• P2Y12 Inhibitors Show No Significant Effect in Non-Critically Ill, Hospitalized COVID-19 Patients

    In patients hospitalized with COVID-19 who were not critically ill, the use of P2Y12 inhibitors did not meaningfully increase the number of days alive or reduce the need for cardiovascular or respiratory organ support, according to new study data.

    However, the effect of P2Y12 inhibitor treatment on critically ill patients is still being tested.

    Jeffrey S. Berger MD, MS, of NYU Langone Health, presented these findings from the ACTIV-4a study Monday at the American Heart Association Scientific Sessions 2021 virtual meeting.

    Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, have a significant risk for morbidity and all-cause mortality. Thrombosis and inflammation contribute to this risk.

    Previous data show that a therapeutic dose of heparin increased the number of days alive and freedom from the need for organ support in moderately ill COVID-19 patients.

    Even so, nearly a quarter of patients receiving heparin still died or received intensive care-level support, highlighting the need for more therapies in these patients, Berger said.

    Increased platelet activity is associated with increased severity of COVID-19.

    ACTIV-4a study

    The ACTIV-4a study investigators hypothesized that the benefits and risks of P2Y12 inhibitors may vary according to the severity of COVID-19. They prospectively stratified study patients hospitalized with COVID-19 into critically ill and non-critically ill on enrollment. These patients were randomized 1:1 to receive a P2Y12 inhibitor or no P2Y12 inhibitor plus standard-of-care anticoagulation.

    The primary endpoint was the number of days a patient is alive and free or organ support through 21 days. Key secondary endpoints include a composite of major thrombolic events or death. the primary safety endpoint was major bleeding according to the International Society on Thrombosis and Haemostasis.

    To be eligible, patients needed a laboratory-confirmed SARS-CoV-2 infection. Non-critically ill patients needed one of the following criteria: D-dimer level at least twice the upper limit of normal, age 60-84 years, or if less than 60 years, have one of these criteria (receiving more than 2 liters of oxygen per minute, hypertension, diabetes, low kidney function, cardiovascular disease, or body mass index of 35 kg/m2 or more).

    Patients were excluded if more than 72 hours had elapsed since they were admitted to the hospital for COVID-19 or since their SARS-CoV-2 infection was confirmed, if discharge was expected within 72 hours, if they had a contraindication for P2Y12 inhibitors or if they had a clinical requirement for dual antiplatelet therapy.

    Ticagrelor (60 mg twice daily was the preferred P2Y12 inhibitor, but clopidogrel (300 mg load followed by 75 mg daily) and prasugrel (30 mg load followed by 10 mg daily; in patients less than 60 kg or 75 years or older, no load and 5 mg daily, not recommended in patients 75 years or older and less than 60 kg) were allowed.

    The study used an adaptive Bayesian design. The main analysis population was stratified by severe (critically ill, receiving organ support or intensive care) or moderate (hospitalized but not requiring intensive care).

    Superiority could be declared with >99% posterior probability of a proportional odds ratio >1, and futility would be declared with >95% posterior probability of a proportional odds radio <1.2. The study would continue in each patient group until a conclusion of superiority or futility was reached.

    Enrollment was discontinued in the non-critically ill group on June 19, 2021, after a planned adaptive analysis demonstrated that the statistical criterion for futility was met. At the time, 562 participants had been randomized.



    At baseline, patients were of similar age (treatment 53.1 ± 14.1 years vs. control 52.3 ± 12.9 years), about 40% were female, about 60% were white, about 45% were Hispanic, and about 57% were obese. A majority (about 62.5 to 65.5%) were being treated with steroids, but patients in the treatment group had a higher percentage of receiving remdesivir (56%) than those in the control group (47.6%).

    About 98% of all participants adhered to the P2Y12 inhibitor protocol. Ticagrelor was used in 63% and clopidogrel in 37%. About 90% of those receiving clopidogrel received the loading dose in accordance with the study protocol recommendations. The median duration of study drug treatment was 6 days (interquartile range [IQR]: 4, 8 days), and the median length of stay after randomization was 6 days (IQR: 4, 9 days). About 87% of participants randomized to receive a P2Y12 inhibitor and 88% randomized to usual care received a therapeutic dose of heparin by the end of study day 1.

    The adjusted odds ratio of an effect of a P2Y12 inhibitor on the number of organ support-free days was 0.83 (95% credible interval: 0.55-1.25. The posterior probability of futility was 96.2%, of inferiority was 81.4% and of superiority was 18.6%. In prespecified subgroup analyses, the treatment effect did not vary meaningfully by age, sex, race or several other variables.

    The adjusted hazard ratio of an effect of a P2Y12 inhibitor on the composite of death or organ support was 1.19 (95% confidence interval [CI]: 0.84-1.68; p=0.34).

    The adjusted odds ratio of a treatment effect on the key secondary outcome was 1.42 (95% CI: 0.64-3.13).

    Berger noted that while there appears to be no benefit for P2Y12 inhibitor treatment on non-critically ill, hospitalized COVID-19 patients, testing of critically ill patients continues. He added that P2Y12 inhibitors showed a low rate of major bleeding (approximately a 1% increase in absolute risk).

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