Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke: A Post Hoc Analysis From the AUGUSTUS Trial

M Cecilia Bahit; Amit N Vora; Zhuokai Li; Daniel M Wojdyla; Laine Thomas; Shaun G Goodman; Ronald Aronson; J Dedrick Jordan; Brad J Kolls; Keith E Dombrowski; Dragos Vinereanu; Sigrun Halvorsen; Otavio Berwanger; Stephan Windecker; Roxana Mehran; Christopher B Granger; John H Alexander; Renato D Lopes

doi:10.1001/jamacardio.2022.1166

. 2022 May 25;7(7):682–689. doi: 10.1001/jamacardio.2022.1166

Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke

A Post Hoc Analysis From the AUGUSTUS Trial

M Cecilia Bahit ¹, Amit N Vora ^2,³, Zhuokai Li ³, Daniel M Wojdyla ³, Laine Thomas ³, Shaun G Goodman ^4,⁵, Ronald Aronson ⁶, J Dedrick Jordan ⁷, Brad J Kolls ^3,⁷, Keith E Dombrowski ⁸, Dragos Vinereanu ⁹, Sigrun Halvorsen ¹⁰, Otavio Berwanger ¹¹, Stephan Windecker ¹², Roxana Mehran ^13,¹⁴, Christopher B Granger ³, John H Alexander ³, Renato D Lopes ^3,^✉

¹INECO Neurociencias Oroño, Fundación INECO, Rosario, Santa Fe, Argentina

²UPMC Heart and Vascular Institute, Harrisburg, Pennsylvania

³Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina

⁴Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada

⁵Terrence Donnelly Heart Center, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada

⁶Bristol Myers Squibb, Lawrenceville, New Jersey

⁷Department of Neurology, Duke University School of Medicine, Durham, North Carolina

⁸Department of Neurosurgery and Brain Repair, University of South Florida, Tampa

⁹Carol Davila University of Medicine and Pharmacy, University and Emergency Hospital, Bucharest, Romania

¹⁰Department of Cardiology, Oslo University Hospital, Oslo, Norway

¹¹Hospital Israelita Albert Einstein, São Paulo, Brazil

¹²Swiss Cardiovascular Center, Bern, Switzerland

¹³Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York

¹⁴Cardiovascular Research Foundation, New York, New York

Accepted for Publication: April 5, 2022.

Published Online: May 25, 2022. doi:10.1001/jamacardio.2022.1166

^✉

Corresponding Author: Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, 200 Morris St, Durham, NC 27701 (renato.lopes@dm.duke.edu).

Author Contributions: Dr Lopes had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Bahit, Wojdyla, Goodman, Vinereanu, Berwanger, Mehran, Granger, Alexander, Lopes.

Acquisition, analysis, or interpretation of data: Vora, Li, Wojdyla, Thomas, Goodman, Aronson, Jordan, Kolls, Dombrowski, Vinereanu, Halvorsen, Berwanger, Windecker, Mehran, Alexander, Lopes.

Drafting of the manuscript: Bahit, Aronson, Dombrowski, Lopes.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Bahit, Li, Wojdyla, Thomas.

Obtained funding: Vinereanu, Alexander, Lopes.

Administrative, technical, or material support: Aronson, Jordan, Dombrowski, Alexander, Lopes.

Supervision: Goodman, Dombrowski, Vinereanu, Halvorsen, Mehran, Alexander, Lopes.

