• Precision Medicine Lowers DAPT Bleeds in STEMI

    Trial also hits noninferiority mark for adverse cardiac events

    PARIS -- Selection of P2Y12 inhibitors based on genetic variants that influence response reduced bleeding events without hurting outcomes in ST-segment elevation MI (STEMI) patients getting stented, the POPular Genetics trial showed.

    With CYP2C19 genotype guidance, 5.1% of patients experienced an MI, stent thrombosis, stroke, major bleed, or death compared with 5.9% in the standard care group (P<0.001 for noninferiority), reported Jurriën ten Berg, MD, PhD, of St. Antonius Hospital in Nieuwegein, the Netherlands, here at the European Society of Cardiology (ESC) congress.

    And the strategy was superior at reducing major or minor bleeds as defined by Platelet Inhibition and Patient Outcomes (PLATO) criteria (9.8% vs 12.5%, HR 0.78, 95% CI 0.61-0.98), driven solely by minor bleeds.

    "So now we have a tool where physicians can reduce bleeding complications by using this genotype-guided strategy for selecting oral P2Y12 inhibitors in all those patients with STEMI undergoing primary PCI [percutaneous coronary intervention], without an increase in thrombotic risk," said ten Berg during a press briefing.

    In the investigational arm (n=1,242), all patients were tested for CYP2C19 loss-of-function alleles *2 or *3. Carriers received ticagrelor (Brilinta) or prasugrel (Effient), while noncarriers received clopidogrel (Plavix). No genetic testing was performed in the standard treatment arm (n=1,246), in which patients largely went on to receive ticagrelor or prasugrel. Nearly all patients in both cohorts received dual antiplatelet therapy (DAPT) with aspirin.

    Results of the open-label randomized trial were presented at a late-breaking session and simultaneously published in the New England Journal of Medicine.

    While guidelines from the American Academy of Cardiology/American Heart Association (ACC/AHA) recommend any of the three P2Y12 inhibitors for STEMI patients undergoing primary PCI, guidelines from ESC began recommending the two more potent P2Y12 inhibitors -- ticagrelor or prasugrel -- for first-line dual antiplatelet therapy in 2011.

    AHA expert Richard Becker, MD, of the University of Cincinnati Heart, Lung and Vascular Institute, told MedPage Today that clopidogrel is still widely used in the U.S. and testing for CYP2C19 status is not routine. If started on clopidogrel, patients who experience an event are assumed to be non-responders and transitioned to ticagrelor or prasugrel.

    Based on these data alone, he said he doubts any change will occur in ACC/AHA guidelines, but called the POPular findings "intriguing" and a great starting point for using precision medicine to guide use of P2Y12 receptor antagonists.

    "It's really the only study that thus far has shown the potential utilization of gene-based precision-based drug selection," he said. "Before it finds its way into guidelines, it would have to be reproduced, likely in a larger patient cohort really to look specifically at, do you really maintain noninferior benefit comparing clopidogrel relative to ticagrelor?"

    Becker pointed to subanalyses of the large phase III trials of PLATO and TRITON-TIMI that looked at CYP2C19 status and still showed superiority with the more potent antiplatelets in those carrying loss-of-function alleles.

    Asked if the trial would alter European guidelines, ten Berg said he believed it would, perhaps if the ongoing TAILOR-PCI Study ends up showing consistent results with POPular Genetics. He added that all the centers that participated in the current trial will continue to use the genotype-guided strategy. 

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    Jurriën ten Berg, MD, PhD, presenting the results at ESC

    With a point-of-care system, the test can be done while the patient undergoes PCI, he noted, and results are returned within an hour.

    In the past, testing could take up to 3 weeks, said ten Berg, by which point a patient might have already died from a stent thrombosis -- most cases occur within days and the remaining within 30 days.

    "I'm sure it will change practice," said ESC spokesperson Kurt Huber, MD, PhD, of the Medical University of Vienna, who noted that ticagrelor and prasugrel are not necessarily available in all countries or to all patients due to the higher costs.

    The trial randomized 2,488 STEMI patients undergoing PCI to either the genotype-guided treatment or standard treatment at 10 centers in Europe.

    Following primary PCI, patients went on to the P2Y12 inhibitor for at least 12 months, and drug adherence was similar between the genotype-guided (84.5%) and standard groups (82.0%).

    For patients with CYP2C19 loss-of-function alleles in the genotype-guided arm, 38% received ticagrelor and 1% received prasugrel. The remaining 61% of patients -- the noncarriers -- received clopidogrel. In the control arm, 91% were treated with ticagrelor, 2% with prasugrel, and 7% with clopidogrel, according to local protocol.

    Ten Berg said that prasugrel is not typically used in the Netherlands, where eight of the centers in the trial were located, but that this might change given that the drug lowered rates of ischemic events versus ticagrelor in the head-to-head ISAR REACT 5 trial, which was also presented at ESC.

    For secondary endpoints, no significant differences were observed for the combined thrombotic outcome of MI, stent thrombosis, stroke, or death from vascular causes for the genotype-guided group (2.7%) versus standard group (3.3%) or for other thrombotic outcomes.

     

    The trial was funded by the Netherlands Organization for Health Research and Development. The Spartan RX system and reagents used were provided by Spartan Bioscience free of charge.

    Ten Berg disclosed non-financial support from Spartan RX, as well as financial relationships with AstraZeneca, Daiichi Sankyo, Eli Lilly, The Medicines Company, Accumetrics, Boehringer-Ingelheim, Bayer, BMS, Pfizer, and Ferrer.

    Source:

    New England Journal of Medicine

    Source Reference: Claassens DMF, et al "A genotype-guided strategy for oral P2Y12 inhibitors in primary PCI" N Engl J Med 2019; DOI: 10.1056/NEJMoa1907096.

    Read the original article on Medpage Today: Precision Medicine Lowers DAPT Bleeds in STEMI

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