European Heart Journal

Eur Heart J. 39(19): 1726-1735a

Safety and efficacy of dual vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of randomized clinical trials

Harsh B Golwala¹, Christopher P Cannon¹², Ph Gabriel Steg³, Gheorghe Doros²⁴, Arman Qamar¹, Stephen G Ellis⁵, Jonas Oldgren⁶, Jurrien M ten Berg⁷, Takeshi Kimura⁸, Stefan H Hohnloser⁹, Gregory Y H Lip¹⁰, Deepak L Bhatt¹

1. Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, 75 Francis Street Boston, MA 02115, USA

2. Baim Institute for Clinical Research, 930 Commonwealth Ave#3, Boston, MA 02215, USA

3. FACT, French Alliance for Cardiovascular Trials; Hôpital Bichat, AP-HP; Université Paris-Diderot; and INSERM U-1148, Paris, France

4. Department of Biostatistics, School of Public Health, Boston University, 801 Massachusetts Ave Crosstown Center, Boston, MA 02218, USA

5. Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA

6. Uppsala Clinical Research Center and Department of Medical Sciences, Uppsala University, Akademiska sjukhuset, Ing.40, 5 tr, Uppsala 75185, Sweden

7. Department of Cardiology, St. Antonius Hospital Nieuwegein, Koekoekslaan 1, 3435 CM Nieuwegein, Netherlands

8. Department of Cardiovascular Medicine, Kyoto University Hospital, 54 Shogoin Kawaharacho, Sakyo Ward, Kyoto, Kyoto Prefecture 606-8507, Japan

9. Department of Cardiology, Division of Cardiac Electrophysiology, Johann Wolfgang Goethe University, Building 23 C, Theodor Stern Kai 7, 60590 Frankfurt, Germany

10. Institute of Cardiovascular Sciences, University of Birmingham, Birmingham B 12 7QH, UK

Corresponding author. Tel: 1-857-307-1992, Fax: 1-857-307-1955, Email: dlbhattmd@post.harvard.edu

See page 1736 for the editorial comment on this article (doi: 10.1093/eurheartj/ehy216)

© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.

DOI: 10.1093/eurheartj/ehy162

Published in print: 14 May 2018

Published online: 13 April 2018

See "The times they are a changin'." in volume 39 on page 1736.

Abstract

Aims

Of patients with atrial fibrillation (AF), approximately 10% undergo percutaneous coronary intervention (PCI). We studied the safety and efficacy of dual vs. triple antithrombotic therapy (DAT vs. TAT) in this population.

Methods and results

A systematic review and meta-analysis was conducted using PubMed, Embase, EBSCO, Cochrane database of systematic reviews, Web of Science, and relevant meeting abstracts for Phase 3, randomized trials that compared DAT vs. TAT in patients with AF following PCI. Four trials including 5317 patients were included, of whom 3039 (57%) received DAT. Compared with the TAT arm, Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding showed a reduction by 47% in the DAT arm [4.3% vs. 9.0%; hazard ratio (HR) 0.53, 95% credible interval (CrI) 0.36–0.85, I² = 42.9%]. In addition, there was no difference in the trial-defined major adverse cardiac events (MACE) (10.4% vs. 10.0%, HR 0.85, 95% CrI 0.48–1.29, I² = 58.4%), or in individual outcomes of all-cause mortality, cardiac death, myocardial infarction, stent thrombosis, or stroke between the two arms.

Conclusion

Compared with TAT, DAT shows a reduction in TIMI major or minor bleeding by 47% with comparable outcomes of MACE. Our findings support the concept that DAT may be a better option than TAT in many patients with AF following PCI.

[Image: ehy162f8] View larger version

Introduction

Atrial fibrillation (AF) is a major global health problem affecting 33.5 million individuals worldwide.¹ Oral anticoagulation (OAC) with either vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) is the mainstay for prevention of thrombo-embolic events in this population.² Approximately 5–10% of these patients also undergo percutaneous coronary intervention (PCI) for concomitant coronary artery disease (CAD).³ This overlap poses significant challenges since prior data from randomized trials have shown superiority of dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor over aspirin and VKA for prevention of stent thrombosis and major adverse cardiac events (MACE) in patients post-PCI.⁴,⁵ Consequently, most patients with AF following PCI are subjected to treatment with a combination of both these therapies (DAPT plus OAC), the so-called ‘triple antithrombotic therapy (TAT)’ approach.

While this approach is reasonable and endorsed by American College of Cardiology/American Heart Association/European Society of Cardiology guidelines⁶,⁷ as well as expert consensus8–10 for varying durations, the evidence supporting the same is sparse. A major limitation of TAT is bleeding.¹¹ One proposed approach is to curtail the TAT to a minimum duration with a goal to reduce bleeding events. However, this strategy has been challenged by data from the What is the Optimal AntiplatElet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary StenTing (WOEST) as well as Intracoronary Stenting and Antithrombotic Regimen: Testing of a Six-Week vs. a Six-Month Clopidogrel Treatment Regimen In Patients With Concomitant Aspirin and OraL Anticoagulant Therapy Following Drug-Eluting Stenting (ISAR-TRIPLE) trials which demonstrated that many of the bleeding events occur in the first few weeks after the initiation of TAT.¹²,¹³

