Point-of-care testing of platelet P2Y12-inhibition in patients with acute coronary syndrome

Sammanfattning: Background: The point-of-care platelet function test Plateletworks® has been shown to identify patients with high platelet aggregation despite P2Y12 inhibition, also known as high-on-treatment platelet reactivity (HPR), who have increased risk for ischemic cardiovascular events. However, this platelet function assay has not been sufficiently validated. Patients who instead have excessive platelet inhibition are at risk for bleeding but predictive value of the Plateletworks® assay regarding bleeding has not been shown. Clopidogrel is today largely replaced by newer P2Y12 inhibitors such as ticagrelor due to improved outcome. The drug uptake after a 180 mg loading dose (LD) of ticagrelor has, however, not been thoroughly investigated in patients with non ST-segment elevation myocardial infarction (NSTEMI). Patients with ST-segment elevation myocardial infarction (STEMI) have a slower uptake of ticagrelor, likely due to morphine-induced inhibition of gastrointestinal motility. Aims I: To identify patients pretreated with clopidogrel at increased risk for adverse clinical events after coronary angiography; II: To investigate the relation between platelet reactivity and the 30-day incidence of bleeding complications, as defined by two relevant bleeding definitions in clopidogrel-treated patients; III: To evaluate the ticagrelor uptake and platelet P2Y12 inhibition in patients with NSTEMI not receiving opioids and compare these data with those of patients with stable coronary artery disease (SCAD); IV: To evaluate if the peripheral opioid antagonist methylnaltrexone could improve platelet inhibition after a LD of 180 mg ticagrelor in morphine treated patients with STEMI. Methods: Study I and II were observational, prospective studies based on the same cohort of 491 patients on clopidogrel who underwent coronary angiography. Platelet aggregation was measured with adenosine diphosphate-induced platelet function testing (Plateletworks®) and a cut-off was established for prediction of the respective primary outcome variable. In Study I, Patients were followed for three months, and the primary endpoint was myocardial infarction. In Study II, the primary endpoint was incidence of bleeding within 30 days as defined by the BARC and ARMYDA-BLEEDS bleeding definitions. Study III was an observational, prospective study on 40 NSTEMI patients and 20 controls. Both groups received a 180 mg ticagrelor LD and blood samples were taken pre-dose and 1, 2, 3, 4, 5, and 6 hours post LD. Plasma concentrations of ticagrelor and its active metabolite AR-C124910XX were analyzed as well as platelet inhibition. The primary endpoint was the time to maximal ticagrelor concentration (Tmax). Study IV was a multicenter, prospective, randomized, controlled trial in STEMI patients treated with morphine and ticagrelor. Patients were randomized to a blinded intravenous injection of either methylnaltrexone or 0.9% sodium chloride. The proportion of patients with HPR and the plasma concentrations of ticagrelor and AR-C124910XX were assessed at baseline, one, and two hours. Results I: A cut-off of 82.3% platelet aggregation was found to predict myocardial infarction and thus defined HPR. In total 39.9% (n=196/491) had HPR. At three months follow-up the event rates of myocardial infarction (MI) and rehospitalization, respectively, were higher in patients with HPR (5.1% vs. 1.7%, p=0.03; and 23.0% vs. 14.2%, p=0.01, respectively). II: In total, 474 patients of the initial cohort of 491 were included. Patients in the lowest platelet aggregation quartile had a higher frequency of ≥type 2 BARC bleeding and ARMYDABLEEDS defined bleeding within 30 days compared with the highest quartile (16.9% vs. 6.7%, p=0.014, and 8.5% vs. 1.7%, p=0.016, respectively). III: The Tmax of ticagrelor did not significantly differ between NSTEMI patients and the controls (2.0h [1.0-3.0]) vs. 2.0h [2.0-3.0], p=0.393). HPR was at one hour seen in 15% of the NSTEMI patients versus 10% of the controls (p=1.0) and at two hours in 3% of the NSTEMI patients compared with none of the controls (p=1.0). IV: A total of 82 patients received either methylnaltrexone (n=43) or placebo (n= 39). Methylnaltrexone administration did not significantly affect prevalence of HPR at two hours after inclusion, the primary end-point, compared with placebo (54% vs. 51%, p=0.84). Plasma concentrations of ticagrelor and its active metabolite did not differ significantly between the groups over time. Conclusions I: Testing with Plateletworks® identified patients at increased risk of myocardial infarction and rehospitalization within three months after coronary angiography. II: Patients in the lowest platelet aggregation quartile had a significantly higher incidence of bleeding according to BARC and ARMYDA-BLEEDS definitions within 30 days III: The uptake of ticagrelor was not significantly slower in NSTEMI patients compared with the SCAD controls with adequate onset of platelet inhibition in both groups. IV: Methylnaltrexone did not significantly improve platelet reactivity or plasma concentrations of orally administered ticagrelor in STEMI patients receiving morphine.