS trial.
Moreover, use of ticagrelor (Brilinta, AstraZeneca) did not increase major bleeding, but did increase the rate of minor bleeding at 30 days.
“These results support the use of clopidogrel as the standard of care for elective PCI,” Johanne Silvain, MD, PhD, professor of cardiology at Sorbonne University and director of the ICU at the Institut de Cardiologie of the Hospital Pitié-Salpêtrière in Paris, said during a press conference at the virtual American Heart Association Scientific Sessions.
The ALPHEUS trial enrolled 1,910 troponin-negative adults who were undergoing nonemergent PCI. Patients had at least one high-risk feature and a negative troponin, or moderately positive and decreasing troponin, before PCI. The mean age was 66 years and about 80% were men. The phase 3b, randomized, open-label trial was performed at 44 centers in France and five in the Czech Republic.
Patients with stable CAD were randomly assigned to receive a ticagrelor loading dose of 180 mg or clopidogrel loading dose of 300 mg or 600 mg before planned PCI. Thereafter, patients were continued on ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 30 days. The primary outcome was a composite of PCI-related type 4a or 4b MI or major myocardial injury within 48 hours or at discharge.
Results showed no difference in outcomes at 48 hours or 30 days:
- Primary outcome of PCI-related MI or major myocardial injury at 48 hours or discharge occurred in 35.5% of the ticagrelor group vs. 36.2% of the clopidogrel group (OR = 0.97; 95% CI, 0.8-1.17; P = .75)
- MI (type 4a) only alone occurred in 8.5% vs. 8.2%, respectively (OR = 1.03; 95% CI, 0.63-1.68; P = .79)
- Stent thrombosis (type 4) only occurred in 0.3% of both groups (OR = 1; 95% CI, 0.2-4.97; P = 1)
- Major myocardial injury only occurred in 26.7% vs. 27.7%, respectively (OR = 0.95; 95% CI, 0.78-1.17; P = .61)
- Main secondary outcome of periprocedural MI and any form of myocardial injury occurred in 77.6% of the ticagrelor group vs. 76.8% of the clopidogrel group (OR = 1.05; 95% CI, 0.84-1.3; P = .67)
“The higher level of platelet inhibition obtained with ticagrelor does not translate into a reduction of periprocedural MI or myocardial injury within 48 hours of high-risk PCI performed in stable coronary patients,” Silvain said.
The primary safety outcome of major bleeding occurred in one patient assigned ticagrelor at 48 hours and was similar between treatment groups at 30 days (0.5% vs. 0.2%; OR = 2.51; 95% CI, 0.49-13; P = .29).
However, nuisance or minor bleeding events (BARC 1 or 2) were observed more frequently in the ticagrelor group at 30 days (11.2% vs. 7.5%; OR = 1.54; 95% CI, 1.12-2.11; P = .007).
Dyspnea was more frequent in the ticagrelor group (11.2% vs. 0.5%) and led to more frequent discontinuation of the study drug (2.2% vs. 0.4%), Silvain said.
Additionally, observed rates of non-MI clinical events including death, stroke and revascularization were very low and consistent between groups.
The antiplatelet therapies studied in this trial are “among the best studied agents in coronary disease,” Stephen D. Wiviott, MD, vice president for Clinical Trials Research and Administration at Mass General Brigham, senior investigator for the TIMI Study Group, Brigham and Women’s Hospital, said during a discussant presentation at a press conference.
However, uncertainty remains surrounding antiplatelet therapy for stable CAD PCI in the clinical guidelines, he said. “The AHA/American College of Cardiology don’t offer any guidance and the European Society of Cardiology indicates that there’s a divergence of opinion,” he said.
In the United States, 480,000 patients underwent PCI in 2019; of those, about one-third were elective procedures for stable CAD, Wiviott said.
“This trial does not support the use of more potent P2Y12 antagonists for elective PCI, given that there was not ischemic benefit. Based on these results, and consistent with similar trials, aspirin and clopidogrel should remain the standard of care for this population,” Wiviott said.
Reference:
Perspective
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Roxana Mehran, MD
The simple answer from this trial is that in stable coronary disease, the early events after PCI will not be altered by a more potent P2Y12 inhibitor. What we don’t know is what happens down the line. We know that out to 1 or 2 years, dual antiplatelet therapies with potent P2Y12 inhibitors have been effective compared with DAPT with clopidogrel in high-risk patients. It will be interesting to see where this goes.
What I think is more important from ALPHEUS is that we have a lot of work to do to understand periprocedural MI. I do not think we have a clear-cut best way to define MI vs. myocardial injury, or to identify what is clinically important. Once we accomplish that, it should be used as the endpoint of interest.
Fifteen years ago, our group wrote a paper showing there was a correlation between creatinine kinase-MB elevation and the burden of atherosclerosis. This means myocardial injury, especially in stable syndromes, may be mediated by a non-platelet-mediated mechanism such as the burden of atherosclerosis or plaque that is embolized distally, as opposed to thrombotic or thromboembolic events in which a potent P2Y12 inhibitor works well. In other words, it is not going to work on things that it does not work on.
The 30% rate of myocardial injury gives PCI a bad name, regardless of what P2Y12 inhibitor is used. A similar rate after CABG is likely. What this means is we have to identify whether the injury is clinically significant, ie, does it have significant impact on the morbidity and mortality of those patients? Data have shown that only severe elevations associated with some angiographic abnormalities are an important marker for clinical events down the line. So this is difficult to evaluate.
The investigators did a great job of bringing in patients with demographic risk as well as anatomic risk to enrich the population for clinical events, but the modifier was not a more potent agent.
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Silvain J, et al. LBS.03: Current challenges in coronary and valve disease. Presented at: American Heart Association Scientific Sessions; Nov. 13-17, 2020 (virtual meeting).
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