In the last several years, a number of randomized trials¹⁴,¹⁵ have attempted to evaluate the strategy of dual antithrombotic therapy (DAT) vs. TAT in this patient population with DAT defined as a combination of one antiplatelet agent and an anticoagulant.¹⁶,¹⁷ In aggregate, studies have suggested reduction in bleeding by almost half in patients on DAT compared with TAT.18–21 These results are complemented by similar incidence of thrombo-embolic and MACE between the two groups. A major criticism for all the randomized trials is that none of them is sufficiently powered to assess thrombo-embolic (efficacy) outcomes. To reduce the selection bias introduced by observational data and to enhance the power for assessment of efficacy outcomes, we conducted a systematic review and meta-analysis of Phase 3, randomized trials examining DAT vs. TAT in patients with AF, following PCI with inclusion of the most recently published Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (RE-DUAL PCI) trial, which is the largest of all the trials on this topic to date.

Methods

Search strategy and selection criteria

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for the systematic review and meta-analysis. All relevant Phase 3 randomized clinical trials comparing TAT (defined as DAPT plus an OAC) vs. DAT (defined as single antiplatelet agent plus an OAC) in patients with AF following PCI were eligible for inclusion. The primary exclusion criteria were observational non-randomized studies, registry data, ongoing trials without results, editorials, case series, and duplicate studies. A digital computerized search was conducted through PubMed, Embase, EBSCO, Cochrane database of systematic reviews, and Web of Science from its inception up to 25 July 2017 using the following search terms in various combinations: ‘percutaneous coronary intervention’, ‘coronary stenting’, ‘coronary angioplasty’, ‘stents, angioplasty’, ‘PCI’, ‘triple antiplatelet therapy’, ‘dual antiplatelet therapy’, ‘triple antithrombotic therapy’, ‘triple therapy’, ‘dual therapy’, ‘double therapy’, ‘anticoagulants’, ‘antiplatelets’, ‘platelet aggregation inhibitors’, 'vitamin K antagonists’, ‘warfarin’, ‘dabigatran’, ‘rivaroxaban’, ‘apixaban’, ‘edoxaban’, ‘aspirin’, ‘thienopyridine’, ‘clopidogrel’, ‘atrial fibrillation’, and ‘randomized clinical trial’. In addition, references of prior systematic reviews/meta-analysis, as well as abstracts from major cardiology meetings were screened for related studies. There were no restrictions on language, publication date, or publication status. Two investigators (H.G., A.Q.) independently reviewed the titles/abstracts and studies to determine their eligibility to meet the inclusion criteria. The same authors (H.G., A.Q.) independently extracted all the relevant outcomes of interest into a structured data set. The entire tabulated data set was reviewed, and disagreements were resolved via consensus and by a third author (D.L.B.).

Data analysis

We extracted information about the following outcomes from individual trials as well as their Supplementary material online¹²–¹⁵,²²: Thrombolysis in Myocardial Infarction (TIMI) major and minor bleeding, intracranial bleeding, all-cause mortality, cardiac death, myocardial infarction (MI), stent thrombosis, and stroke. It is important to note that ISAR-TRIPLE had a slightly different trial design compared with other trials included in the analysis. In ISAR-TRIPLE trial, patients in both the arms were treated with the same triple therapy for the first 6 weeks, after which the DAT group received aspirin and warfarin whereas the TAT group received aspirin, clopidogrel, and warfarin. Henceforth, to have a valid comparison, our analysis incorporated the event data from landmark analysis of the ISAR-TRIPLE trial.

The primary safety outcome was a composite of TIMI major or minor bleeding. The secondary safety outcome was intracranial bleeding. The primary efficacy outcome was ‘trial defined MACE’ which followed the definition of MACE in the respective trials (Supplementary material online, Table S3). Secondary efficacy outcomes were the individual components of the primary efficacy outcome as well as cardiac death and stent thrombosis.

Effect size calculation

It was anticipated that the length of follow-up will differ between trials. Consequently, hazard ratios (HRs) with 95% confidence intervals for each endpoint were extracted for each of the trials when reported. For studies in which HR was not reported, the log (HR) and its variance were estimated using a previously validated method, as follows²³,²⁴:

Log-HR = 2 * [(# observed events Group 1) −  (# observed events Group 2)]/[(# observed events Group 1) + (# observed events Group 2)]

Variance (log-HR) = 4/[(# observed events Group 1) + (# observed events Group 2)].

Statistical analysis

To accommodate the anticipated heterogeneity across studies, we used random effects meta-analysis to synthesize results. In particular, we used a Bayesian hierarchical model to estimate the random effects model. We assumed a Gaussian distribution for random effects. The freely available, open-source programme OpenBUGS (Bayesian inference using Gibbs Sampling) was used to fit the model.²⁵ Non-informative priors (normal distribution with mean = 0, standard deviation = 1000) for the overall mean HR and inverse-gamma (0.001, 0.001) for the between study variance was used. Convergence of the Markov Chain Monte Carlo sampler was assessed using the Brooks–Gelman–Rubin method.²⁶ In particular, we employed four chains; convergence of the sampler was established if the ratio of within-chain and between-chain variability for the four chains starting at different initial values is close to 1.

Heterogeneity across studies was assessed using the Cochran Q test. Higgins I² statistics was used to determine the degree of in between study heterogeneity (I² < 25%—low, 25–50%—moderate, and >50%—high degree of heterogeneity). Sensitivity analyses were conducted to investigate the robustness of our results to assess whether any of the included studies had a large influence on the results.

