Ticagrelor or clopidogrel dual antiplatelet therapy following a pharmacoinvasive strategy in ST‐segment elevation myocardial infarction

Abstract Objectives To describe and evaluate outcomes in STEMI patients sustained on clopidogrel compared to those switched to ticagrelor following fibrinolysis. Background World‐wide, many STEMI patients cannot achieve timely PCI and therefore require fibrinolysis. Although comparable 30‐day and 1‐year safety was shown with clopidogrel or ticagrelor in the TREAT study, there is paucity of long‐term outcomes in pharmacoinvasive treated STEMI. Methods We conducted an observational cohort study evaluating consecutive pharmacoinvasive STEMI patients treated in a network, comparing those switched to ticagrelor to those sustained on clopidogrel. The primary efficacy composite was one‐year all‐cause death, recurrent myocardial infarction, and stroke with major bleeding and intracranial hemorrhage (ICH) as the safety outcomes. Multivariable Cox regression model was used to examine the association between P2Y12 inhibitor and outcomes with inverse probability weighting. Results Of 1426 pharmacoinvasive STEMI patients, 28% (n = 396) were converted to ticagrelor at a mean of 9.9 h after fibrinolysis with comparable GRACE Risk Scores (median; 158 vs 157, p0.352). The primary composite occurred in 3.5% of ticagrelor and 7.0% of clopidogrel treated patients (p0.014). Following adjustment, ticagrelor was associated with a 54% lower composite outcome (adjusted HR 0.46, 95% confidence interval 0.26–0.84). Major bleeding 6.3% vs 6.1% (NS) and ICH 0.0% vs 0.2% (NS) were similar. Conclusions In a prospective STEMI cohort, switching to ticagrelor compared with sustaining clopidogrel following fibrinolysis pharmacoinvasive reperfusion reduced recurrent ischemic events at 1‐year with no differences in major bleeding or ICH. Aligned with randomized data, these findings provide support to switch pharmaco‐invasively treated STEMI patients.


| INTRODUCTION
The prognostic benefit associated with dual antiplatelet therapy (DAPT) following acute coronary syndromes (ACS) has been well established. 1,2 However, the persistent risk of recurrent ischemia following the index ACS presentation on traditional clopidogrel based DAPT has led to the need to intensify existing secondary prevention therapies. As such, newer and more potent oral P2Y12 antagonistsprasugrel and ticagrelor-have been preferentially endorsed over clopidogrel in ST elevation myocardial infarction (STEMI) patients following primary percutaneous coronary intervention (PCI). [3][4][5] Randomized trials that demonstrated superior efficacy of ticagrelor and prasugrel however excluded STEMI patients treated with a contemporary fibrinolytic pharmaco-invasive strategy. [6][7][8][9] As such, in the absence of high-quality data, guidelines continue to recommend clopidogrel as the agent of choice for STEMI patients receiving pharmacological reperfusion although there is acknowledgement that switching from clopidogrel to a more potent P2Y12 antagonist seems reasonable once the patient has stabilized (48 h). [3][4][5] Clinical practice guidelines however provide no recommendations on whether to switch clopidogrel for a more potent P2Y12 antagonist after cardiac catheterization in this sub-group of patients. Intuitively, the observed efficacy benefit associated with the more potent P2Y12 antagonists with primary PCI should be translated to pharmacoinvasively treated patients, however, the increase in TIMI major non-CABG bleeding observed within PLATO 7 and TRITION TIMI 38 6 trials raises potential safety concerns with switching early after fibrinolysis.
The ticagrelor in patients With ST-elevation myocardial infarction treated with pharmacological thrombolysis (TREAT) study demonstrated the safety of switching from clopidogrel to ticagrelor within 24 h following fibrinolysis which was consistent at 30 days and 1 year. 10,11 Our objective is to describe the pattern of in-hospital P2Y12 antagonist switching following fibrinolysis and second to evaluate associated clinical outcomes of pharmaco-invasively treated STEMI being discharged on ticagrelor compared to clopidogrel within a comprehensive STEMI network of care.

