Article Text

Original research
Aspirin versus P2Y12 inhibitors with anticoagulation therapy for atrial fibrillation
  1. Hidehira Fukaya1,
  2. Junya Ako1,
  3. Satoshi Yasuda2,3,
  4. Koichi Kaikita4,5,
  5. Masaharu Akao6,
  6. Tetsuya Matoba7,
  7. Masato Nakamra8,
  8. Katsumi Miyauchi9,
  9. Nobuhisa Hagiwara10,
  10. Kazuo Kimura11,
  11. Atsushi Hirayama12,
  12. Kunihiko Matsui13,
  13. Hisao Ogawa14
  1. 1 Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
  2. 2 Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
  3. 3 Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
  4. 4 Division of Cardiovascular Medicine and Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
  5. 5 Department of Cardiovascular Medicine, Kumamoto University, Kumamoto, Kumamoto, Japan
  6. 6 Department of Cardiology, National Hospital Organisation Kyoto Medical Center, Kyoto, Kyoto, Japan
  7. 7 Department of Cardiovascular Medicine, Kyushu University, Fukuoka, Fukuoka, Japan
  8. 8 Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Meguro-ku, Tokyo, Japan
  9. 9 Department of Cardiovascular Medicine, Juntendo Tokyo Koto Geriatric Medical Center, Koto-ku, Tokyo, Japan
  10. 10 Department of Cardiology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan
  11. 11 Cardiovascular Center, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan
  12. 12 Department of Cardiology, Osaka Police Hospital, Osaka, Osaka, Japan
  13. 13 General and Community Medicine, Kumamoto University Hospital, Kumamoto, Kumamoto, Japan
  14. 14 President, Kumamoto University, Kumamoto, Kumamoto, Japan
  1. Correspondence to Professor Junya Ako, Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan; jako{at}kitasato-u.ac.jp

Abstract

Objective Patients with coronary artery disease (CAD) and atrial fibrillation (AF) can be treated with multiple antithrombotic therapies including antiplatelet and anticoagulant therapies; however, this has the potential to increase bleeding risk. Here, we aimed to evaluate the efficacy and safety of P2Y12 inhibitors and aspirin in patients also receiving anticoagulant therapy.

Methods We evaluated patients from the Atrial Fibrillation and Ischaemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial who received rivaroxaban plus an antiplatelet agent; the choice of antiplatelet agent was left to the physician’s discretion. The primary efficacy and safety end points, consistent with those of the AFIRE trial, were compared between P2Y12 inhibitors and aspirin groups. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation or death from any cause. The primary safety end point was major bleeding according to the International Society on Thrombosis and Haemostasis criteria.

Results A total of 1075 patients were included (P2Y12 inhibitor group, n=297; aspirin group, n=778). Approximately 60% of patients were administered proton pump inhibitors (PPIs) and there was no significant difference in PPI use in the groups. There were no significant differences in the primary end points between the groups (efficacy: HR 1.31; 95% CI 0.88 to 1.94; p=0.178; safety: HR 0.79; 95% CI 0.43 to 1.47; p=0.456).

Conclusions There were no significant differences in cardiovascular and bleeding events in patients with AF and stable CAD taking rivaroxaban with P2Y12 inhibitors or aspirin in the chronic phase.

Trial registration number UMIN000016612; NCT02642419.

  • coronary artery disease
  • atrial fibrillation

Data availability statement

Data are available on reasonable request.

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Introduction

The administration of multiple antithrombotic therapies has the potential to increase the risk of bleeding complications. Antiplatelet therapy for patients with coronary artery disease (CAD) and anticoagulation therapy for patients with atrial fibrillation (AF) are indispensable to prevent stent thrombosis or thromboembolic events.1 2 Recent guidelines3–5 recommend a shorter term of dual antiplatelet therapy after percutaneous coronary intervention, and oral anticoagulant monotherapy 12 months after percutaneous coronary intervention for patients with AF, to suppress bleeding complications.

The Atrial Fibrillation and Ischaemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial6 showed that rivaroxaban monotherapy was not inferior to a combination of rivaroxaban and single antiplatelet therapy in terms of efficacy, and was superior in terms of safety in patients with stable CAD and AF. This trial provided evidence for the development of an antithrombotic strategy for these patients. However, some patients require potent antiplatelet therapy due to a higher thromboembolic risk even on oral anticoagulant therapy.7

Although the AFIRE trial revealed evidence regarding oral anticoagulant monotherapy, co-prescription with antiplatelet agents—that is, P2Y12 inhibitors or aspirin—was at the discretion of the physician. In this study, we sought to evaluate the efficacy and safety of P2Y12 inhibitors and aspirin in patients with stable CAD and AF, who were undergoing oral anticoagulant therapy, and who were enrolled in the AFIRE trial.

Methods

Trial design and oversight

The AFIRE trial was a randomised, multicentre, open-label, parallel-group trial conducted in Japan. The full methods of the AFIRE trial have been reported,8 as well as the primary results.6 In brief, the included patients were men and women aged ≥20 years, diagnosed with AF and stable CAD with a baseline CHADS2 score ≥1, and who met at least one of the following criteria: history of percutaneous coronary intervention, including angioplasty with or without stenting, at least 1 year prior to enrolment; history of angiographically confirmed CAD (stenosis of 50% or greater) not requiring revascularisation or history of coronary artery bypass grafting at least 1 year prior to enrolment. Key exclusion criteria were a history of stent thrombosis, a coexisting active tumour and poorly controlled hypertension. A total of 2240 patients were enrolled at 294 centres from 23 February 2015 to 30 September 2017 in Japan, 2236 of whom were randomised, and 2215 were included in the modified intention-to-treat population. The median follow-up period was 24.1 months (IQR 17.3–31.5). Patients were randomly assigned in equal numbers to groups receiving either rivaroxaban monotherapy (10 mg once daily for patients with a creatinine clearance of 15–49 mL/min or 15 mg once daily for patients with a creatinine clearance of ≥50 mL/min) or combination therapy with rivaroxaban and single antiplatelet therapy with a P2Y12 inhibitor or aspirin, according to the discretion of the treating physician. All participants provided written informed consent before enrolment. The trial was designed and led by an executive steering committee. Data were reviewed by an independent data and safety monitoring committee.