The methodological quality of the randomized trials was assessed by Cochrane’s Collaboration tool for assessing risk of bias. For each trial, bias was assessed qualitatively as low risk, intermediate risk, or high risk of bias by independent investigators. Publication bias was not assessed as there were small number of studies (<10) included in the analysis.

Results

A total of 232 studies were screened for eligibility, out of which four Phase 3, randomized trials including 5317 patients assessing the strategy of DAT vs. TAT in AF patients following PCI were included in the final analysis (Figure 1). Characteristics of the individual trials included in the analysis with its primary and secondary outcomes are depicted in the Supplementary material online, Table S1. One TAT arm of PIONEER AF-PCI¹⁴ (aspirin, P2Y12 inhibitor, and low dose rivaroxaban 2.5 mg twice daily, 709 patients) was not included in the analysis as rivaroxaban 2.5 mg is not an approved dose for thrombo-embolic protection in patients with AF. Baseline characteristics of patients enrolled in the four trials included in this meta-analysis are shown in Table 1. Mean follow-up ranged from 9 to 14 months. Mean age of patients across the trials was 70.9 years in the DAT arm and 71.1 years in the TAT arm. About 47% patients in the DAT arm and 45% patients in the TAT arm underwent PCI for acute coronary syndrome (ACS), whereas the remaining 53% and 55% patients in the DAT and the TAT arm, respectively underwent PCI for non-ACS indications. Approximately, 75% of patients in the DAT arm and 82% of patients in the TAT arm had a CHA₂DS₂VASc score of >2. Furthermore, 66% of patients in the DAT arm and 71% of patients in the TAT arm had a HAS-BLED score of ≥3. Atrial fibrillation was present in 100% patients in the PIONEER AF-PCI and RE-DUAL PCI trials, whereas AF was present in 84% and 69% of patients enrolled in ISAR-TRIPLE and WOEST, respectively. All the trials were judged to be at low risk of bias via the Cochran’s Collaboration tool for risk assessment (Supplementary material online, Table S2).

See full tableTable 1. Baseline characteristics of patients in intention-to-treat analysis of randomized trials included in the analysis

Figure 1View larger versionFigure 1. Study selection.

Compared with patients in the TAT arm, patients in the DAT arm demonstrated a 47% relative reduction in the risk of TIMI major or minor bleeding [4.3% vs. 9.0%; HR 0.53, 95% CrI 0.36–0.85, I² = 42.9%] (Figure 2). The risk of intracranial bleeding was 42% lower, although not achieving statistical significance (HR 0.58, 95% CrI 0.23–1.49, I² = 0%) (Figure 3). These outcomes did not differ when dabigatran 110 mg or 150 mg doses were analysed separately for the meta-analysis (Supplementary material online, Figures S2A, B and S3A, B).

Figure 2View larger versionFigure 2. Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding. Data are n/N unless otherwise indicated. Hazard ratio <1 favours dual antithrombotic therapy and hazard ratio >1 favours triple antithrombotic therapy. CrI, credible interval; DAT, dual antithrombotic therapy; TAT, triple antithrombotic therapy.

Figure 3View larger versionFigure 3. Intracranial bleeding. Data are n/N unless otherwise indicated. Hazard ratio <1 favours dual antithrombotic therapy and hazard ratio >1 favours triple antithrombotic therapy. Note: Primary haemorrhagic stroke reported in PIONEER AF-PCI trial was included as intracranial bleeding. Landmark analysis of ISAR-TRIPLE did not separately report intracranial bleeding rates and henceforth, the total reported event rates of intracranial bleeding reported in the trial are used. CrI, credible interval; DAT, dual antithrombotic therapy; TAT, triple antithrombotic therapy.

‘Trial-defined MACE’ occurred in 10.4% patients in the DAT arm compared with 10.0% patients in the TAT arm (HR 0.85, 95% CrI 0.48–1.29, I² = 58.4%) (Figure 4). Inclusion of original results of the ISAR-TRIPLE trial did not alter our efficacy outcome results of trial-defined MACE (Supplementary material online, Figure S1). The individual end-points of all-cause mortality (HR 0.85, 95% CrI 0.46–1.37, I² = 39.3%), cardiac death (HR 0.89, 95% CrI 0.41–1.54, I² = 28.7%), MI (HR 1.07, 95% CrI 0.58–1.95, I² = 15.8%), stent thrombosis (HR 1.00, 95% CrI 0.32–2.82, I² = 32.1%), and stroke (HR 0.94, 95% CrI 0.45–1.84, I² = 0%) did not differ between the two groups (Figures 5–7). These outcomes did not differ when dabigatran 110 mg or 150 mg doses were analysed separately for the meta-analysis (Supplementary material online, Figures S4–S9). One-study-omitted sensitivity analysis showed that individual study data did not influence our results (Supplementary material online, Figures S10 and S11).

Figure 4View larger versionFigure 4. Trial-defined major adverse cardiac events. Data are n/N unless otherwise indicated. Hazard ratio <1 favours dual antithrombotic therapy and hazard ratio >1 favours triple antithrombotic therapy. CrI, credible interval; DAT, dual antithrombotic therapy; MI, myocardial infarction; TAT, triple antithrombotic therapy.

