Personalized approach to antiplatelet drug selection may improve clinical outcomes

ORLANDO, Fla. — Selection of antiplatelet therapy based on genetic information in addition to a patient’s clinical characteristics reduced ischemic and bleeding complications in patients with ACS, researchers reported at the American College of Cardiology Scientific Session.

Perspective from Craig Beavers, PharmD ; Dmitriy N. Feldman, MD, FACC, FSCAI, FSVM

“Clopidogrel leads to substantial variability in patient responses, which limits its effectiveness. Part of this variability is of genetic origin,” Diego Ardissino, MD, director of the cardiology division at the Azienda Ospedaliero-Universitaria di Parma, Italy, and professor of cardiology at the University of Parma, said during a presentation. “The PHARMCLO study was designed to test the hypothesis that selecting antiplatelet therapy on the basis of a combination of genetic information and patients’ clinical characteristics would lead to better clinical outcomes in comparison with standard of care based on clinical characteristics alone.”

The randomized, multicenter trial included 888 unselected patients hospitalized for STEMI and non-STEMI who were assigned to treatment with a P2Y12 receptor antagonist based clinical characteristics or clinical characteristics (n = 440) and the presence of ABCB1, 2C19*2 or 2C19*17 genotypes (n = 448).

At 12 months, the primary outcome — a composite of CV death or first occurrence of nonfatal MI, nonfatal stroke or Bleeding Academic Research Consortium (BARC) 3- to 5-defined major bleeding — occurred less frequently in the pharmacogenomics arm vs. the standard-of-care arm (15.9% vs. 25.9%; HR = 0.58; 95% CI, 0.43-0.78; P < .001).

Additionally, fewer ischemic endpoints occurred in the pharmacogenomics arm compared with the standard-of-care arm (13% vs. 21.4%; HR = 0.57; 95% CI, 0.41-0.8; P < .001). There were also fewer bleeding endpoints in the pharmacogenomics arm, but the difference was not statistically significant (4.2% vs. 6.8%; HR = 0.62; 95% CI, 0.35-1.1; P = .1).

Notably, results showed a significant difference in frequency distribution of P2Y12 receptor antagonists in both study arms, with more patients receiving ticagrelor (Brilinta, AstraZeneca) in the pharmacogenomics arm (42.6% vs. 32.7%; P = .02) and more patients receiving clopidogrel in the standard-of-care arm (50.7% vs. 43.3%; P = .02). Prasugrel was used equally in both study arms.

The researchers also evaluated the primary endpoint in patients treated with clopidogrel. In this group, 24.7% patients in the pharmacogenomic arm vs. 35.4% in the standard-of-care arm experienced the primary endpoint (HR = 0.68; 95% CI, 0.47-0.97; P = .03).

Ardissino said this was a high-risk population, with the mean age at 71 years and more than one-quarter of patients aged older than 80 years. Twenty-one percent of patients had a previous MI, and nearly all patients had a typical rise and fall of cardiac enzyme. Revascularization was performed in 72% of patients, with the majority being treated with PCI.

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Importantly, Ardissino noted that the researchers originally planned to enroll more than 3,600 patients. However, the trial was terminated early by the Ethics Committee of Modina because of the lack of in vitro diagnosis certification for the ST Q3 instrument — the tool used for genotyping patients.

The smaller-than-expected sample size due to early termination accounts for the wide confidence intervals, he said.

“The implementation of multiple genotyping to guide antiplatelet therapy in ACS is feasible across different institutions, and a more personalized approach to the selection of antiplatelet therapy may lead to clinically meaningful reduction in ischemic and bleeding complications,” Ardissino said. “Future studies of genotype-guided antiplatelet therapy are required to confirm these data and clarify the cost-efficacy of genotyping in the challenging setting of ACS before implementing it in everyday clinical practice.” – by Melissa Foster

References:

Ardissino D. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 10-12, 2018; Orlando, Fla.

Notarangelo FM, et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.02.029.

Disclosure: The researchers report no relevant financial disclosures.

Perspective

Craig Beavers, PharmD

This is an outstanding study and we can appreciate its various aspects, especially the inclusion of a high-risk patient population. The findings do add a piece to the overall puzzle of the use of genetic information in this area, but we haven’t completely outlined its role or what the benefits may be. However, it is exciting to see the change in clinical outcomes. In terms of looking at genetics, the study does add some value and I look forward to its implications as well as other studies in this area coming down the pike.

Craig Beavers, PharmD

Member, ACC Cardiovascular Team Council

Cardiovascular Clinical Pharmacy Coordinator

Assistant Adjunct Professor

University of Kentucky Healthcare and College of Pharmacy

Disclosures: Beavers reports no relevant financial disclosures.

Perspective

Dmitriy N. Feldman, MD, FACC, FSCAI, FSVM

The authors performed a prospective, multicenter, randomized study, which examined whether selecting antiplatelet therapy on the basis of a patient’s genetic characteristics leads to better clinical outcomes than the standard of care. They included patients with ACS (STEMI, 28%; non-STEMI, 68%), of whom 96% underwent angiography and 62% underwent PCI.

Patients were randomly assigned to the standard-of-care or the pharmacogenomic arm in which, in addition to clinical variables, clopidogrel, prasugrel or ticagrelor were selected on the basis of a study-specific algorithm that included the genotyping of ABCB1, CYP2C19*2, CYP2C19*17. The trial enrolled 888 patients — comprising about 25% of planned enrollment — but the study was prematurely stopped due to regulatory reasons. The primary endpoint (CV death and the first occurrence of nonfatal MI, nonfatal stroke and BARC 3- to 5-defined major bleeding) occurred in 15.9% of the pharmacogenomic arm and 25.9% of the standard of care arm (HR = 0.58; P < .001).

This interesting trial tested a strategy of pharmacogenomic-based P2Y12 agent selection in a vulnerable ACS population. On the heels of several negative trials of platelet function testing-based P2Y12 selection (GRAVITAS, TRIGGER-PCI, ARCTIC), the tide may be turning in support of a genomic-based strategy to select the appropriate P2Y12 therapy.

Unfortunately, the trial was terminated early. But, despite being underpowered, the study demonstrated encouraging benefit of genomic-based strategy for both ischemic and bleeding endpoints.

However, a number of concerns should be acknowledged. First, there was a high rate (50%) of clopidogrel use in the standard of care arm in this mostly STEMI and non-STEMI population, despite the guidelines’ recommendations based on PLATO and TRITON TIMI 38 trials data. Second, there was a high event rate in the standard-of-care group, with about one-quarter of patients with ACS having had an ischemic or bleeding event. Third, the choice of ABCB1 testing is debatable and a more simplified approach of only CYP2C19 testing might have been preferred. Finally, the difference in MIs was partly driven by post-PCI and post-CABG infarctions. The magnitude of the combined ischemic and bleeding effects seems to be excessive, given that the absolute differences in clopidogrel use was only 7% between the two groups and the absolute difference in ticagrelor use was only 10% between the two groups.

Despite these concerns, the results are provocative and should lead to a large randomized trial that would test the efficacy and cost-effectiveness of the tailored genomic-based P2Y12 agent selection in ACS.

Dmitriy N. Feldman, MD, FACC, FSCAI, FSVM

Associate Professor of Medicine

Weill Cornell Medical College/ NewYork-Presbyterian Hospital

Greenberg Division of Cardiology, Department of Medicine

Director, Endovascular Services

Director, Interventional Observation/Telemetry Unit

Disclosures: Feldman reports no relevant financial disclosures.