Oral Anticoagulation for the Prevention of Thromboembolic Events in Patients With Anterior ST-Segment Elevation Myocardial Infarction

Abstract

Objectives. The objective is to assess the comparative effectiveness and safety of dual-antiplatelet therapy (DAPT) vs triple therapy (TT) with DAPT + oral anticoagulant (OAC) in patients with anterior ST-segment elevation myocardial infarction (STEMI) and with new-onset anterior/apical wall-motion abnormalities (WMAs) treated with primary percutaneous coronary intervention (PCI). Background. Patients with STEMI and new-onset anterior/apical WMA may benefit from the addition of OAC to prevent left ventricular thrombus and cardioembolic events. Methods. A multicenter, retrospective cohort study was conducted. Patients with a concomitant indication for OAC were excluded. Patients discharged on TT were compared with patients discharged on DAPT using adjusted Cox proportional hazards analysis and inverse probability of treatment weighting. The primary endpoint was the net adverse clinical event (NACE) rate at 6 months (composite of all-cause mortality, non-fatal MI, stroke, or transient ischemic attack, systemic thromboembolism or type 3 or 5 Bleeding Academic Research Consortium [BARC] bleeding). Results. A total of 1666 patients were included, among which 627 were treated with TT and 1039 were treated with DAPT. A NACE occurred in 55 patients (6.03 per 100 patient-years) in the TT group and in 74 patients (7.18 per 100 patient-years) in the DAPT group (adjusted hazard ratio, 0.86; 95% confidence interval, 0.55-1.32). Adjusted risk of the individual components of the primary endpoint, ischemic events, and bleeding events were similar between both groups (P>.05 for all). Conclusions. The addition of OAC to DAPT in anterior STEMI patients with new-onset WMA treated with PCI was not associated with a significant reduction in NACE.

Keywords: acute myocardial infarction, adjunct pharmacology, anticoagulation

Patients hospitalized for an acute anterior ST-segment elevation myocardial infarction (STEMI) are at risk of developing left ventricular (LV) dysfunction and anterior/apical wall-motion ­abnormalities (WMAs).^1,2 Subendocardial tissue injury, coupled with the pro­inflammatory state caused by prolonged ischemia and with relative blood stasis resulting from the new WMA, contributes to prothrombotic conditions, potentially leading to the formation of LV thrombus and cardioembolic events.^3-7 Acute MI is the second-most frequent cause of LV thrombus, after heart failure.⁸ Based on expert opinion and on studies antedating the contemporary era of timely mechanical reperfusion and potent dual antiplatelet therapy (DAPT),^9-12 the current American College of Cardiology Foundation/American Heart Association guidelines suggest considering oral anticoagulation (OAC) for patients with STEMI and anterior apical akinesis or dyskinesis (class IIb, level C).¹³ While these are low-grade recommendations, many centers still prescribe triple therapy (TT) as a standard of care for patients with anterior WMA after STEMI without other concurrent indication for OAC.^6,9,14-16 However, there are no randomized controlled trial data to inform about the safety and efficacy of OAC after STEMI to prevent LV thrombus.¹⁷

DAPT was shown to be superior to aspirin alone in the prevention of ischemic events following a myocardial infarction,^5,6 with incremental benefits observed with newer generations of more potent P2Y₁₂ receptor inhibitors.^18-21 DAPT might thus be sufficient to prevent the development of LV thrombus in the current era. Since bleeding following PCI is associated with an adverse prognosis, the trade-off between safety and efficacy of an additional OAC in the setting of DAPT should be questioned.^22,23 The ATLAS ACS 2-TIMI 51 and APPRAISE-2 randomized trials showed that the addition of an OAC following acute coronary syndrome provided mixed results regarding diminution of ischemic events, and a higher risk of major bleeding.^24,25 However, whether the expected benefits of OAC for prevention of cardioembolic events in the high-risk group of patients with STEMI and new-onset anterior and /or apical WMA are offset by the increased bleeding risk remains unsettled.²⁶

In the face of ongoing clinical equipoise regarding the antithrombotic management of patients with new-onset anterior WMA following STEMI, the MAGIC (MAnaGement of STEMI with anterIor wall-motion abnormalities using triple vs double anti-thrombotIC therapy) study has been designed to assess the comparative effectiveness and safety of TT (DAPT in addition to OAC) vs DAPT alone in patients with anterior STEMI and new-onset anterior or apical WMA treated with primary percutaneous coronary intervention (PCI).