Conflict of Interest Disclosures: Dr Bahit reported other fees from Bristol Myers Squibb and Pfizer during the conduct of the study and other from Merck Sharp & Dohme, CSL Behring, Vifor, and Boehringer Ingelheim outside the submitted work. Dr Vora reported grants from Medtronic outside the submitted work. Dr Thomas reported grants from Akili Interactive Labs, Amgen, Gilead, and Novartis. Dr Goodman reported grants and other fees from Amgen, Bristol Myers Squibb/Pfizer, Bayer, Boehringer Ingelheim, Anthos Therapeutics, AstraZeneca, CSL Behring, Daiichi-Sankyo, Eli Lilly, Esperion, Fenix Group International, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, Janssen/Johnson & Johnson, Luitpold Pharmaceuticals, Matrizyme, Merck, Novartis, Novo Nordisk, Pendopharm, Regeneron, Sanofi, Servier, Tenax Therapeutics, and Valeo Pharma outside the submitted work and salary support and honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto, Canadian Heart Research Centre, MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Center for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, PERFUSE Research Institute, and TIMI Study Group (Brigham Health). Dr Aronson reported being a salaried employee of Bristol Myers Squibb during the conduct of the study and owning stock in Bristol Myers Squibb outside the submitted work. Dr Kolls reported grants from Pfizer and Bristol Myers Squibb during the conduct of the study. Dr Vinereanu reported grants from Bristol Myers Squibb and Pfizer during the conduct of the study and grants and/or personal fees from Bayer, Boehringer Ingelheim, Pfizer, Novartis, and Daiichi Sankyo outside the submitted work. Dr Halvorsen reported personal fees from Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Sanofi, and Merck outside the submitted work. Dr Berwanger reported grants and consulting fees from AstraZeneca, Bayer, Pfizer, Servier, Amgen, Novartis, and Boehringer Ingelheim and consulting fees from Sanofi and Novo Nordisk outside the submitted work. Dr Windecker reported institutional research and educational grants from Abbott, Amgen, AstraZeneca, Bristol Myers Squibb, Bayer, Biotronik, Boston Scientific, Cardinal Health, Cardiovalve, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Johnson & Johnson, Medicure, Medtronic, Novartis, Polares, OrPha Suisse, Pfizer, Regeneron, Sanofi-Aventis, Sinomed, Terumo, and V-Wave outside the submitted work; reported serving as unpaid advisory board member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Biotronik, Cardiovalve, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave and Xeltis; and reported being a member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. Dr Mehran reported grants from Abbott, Abiomed, Alleviant, AM Pharma, Applied Therapeutics, Arena, AstraZeneca, Bayer, Beth Israel Deaconess, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb/Sanofi, CardiaWave, CellAegis, CeloNova, CERC, Chiesi, Concept Medical, CSL Behring, DSI, Duke University, Eli Lilly/Daiichi Sankyo, Humacyte, Insel Gruppe, Janssen, Medtronic, Novartis, OrbusNeich, Philips, Vivasure, and Zoll; and personal and other fees from Abbott Vascular, Boston Scientific, CIRM, Cine-Med Research, Janssen, WebMD, Idorsia Pharmaceuticals, Medscape, Medtronic, Novartis, Philips, Siemens Medical Solutions, Roivant Sciences, Sanofi, Spectranetics/Philips/Volcano Corporation, Bristol Myers Squibb, Novartis, Watermark Research, American Medical Association Scientific Advisory Board, SCAI Women in Innovations, and Biosensors Scientific Advisory Board (spouse); equity of less than 1% from Applied Therapeutics, Claret Medical, Elixir Medical, STEL, ControlRad (spouse); and being an executive committee member for Janssen Pharmaceuticals and Bristol Myers Squibb outside the submitted work. Dr Granger reported research grants from Akros, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Pfizer, Armetheon, US Food and Drug Administration, GlaxoSmithKline, The Medicines Company, Medtronic Foundation, Medtronic, and Novartis and consulting fees from Abiomed, Alnylam Pharma, Anthos, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardionomic, Celecor Therapeutics, Correvio, Daiichi Sankyo, Espero, Janssen, Pfizer, Philips, AbbVie, Armetheon, AstraZeneca, Eli Lilly, Gilead, GlaxoSmithKline, HengRui, Hoffmann-La Roche, The Medicines Company, National Institutes of Health, Novartis, Sirtex, Reata, Verseon, Apple, Medscape, Medtronic, Merck, Novo Nordisk, Roche Diagnostics, Rho Pharmaceuticals, and Tenac.io. Dr Alexander reported grants from Bristol Myers Squibb during the conduct of the study and grants and/or personal fees from AbbVie, Akros, AtriCure, Bayer, Bristol Myers Squibb, CryoLife, CSL Behring, Ferring, Humacyte, Janssen, Pfizer, and Portola outside the submitted work. Dr Lopes reported grants from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi and personal consulting fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Pfizer, Portolz, and Sanofi outside the submitted work. No other disclosures were reported.

Funding/Support: The AUGUSTUS trial and this analysis were supported by Bristol Myers Squibb and Pfizer and coordinated by the Duke Clinical Research Institute.

Role of the Funder/Sponsor: The study sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication but were given the opportunity to review and comment on the manuscript.

Additional Contributions: Elizabeth E. S. Cook, from the Duke Clinical Research Institute, provided editorial assistance. She was not compensated outside of her salary.

Data Sharing Statement: See Supplement 2.

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Corresponding author.

PMCID: PMC9134037 PMID: 35612866

This randomized clinical trial analyzes data comparing treatment regimens according to prior stroke, transient ischemic attack, or thromboembolism to determine the safety and efficacy of apixaban, vitamin K antagonists, and aspirin.

Key Points

Question

In patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention receiving a P2Y12 inhibitor, does treatment effect vary according to prior stroke, transient ischemic attack (TIA), or thromboembolism (TE)?

Findings

In this randomized clinical trial, a post hoc analysis found that patients with vs without prior stroke/TIA/TE had a higher risk of ischemic and bleeding events. Among those with prior stroke/TIA/TE, patients treated with apixaban had less bleeding, death, or hospitalization than patients treated with vitamin K antagonists; patients treated with aspirin had a higher bleeding risk than those receiving placebo.

Meaning

The safety and efficacy of apixaban compared with vitamin K antagonists were consistent with the overall trial findings, irrespective of history of stroke/TIA/TE.

Abstract

Importance

Data are limited regarding the risk of cerebrovascular ischemic events and major bleeding in patients with atrial fibrillation (AF) and recent acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI).

Objective

Determine the efficacy and safety of apixaban or vitamin K antagonists (VKA) and aspirin or placebo according to prior stroke, transient ischemic attack (TIA), or thromboembolism (TE).

Design, Setting, and Participants

In this prospective, multicenter, 2-by-2 factorial, randomized clinical trial, post hoc parallel analyses were performed to compare randomized treatment regimens according to presence or absence of prior stroke/TIA/TE using Cox proportional hazards models. Patients with AF, recent ACS or PCI, and planned use of P2Y12 inhibitors for 6 months or longer were included; 33 patients with missing data about prior stroke/TIA/TE were excluded.

Interventions

Apixaban (5 mg or 2.5 mg twice daily) or VKA and aspirin or placebo.

Main Outcomes and Measures

Major or clinically relevant nonmajor (CRNM) bleeding.

