ABSTRACT & COMMENTARY
Prehospital Ticagrelor Administration in STEMI Patients Falls Short
By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco, Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Montalescot G, et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med 2014;371:1016-1027.
The preferred treatment for patients presenting with ST-segment elevation myocardial infarction (STEMI) is primary percutaneous coronary intervention (PCI). Optimization of pharmacotherapy before, during, and after primary PCI has the potential to improve outcomes. Antiplatelet therapy with both aspirin and P2Y12 inhibitors such as clopidogrel is a cornerstone of treatment for PCI. In the setting of acute coronary syndromes, more potent inhibition of the platelet P2Y12 receptor with newer agents including ticagrelor and prasugrel has been shown to reduce downstream ischemic events. The results with ticagrelor were particularly positive in the STEMI subgroup of the PLATO trial. These results were seen with in-hospital administration of the drug; whether earlier administration would be beneficial was not known.
The ATLANTIC study sought to answer the following question: In STEMI patients, does pre-hospital administration of ticagrelor have an advantage over later administration in the cardiac catheterization laboratory in terms of efficacy of coronary reperfusion? In the current environment, where both upstream and intraprocedural use of glycoprotein IIb/IIIa inhibitors in STEMI has been waning, this is a constructive inquiry. To answer this, Montalescot and colleagues randomized 1862 patients presenting with STEMI of < 6 hours’ duration to receive ticagrelor either in the ambulance or in the hospital. As primary endpoints, they chose to look at ST-segment resolution pre-PCI, as well as the percentage of patients who did not have normal (TIMI grade 3) flow in the infarct artery at the time of initial angiography. These endpoints mirror those that have shown significant changes in prior studies of upstream use of glycoprotein inhibitors in STEMI. Multiple secondary endpoints were also prespecified, including rates of major adverse cardiovascular events and definite stent thrombosis at 30 days, and ST-segment resolution and TIMI 3 flow at the end of the PCI procedure. The makers of ticagrelor, AstraZeneca, sponsored the study.
During the study, an impressive 1862 patients out of the 1875 enrolled provided written informed consent. A total of 909 patients were randomly assigned to prehospital ticagrelor, while 953 were assigned to receive the drug later in the hospital. This was a mammoth undertaking involving 102 ambulance services and 112 PCI centers in 13 countries. The median time from symptom onset to diagnostic ECG was 78 minutes, while the time from randomization to cardiac catheterization averaged a swift 48 minutes. The median time difference in ticagrelor administration between the pre-hospital and in-hospital groups was only 31 minutes.
In terms of the primary endpoint, the earlier administration of ticagrelor had no significant effect — neither ST-segment resolution nor occurrence of TIMI 3 flow by the time of initial angiography was significantly affected. The combined secondary endpoint, including the composite of death, MI, stroke, urgent revascularization, and stent thrombosis, was not significantly different between the groups. In an interesting twist, however, stent thrombosis at both 24 hours (0 of 906 patients [0%] in the prehospital group vs 8 of 952 [0.8%] in the in-hospital group, P = 0.008) and 30 days (2 of 906 [0.2%] vs 11 of 952 [1.2%], P = 0.02) was significantly reduced in the early ticagrelor group. As might be expected, there was no difference in bleeding related to the timing of ticagrelor administration.
COMMENTARY
In 2001, Dr. Montalescot published the ADMIRAL study, in which 300 patients with STEMI were randomized to receive either the glycoprotein IIb/IIIa inhibitor abciximab or placebo prior to cardiac catheterization. The abciximab group showed a remarkable benefit both in terms of pre-PCI vessel patency as well as 30-day clinical outcomes. More recent STEMI trials of upstream IIb/IIIa inhibitor use, such as the influential ON-TIME2 study, showed positive effects on ST-segment resolution but not on clinical endpoints. Is it surprising that the current study failed in its primary endpoints? Not really. Much has changed since the ADMIRAL study more than a decade ago. One important difference comes from the door-to-balloon effort that has so dramatically shortened the time to cardiac catheterization. In ATLANTIC, the difference in time of ticagrelor administration between the pre- and in-hospital groups was a scant 31 minutes. Looking for a difference in vessel patency so shortly after administration of an oral agent, even a very potent one such as ticagrelor, seems like a lot to expect. In addition, approximately 30% of patients received a glycoprotein IIb/IIIa inhibitor before PCI, further blunting the effect of ticagrelor timing.
ATLANTIC was not a complete bust, however. Although the numbers were small, the positive effect on early stent thrombosis was clear. And this effect is biologically plausible, especially in the environment where IIb/IIIa inhibitors are used in a minority of cases. All by itself, this is a good reason to consider giving ticagrelor or alternate antiplatelet agents as soon as practicable in cases of confirmed STEMI.