Methods

The MAGIC initiative was a retrospective, multicenter, observational study conducted at 8 academic centers in the province of Quebec, Canada. The study is reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.²⁷ The study protocol was consistent with the Declaration of Helsinki. In keeping with the regulations regarding multicenter studies in the province of Quebec, central ethics approval of the project was obtained from the Montreal Heart Institute research ethics committee.

Patients hospitalized between 2009 and 2017 with a diagnosis of acute myocardial infarction according to discharge summary codes ICD-9 (410) or ICD-10 (I.21) were screened for eligibility at each participating center. All medical records of patients identified with an acute MI were subsequently manually reviewed by trained investigators for eligibility. Inclusion criteria were: ≥18 years old; anterior STEMI treated with primary PCI; and ≥1 anterior or apical segment with hypokinesis, akinesis, dyskinesis, or aneurysm at the first transthoracic echocardiography performed during index hospitalization. Patients with known pre-existing LV anterior akinesis/dyskinesis or LV ejection fraction ≤40%, concomitant established indication for or contraindication to OAC, coronary artery bypass graft performed during index hospitalization, LV thrombus diagnosed during index hospitalization, in-hospital mortality, and antithrombotic strategy at discharge other than DAPT or TT were excluded from the study. Eligible patients were divided into 2 groups according to their discharge antithrombotic therapy: TT group (DAPT + OAC) or DAPT group (aspirin + P2Y₁₂ receptor inhibitors only). Baseline and follow-up data up to 1 year of the index event were extracted from hospital medical records and recorded in a standardized, denominalized electronic form. In case of missing follow-up data, patients were contacted by telephone to obtain follow-up data based on a standardized script approved by the central institutional board review.

The primary endpoint is out-of-hospital net adverse clinical event (NACE), defined as a composite of all-cause mortality, non-fatal MI, stroke or transient ischemic attack, systemic thromboembolism, or type 3 or 5 bleeding according to Bleeding Academic Research Consortium (BARC) at 6 months. The secondary exploratory endpoints are the out-of-hospital individual components of the primary endpoint, an ischemic events composite endpoint (all-cause mortality, non-fatal MI, ischemic stroke or transient ischemic attack, or systemic thromboembolism), an irreversible events composite endpoint (all-cause mortality, non-fatal MI, stroke, systemic thromboembolism with limb loss or intracranial bleeding), intracranial bleeding, and any bleeding at 6 months. MI, stroke, transient ischemic attack, and systemic thromboembolism are defined according to the American College of Cardiology/American Heart Association key data elements and definitions for cardiovascular endpoint events in clinical trials.²⁸ Bleeding types were defined according to BARC definitions.²⁹

Statistical analysis. Statistical analyses were prespecified prior to data analysis. Continuous data are expressed as mean ± standard deviation, and nominal/ordinal data are expressed as counts with percent proportions. Absolute standardized differences (ASDs) between the TT and DAPT groups are reported.^30,31 Counts with event rate (per 100 patient-years) are used as summary statistics for the primary and secondary endpoints. A 2-group comparison of the primary and secondary endpoints between the TT and DAPT groups was made using unadjusted Cox proportional hazards analysis, after verification of the proportional hazards assumption. Adjustment for confounders was performed using 2 different statistical models: (1) direct multivariable Cox proportional hazards analysis (primary analysis); and (2) propensity-score inverse probability of treatment weighting analysis using the PSMATCH procedure in SAS. The absolute standardized mean differences based on weighted observations were lower than the recommended upper limit of 0.25 for the vast majority of the variables, indicating successful treatment weighting (Supplemental Table S1 and Supplemental Table S2).³⁰ For variables with more than 2 categories, the ASD was calculated by comparing the treatments in each level of the variable separately.

