Novel GPVI inhibitor may lower bleeding risk during PCI for CAD
Click Here to Manage Email Alerts
A higher dose of a glycoprotein VI inhibitor in patients with CAD who underwent PCI resulted in more pronounced platelet inhibition without increasing bleeding risk, researchers found in the ISAR PLASTER trial.
The 160 mg dose of the soluble dimeric glycoprotein VI-Fc fusion protein (Revacept, AdvanceCor), which was given on top of standard dual antiplatelet therapy, did not significantly affect myocardial injury in patients with chronic coronary syndrome at low ischemic risk, and better inhibited platelets without raising bleeding risk compared with a 80 mg dose of the drug and placebo, according to the trial presented at the European Society of Cardiology Congress.
“This novel therapeutic concept should be further explored in clinical scenarios with a high ischemic risk,” Steffen Massberg, MD, professor of cardiology and director of the department of cardiology at University Clinic Munich at Ludwig-Maximilians University, said during the presentation.
“The development of drugs that block platelets without increasing bleeds is a major medical need,” Massberg said during the presentation. “There is a novel drug, so-called GPVI inhibitors that actually might meet this requirement.”
In this multicenter, randomized, double-blind trial, researchers analyzed data from 334 patients with chronic coronary syndromes with an indication for PCI who were receiving dual antiplatelet therapy and had a normal high-sensitivity cardiac troponin T level.
Patients were assigned 160 mg of the glycoprotein VI (GPVI) inhibitor (n = 120; mean age, 67 years; 32% women), 80 mg of the GPVI inhibitor (n = 121; mean age, 67 years; 20% women) or placebo (n = 93; mean age, 68 years; 20% women). All treatments were administered intravenously before PCI and were added on top of standard dual antiplatelet therapy.
“Interestingly, GPVI plays an important role in atherothrombosis, but it is not involved, at least not relevantly involved, in hemostasis, making it an interesting candidate for inhibition,” Massberg said during the presentation. “Revacept is a form of GPVI that binds to exposed collagen. It does not bind to platelets for platelet inhibition, but it acts as sort of a lesion-directed competitive inhibitor to platelet-exposed GPVI, sort of like a lesional plaster.”
The primary endpoint was death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin T five or more times the upper limit of normal at 48 hours. Secondary endpoints included peak high-sensitivity cardiac troponin T at 48 hours and MACE at 30 days, defined as all-cause mortality, MI, stroke, PCI-related MI, urgent coronary revascularization and definite stent thrombosis. The safety endpoint was Bleeding Academic Research Consortium type 2 bleeding or higher at 30 days.
At 48 hours, collagen-induced platelet aggregation was significantly reduced in patients assigned 160 mg of the GPVI inhibitor compared with the other groups (P = .018). Minimal difference was observed in the three groups regarding adenosine diphosphate-induced platelet aggregation (P = .11).
Death or myocardial injury occurred in 24.3% of the entire cohort. This did not significantly differ in the three study groups (P = .975).
“Since there was only one death in the whole cohort, the result of the primary endpoint is practically driven by the rise in troponin T,” Massberg said during the presentation.
There was no difference in high-sensitivity cardiac troponin T in the patients assigned 160 mg of the GPVI inhibitor (28 ng/L), those assigned 80 mg of the GPVI inhibitor (31.5 ng/L) and patients assigned placebo (32 ng/L; P = .443).
The rate of MACE at 30 days was 2.5% for the entire cohort, with no significant difference between the groups (P = .91). When individual components of MACE were assessed, this event rate was primarily driven by MI, which also did not significantly differ between the groups. At 30 days, there was only one death, of a patient in the GPVI inhibitor 80 mg group.
Safety at 30 days were similar in the three groups (P = .362).
“It was very surprising and interesting to see that although Revacept, particularly the high dose, blocked patients more efficiently than placebo, this did not translate into an increase in bleeding complications,” Massberg said.
Perspective
Back to Top
Dominick J. Angiolillo, MD, PhD
This is a technology the investigators have been working on for a number of years. It was nice to see that they have moved forward with a phase 2 investigation showing overall favorable safety findings.
As the authors also acknowledge, these data do set the foundation for larger studies in patients at higher risk for thrombotic complications to see the benefit of this novel strategy.
It is always nice to see investigators thinking outside the box and looking at novel targets. One of the advantages of studying thrombosis is that there are so many targets. The question always becomes which one of these is the best target to be considered for our patients. When I say which one is the best to be considered, it is the one that can prevent thrombotic complications in the safest way.
GPVI appears to be novel in this study, but in reality, it is a target that has been under investigation for a number of years including by this group.
Our colleagues from Germany have spearheaded this line of investigation and did a very nice job of moving forward with this phase 2 investigation. However, we definitely need the larger phase 3 study to confirm whether this proof-of-concept strategy can be implemented into clinical practice.
The key thing here is that the data clearly show that when targeting collagen-induced platelet aggregation, there was a dose response in inhibition, so the drug essentially does what it is supposed to do without affecting, for example, adenosine diphosphate-induced platelet aggregation. The study truly expands upon a lot of earlier work on this drug done by the same group of investigators, so it is nice to see this in the clinical setting of patients undergoing PCI.
This occurred without any signals of harm, bearing in mind that this is still a phase 2 study of limited sample size. There were no signals in terms of reduction of MI from the efficacy standpoint, but we also need to keep in mind that this was a very low-risk population where thrombotic complications are extremely low. Observing a treatment effect is very unlikely. This is the reason why we need studies conducted in patient populations where we are more likely to see a treatment effect.
The researchers should be commended for bringing this concept to the next level, and hopefully we will see this further extrapolated into larger clinical trials.
Collapse
Massberg S, et al. Latest Findings in Coronary Artery Disease (Chronic). Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 1, 2020 (virtual meeting).
Click Here to Manage Email Alerts