Review of the ACCOAST trial

Pretreatment with Prasugrel in Non–ST-Segment Elevation myocardial infarction

N Engl J Med 2013;369:999-1010

Background: Adding P2Y12 inhibitors to aspirin improves outcomes in patients with acute coronary syndrome. Yet, debate persisted regarding the optimal timing for administering these drugs in patients undergoing percutaneous coronary intervention (PCI). The ATLANTIC trial showed that pre-hospital administration of ticagrelor did not improve outcomes compared to in-hospital administration, in patients with ST elevation myocardial infarction.

The ACCOAST trial sought to test the hypothesis that administering the P2Y12 inhibitor, prasugrel, 2-48 hours before angiography in non-ST elevation myocardial infarction patients is superior to administering it during PCI.

Patients: Patients were enrolled if they had non-ST elevation myocardial infarction. Patients were scheduled to undergo angiography with possible PCI within 2-48 hours after randomization. Patients were excluded if they had cardiogenic shock, refractory ventricular arrhythmias, prior hemorrhagic or ischemic stroke or TIA, history of intracranial neoplasms, history of intracranial AV malformations or aneurysm, surgery within 4 weeks, active bleeding or history of bleeding diathesis or had high risk of bleeding based on the judgement of the investigator.

Baseline characteristics: The average age of patients was 64 years with 72% being men. The average weight was 82 kg. About 20% had diabetes, 45% had hyperlipidemia, 62% had hypertension and 33% were current smokers. Creatinine clearance was ≤ 30 ml/min in 3% of the patients and GRACE score was < 140 in 77% of them. Beta-blockers were given in 84% of the patients, statins in 90%, angiotensin-receptor blockers in 13% and ACE inhibitors in 70%.

After randomization, 68.7% of the patients underwent PCI while 25.1% were treated medically. CABG within 7 days was performed in 6.2% of the patients.

Procedures: Patients were randomized 1:1 to receive pretreatment with prasugrel or matching placebo (control group). Those in the pretreatment group received a 30 mg loading dose of prasugrel before coronary angiography with an additional 30 mg if angiography confirmed the need for PCI. Patients in the control group received placebo before coronary angiography and a 60 mg loading dose of prasugrel in patients undergoing PCI. Only the initial 30 mg loading dose of prasugrel or placebo were administered, if a decision, after coronary angiography, was made to pursue CABG or medical therapy.

Endpoints: The primary efficacy end point was a composite endpoint of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or the need for rescue therapy with glycoprotein IIb/IIIa inhibitors. Follow up for the primary endpoint was 7 days post randomization. Secondary endpoints included death from any cause, stent thrombosis and a composite endpoint of death from cardiovascular causes, myocardial infarction, or stroke.

Safety end points were major or minor bleeding according to Thrombolysis in Myocardial Infarction (TIMI) criteria.

Statistical analysis was performed on the intention-to-treat principle. To achieve 80% power with two-sided alpha of 0.05 for detecting 24% relative risk reduction in the pretreatment compared to the control group, 400 patients with the primary outcome and approximately 4,100 enrolled patients would be needed.

Results: The trial randomized 2,037 patients to the pre-treatment group and 1,996 to the control group. The median time from the initial loading dose to PCI was 4.3 hours.

The incidence of the composite primary end point was similar between both treatment groups (10.0% in the pre-treatment group vs 9.8% in the control group, HR: 1.02, 95% CI: 0.84 – 1.25; p= 0.81). There was no significant difference between both treatment groups in any of the components of the primary end point, death from any cause, or stent thrombosis. Results were similar for patients who underwent PCI (about two thirds of study participants).

There were more major bleeding events at 7 days in the pretreatment group (2.6% vs 1.4%, HR: 1.90, 95%: 1.19 – 3.02; p= 0.006). Major bleeding events not related to CABG were also higher in the pre-treatment group (1.3% vs 0.5%; p= 0.003). In the PCI cohort, 12 patients in the pre-treatment group had life-threatening bleeding compared to 2 in the control group. Most bleedings in this cohort were access site bleeding, pericardial bleeding and retroperitoneal bleeding.

Subgroup analysis for the primary efficacy endpoint did not identify any subgroup who would benefit from pre-treatment with prasugrel.

Conclusion: In patients with non-ST elevation myocardial infarction undergoing coronary angiography within 48 hours of admission, pre-treatment with prasugrel did not improve ischemic events and resulted in more major bleeding.

The results of this trial led to the recommendation that prasugrel should be used after coronary anatomy is defined and PCI is chosen as the treatment strategy. This approach will reduce the risk of bleeding complications without increasing the risk of ischemic events.