Figure 5View larger versionFigure 5. All-cause mortality and cardiac death. Data are n/N unless otherwise indicated. Hazard ratio <1 favours dual antithrombotic therapy and hazard ratio >1 favours triple antithrombotic therapy. CrI, credible interval; DAT, dual antithrombotic therapy; TAT, triple antithrombotic therapy.

Figure 6View larger versionFigure 6. Myocardial infarction and stent thrombosis. Data are n/N unless otherwise indicated. Hazard ratio <1 favours dual antithrombotic therapy and hazard ratio >1 favours triple antithrombotic therapy. Note: There were no events of stent thrombosis in either group in the Landmark Analysis of the ISAR-TRIPLE trial and hence not included in this analysis. CrI, credible interval; DAT, dual antithrombotic therapy; TAT, triple antithrombotic therapy.

Figure 7View larger versionFigure 7. Stroke. Data are n/N unless otherwise indicated. Hazard ratio <1 favours dual antithrombotic therapy and hazard ratio >1 favours triple antithrombotic therapy. CrI, credible interval; DAT, dual antithrombotic therapy; TAT, triple antithrombotic therapy.

Take home figureView larger versionTake home figure. Summary of bleeding and ischaemic risks for dual versus triple antithrombotic therapy.

Discussion

Our systematic review and meta-analysis demonstrates several findings that may impact clinical care. First, in patients with AF following PCI, DAT reduces the composite of TIMI major or minor bleeding by 47% compared with TAT. Second, DAT seems comparable to TAT in reducing the trial-defined MACE. Finally, there is no statistically significant difference in individual outcomes of all-cause mortality, cardiac death, MI, stent thrombosis, or stroke between the two arms.

Up to 30% of patients with AF are found to have concomitant CAD, of whom 5–10% undergo PCI.³ It is evident that treating these patients with OAC for thrombo-embolic protection is essential; however, treatment of CAD post-PCI with antiplatelet agents is also equally important. Prior studies have demonstrated that TAT after PCI in these patients is associated with a two-fold increase in bleeding compared with DAT.¹¹,¹⁹,²⁰,²⁷ It is also known that bleeding events post-PCI are associated with worse outcomes.²⁸ In our analysis, we found that DAT was associated with a 47% reduction in the composite of TIMI major or minor bleeding compared with TAT. These findings have significant clinical implications, as bleeding is associated with interruption of antithrombotic therapy which in turn is associated with MACE.²⁹ Furthermore, intracranial bleeding, one of the most dreadful and feared complications of TAT, showed a strong numerical trend towards reduction with DAT, particularly driven by patients enrolled in trials evaluating NOACs. This finding is crucial for management of patients at high risk of bleeding in which TAT may carry an even higher risk.

While all the four trials¹²–¹⁵ have demonstrated a reduction in bleeding with DAT compared with TAT, a criticism of all these trials is that they were underpowered to assess efficacy outcomes. In our pooled analysis, we found that DAT may not only reduce bleeding events but is comparable to TAT for the reduction of MACE (Take home figure). These results support the data from prior observational studies.¹⁸,²¹ The precise reasons for similar efficacy of DAT vs. TAT cannot be elucidated from our analysis; however, several mechanisms are possible. Newer generation drug-eluting stents with extremely low (<1%) incidence of stent thrombosis may have played a role.³⁰ In addition, clopidogrel on a biological basis has more platelet inhibition compared with aspirin with less gastrointestinal bleeding which could in combination with OAC avoid the need for aspirin.³¹,³² This hypothesis has been supported by two randomized trials which demonstrated that OAC is equivalent (or even better) than aspirin for protection against thrombotic events.⁵,³³ Finally, increased bleeding related to TAT has been shown to interrupt DAPT which in turn could increase MACE in the TAT arm.²⁹,³⁴,³⁵

Our results may have several clinical implications. In an era where the balance of ischaemic vs. bleeding benefit after PCI is gaining importance, it is prudent that we understand the best approach to antithrombotic therapy in patients with AF following PCI. In this context, several factors that may affect therapeutic decision-making as listed by the recent 2017 ESC focused update on DAPT in CAD (i.e. risk stratification via assessment of ischaemic and bleeding risks using predictor tools such as the CHA₂DS₂-VASc and HAS-BLED scoring systems) should be emphasized.³⁶ Our study demonstrates that DAT is better than TAT for bleeding outcomes and comparable to TAT for efficacy outcomes. Taking this a step further, the major question that yet remains unanswered is the most appropriate combination for DAT (aspirin, clopidogrel, prasugrel, or ticagrelor with VKAs or any specific NOAC) which provides us with the right balance for minimizing thrombo-embolic vs. bleeding risks in an individual patient. With several such combinations possible, future trials are needed to answer these critical questions.