Results

Of 4581 patients included, 633 (13.8%) had prior stroke/TIA/TE. Patients with vs without prior stroke/TIA/TE were older; had higher CHA₂DS₂-VAS_C and HAS-BLED scores; and more frequently had prior bleeding, heart failure, diabetes, and prior oral anticoagulant use. Apixaban was associated with lower rates of major or CRNM bleeding and death or hospitalization than VKA in patients with (hazard ratio [HR], 0.69; 95% CI, 0.46-1.03) and without (HR, 0.68; 95% CI, 0.57-0.82) prior stroke/TIA/TE. Patients without prior stroke/TIA/TE receiving aspirin vs placebo had higher rates of bleeding; this difference appeared less substantial among patients with prior stroke/TIA/TE (P = .01 for interaction). Aspirin was associated with numerically lower rates of death or ischemic events than placebo in patients with (HR, 0.71; 95% CI, 0.42-1.20) and without (HR, 0.93; 95% CI, 0.72-1.21) prior stroke/TIA/TE (not statistically significant).

Conclusions and Relevance

The safety and efficacy of apixaban compared with VKA was consistent with the AUGUSTUS findings, irrespective of prior stroke/TIA/TE. Aspirin increased major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE. Although aspirin may have some benefit in patients with prior stroke, our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for the majority of patients with AF and ACS and/or PCI, regardless of prior stroke/TIA/TE status.

Trial Registration

ClinicalTrials.gov Identifier: NCT02415400

Introduction

Choosing the ideal antithrombotic therapy strategy for patients with atrial fibrillation (AF) treated with dual antiplatelet therapy for acute coronary syndrome (ACS) and/or recent percutaneous coronary intervention (PCI) can be challenging. Recent data from randomized trials and subsequent meta-analyses demonstrated the benefit of a dual-pathway strategy with a P2Y12 inhibitor coupled with oral anticoagulation, without aspirin, as the optimal strategy to balance the ischemic and bleeding risks.¹ In the AUGUSTUS trial,² apixaban resulted in less bleeding and fewer hospitalizations than vitamin K antagonist (VKA), and aspirin resulted in more bleeding than placebo, in patients with AF and ACS and/or PCI treated with a P2Y12 inhibitor.

Patients with a history of stroke may be at increased risk for both ischemic and bleeding outcomes. Prior studies have demonstrated that AF, prior stroke, transient ischemic attack (TIA), and thromboembolism (TE) are associated with an increased risk of recurrent stroke/TE and major bleeding.^3,4 Prior stroke was also associated with an increased risk of subsequent stroke, particularly intracranial hemorrhage (ICH), in patients treated with elective PCI or during ACS.^5,6,7 However, data are limited regarding the risk of cerebrovascular ischemic events and major bleeding in patients with AF with recent ACS/PCI. Because of its 2-by-2 factorial design, the AUGUSTUS trial² provides a unique opportunity to further understand the clinical characteristics and ischemic and bleeding outcomes stratified by prior stroke status in patients with AF and recent ACS/PCI who were treated with apixaban or VKA and aspirin or placebo.

Methods

The design⁸ and results² of the AUGUSTUS trial (NCT02415400) have been published. In brief, AUGUSTUS was a prospective, multicenter, 2-by-2 factorial, randomized clinical trial comparing apixaban with VKA and aspirin with placebo in patients with AF who had a recent ACS or underwent PCI (or both). The study was approved by ethics committees at participating sites, and all patients provided written informed consent before enrollment.

Eligible patients met the following inclusion criteria: age 18 years or older; previous, persistent, permanent, or paroxysmal AF and planned long-term use of an oral anticoagulant; recent ACS or PCI; and planned use of a P2Y12 inhibitor for at least 6 months. Patients using anticoagulation for other conditions (eg, prosthetic valves, venous thromboembolism, and mitral stenosis) were not eligible. Other key exclusion criteria were severe kidney insufficiency; a history of ICH; recent or planned coronary artery bypass graft surgery; coagulopathy or ongoing bleeding; and contraindication to a VKA, apixaban, all P2Y12 inhibitors, or aspirin. Patients’ baseline risk for stroke and bleeding was assessed using CHA₂DS₂-VASc and a modified HAS-BLED at time of randomization.⁹ For the calculation of HAS-BLED score, patients not taking a VKA were assumed to not have a labile international normalized ratio.

Randomization was stratified according to indication (ACS or PCI) at enrollment. In accordance with the apixaban label instructions for stroke prevention in patients with AF, patients randomized to receive apixaban were directed to take 5 mg twice daily or 2.5 mg twice daily if they met 2 or more of the following dose-adjustment criteria: age 80 years or older, weight 60 kg or less, and creatinine 1.5 mg/dL or greater (to convert to μmol/L, multiply by 88.4). Patients randomly assigned to receive VKA had the dose adjusted to reach a target international normalized ratio within a range of 2.0 to 3.0. For the comparison of aspirin with placebo, patients received aspirin at a dose of 81 mg or matching placebo once daily. The treatment regimen comparing apixaban with VKA was open-label; however, the regimen comparing aspirin with matching placebo was double-blind. After 6 months, patients were transitioned from their 2 trial interventions to antiplatelet and anticoagulant therapy according to the local standard of care.

