Review of the ATLANTIC trial

Pre-hospital Ticagrelor in ST-Segment Elevation Myocardial Infarction

N Engl J Med 2014;371:1016-1027

Background: Prior trials have demonstrated that combining P2Y12 inhibitors with aspirin in patients with acute coronary syndrome reduces cardiovascular events. Prasugrel, in the TRITON-TIMI 38 trial, and ticagrelor, in the PLATO trial, were administered in the hospital.

Older trials had suggested that early administration of glycoprotein IIb/IIIa inhibitors improves outcomes in patients with ST elevation myocardial infarction (STEMI).

The ATLANTIC trial sought to test the hypothesis that pre-hospital compared to in-hospital administration of the P2Y12 inhibitor, ticagrelor, improves outcomes in patients with STEMI.

Patients: Patients were enrolled if they had STEMI and had experienced symptoms for at least 30 minutes but no longer than 6 hours, and were expected to have EKG to balloon inflation of less than 120 minutes. Patients were excluded if they had prior intracranial bleeding, moderate to severe liver disease, gastrointestinal bleeding within 6 months, planned fibrinolytic therapy or required dialysis.

Baseline characteristics: The average age of patients was 61 years with 80% being men. The average weight was 80 kg. About 14% had diabetes, 9% had prior myocardial infarction, 4% had chronic obstructive pulmonary disease and 2% had chronic renal failure. TIMI risk score was 0-2 in 61% of the patients. About 90% had Killip class I. Coronary angiography was performed in 98% of the patients and percutaneous coronary intervention (PCI) with stent placement was performed in 82%. The use of glycoprotein IIb/IIIa inhibitors was high in the study and was administered before percutaneous coronary intervention in 29% of the patients.

Procedures: Patients were randomized 1:1 to receive ticagrelor en route to the hospital/ catheterization lab (group 1) or at the catheterization lab (group 2). In group 1, patients received ticagrelor 180mg en route to the hospital and placebo in the catheterization lab. In group 2, patients received placebo en route to the hospital and ticagrelor 180mg in the catheterization lab. Following that, all patients received ticagrelor 90mg twice daily for at least 30 days and the treatment was recommended to continue for 12 months. Clinical endpoints were adjudicated up to 30-days post randomization.

Endpoints: There were two coprimary endpoints – proportion of patients who did not have 70% or greater resolution in their ST-segment elevation before PCI and proportion of patients without TIMI grade III flow in the infarcted artery before PCI. Review of EKG and angiographic data was blinded.

A secondary prespecified endpoint included the composite of all-cause death, myocardial infarction, stent thrombosis, stroke or urgent revascularization at 30 days.

Analysis was performed based on the modified intention-to-treat principle, defined as patients who received at least one loading dose of the study drug. Patients with missing EKG or angiographic data were excluded from the primary endpoint analysis.

The sample size estimate was based on an anticipated event rate of 15% in the control group for the EKG endpoint. They estimated that 779 patients would be needed in each group to show a 6% absolute difference with 80% power and an alpha of 2.5%.

Results: The trial randomized 1,862 patients, 909 patients to the prehospital group and 953 to the in-hospital group. The median time from randomization to angiography was 48 minutes and the median time between the two loading doses was 31 minutes.

There was no significant difference in the proportion of patients who did not have 70% or more ST segment resolution before PCI (86.8% for the pre-hospital group vs 87.6% for the in-hospital group, OR: 0.93, 95% CI: 0.69 – 1.25; p= 0.63) or the proportion of patients who did not have TIMI III flow in the infarcted artery before PCI (82.6% for the pre-hospital group vs 83.1% for the in-hospital group, OR: 0.97, 95% CI: 0.75 – 1.25; p= 0.82).

There was also no significant difference for the secondary composite endpoint (4.5% vs 4.4%, OR: 1.03, 95% CI: 0.66 – 1.60; p= 0.91). Stent thrombosis at 30-days was lower in the pre-hospital group (0.2% vs 1.2%, OR: 0.19, 95% CI: 0.04 – 0.86; p= 0.02). Myocardial infarction was not significantly different between both groups (0.8% vs 1.1%; p= 0.53). All-cause death was numerically higher in the pre-hospital group (3.3% vs 2.0%, OR: 1.68, 95% CI: 0.94 – 3.01; p= 0.08).

Major bleeding not related to CABG was not significantly different between both treatment groups (1.3% in both groups using the TIMI criteria and 2.9% in the pre-hospital group vs 2.5% in the in-hospital group, using the STEEPLE criteria).

Conclusion: In patients with STEMI, pre-hospital administration of ticagrelor did not improve outcomes compared to in-hospital administration. Although pre-hospital administration of ticagrelor reduced stent thrombosis at 30-days, this did not reduce all-cause mortality. In fact, all-cause mortality was numerically higher in the pre-hospital group.

A notable finding is that within the in-hospital group, definite stent thrombosis occurred in 1.2% of patients while 1.1% were adjudicated to have myocardial infarction. Stent thrombosis is a serious condition that leads to myocardial infarction. The trial protocol used many definitions for myocardial infarction. This underscores the complexity of counting and adjudicating events in clinical trials and highlights the importance of relying on outcomes less susceptible to bias, such as mortality.