This meta-analysis has limitations. First, we used trial level data for assessment of outcomes, and hence we could not evaluate if baseline characteristics across various trials were different. Furthermore, several patient level characteristics (e.g. older age, diabetes, renal failure, or prior history of bleeding) as well as procedure related factors (e.g. coronary anatomy complexity, stent length, left main stenting) which could affect the intensity/duration of antithrombotic therapy use were not analysed in our study. Second, we pooled results of all the patients included in WOEST and ISAR-TRIPLE trials, although 69% of patients in the WOEST trial and 84% patients in ISAR-TRIPLE trial had AF. However, subgroup analysis of these trials did not demonstrate any statistical differences in their primary outcomes based on indication of OAC (AF, mechanical valves, or others), and hence we feel that inclusion of all patients enrolled in these trials would be unlikely to affect the final summary estimates of the meta-analysis. Third, in the studies included in our analysis, apart from ISAR-TRIPLE which had aspirin as the antiplatelet agent, the other three trials used a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) combined with either warfarin (WOEST) or NOACs (PIONEER AF, RE-DUAL PCI). However, our one-study-omitted sensitivity analysis does affirm that removal of the ISAR-TRIPLE trial from the analysis does not affect our primary analysis estimate for either safety or efficacy outcomes, indicating robustness of our results. Fourth, due to limited number of studies reporting the data, we could not analyse interaction between several key subgroups such as type of index event (ACS vs. non-ACS), type of stent (drug-eluting vs. bare-metal), CHA₂DS₂/HAS-BLED risk score etc. and MACE. Finally, substantial heterogeneity exists in between trials in terms of trial design as well as type and duration of antiplatelet/antithrombotic therapy used, which could affect interpretation of our results.

In summary, our systematic review and meta-analysis supports that DAT may be a better option than TAT in many patients with AF following PCI.

Supplementary Material

Open In Web Browser

Supplementary Material

Open In Web Browser

Acknowledgements

We acknowledge the help rendered by Jacqueline Cellini, Reference and Education Librarian at the Countway Library of Medicine at Harvard Medical School, in formulation and execution of the search strategy and systematic review. G.D. performed the statistical analyses, and his time was paid for by Baim Clinical Research Institute. Open access for this article was paid for by Boehringer Ingelheim.

Funding

The systematic review and meta-analysis analysis was funded by Baim Clinical Research Institute. H.B.G. and D.L.B. had full access to all the data in the study and take the responsibility for the decision to submit the manuscript for publication.

Conflict of interest: C.C. reports research Grants from Amgen, Arisaph, Boehringer-Ingelheim (BI), Bristol-Myers Squibb (BMS), Daiichi Sankyo, Janssen, Merck, and Takeda; consulting fees from Alnylam, Amarin, Amgen, Arisaph, Astra Zeneca, BI, BMS, Eisai, GlaxoSmithKline, Kowa, Lipimedix, Merck, Pfizer, Regeneron, Sanofi, and Takeda; P.G.S. receiving fees for serving on a steering committee from Amarin, Janssen, and CSL Behring, fees for serving on a steering committee and lecture fees from AstraZeneca, lecture fees and consulting fees from Bayer and Bristol-Myers Squibb, fees for preparation of educational material from Boehringer Ingelheim, consulting fees and fees for serving on a data and safety monitoring board from Lilly and Merck Sharpe & Dohme, consulting fees from Novartis and Regeneron, fees for serving on a critical event committee from Pfizer, grant support, fees for serving on a steering committee, and consulting fees from Sanofi, and grant support, fees for serving on a steering committee, consulting fees, and fees for serving on a data and safety monitoring board from Servier; G.D. receiving fees from Baim Clinical Research Institute during the conduct of the study; A.Q. is supported by a postdoctoral training grant from the National Heart, Lung, and Blood Institute of the National Institute of Health (T32 HL 007604); S.G.E. has served as a consultant for Abbott Vascular, Boston Scientific, and Medtronic; J.O. receiving lecture fees and consulting fees, paid to his institution, from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, and Sanofi; J.M.T. receiving grant support, advisory board fees, consulting fees, and lecture fees from AstraZeneca, advisory board fees, consulting fees, and lectures fees from Eli Lilly, Daiichi Sankyo, The Medicines Company, Accumetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Bayer, and grant support from ZonMw and AstraZeneca; T.K. reports grants from Boerhringer Ingelheim, during the conduct of the study; S.H.H. receiving consulting fees and fees for serving on a speaker bureau from Boehringer Ingelheim, Bayer Healthcare, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Medtronic, and Zoll; G.Y.L. receiving lecture fees from Bayer and Roche, consulting fees from Bayer Janssen and Biotronik, and lecture fees and consulting fees from Bristol-Myers Squibb Pfizer, Medtronic, Boehringer Ingelheim, Microlife, and Daiichi Sankyo; D.L.B. discloses the following relationships - Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committees, including for his role in RE-DUAL PCI), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, PLx Pharma, Takeda. All other authors report no conflict of interest.

Articles from European Heart Journal are provided here courtesy of Oxford University Press

PMC Copyright Notice

The articles available from the PMC site are protected by copyright, even though access is free. Copyright is held by the respective authors or publishers who provide these articles to PMC. Users of PMC are responsible for complying with the terms and conditions defined by the copyright holder.

Users should assume that standard copyright protection applies to articles in PMC, unless an article contains an explicit license statement that gives a user additional reuse or redistribution rights. PMC does not allow automated/bulk downloading of articles that have standard copyright protection.

See the copyright notice on the PMC site, https://www.ncbi.nlm.nih.gov/pmc/about/copyright/, for further details and specific exceptions.