Based on subject-matter knowledge, covariates judged a priori as potential confounders were included in the 2 models. Variables with >20% missing values were not eligible as candidate variables in the model. Variables retained in the direct multivariable Cox proportional hazards analysis are year of procedure, age, female sex, current smoking, hypertension, diabetes, chronic kidney disease, previous stroke or transient ischemic attack, hemoglobin, LV ejection fraction, and proton pump inhibitor prescription at discharge. Variables retained in the propensity score inverse probability of treatment weighting analysis are year of procedure, age, female sex, current smoking, hypertension, diabetes, dyslipidemia, previous stroke or transient ischemic attack, previous MI, previous PCI, previous coronary artery bypass graft, chronic kidney disease, culprit artery, number of stents, drug-eluting stent use, multivessel coronary artery disease, multivessel PCI, hemoglobin, LV ejection fraction, LV aneurysm, proton pump inhibitor, and P2Y₁₂ receptor inhibitor prescription at discharge. Unadjusted and adjusted hazard ratios (HRs) from the 2 statistical models are reported for the primary and secondary endpoints, with 95% confidence intervals (CIs). As a subgroup analysis, a 2-group comparison of NACE, ischemic events, and bleeding between the TT and DAPT groups was made using unadjusted Cox proportional hazards analysis in the following subgroups: worse WMA is akinetic or dyskinetic; 4 apical segments akinetic; stroke risk score ≥3;³² LV ejection fraction <30%; and LV ejection fraction <40%. To examine for a possible interaction between treatment groups (TT vs DAPT) and selected subgroups, a Cox proportional hazard model was built, including both variables and an interaction term.

All statistical analyses were conducted using SAS 9.4 statistical software (SAS Institute). Except for the primary endpoint, all of the analyses are considered exploratory. A 2-tailed P-value <.05 was considered statistically significant for all analyses. No correction for multiple analyses was performed in keeping with the exploratory nature of the analysis.

Results

From 2009 to 2017, a total of 2069 patients met the eligibility criteria. However, 403 patients had no 6-month follow-up data available and were excluded from the primary analysis, mostly because they were treated at a hub center for their primary PCI, and were immediately transferred to a spoke non-study center for their hospitalization. Baseline characteristics of patients lost to follow-up were similar to those of patients who were included in the study, with the exception of the year of index MI (Supplemental Table S3). A total of 1666 patients were therefore included in the primary analysis, of whom 627 (37.6%) were treated with TT and 1039 (62.4%) were treated with DAPT at discharge. The majority of patients in the TT group had an intended duration of OAC of 3-6 months (70.31%). Median follow-up duration was 182 days in both treatment groups. Baseline characteristics were largely similar between the TT and DAPT groups (Table 1). However, patients in the TT group were younger (60.70 ± 11.49 years vs 62.47 ± 12.49 years; ASD=0.15) and had more hyperlipidemia (60.54% vs 53.08%; ASD=0.15) compared with patients in the DAPT group. TT was more frequent in the early study period and DAPT was more frequent in the later study period.

Clinical, paraclinical, and procedural characteristics of each group are reported in Table 2. More patients in the TT group presented with a Killip 3 or 4 MI (20.33% vs 10.95%, respectively; ASD=0.26). Patients underwent an echocardiographic evaluation of LV function at a mean of 6 days following the index event. Mean LV ejection fraction was lower in the TT group than in the DAPT (35.48 ± 8.46% vs 43.55 ± 10.16%; ASD=0.86). Patients in the TT group were more likely to have a higher wall-motion score index (1.96 ± 0.32 vs 1.69 ± 0.35; ASD=0.82) and to have LV aneurysm on echography (5.37% vs 1.89%; ASD=0.19), but were less likely to have received a drug-eluting stent (44.37% vs 62.74%; ASD=0.37). Medication at discharge, at 3 months, and at 6 months is presented in Table 3. Patients in the TT group were more likely to be prescribed clopidogrel over more potent P2Y₁₂ inhibitors (93.62% vs 51.40%; ASD=1.11), a protein pump inhibitor (75.40% vs 59.42%; ASD=0.35), and mineralocorticoid receptor antagonists (22.76% vs 6.56%; ASD=0.47) at discharge. The intended duration of OAC planned at discharge from the STEMI hospitalization and actual duration of OAC in the TT group is detailed in Figure 1. In the TT group, 249 patients (45.87%) were treated with OAC at 3 months and 59 patients (11.50%) were treated with OAC at 6 months.

