STEMI Trial Fails to Support Post-PCI Anticoagulation
Ted Bosworth
September 15, 2023
The first randomized trial to evaluate postprocedural anticoagulation (PPA) in patients undergoing a primary percutaneous coronary intervention (PCI) for an ST-segment elevation myocardial infarction (STEMI) did not associate significant benefit — or significant harm — with any of the three tested regimens relative to placebo.
There has been a signal from nonrandomized studies that PPA reduces the risk for ischemic events, but no controlled prospective trials have evaluated the risk-benefit relationship in STEMI patients, said Yan Yan, MD, a researcher in Beijing Anzhen Hospital, Beijing, China.
The results of the randomized trial, called RIGHT, were presented at the European Society of Cardiology (ESC) Congress 2023 on August 28 by Yan, on behalf of a team of coinvestigators led by Nie Shaoping, MD, PhD, a cardiologist affiliated with Capital Medical University, Beijing.
The bottom line is that "routine PPA with low-dose anticoagulation after primary PCI in STEMI patients is safe, but it does not improve ischemic outcome at 30 days," Yan concluded.
Objective Study
In her presentation, Yan explained that an objective study has been needed to validate the common use of empirically administered PPA. According to Yan, PPA is being offered to up to 40% of STEMI patients in Europe, with even higher rates in China.
In the investigator-initiated RIGHT trial, 2856 STEMI patients undergoing PCI were randomized to PPA or placebo in a 1:1 ratio. In the PPA arm, patients received one of three low-dose anticoagulation regimens over 48 hours or until discharge if this was longer: 0.2 mg/kg per hour of bivalirudin administered intravenously; 40 mg of enoxaparin administered subcutaneously, or 10 U/kg per hour of unfractionated heparin (UFH) to maintain an activated coagulation time between 150 and 200 seconds.
Each of the 53 participating Chinese centers selected one of the anticoagulation regimens. Matching placebos were employed in the double-blind design. All received bivalirudin anticoagulation during PCI. Exclusion criteria included unstable disease, such as cardiogenic shock, prior coronary artery bypass grafting, or an indication for anticoagulation other than PPA.
For the composite primary endpoint of all-cause death, non-fatal MI, nonfatal stroke, stent thrombosis, or urgent revascularization at 30 days, there was no difference between PPA and placebo. The event rate in both arms was 2.5%.
There were also no significant differences between PPA and placebo for any of the secondary ischemic endpoints, which included the individual components of the primary endpoint and cardiovascular death.
For the primary safety endpoint of Bleeding Academic Research Consortium (BARC) grade 3 to 5 bleeding, the slight increase in events among those in the placebo group did not approach statistical significance (P = .551). On other definitions of bleeding, which were secondary endpoints, PPA and placebo also did not differ significantly.
Compared for safety, the three anticoagulation regimens performed similarly with no significant interaction for the primary endpoint (P = .679).
For efficacy, the differences did range sufficiently to produce a significant interaction (P = .01) with enoxaparin appearing to be more effective, UFH less effective, and bivalirudin falling in between. This led Yan to speculate that the three anticoagulants "may not be equivalent," although she said larger trials are needed to explore potential differences.
Design Flawed?
The ESC-invited discussant, Pascal Vranckx, MD, PhD, medical director, Cardiac Critical Care Services, Hartcentrum Hasselt, Belgium, liked the question being asked in the study, but concluded that the design was flawed.
"There are a variety of anticoagulants employed in a variety of doses [for PPA] but we have very limited data. The research question is totally appropriate," he said. However, he asked, "What went wrong? Was it the drugs, the trial, or both?"
The problem, he thinks, is the dose. Much of the design of RIGHT was based on the 2015 MATRIX trial, which did show a benefit from a single dose of bivalirudin following PCI relative to two other comparators. In that study, STEMI patients randomized to bivalirudin received a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour for at least 4 hours. The comparators were UFH or a control arm of low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors.
At 30 days, bivalirudin was associated with a 40% reduction (hazard ratio, 0.60; P = .001) relative to control for the composite primary endpoint of death or bleeding. Vranckx pointed out that MATRIX was a trial of a single-dose prolongation of PPA, whereas RIGHT was "a prolongation of a prolongation," but he believes MATRIX data support higher doses of anticoagulation, particularly of bivalirudin.
"Perhaps low dose bivalirudin is not the way to go," he speculated.
He further advised the authors to reevaluate the expected benefit from PPA following STEMI. In MATRIX, the risk for events was highly concentrated in the immediate period after PCI, suggesting that the opportunity to reduce risk is much lower as anticoagulation is prolonged. He suggested that the low number of events in RIGHT are consistent with the diminishing risk for events over time.
Nevertheless, Vranckx praised the authors for addressing a research question that is "timely and highly relevant." He called the data "important" by drawing attention to a potential target for risk reduction, and encouraged additional trials to determine what PPA strategy, if any, can further reduce early ischemic events after PCI.
European Society of Cardiology (ESC) Congress 2023. Presented August 28, 2023.
Yan and colleagues report financial relationships with Abbott, Boston Scientific, East China Pharmaceuticals, Saniju Medical and Pharmaceuticals, and Jiangsu Hengrui Pharmaceuticals, which provided funding for this study. Vranckx reports no potential conflicts of interest
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