The primary outcome for both factorial comparisons was major bleeding or clinically relevant nonmajor (CRNM) bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH). Bleeding was defined as ISTH major bleeding if it resulted in death, occurred in a critical organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, intramuscular with compartment syndrome, or pericardial), or was associated with either a decrease in the hemoglobin level of at least 2 g/dL or a transfusion of at least 2 units of packed red blood cells. Bleeding was defined as CRNM bleeding if it resulted in hospitalization, medical or surgical intervention for bleeding, an unscheduled clinic visit, or a change in physician-directed antithrombotic therapy.¹⁰

Secondary outcomes included the composite of death or hospitalization and the composite of death or ischemic events (stroke, myocardial infarction, stent thrombosis [definite or probable], or urgent revascularization). Exploratory outcomes included individual components of the secondary outcomes. All bleeding and ischemic events (except for urgent revascularization) were independently adjudicated by the Clinical Events Classification Committee at Duke Clinical Research Institute, whose members were unaware of the trial group assignments.

Statistical Analysis

In this post hoc analysis, patient characteristics at baseline are presented according to the presence of prior stroke/TIA/TE. Continuous variables were summarized as median (IQR) or mean (SD) and compared between patients with and without prior stroke/TIA/TE using the t test or Wilcoxon rank sum test. Categorical variables were summarized as counts with percentages and compared using the Pearson χ² test or Fisher exact test. Missing values were excluded from the denominators for the percentages.

Using the Kaplan-Meier method, the cumulative incidence was estimated for safety outcomes (ISTH major or CRNM bleeding) at 6 months from the start of the intervention and for efficacy outcomes at 6 months from randomization. The log-rank test was used to compare the cumulative incidence of the outcomes between patients with and without prior stroke/TIA/TE.

The treatment effect of apixaban compared with VKA on the outcomes was assessed using Cox proportional hazards models that included the treatment group, the presence of prior stroke/TIA/TE, and the interaction between the two. Similar analyses were performed to assess the treatment effect of aspirin compared with placebo on the outcomes. Results are presented as hazard ratios (HRs) with 95% CIs and P values for interaction. The proportional hazard assumption was assessed using weighted Schoenfeld residuals. The proportional hazard assumption was met for both comparisons (anticoagulant and antiplatelet) for all end points in both subgroups (prior stroke/TIA/TE and no prior stroke/TIA/TE), except for death or ischemic events in the subgroup of patients without prior stroke/TIA/TE for the apixaban vs VKA comparison. Because the departure from the proportional hazard assumption was mild, we decided to include average HRs. For all analyses, a 2-sided P value of less than .05 was considered statistically significant, and no corrections for multiple testing were applied. All statistical analyses were performed using SAS version 9.4 (SAS Institute).

Results

Of the 4614 patients enrolled in AUGUSTUS, 33 had no data on prior stroke/TIA/TE and were excluded; therefore, this analysis included the remaining 4581 patients. Of those, 633 (13.8%) had a history of stroke/TIA/TE. The Table presents demographic and clinical characteristics of patients with and without prior stroke/TIA/TE. Patients with prior stroke/TIA/TE were older and were more likely to have a history of bleeding, heart failure, and diabetes compared with those without prior stroke/TIA/TE. In addition, they had higher CHA₂DS₂-VASC and HAS-BLED scores, along with higher rates of prior oral anticoagulant use, and a longer time from ACS or PCI to randomization when compared with those without prior stroke/TIA/TE. A HAS-BLED score was calculated in 4405 of 4614 patients (95%) in AUGUSTUS. Among patients assigned to receive apixaban, a higher proportion of patients with prior stroke/TIA/TE received the adjusted dose (2.5 mg twice daily) than patients without prior stroke/TIA/TE.

Table. Patient Baseline Characteristics According to Presence of Prior Stroke, Transient Ischemic Attack, or Thromboembolism.

	No./total No. (%)			P value
	Overall (n = 4581)	Prior stroke/TIA/TE (n = 633)	No prior stroke/TIA/TE (n = 3948)	P value
Age, median (IQR), y	71 (64-77)	72 (66-78)	70 (64-77)	<.001
Female sex	1329/4581 (29.0)	183/633 (28.9)	1146/3948 (29.0)	.95
Male sex	3252/4581 (71.0)	450/633 (71.1)	2802/3948 (71.0)
Race and ethnicity^a				.17
American Indian and Alaska Native	16/4524 (0.4)	3/624 (0.5)	13/3900 (0.3)
Asian	140/4524 (3.1)	20/624 (3.2)	120/3900 (3.1)
Black	59/4524 (1.3)	14/624 (2.2)	45/3900 (1.2)
White	4152/4524 (91.8)	570/624 (91.3)	3582/3900 (91.8)
Other	157/4524 (3.5)	17/624 (2.7)	140/3900 (3.6)
Serum creatinine, mg/dL				.61
<1.5	4128/4504 (91.7)	565/620 (91.1)	3563/3884 (91.7)
≥1.5	376/4504 (8.3)	55/620 (8.9)	321/3884 (8.3)
CHA₂DS₂-VASc score, mean (SD)	3.9 (1.6)	5.9 (1.4)	3.6 (1.3)	<.001
HAS-BLED score, mean (SD)	2.9 (0.9)	3.7 (1.0)	2.7 (0.9)	<.001
Prior bleeding	50/4561 (1.1)	16/632 (2.5)	34/3929 (0.9)	<.001
Hypertension leading to medication use	4073/4581 (88.9)	576/633 (91.0)	3497/3948 (88.6)	.07
Heart failure	1973/4581 (43.1)	301/633 (47.6)	1672/3948 (42.4)	.01
Diabetes	1678/4581 (36.6)	264/633 (41.7)	1414/3948 (35.8)	.004
Concomitant P2Y12 inhibitor at randomization				.09
Clopidogrel	4142/4469 (92.7)	557/615 (90.6)	3585/3854 (93.0)
Prasugrel	49/4469 (1.1)	8/615 (1.3)	41/3854 (1.1)
Ticagrelor	278/4469 (6.2)	50/615 (8.1)	228/3854 (5.9)
Previous use of oral anticoagulant	2247/4581 (49.1)	344/633 (54.3)	1903/3948 (48.2)	.004
Qualifying index event				.38
ACS and PCI	1705/4564 (37.4)	222/629 (35.3)	1483/3935 (37.7)
Medically managed ACS	1095/4564 (24.0)	163/629 (25.9)	932/3935 (23.7)
Elective PCI	1764/4564 (38.7)	244/629 (38.8)	1520/3935 (38.6)
No. of days from ACS or PCI to randomization, mean (SD)	6.6 (4.2)	7.0 (4.2)	6.6 (4.2)	.006
Reduced-dose apixaban (2.5 mg) in patients randomized to receive apixaban	227/2274 (10.0)	37/324 (11.4)	190/1950 (9.7)	.35