References

SS ChughR HavmoellerK NarayananD SinghM RienstraEJ BenjaminRF GillumYH KimJH McAnulty JrZJ ZhengMH ForouzanfarM NaghaviGA MensahM EzzatiCJ. Murray Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation2014;129:837–847.24345399

S ConnollyJ PogueR HartM PfefferS HohnloserS ChrolaviciusM PfefferS HohnloserS. Yusuf Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet2006;367:1903–1912.16765759

S KralevK SchneiderS LangT SuselbeckM. Borggrefe Incidence and severity of coronary artery disease in patients with atrial fibrillation undergoing first-time coronary angiography. PLoS One2011;6:e24964.21957469

A SchomigFJ NeumannA KastratiH SchuhlenR BlasiniM HadamitzkyH WalterEM Zitzmann-RothG RichardtE AltC SchmittK. Ulm A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med1996;334:1084–1089.8598866

MB LeonDS BaimJJ PopmaPC GordonDE CutlipKK HoA GiambartolomeiDJ DiverDM LasordaDO WilliamsSJ PocockRE. Kuntz A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med1998;339:1665–1671.9834303

CT JanuaryLS WannJS AlpertH CalkinsJE CigarroaJC Cleveland JrJB ContiPT EllinorMD EzekowitzME FieldKT MurrayRL SaccoWG StevensonPJ TchouCM TracyCW. Yancy 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol2014;64:2246; e1–76.

P KirchhofS BenussiD KotechaA AhlssonD AtarB CasadeiM CastellaHC DienerH HeidbuchelJ HendriksG HindricksAS ManolisJ OldgrenBA PopescuU SchottenB Van PutteP VardasS AgewallJ CammG Baron EsquiviasW BudtsS CarerjF CasselmanA CocaR De CaterinaS DeftereosD DobrevJM FerroG FilippatosD FitzsimonsB GorenekM GuenounSH HohnloserP KolhGY LipA ManolisJ McMurrayP PonikowskiR RosenhekF RuschitzkaI SavelievaS SharmaP SuwalskiJL TamargoCJ TaylorGIC VanAA VoorsS WindeckerJL ZamoranoK. Zeppenfeld 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J2016;37:2893–2962.27567408

DJ AngiolilloSG GoodmanDL BhattJW EikelboomMJ PriceDJ MoliternoCP CannonJF TanguayCB GrangerL MauriDR HolmesCM GibsonDP. Faxon Antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention: a North American Perspective—2016 update. Circ Cardiovasc Interv2016;9:e004395.27803042

GY LipS WindeckerK HuberP KirchhofF MarinJM Ten BergKG HaeuslerG BorianiD CapodannoM GilardU ZeymerD LaneRF StoreyH BuenoJP ColletL FauchierS HalvorsenM LettinoJ MoraisC MuellerTS PotparaLH RasmussenA RubboliJ TamargoM ValgimigliJL. Zamorano Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J2014;35:3155–3179.25154388

D CapodannoDJ. Angiolillo Management of antiplatelet and anticoagulant therapy in patients with atrial fibrillation in the setting of acute coronary syndromes or percutaneous coronary interventions. Circ Cardiovasc Interv2014;7:113–124.24550531

ML HansenR SørensenMT ClausenML Fog-PetersenJ RaunsøN GadsbøllGH GislasonF FolkeSS AndersenTK SchrammSZ AbildstrømHE PoulsenL KøberC. Torp-Pedersen Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med2010;170:1433–1441.20837828

WJ DewildeT OirbansFW VerheugtJC KelderBJ De SmetJP HerrmanT AdriaenssensM VrolixAA HeestermansMM VisJG TijsenAW van’t HofJM. ten Berg Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet2013;381:1107–1115.23415013

KA FiedlerM MaengJ MehilliS Schulz-SchupkeRA ByrneD SibbingP HoppmannS SchneiderM FusaroI OttSD KristensenT IbrahimS MassbergH SchunkertKL LaugwitzA KastratiN. Sarafoff Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent implantation: the ISAR-TRIPLE Trial. J Am Coll Cardiol2015;65:1619–1629.25908066

CM GibsonR MehranC BodeJ HalperinFW VerheugtP WildgooseM BirminghamJ IanusP BurtonM van EickelsS KorjianY DaaboulGY LipM CohenS HustedED PetersonKA. Fox Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med2016;375:2423–2434.27959713

CP CannonDL BhattJ OldgrenGYH LipSG EllisT KimuraM MaengB MerkelyU ZeymerS GropperM NordabyE KleineR HarperJ ManassieJL JanuzziJM Ten BergPG StegSH. Hohnloser Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med2017;377:1513–1524.28844193

M LambertsGH GislasonGY LipJF LassenJB OlesenAP MikkelsenR SorensenL KoberC Torp-PedersenML. Hansen Antiplatelet therapy for stable coronary artery disease in atrial fibrillation patients taking an oral anticoagulant: a nationwide cohort study. Circulation2014;129:1577–1585.24470482

M LambertsGH GislasonJB OlesenSL KristensenAM Schjerning OlsenA MikkelsenCB ChristensenGY LipL KoberC Torp-PedersenML. Hansen Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol2013;62:981–989.23747760

N AgarwalA JainAN MahmoudR BishnoiH GolwalaA KarimiMK MojadidiJ GargT GuptaNK PatelS WayangankarRD. Anderson Safety and efficacy of dual versus triple antithrombotic therapy in patients undergoing percutaneous coronary intervention. Am J Med2017;130:1280–1289.28460853

