No difference in outcomes for different pre-treatment duration with P2Y12 inhibitor in NSTEMI patients
Interval From Initiation of Prasugrel to Coronary Angiography in Patients With Non–ST-Segment Elevation Myocardial Infarction
Introduction and methods
In patients with non–ST-segment elevation myocardial infarction (NSTEMI) who undergo invasive strategies, pre-treatment with P2Y12 inhibitors may result in increased risk of bleeding or delay of coronary artery bypass grafting (CABG). The ACCOAST (A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction) trial therefore assessed a strategy of pre-treatment with prasugrel in NSTEMI patients, with the result of no ischemic benefit, but an increase in bleeding regardless of the vascularization strategy [1-3].
One of the questions remaining after these first results was whether timing of prasugrel had an impact on outcomes, because a short duration may have resulted in insufficient activation or incomplete protection. Mean delay between loading dose (LD) of prasugrel or placebo and coronary angiography was 4.3 hours (according to protocol angiography had to take place <48 hours after randomization). Therefore, this pre-specified analysis investigated whether duration of pre-treatment with prasugrel resulted in different outcomes.
The ACCOAST trial enrolled 4033 NSTEMI patients who were randomized 1:1 to receive pre-treatment with prasugrel or placebo in addition to aspirin and standard care. In the pre-treatment arm, additional 30 mg prasugrel was given at time of PCI after angiography. In the no pre-treatment arm, 60 mg of prasugrel was given after angiography in patients undergoing PCI. Patients undergoing CABG or medical management did not receive the second LD of prasugrel in the pre-treatment arm or the 60 mg prasugrel in the no pre-treatment arm. Patients treated with PCI received a daily maintenance dose of prasugrel in combination with aspirin through the follow-up visit at 30 days.
For this analysis (n=4001), the trial population was divided into quartiles based on the time of first LD of treatment to the beginning of coronary angiography, 0.1 to 2.5 h, 2.5 to 3.9 h, 3.9 to 13.6 h, and >13.6 h.
Primary composite endpoint was time to first occurrence of CV death, MI, stroke, urgent revascularization, glycoprotein IIb/IIIa inhibitor bailout through 7 days from randomization. Safety endpoints were TIMI major and minor bleedings.
- No interaction was observed between pre-treatment with prasugrel, pre-treatment duration and the primary efficacy endpoint (P=0.17), nor for individual endpoints.
- Looking at the PCI population alone, there was a borderline significant interaction between primary endpoint and pre-treatment duration of prasugrel (P=0.049).
- There was no interaction between bleeding and pre-treatment duration in the total and PCI alone populations (all TIMI major bleeding: P=0.37 and P=0.87 for total and PCI population, respectively).
In NSTEMI patients, different time intervals of pre-treatment with prasugrel until angiography did not show differences in ischemic outcomes and bleeding, indicating that even with a short time interval (0.1-2.5 hr) there was sufficient activation of prasugrel.
In an editorial comment , Capodanno and Angiolillo state that although ACCOAST showed negative results for pre-treatment with prasugel, uncertainty remains of timing of other P2Y12 inhibitors. They discuss the results of a meta-analysis, SCAAR registry, and the PLATO trial and conclude that the efficacy and safety of pre-treatment with ticagrelor has never been formally tested in a randomized clinical trial with NSTEMI patients. Although guidelines in Europe and US have differed on use of pre-treatment with P2Y12 inhibitors, currently they both state that before angiography, pre-treatment with P2Y12 inhibitor should consist of ticagrelor or clopidogrel, favoring the former, and prasugrel is contraindicated by the ESC guidelines and not endorsed by the ACC/AHA guidelines. Prasugrel is only an option when PCI is decided.
Furthermore, Capodanno and Angiolillo discuss the possibility of some benefit of pre-treatment in patients with delayed PCI times. In addition, they mention that factors such as reduced access site bleeding because most of the PCI procedures are performed through the radial vascular access and unlikelihood of CABG in context of ACS should also be considered. They end by hypothesizing that cangrelor could be a downstream option instead of pre-treatment with P2Y12 inhibitors in patients undergoing PCI, particularly in acute settings.