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Abbreviations: ACS, acute coronary syndrome; PCI, percutaneous coronary intervention; TE, thromboembolism; TIA, transient ischemic attack.

SI conversion factor: To convert creatinine to μmol/L, multiply by 88.4.

^{^a}

Race and ethnicity data for the patients were determined by the investigator and recorded on the case-report forms. The category other includes those not in the other listed groups.

Cumulative Incidence of Outcomes by the Presence of Prior Stroke/TIA/TE

Compared with patients without prior stroke/TIA/TE, patients with prior stroke/TIA/TE had a 3-fold higher risk of ischemic stroke (1.60% vs 0.50%; P = .002) and were more likely to have ISTH major or CRNM bleeding (17.1% vs 13.0%; P = .02), death or hospitalization (30.6% vs 25.2%; P = .003), and death or ischemic events (9.4% vs 6.1%; P = .001) (Figure 1). Kaplan-Meier curves for all 4 groups for ISTH major or CRNM bleeding, death or hospitalization, and death or ischemic events are included in eFigures 1-3 in Supplement 1.

Figure 1. — ISTH indicates International Society on Thrombosis and Haemostasis.

Treatment Effect of Apixaban vs VKA on Outcomes by the Presence of Prior Stroke/TIA/TE

There was no significant interaction between the anticoagulant treatment and prior stroke/TIA/TE on any of the outcomes. Patients treated with apixaban had a lower risk of ISTH major or CRNM bleeding and death or hospitalization than those receiving VKA among patients with no prior stroke/TIA/TE. Consistent with the main trial results, patients with and without prior stroke/TIA/TE who were treated with apixaban had fewer ischemic strokes, fewer major bleeding events, and fewer deaths or hospitalizations than patients treated with VKA. There were no significant differences in any other outcomes between apixaban and VKA (Figure 2).

Figure 2. — CRNM indicates clinically relevant nonmajor; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis.

Treatment Effect of Aspirin vs Placebo on Outcomes by the Presence of Prior Stroke/TIA/TE

There was a significant interaction between the antiplatelet treatment and prior stroke/TIA/TE for ISTH major or CRNM bleeding (Figure 3). Patients treated with aspirin had a higher risk of bleeding than those in the placebo group among patients without prior stroke/TIA/TE. While there were no significant differences between aspirin and placebo observed among patients with prior stroke/TIA/TE, aspirin was associated with numerically lower rates of death or ischemic events than placebo in patients with prior stroke/TIA/TE (HR, 0.71; 95% CI, 0.42-1.20). There were no significant differences in any other outcomes between aspirin and placebo.

Discussion

The AUGUSTUS trial provided a unique opportunity to assess the overall risk of stroke, bleeding, and ischemic events in patients with AF presenting with ACS and/or undergoing PCI and the treatment effect of apixaban compared with warfarin and aspirin compared with placebo. In this subgroup analysis of the AUGUSTUS trial, patients with prior stroke/TIA/TE had a 3-fold increased risk of ischemic stroke and a higher risk of ISTH major or CRNM bleeding, death or hospitalization, and death or ischemic events than those without prior stroke/TIA/TE. The safety and efficacy of apixaban compared with VKA was consistent with the overall trial findings, irrespective of history of stroke/TIA/TE. Aspirin increased major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE.

Until the publication of trials assessing dual antithrombotic therapy with direct oral anticoagulants,^2,11,12,13 patients with AF presenting with ACS and/or PCI represented a clinical challenge because of their elevated risk of stroke, stent thrombosis, and bleeding. Three of these 4 studies (RE-DUAL PCI, AUGUSTUS, and ENTRUST-AF PCI) included patients who had a history of stroke/TIA/TE.^2,12 Patients with AF and prior stroke/TIA/TE have an increased risk of recurrent stroke or embolic events³; the CHA₂DS₂-VASc score assigns additional weight to prior stroke/TIA/TE. Several studies with direct oral anticoagulants have also shown an increased risk of stroke or systemic embolism in patients with prior stroke/TIA.^4,14,15,16

In a subgroup analysis of the ARISTOTLE study,⁴ patients with previous stroke or TIA had a 2- to 3-times higher risk of stroke or systemic embolism, major bleeding, ICH, and mortality than those without previous stroke or TIA. Risk of major bleeding was about one-third higher in patients with previous stroke than in those without, whereas rates of gastrointestinal bleeding were similar between groups. In AUGUSTUS, patients with and without prior stroke/TIA/TE who were treated with apixaban seemed to have fewer strokes, fewer major bleeding events (including ICH), and lower mortality than patients treated with warfarin, although these benefits were not all statistically significant. The present analysis extends these findings from the AUGUSTUS trial by showing overall better safety and efficacy with apixaban compared with VKA in patients with prior stroke/TIA/TE.