C BavishiA KoulovaS BangaloreA SawantS ChatterjeeS AtherJ ValenciaN SarafoffA RubboliJK AiraksinenGY LipJE. Tamis-Holland Evaluation of the efficacy and safety of dual antiplatelet therapy with or without warfarin in patients with a clinical indication for DAPT and chronic anticoagulation: a meta-analysis of observational studies. Catheter Cardiovasc Interv2016;88:E12–E22.26354765

F D’AscenzoS TahaC MorettiP OmedeW GrossomarraJ PerssonM LambertsW DewildeA RubboliS FernandezE CerratoI MeynetF BalloccaU BarberoG QuadriF GiordanaF ConrottoD CapodannoJ DiNicolantonioS BangaloreM ReedP MeierG ZoccaiF. Gaita Meta-analysis of randomized controlled trials and adjusted observational results of use of clopidogrel, aspirin, and oral anticoagulants in patients undergoing percutaneous coronary intervention. Am J Cardiol2015;115:1185–1193.25799015

J LiuM FanJ ZhaoB ZhaoC ZhangC LiuY. Dong Efficacy and safety of antithrombotic regimens after coronary intervention in patients on oral anticoagulation: traditional and Bayesian meta-analysis of clinical trials. Int J Cardiol2016;205:89–96.26724753

CM GibsonDS PintoG ChiD ArbetterM YeeR MehranC BodeJ HalperinFW VerheugtP WildgooseP BurtonM van EickelsS KorjianY DaaboulP JainGY LipM CohenED PetersonKA. Fox Recurrent hospitalization among patients with atrial fibrillation undergoing intracoronary stenting treated with 2 treatment strategies of rivaroxaban or a dose-adjusted oral vitamin K antagonist treatment strategy. Circulation2017;135:323–333.27881555

MK ParmarV TorriL. Stewart Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med1998;17:2815–2834.9921604

A. Tsiatis The asymptomatic joint distribution of the efficient scores test for the proportional hazards model calculated over time. Biometrik1981;68:311–315.

D LunnD SpiegelhalterA ThomasN. Best The BUGS project: evolution, critique and future directions. Stat Med2009;28:3049–3067.19630097

Brooks SP GA. Alternative methods for monitoring convergence of iterative simulations. J Comput Graph Stat1998;7:434–325.

M LambertsJB OlesenMH RuwaldCM HansenD KarasoySL KristensenL KoberC Torp-PedersenGH GislasonML. Hansen Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation2012;126:1185–1193.22869839

AK ChhatriwallaAP AminKF KennedyJA HouseDJ CohenSV RaoJC MessengerSP. Marso Association between bleeding events and in-hospital mortality after percutaneous coronary intervention. Jama2013;309:1022–1029.23483177

R MehranSV RaoDL BhattCM GibsonA CaixetaJ EikelboomS KaulSD WiviottV MenonE NikolskyV SerebruanyM ValgimigliP VranckxD TaggartJF SabikDE CutlipMW KrucoffEM OhmanPG StegH. White Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation2011;123:2736–2747.21670242

AA BavryDL. Bhatt Appropriate use of drug-eluting stents: balancing the reduction in restenosis with the concern of late thrombosis. Lancet2008;371:2134–2143.18572082

DL BhattAT HirschPA RinglebW HackeEJ. Topol Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. CAPRIE investigators. Am Heart J2000;140:67–73.10874265

CAPRIE Steering Committee . A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet1996;348:1329–1339.8918275

M HurlenM AbdelnoorP SmithJ ErikssenH. Arnesen Warfarin, aspirin, or both after myocardial infarction. N Engl J Med2002;347:969–974.12324552

DL. Bhatt When is a double better than a TRIPLE? Stenting in patients with atrial fibrillation. J Am Coll Cardiol2015;65:1630–1632.25908067

DL. Bhatt O PIONEERs! The beginning of the end of full-dose triple therapy with warfarin? Circulation 2017;135:334–337.27881554

M ValgimigliH BuenoRA ByrneJP ColletF CostaA JeppssonP JuniA KastratiP KolhL MauriG MontalescotFJ NeumannM PetricevicM RoffiPG StegS WindeckerJL ZamoranoGN. Levine 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J2018;39:213–260.28886622

[Back]

[Back]

[Back]

Table 1.

Baseline characteristics of patients in intention-to-treat analysis of randomized trials included in the analysis

WOEST¹²

ISAR-TRIPLE¹³

PIONEER AF-PCI¹⁴

RE-DUAL PCI¹⁵

Combined

DAT (n = 279)
TAT (n  = 284)
DAT (n = 307)
TAT (n = 307)
DAT (n = 709)
TAT (n = 706)
DAT (n = 981)
DAT (n = 763)
TAT (n = 981)
DAT (n= 3039)
TAT (n= 2278)

Dabigatran 110 mg
Dabigatran 150 mg

Age (years)
70.3 (7.0)
69.5 (8.0)
73.9 (7.7)
73.3 (8.7)
70.4 (9.1)
69.9 (8.7)
71.5 (8.9)
68.6 (7.6)
71.7 (8.9)
70.9
71.1

Female (%)
23
18
25
21
26
27
26
22
24
25
23

BMI (kg/m²)
27.5 (4.3)
27.9 (4.2)
27.5 (4.2)
27.9 (4.6)
28.6 (25.7–32.4)
29.0 (25.8–32.8)
NR
NR
NR
27.9
28.2