| Vital heart response
The vital heart response (VHR) program is a regional reperfusion network of care, developed in 2005 (involving all admitting hospitals with a referral population of approximately 2 000 000 inhabitants), to implement timely, and evidence-based reperfusion therapies to maximize the outcomes of STEMI patients in Central and Northern Alberta. In brief, a 24-h on call VHR cardiologist co-ordinates care between the pre-hospital emergency medical services or physicians in non-PCI capable hospital emergency rooms, and based on the clinical scenario, an electronically transmitted ECG, and estimated timings of transfer, decides on 1 of the 2 reperfusion options (pharmacoinvasive or primary PCI). 12 In the pharmacoinvasive (PI) strategy which has been consistently applied since VHR inception, bolus weight-based tenecteplase (TNK), aspirin, clopidogrel and enoxaparin is administered according to guideline recommendations and followed by either rescue PCI or scheduled angiography (within 6-24 h) consistent with the STrategic Reperfusion Early after Myocardial infarction study. 9

| Definition of end-points
The primary efficacy endpoint was defined as time to first event of a composite of all-cause death, recurrent MI or stroke within 1 year from first medical contact (FMC) and primary safety endpoint was major bleeding within 1 year. Follow-up was complete at index hospital discharge in all patients; between discharge and 1 year, 6.8% (n = 98) of patients either could not be linked with follow-up data or they left the province. These patients were censored at either discharge or end of the last fiscal year in the AHCIP registry.

| Statistical analysis
Continuous variables were reported as medians with 25th and 75th percentiles, whereas categorical variables were presented as count and percentages. Differences between groups (no switch versus switch) were tested using Wilcoxon rank-sum test for continuous variables and the χ 2 test or Fisher's exact test for categorical variables.
Kaplan-Meier curves were used to display the unadjusted relationship between switch and the primary efficacy endpoint (i.e., the time to the first occurrence of all-cause death, recurrent MI, or stroke within 1 year [ Figure 1]) with comparison between groups using the log-rank test.
Kaplan-Meier estimated rates and 95%CI within 1 year were also reported.
The relative association between switch and primary efficacy endpoint and association between switch and primary safety endpoint were examined using Cox proportional hazard regression. Unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CI) were reported.

| Inverse probability weighting adjusted analysis
To account for selection bias and confounders, the association between switch and primary efficacy endpoint and association between switch and primary safety endpoint were adjusted using an inverse probability

| DISCUSSION
Within a comprehensive regional STEMI network of care, this study pro-  Infarction (TALOS-AMI) suggested sustained efficacy and enhanced safety converting from ticagrelor to clopidogrel based dual antiplatelet therapy at 1 month following myocardial infarction with stenting. 20 In the future, head to head comparisons of the multiple antiplatelet strategies in a large scale appropriately powered megatrial would help guide clinical care.

| Limitations
The current analysis is based on observational data and despite IPW adjustments for baseline variables there may be inherent patient related bleeding risk differences including patient age driving clinical decisions on the choice of the P2Y12 antagonist. In-hospital procedures and medications were not adjusted since those characteristics may confounded with switching. Additionally, we did not evaluate the effects on patients who had ticagrelor switched to clopidogrel for any clinical indication. Accordingly, given the observational nature of this study, despite adjustment of clinical outcomes for baseline risk, significant confounding may exist.

| CONCLUSION
In a large prospective STEMI registry, we found switching patients to ticagrelor compared with sustaining clopidogrel therapy following fibrinolysis pharmacoinvasive reperfusion was associated with reduced recurrent ischemic events at 1-year. Additionally, switching was not associated with differences in major bleeding or ICH. These findings provide support for switching to ticagrelor in pharmacoinvasive reperfusion patients and add to randomized clinical trial results.

ACKNOWLEDGMENTS
We would like to acknowledge Cynthia M. Westerhout, PhD for review the manuscript and Carolyn Nilson and Chai Paterson for their dedication to the VHR registry.

CONFLICT OF INTEREST
Dr. Welsh reports grants and personal fees from Astra Zeneca, Bayer, and Boehringer Ingelheim outside the submitted work. Dr. Tyrrell reports personal fees from Astra Zeneca and Bayer. Dr. Bainey reports personal fees from Astra Zeneca and Bayer.

DATA AVAILABILITY STATEMENT
Data Availability Statement: Data cannot be shared publicly because it was provided by the Government of Alberta under the terms of a research agreement stipulating that we do not publicly share the data.
Data are available by contacting health.resdata@gov.ab.ca for researchers who meet the criteria for access to confidential information.