Prior studies have demonstrated that previous stroke is also associated with an increased risk of subsequent stroke, particularly ICH, in patients treated with PCI, either electively or following ACS.^5,6,7 In an analysis using the British Cardiovascular Intervention Society database⁵ that included more than 500 000 patients, prior stroke was associated with a 1.7-times higher risk of ischemic stroke in patients undergoing PCI or ACS and a 4-fold increased risk of hemorrhagic stroke after elective PCI. In a pooled cohort of 19 475 patients from 3 Japanese studies in PCI,⁶ the authors assessed the influence of prior stroke on ischemic and bleeding outcomes after PCI. Prior hemorrhagic stroke and prior ischemic stroke, compared with no prior stroke, were associated with a significant 4.4- and 1.5-fold increased risk of ICH, respectively. There was also a 1.5-fold statistically significant increased risk for ischemic events, driven mainly by higher risk for ischemic stroke in patients with prior hemorrhagic stroke and prior ischemic stroke compared with no prior stroke.

To our knowledge, this is the first study to analyze the risk of stroke, bleeding, and ischemic events in a contemporary cohort of patients who had prior stroke/TIA/TE and AF who were presenting with ACS or undergoing PCI. Patients with prior stroke/TIA/TE were older and had higher CHA₂DS₂-VASC, even when prior stroke was excluded from the score. The higher mean HAS-BLED score of patients with prior stroke/TIA/TE compared with patients without prior stroke was primarily driven by the presence of prior stroke. This analysis found that patients with prior stroke/TIA/TE had an increased risk of ischemic and bleeding events compared with those without prior stroke/TIA/TE. The treatment effect of apixaban compared with warfarin was consistent with the overall AUGUSTUS study results regarding recurrent ischemic stroke, ISTH major or CRNM bleeding, and death or hospitalization.

Aspirin increased ISTH major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE. The magnitude of harm with aspirin compared with placebo is more pronounced in patients without prior stroke/TIA/TE than in those with prior stroke/TIA/TE. Aspirin increases the risk of ISTH major or CRNM bleeding in patients with and without prior stroke/TIA/TE. This finding might be due to a differential risk of aspirin use in patients with or without prior stroke/TIA/TE. As described in the Table, patients with prior stroke/TIA/TE had significantly more prior bleeding events compared with those without stroke/TIA/TE. The use of the P2Y12 inhibitors prasugrel and ticagrelor was higher in patients with vs without prior stroke/TIA/TE; clopidogrel use was similar between the 2 groups. There is no clear benefit of aspirin compared with placebo regarding death or ischemic events in patients with or without prior stroke, although we did observe a nonsignificant decrease in death or ischemic events in patients with prior stroke/TIA/TE assigned to receive aspirin. As such, there may be a role for aspirin in patients with prior stroke/TIA/TE in appropriate clinical situations.

Limitations

This study has some limitations that warrant consideration. We captured whether study participants had a history of the aggregate of stroke/TIA/TE but not the individual components alone. It is possible that each specific event may confer a differential risk of future ischemic or bleeding events. Further, we did not use specific definitions for each of these events; thus, the true frequency of prior stroke, TIA, and TE beyond a documented history is unknown. The characteristics of the 33 excluded patients may be different from the overall study population, but they account for less than 1% of the overall study population. Individuals from racial and ethnic minority groups, and Black patients in particular, were marginally represented in this study. Further, this is a post hoc analysis subject to type I error, and subgroup analyses are prone to resulting in chance findings and are typically underpowered to show robust findings in the independent subgroups. These results should be considered provocative and a basis for future dedicated trials.

Conclusions

Among patients with AF presenting with ACS and/or PCI, those with a history of stroke/TIA/TE had a higher risk of ischemic and bleeding events than those without. Among patients with prior stroke/TIA/TE, patients treated with apixaban had less bleeding, death, and hospitalization than those treated with VKA, whereas patients treated with aspirin had a higher bleeding risk than those treated with placebo. Although it is possible that aspirin might have some benefit in patients with prior stroke, in general, our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for the majority of patients with AF and ACS and/or PCI, regardless of prior stroke/TIA/TE status.

Supplement 1.

eFigure 1. Kaplan-Meier curves for ISTH major or CRNM bleeding in patients with (A) and without (B) prior stroke/TIA/TE

eFigure 2. Kaplan-Meier curves for death or hospitalization in patients with (A) and without (B) prior stroke/TIA/TE

eFigure 3. Kaplan-Meier curves for death or ischemic events in patients with (A) and without (B) prior stroke/TIA/TE

Click here for additional data file.^{(262.3KB, pdf)}

Supplement 2.

