By Jeffrey Zimmet, MD, PhD

Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center

Dr. Zimmet reports no financial relationships relevant to this field of study.

SYNOPSIS: In a large retrospective analysis of patients in Sweden treated with primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction, a propensity-matched group of patients who received oral P2Y12 inhibitors at initial medical contact did not show improved outcomes vs. those receiving these agents at the time of PCI.

SOURCE: Redfors B, Dworeck C, Haraldsson I, et al. Pretreatment with P2Y12 receptor antagonists in ST-elevation myocardial infarction: A report from the Swedish Coronary Angiography and Angioplasty Registry. Eur Heart J 2019;40:1202-1210.

Both current European and U.S. guidelines recommend that patients presenting with ST-elevation myocardial infarction (STEMI) receive aspirin and a P2Y12 receptor antagonist as soon as practical after diagnosis, on the way to percutaneous revascularization. However, the data supporting this practice are limited.

Using the prospective Swedish Coronary Angiography and Angioplasty Registry (SCAAR) database, Redfors et al set out to compare outcomes in STEMI patients who were treated with clopidogrel, prasugrel, or ticagrelor at the time of first medical contact and diagnosis (“pretreated” patients) with those who received these medications later in the cardiac catheterization laboratory. During the study period (early 2005 to late 2016), 53,146 patients who received primary percutaneous coronary intervention (PCI) for STEMI were identified. After excluding patients who did not receive aspirin early, those who were treated with thrombolytics, and those with incomplete or missing data, 44,804 patients remained for analysis. Overall, 84.5% of patients were pretreated with these medications. Pretreated patients were significantly different from non-pretreated patients. They were on average younger, were more likely to be smokers, and had lower prevalence of other diagnoses (including diabetes, hypertension, hyperlipidemia, prior MI or stroke, congestive heart failure, and prior coronary revascularization). Furthermore, during the PCI procedure, pretreated patients were more likely to have radial artery access and were less likely to receive a GII2b/IIIa receptor antagonist or to have complex coronary disease. Pretreated patients were more likely to undergo complete revascularization during the index procedure and were less likely to develop cardiogenic shock. The median time from first medical contact to start of PCI was 74 minutes.

After propensity score adjustment, the authors found no difference in 30-day mortality between the pretreated and non-pretreated groups (odds ratio [OR], 1.08; 95% confidence interval [CI], 0.95-1.24; P = 0.313). Similarly, patency of the infarct-related artery (IRA) at first angiography was not significantly higher in pretreated patients, with approximately 68% found to have IRA occlusion. Likewise, there was not a significant difference in definite stent thrombosis (0.6% of each group), in-hospital bleeding, or neurologic complications. Although cardiogenic shock was more frequent among patients without pretreatment (5.3% vs. 2.7%; unadjusted OR, 0.50; 95% CI, 0.45-0.57; P < 0.001), this difference was no longer statistically significant after propensity score adjustment. The authors concluded that pretreatment of STEMI patients at initial patient contact and diagnosis with P2Y12 inhibitors was not associated with improvement in clinical outcomes, including 30-day mortality, IRA patency, or stent thrombosis compared to treatment at the time of PCI.

COMMENTARY

Prior to this study, the major work examining early P2Y12 inhibition in STEMI was the 2014 ATLANTIC trial. Those authors randomized more than 1,800 STEMI patients to receive ticagrelor either in the prehospital setting or in the cardiac cath lab. It is well known that ATLANTIC showed no difference between the groups in its two coprimary endpoints, which were ST-segment resolution and Thrombolysis In Myocardial Infarction flow in the IRA at initial angiography. Notably, early administration of ticagrelor showed a significant risk reduction in the secondary endpoint of stent thrombosis (ST), although due to small numbers (21 ST events within 30 days), this did not affect the overall statistics regarding death and MI. This difference in ST was found despite an average difference of only 31 minutes in the timing of loading doses between the two groups.

The strengths of the SCAAR analysis lie in the enormous size of the cohort in combination with remarkably complete data collection. However, this remains a retrospective study, with all its attendant weaknesses. One major issue is that guidelines recommended prehospital administration of P2Y12 agents and a large majority of patients (85.3%) in this study received these drugs drugs at first medical contact and diagnosis. Something about the patients who were not treated at initial presentation prevented early administration in contradiction to guidelines. Among the measured variables (age, diabetes, and coronary artery disease history), the two groups were quite different. Thus, despite the propensity analysis, residual confounding is highly likely here.

However, even assuming relatively well-matched groups, is it reasonable to expect a difference in outcomes referable to timing of oral P2Y12 inhibitor administration? Although the time difference between first medical contact and start of PCI was longer (average, 72 minutes) in this study compared with ATLANTIC, the precise medication administration times are not recorded, such that the actual time between medication administration and first angiography likely is shorter than this value. While the ATLANTIC authors used the relatively faster-onset agent ticagrelor exclusively, the SCAAR cohort received clopidogrel in 58.3% of cases, with ticagrelor and prasugrel representing 35.3% and 5.3% of the total, respectively. With oral agents whose time to peak effect is measured in multiple hours, it is unlikely that a difference of scarcely over an hour in administration of the oral loading dose would affect IRA patency at first angiography. The result we see is precisely what one would expect empirically.

From a practical perspective, giving an upstream loading dose of P2Y12 inhibitors has little downside in patients presenting with STEMI. There is no added cost, as one is giving the same agent at an earlier time, and the risk of requiring urgent surgery in the current era is minimal. Furthermore, it is easier to administer oral pills to an upright patient during transport vs. when the patient is lying flat on a cath lab table. Thus, for the average STEMI patient, the negative result of this study should not affect practice.