A NACE occurred in 55 patients (6.03 per 100 patient-year) in the TT group and in 74 patients (7.18 per 100 patient-year) in the DAPT group (unadjusted HR, 1.14; 95% CI, 0.80-1.32) (Table 4). There was no significant difference in the unadjusted rate of the individual components of the primary endpoint or of the other secondary endpoints between the TT and DAPT groups, with the exception of any bleeding (5.15 per 100 patient-year in the TT group vs 4.17 per 100 patient-year in the DAPT group; unadjusted HR, 1.72; 95% CI, 1.14-2.61). Following multivariable adjustment, there was no significant difference in the rate of NACE (adjusted HR, 0.86; 95% CI, 0.55-1.32) or in the secondary endpoints between both groups. Propensity score covariate adjustment yielded similar results with no significant difference in the rate of NACE (adjusted HR, 0.89; 95% CI, 0.55-1.45). There was no significant interaction between treatment groups and the prespecified subgroups (Table 5, Supplemental Table S4, Supplemental Table S5).

Discussion

In this observational, multicenter study leveraging granular data collected specifically to answer the study question, the addition of OAC to DAPT in patients with anterior STEMI and new-onset anterior or apical WMA treated with PCI was not associated with a mitigation of the risk of NACE at 6 months. Despite the fact that patients treated with TT presented more baseline high-risk thromboembolic characteristics (lower ejection fraction, higher wall motion score index, and more LV aneurysms), there was no sizeable difference in the rate of ischemic events between both groups with unadjusted and adjusted analyses using propensity score. In addition, TT significantly increased bleeding risk upon unadjusted analysis. Even if this association was no longer significant after multivariable adjustment, this trend is concerning given the fact that post-PCI bleeding is associated with an adverse clinical prognosis in terms of mortality.²² Among the previous randomized controlled trials studying the safety and efficacy of adding a novel oral anticoagulant in acute coronary syndrome patients undergoing PCI, but without specific inclusion of participants with new-onset WMA, only 1 trial suggested an ischemic benefit, but at the expense of an increase in major bleeding in the setting of TT.^24,25,33 However, currently, no randomized trial evaluated the role of the addition of OAC in a high-risk subset of patients with anterior or apical WMA following STEMI.

Our study, the largest observational study addressing this question to our knowledge, has important implications because even in the current era, a large number of cardiologists consider the use of OAC prophylaxis for this condition according to 2 recent surveys, especially in the presence of LV dysfunction or if at least half of the apex presents WMA.^14,15 The findings of our study are consistent with 2 smaller-scale observational studies, which also failed to show a clear benefit of routine anticoagulation in this clinical context, at the expense of an increased risk in major bleeding.^6,9 In a single-center observational study, Le May et al identified 460 patients presenting with an anterior STEMI and apical akinesis or dyskinesis undergoing PCI. Among them, 131 (28.5%) were treated with a vitamin K antagonist in addition to DAPT.⁹ Patients treated with OAC had a higher rate of NACE (defined as all-cause mortality, stroke, reinfarction, and major bleeding) (14.7% vs 4.6%; P<.01) and of major bleeding (8.5% vs 1.8%; P<.01) than those treated with DAPT at 6 months.⁹ Allocation to vitamin K antagonist therapy was an independent predictor of NACE after propensity score analysis. Shavadia et al reported no benefits with TT at 12 months in terms of the composite of recurrent ischemia, stroke/transient ischemic attack/systemic embolism, or all-cause death in a series of 436 consecutive patients with anterior STEMI and LV ejection fraction ≤40%.⁶ Our study, which included twice as many patients as those 2 previous studies combined, and representing the practice of 8 clinical sites, confirms that TT is not associated with sizeable clinical benefit in patients with new-onset WMA after anterior STEMI treated with PCI and DAPT.