Data sharing statement

Click here for additional data file.^{(13.1KB, pdf)}

References

1.Lopes RD, Hong H, Harskamp RE, et al. Optimal antithrombotic regimens for patients with atrial fibrillation undergoing percutaneous coronary intervention: an updated network meta-analysis. JAMA Cardiol. 2020;5(5):582-589. doi: 10.1001/jamacardio.2019.6175 [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Lopes RD, Heizer G, Aronson R, et al. ; AUGUSTUS Investigators . Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. 2019;380(16):1509-1524. doi: 10.1056/NEJMoa1817083 [DOI] [PubMed] [Google Scholar]
3.Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest. 2010;137(2):263-272. doi: 10.1378/chest.09-1584 [DOI] [PubMed] [Google Scholar]
4.Easton JD, Lopes RD, Bahit MC, et al. ; ARISTOTLE Committees and Investigators . Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol. 2012;11(6):503-511. doi: 10.1016/S1474-4422(12)70092-3 [DOI] [PubMed] [Google Scholar]
5.Myint PK, Kwok CS, Roffe C, et al. ; British Cardiovascular Intervention Society and the National Institute for Cardiovascular Outcomes Research . Determinants and outcomes of stroke following percutaneous coronary intervention by indication. Stroke. 2016;47(6):1500-1507. doi: 10.1161/STROKEAHA.116.012700 [DOI] [PubMed] [Google Scholar]
6.Natsuaki M, Morimoto T, Watanabe H, et al. ; CREDO‐Kyoto PCI/CABG registry cohort‐2, RESET and NEXT trial investigators . Ischemic and bleeding risk after percutaneous coronary intervention in patients with prior ischemic and hemorrhagic stroke. J Am Heart Assoc. 2019;8(22):e013356. doi: 10.1161/JAHA.119.013356 [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Wallentin L, Becker RC, Budaj A, et al. ; PLATO Investigators . Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057. doi: 10.1056/NEJMoa0904327 [DOI] [PubMed] [Google Scholar]
8.Lopes RD, Vora AN, Liaw D, et al. An open-label, 2 × 2 factorial, randomized controlled trial to evaluate the safety of apixaban vs. vitamin K antagonist and aspirin vs. placebo in patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention: rationale and design of the AUGUSTUS trial. Am Heart J. 2018;200:17-23. doi: 10.1016/j.ahj.2018.03.001 [DOI] [PubMed] [Google Scholar]
9.Harskamp RE, Fanaroff AC, Lopes RD, et al. Antithrombotic therapy in patients with atrial fibrillation after acute coronary syndromes or percutaneous intervention. J Am Coll Cardiol. 2022;79(5):417-427. doi: 10.1016/j.jacc.2021.11.035 [DOI] [PubMed] [Google Scholar]
10.Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis . Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692-694. doi: 10.1111/j.1538-7836.2005.01204.x [DOI] [PubMed] [Google Scholar]
11.Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375(25):2423-2434. doi: 10.1056/NEJMoa1611594 [DOI] [PubMed] [Google Scholar]
12.Cannon CP, Bhatt DL, Oldgren J, et al. ; RE-DUAL PCI Steering Committee and Investigators . Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377(16):1513-1524. doi: 10.1056/NEJMoa1708454 [DOI] [PubMed] [Google Scholar]
13.Vranckx P, Valgimigli M, Eckardt L, et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet. 2019;394(10206):1335-1343. doi: 10.1016/S0140-6736(19)31872-0 [DOI] [PubMed] [Google Scholar]
14.Hankey GJ, Patel MR, Stevens SR, et al. ; ROCKET AF Steering Committee Investigators . Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol. 2012;11(4):315-322. doi: 10.1016/S1474-4422(12)70042-X [DOI] [PubMed] [Google Scholar]
15.Diener HC, Connolly SJ, Ezekowitz MD, et al. ; RE-LY study group . Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol. 2010;9(12):1157-1163. doi: 10.1016/S1474-4422(10)70274-X [DOI] [PubMed] [Google Scholar]
16.Rost NS, Giugliano RP, Ruff CT, et al. ; ENGAGE AF-TIMI 48 Investigators . Outcomes with edoxaban versus warfarin in patients with previous cerebrovascular events: findings from ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48). Stroke. 2016;47(8):2075-2082. doi: 10.1161/STROKEAHA.116.013540 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eFigure 1. Kaplan-Meier curves for ISTH major or CRNM bleeding in patients with (A) and without (B) prior stroke/TIA/TE

eFigure 2. Kaplan-Meier curves for death or hospitalization in patients with (A) and without (B) prior stroke/TIA/TE

eFigure 3. Kaplan-Meier curves for death or ischemic events in patients with (A) and without (B) prior stroke/TIA/TE

Click here for additional data file.^{(262.3KB, pdf)}

Supplement 2.

Data sharing statement

Click here for additional data file.^{(13.1KB, pdf)}

[hoi220020r1] 1.Lopes RD, Hong H, Harskamp RE, et al. Optimal antithrombotic regimens for patients with atrial fibrillation undergoing percutaneous coronary intervention: an updated network meta-analysis. JAMA Cardiol. 2020;5(5):582-589. doi: 10.1001/jamacardio.2019.6175 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220020r2] 2.Lopes RD, Heizer G, Aronson R, et al. ; AUGUSTUS Investigators . Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. 2019;380(16):1509-1524. doi: 10.1056/NEJMoa1817083 [DOI] [PubMed] [Google Scholar]

[hoi220020r3] 3.Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest. 2010;137(2):263-272. doi: 10.1378/chest.09-1584 [DOI] [PubMed] [Google Scholar]

[hoi220020r4] 4.Easton JD, Lopes RD, Bahit MC, et al. ; ARISTOTLE Committees and Investigators . Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol. 2012;11(6):503-511. doi: 10.1016/S1474-4422(12)70092-3 [DOI] [PubMed] [Google Scholar]