Diabetes (%)
24
25
28
24
29
31
37
34
39
32
32

Hypertension (%)
69
68
77
76
73
75
NR
NR
NR
73
74

Dyslipidaemia (%)
68
72
74
75
43
45
NR
NR
NR
56
58%

Current smoker (%)
22
15
9
10
5
7
NR
NR
NR
10
9

History of MI (%)
34
35
29
25
20
22
24
24
27
25
26

History of CABG (%)
20
26
24
17
NR
NR
10
10
11
13
15

History of PCI (%)
31
36
NR
NR
NR
NR
33
31
35
32
35

PPI use (%)
34
39
NR
NR
39
37
NR
NR
NR
37
37

Type of index event (%)

 ACS
25
30
33
31
51
52
52
51
48
47
45

 Non-ACS
75
70
67
69
49
48
48
49
52
53
55

Type of stent (%)

 Drug-eluting stent
65
64
99
99
65
66
82
81
84
79
79

 Bare-metal stent
32
30
1
0
33
32
15
16
13
19
19

 Drug-eluting and bare-metal stents
1
4
0
0
2
2
2
1
1
1
1

 PTCA/no stent
2
1
1
1
0
0
1
1
1
1
1

Indication for oral anti coagulation (%)

 Atrial fibrillation
69
69
83
85
100
100
100
100
100
96
95

 Mechanical valve
10
11
6
9
0
0
0
0
0%
1
2

 Other
20
20
12
6
0
0
0
0
0
3
3

CHA₂DS₂-VASc score (%)

 ≤2
NR
NR
5
7
27
21
23
32
20
25
18

 >2
NR
NR
95
93
73
79
77
68
80
75
82

HAS-BLED score (%)

 <3
NR
NR
NR
NR
28
29
33
41
29
34
29

 ≥3
NR
NR
NR
NR
72
71
67
56
71
66
71

Data are mean (SD), median (IQR), or percentage unless otherwise indicated.

BMI, body mass index; CABG, coronary artery bypass grafting; CHA₂DS₂-VASc, stroke risk factor scoring system in which one point is given for history of congestive heart failure, hypertension, age 65-74 years, diabetes, vascular disease, female gender and two points are given for history of age ≥75 years, and stroke or transient ischaemic attack; DAT, dual antithrombotic therapy; HAS-BLED, major bleeding risk factor scoring system in which one point is given to hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drug/alcohol use; MI, myocardial infarction; NR, not reported; PCI, percutaneous coronary intervention; PPI, proton pump inhibitor; PTCA, percutaneous transluminal coronary angioplasty; TAT, triple antithrombotic therapy.

[Back]

[Back]

Figure 1.

Study selection.

[Back]

[Back]

Figure 2.

Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding. Data are n/N unless otherwise indicated. Hazard ratio <1 favours dual antithrombotic therapy and hazard ratio >1 favours triple antithrombotic therapy. CrI, credible interval; DAT, dual antithrombotic therapy; TAT, triple antithrombotic therapy.

[Back]

[Back]

Figure 3.

Intracranial bleeding. Data are n/N unless otherwise indicated. Hazard ratio <1 favours dual antithrombotic therapy and hazard ratio >1 favours triple antithrombotic therapy. Note: Primary haemorrhagic stroke reported in PIONEER AF-PCI trial was included as intracranial bleeding. Landmark analysis of ISAR-TRIPLE did not separately report intracranial bleeding rates and henceforth, the total reported event rates of intracranial bleeding reported in the trial are used. CrI, credible interval; DAT, dual antithrombotic therapy; TAT, triple antithrombotic therapy.

[Back]

[Back]

Figure 4.

Trial-defined major adverse cardiac events. Data are n/N unless otherwise indicated. Hazard ratio <1 favours dual antithrombotic therapy and hazard ratio >1 favours triple antithrombotic therapy. CrI, credible interval; DAT, dual antithrombotic therapy; MI, myocardial infarction; TAT, triple antithrombotic therapy.

[Back]

[Back]

Figure 5.

All-cause mortality and cardiac death. Data are n/N unless otherwise indicated. Hazard ratio <1 favours dual antithrombotic therapy and hazard ratio >1 favours triple antithrombotic therapy. CrI, credible interval; DAT, dual antithrombotic therapy; TAT, triple antithrombotic therapy.

[Back]

[Back]

Figure 6.

Myocardial infarction and stent thrombosis. Data are n/N unless otherwise indicated. Hazard ratio <1 favours dual antithrombotic therapy and hazard ratio >1 favours triple antithrombotic therapy. Note: There were no events of stent thrombosis in either group in the Landmark Analysis of the ISAR-TRIPLE trial and hence not included in this analysis. CrI, credible interval; DAT, dual antithrombotic therapy; TAT, triple antithrombotic therapy.

[Back]

[Back]

Figure 7.

Stroke. Data are n/N unless otherwise indicated. Hazard ratio <1 favours dual antithrombotic therapy and hazard ratio >1 favours triple antithrombotic therapy. CrI, credible interval; DAT, dual antithrombotic therapy; TAT, triple antithrombotic therapy.

[Back]

[Back]

Take home figure.

Summary of bleeding and ischaemic risks for dual versus triple antithrombotic therapy.

[Back]