Given that bleeding following coronary stenting has consistently been associated with an increased risk in mortality,^22,23 the trade-off between effectiveness and safety seems to favor against the use of OAC in addition to DAPT in anterior STEMI patients undergoing PCI. An update of the Canadian Cardiovascular Society guidelines for the use of antiplatelet therapy was published in 2018, recommending the avoidance of the routine use of TT in patients who undergo PCI for an acute coronary syndrome who are at high risk of developing an LV thrombus.³⁴ While the weak evidence for LV thrombus prevention seems to be outweighed by the higher risk of bleeding events in anterior STEMI patients undergoing PCI, a subgroup of this population with additional risk factors for LV thrombus generation may be at higher risk for subsequent cardioembolic events. Ferreira et al identified older age, Killip class 3 or 4, estimated glomerular filtration rate ≤45 mL/min/1.73 m², hypertension history, and previous stroke as independent predictive factors of stroke in STEMI patients with LV dysfunction (LV ejection fraction ≤35%), and computed these predictors in a stroke risk model.³² The 3-year event rates increased for each sextile of the stroke risk score, with a 10.9% risk in the highest risk category.³² These risk factors could serve to target a subpopulation of anterior STEMI patients at higher risk of LV thrombus for whom the addition of OAC to DAPT may be beneficial and may serve to ascertain risk-enhancement strategies in future trials. The low number of patients with a risk stroke risk score ≥5 in our cohort unfortunately precluded the conduct of a meaningful subgroup analysis.

Alternative combinations of antithrombotic agents, such as OAC + antiplatelet monotherapy (commonly referred to as dual pathway) may also deserve consideration. Among patients with atrial fibrillation undergoing PCI and/or suffering from an acute coronary syndrome, recent randomized trials showed that direct OAC as part of a dual-pathway strategy minimizes bleeding risk compared with vitamin K antagonist-based TT, without concerning signal for an increase in clinical ischemic events.^35-38

Study limitations. Our study has some limitations. First, it is an observational study prone to selection bias, and unmeasurable variables could have confounded the results. Multivariable adjustment and propensity score analyses were performed to mitigate this limitation. Second, data were abstracted from patient medical records, giving rise to the possibility of ascertainment bias. However, manual data extraction from medical records allowed for the availability of granular data. Third, the study might not have been sufficiently powered to identify significant differences between groups, despite the fact that it represents the largest retrospective cohort addressing this clinical equipoise, to our knowledge. Since a randomized trial on this topic is unlikely to be conducted in the future, our results may be the most definitive evidence to guide clinicians. Finally, some patients were lost to follow-up because many STEMI patients are referred to tertiary academic hub centers from their community spoke center for their primary PCI, and then return to the spoke center immediately. Since this distribution of patients is solely guided by geographic considerations, this limitation is not expected to induce a meaningful selection bias and to threaten the internal consistency or the external validity of our findings. Accordingly, baseline characteristics of patients lost to follow-up were similar to those of patients included in the study. 

Conclusion

In this multicenter observational study, the addition of OAC to DAPT following acute anterior MI with new-onset anteroapical WMA treated with PCI was associated with similar rates of NACE, ischemic events, and bleeding events compared with DAPT alone. A randomized controlled trial should be performed to provide a definitive answer to this question.

Affiliations and Disclosures

From the ¹University of Montreal, Montreal, QC, Canada; ²CHUM Research Center and Cardiovascular Center, Montreal, QC, Canada; ³Montreal Heart Institute, Montreal, QC, Canada; ⁴Sherbrooke University Hospital Center, QC, Canada; ⁵Division of Cardiology, Department of Medicine, Jewish General Hospital and McGill University, Montreal, QC, Canada; ⁶Sacré-Coeur Hospital, Montreal, QC, Canada; ⁷Quebec Heart and Lung Institute, Quebec, QC, Canada; and ⁸Maisonneuve-Rosemont Hospital, Montreal, QC, Canada.

Funding: This project was partly funded by a grant from the Société Québécoise d’Insuffisance Cardiaque (Montréal, Quebec, Canada). Dr Marquis-Gravel is supported by a Junior 1 Clinical Research Scholar grant from the Fonds de Recherche du Québec – Santé.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Marquis-Gravel reports honoraria or speaker fees from Novartis, JAMP Pharma Corporation, the Canadian Heart Research Center, Pfizer, Amgen, the Population Health Research Institute, and KYE Pharmaceuticals; research funding from Bayer Corporation, the Canadian Institutes of Health Research (CIHR), the Fond de recherche du Québec (FRQS), the Duke Clinical Research Institute, the Montreal Heart Institute, and the University of Montreal.The remaining authors report no conflicts of interest regarding the content herein.

Manuscript accepted August 4, 2022.

Address for correspondence: Guillaume Marquis-Gravel, MD, MSc, Montreal Heart Institute, 5000 Belanger, Montreal, QC, Canada, H1T 1C8. Email: guillaume.marquis.gravel@umontreal.ca

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