[hoi220020r5] 5.Myint PK, Kwok CS, Roffe C, et al. ; British Cardiovascular Intervention Society and the National Institute for Cardiovascular Outcomes Research . Determinants and outcomes of stroke following percutaneous coronary intervention by indication. Stroke. 2016;47(6):1500-1507. doi: 10.1161/STROKEAHA.116.012700 [DOI] [PubMed] [Google Scholar]

[hoi220020r6] 6.Natsuaki M, Morimoto T, Watanabe H, et al. ; CREDO‐Kyoto PCI/CABG registry cohort‐2, RESET and NEXT trial investigators . Ischemic and bleeding risk after percutaneous coronary intervention in patients with prior ischemic and hemorrhagic stroke. J Am Heart Assoc. 2019;8(22):e013356. doi: 10.1161/JAHA.119.013356 [DOI] [PMC free article] [PubMed] [Google Scholar]

[hoi220020r7] 7.Wallentin L, Becker RC, Budaj A, et al. ; PLATO Investigators . Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057. doi: 10.1056/NEJMoa0904327 [DOI] [PubMed] [Google Scholar]

[hoi220020r8] 8.Lopes RD, Vora AN, Liaw D, et al. An open-label, 2 × 2 factorial, randomized controlled trial to evaluate the safety of apixaban vs. vitamin K antagonist and aspirin vs. placebo in patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention: rationale and design of the AUGUSTUS trial. Am Heart J. 2018;200:17-23. doi: 10.1016/j.ahj.2018.03.001 [DOI] [PubMed] [Google Scholar]

[hoi220020r9] 9.Harskamp RE, Fanaroff AC, Lopes RD, et al. Antithrombotic therapy in patients with atrial fibrillation after acute coronary syndromes or percutaneous intervention. J Am Coll Cardiol. 2022;79(5):417-427. doi: 10.1016/j.jacc.2021.11.035 [DOI] [PubMed] [Google Scholar]

[hoi220020r10] 10.Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis . Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692-694. doi: 10.1111/j.1538-7836.2005.01204.x [DOI] [PubMed] [Google Scholar]

[hoi220020r11] 11.Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375(25):2423-2434. doi: 10.1056/NEJMoa1611594 [DOI] [PubMed] [Google Scholar]

[hoi220020r12] 12.Cannon CP, Bhatt DL, Oldgren J, et al. ; RE-DUAL PCI Steering Committee and Investigators . Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377(16):1513-1524. doi: 10.1056/NEJMoa1708454 [DOI] [PubMed] [Google Scholar]

[hoi220020r13] 13.Vranckx P, Valgimigli M, Eckardt L, et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet. 2019;394(10206):1335-1343. doi: 10.1016/S0140-6736(19)31872-0 [DOI] [PubMed] [Google Scholar]

[hoi220020r14] 14.Hankey GJ, Patel MR, Stevens SR, et al. ; ROCKET AF Steering Committee Investigators . Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol. 2012;11(4):315-322. doi: 10.1016/S1474-4422(12)70042-X [DOI] [PubMed] [Google Scholar]

[hoi220020r15] 15.Diener HC, Connolly SJ, Ezekowitz MD, et al. ; RE-LY study group . Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol. 2010;9(12):1157-1163. doi: 10.1016/S1474-4422(10)70274-X [DOI] [PubMed] [Google Scholar]

[hoi220020r16] 16.Rost NS, Giugliano RP, Ruff CT, et al. ; ENGAGE AF-TIMI 48 Investigators . Outcomes with edoxaban versus warfarin in patients with previous cerebrovascular events: findings from ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48). Stroke. 2016;47(8):2075-2082. doi: 10.1161/STROKEAHA.116.013540 [DOI] [PubMed] [Google Scholar]

PERMALINK

Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke

M Cecilia Bahit, MD

Amit N Vora, MD, MPH

Zhuokai Li, PhD

Daniel M Wojdyla, MS

Laine Thomas, PhD

Shaun G Goodman, MD, MSc

Ronald Aronson, MD

J Dedrick Jordan, MD, PhD

Brad J Kolls, MD, PhD

Keith E Dombrowski, MD

Dragos Vinereanu, MD, PhD

Sigrun Halvorsen, MD, PhD

Otavio Berwanger, MD, PhD

Stephan Windecker, MD

Roxana Mehran, MD

Christopher B Granger, MD

John H Alexander, MD, MHS

Renato D Lopes, MD, MHS, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Statistical Analysis

Results

Table. Patient Baseline Characteristics According to Presence of Prior Stroke, Transient Ischemic Attack, or Thromboembolism.

Cumulative Incidence of Outcomes by the Presence of Prior Stroke/TIA/TE

Figure 1. Kaplan-Meier Curves for Outcomes by Presence of Prior Stroke, Transient Ischemic Attack (TIA), or Thromboembolism (TE).

Treatment Effect of Apixaban vs VKA on Outcomes by the Presence of Prior Stroke/TIA/TE

Figure 2. Treatment Effect of Apixaban vs Vitamin K Antagonist (VKA) on Outcomes by Presence of Prior Stroke, Transient Ischemic Attack (TIA), or Thromboembolism (TE).

Treatment Effect of Aspirin vs Placebo on Outcomes by the Presence of Prior Stroke/TIA/TE

Figure 3. Treatment Effect of Aspirin vs Placebo on Outcomes by Presence of Prior Stroke, Transient Ischemic Attack (TIA), or Thromboembolism (TE).

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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