In the present, prespecified subanalysis,8 we analysed the 1075 patients assigned to the combination therapy group, excluding 33 patients receiving dual antiplatelet therapy, single antiplatelet therapy plus drugs that affect antiplatelet function or no antiplatelet therapy after randomisation (figure 1).

Figure 1

Flow chart of the subanalysis study. DAPT, dual antiplatelet therapy; SAPT, single antiplatelet therapy.

End points

The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation and death from any cause. The primary safety end point was major bleeding, defined according to the criteria of the International Society on Thrombosis and Haemostasis. Secondary end points were the individual components of the primary end point, death from any cause, revascularisation (percutaneous coronary intervention and coronary artery bypass grafting, not including those for stenosis observed prior to enrolment in this study, acute myocardial infarction or unstable angina), net adverse clinical events (death from any cause, myocardial infarction, stroke and major bleeding), non-major bleeding and any bleeding events. Blinded adjudication of the end points was conducted by an independent clinical events committee.

Statistical analysis

Continuous variables are presented as mean±SD and were compared using the Wilcoxon rank sum test. Categorical variables are presented as counts and percentages and were compared using the χ2 test or Fisher’s exact test.

The Kaplan-Meier method was used to estimate cumulative event rates, with incidences shown as percentages per patient-year, and differences in the incidences were compared using the log-rank test. A Cox proportional-hazard and Fine-Gray models were used to compare outcomes between the groups, with the results expressed as an HR with a 95% CI. Fine-Gray models were used for nonfatal end points (stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation, major bleeding, non-major bleeding and any bleeding) to account for the competing risk of death. We used a Cox proportional-hazards model to compare outcomes between the two groups and subsequently performed multivariate analysis to adjust for significantly different factors selected by using an unpaired test and factors that were judged clinically significant. The proportional-hazards assumption was examined by investigating the Schoenfeld residuals of the model. All statistical analyses were performed using SAS software, V.9.4 for Windows (SAS Institute, Cary, North Carolina, USA).

Results

Baseline characteristics

In the present subanalysis, a total of 1075 patients who were randomly assigned to combination therapy with rivaroxaban plus a single antiplatelet agent in the AFIRE trial were analysed. Table 1 shows the baseline characteristics of patients according to antiplatelet agent use at baseline. There were 297 (27.6%) patients who received P2Y12 inhibitors and 778 (72.4%) who received aspirin. Approximately 60% of patients were administered proton pump inhibitors (PPIs), and there was no significant difference in PPI use between the P2Y12 inhibitor and aspirin groups. The mean age was 74 years, and 79% of the patients were men. The patient characteristics that were more frequently found in the P2Y12 inhibitor group than in the aspirin group were as follows: dyslipidaemia, previous stroke, previous peripheral arterial disease, previous percutaneous coronary intervention and receipt of drug-eluting coronary stents. There were fewer patients who received bare-metal coronary stents and who had undergone previous coronary artery bypass grafting in the P2Y12 inhibitor group than in the aspirin group.

Table 1

Baseline characteristics according to antiplatelet agent

End points

The incidence of the primary efficacy end point (composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation and death from any cause) in the P2Y12 inhibitor and aspirin groups was 6.76% and 5.28%, respectively (HR 1.31; 95% CI 0.88 to 1.94; p=0.178) (table 2 and figure 2A). The incidences of individual components of the primary end point in the two groups are provided in table 2. The all-cause mortality was higher in the P2Y12 inhibitor group than in the aspirin group, with rates of 4.44% and 2.85% per patient-year, respectively (HR 1.67; 95% CI 1.02 to 2.74; p=0.041). There were no significant differences in the incidence of cardiovascular (2.49% vs 1.75% per patient-year; HR 1.43; 95% CI 0.75 to 2.74; p=0.272) and non-cardiovascular (1.95% vs 1.10% per patient-year; HR 2.09; 95% CI 0.96 to 4.53; p=0.057) death between the two groups. In terms of cardiovascular events, the incidence of ischaemic stroke differed significantly between the two groups (2.16% vs 0.98% per patient-year; HR 2.17; 95% CI 1.02 to 4.64; p=0.041), although there were no significant differences in other end points, including myocardial infarction. These results were consistent in a competing risk analysis with death as the competing risk (online supplemental table S1).

Supplemental material

Table 2

Clinical outcomes*

Figure 2

Primary efficacy and safety end points. Cumulative incidence of (A) the primary efficacy end point, which is a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation and death from any cause; and (B) the primary safety end point, which comprises major bleeding, as defined by the criteria of the International Society on Thrombosis and Haemostasis, in the P2Y12 inhibitor (P2Y12i) and aspirin groups.

The incidence of the primary safety end point (major bleeding) in the P2Y12 inhibitor and aspirin groups was 2.35% and 2.95%, respectively (HR 0.79; 95% CI 0.43 to 1.47; p=0.456) (table 2 and figure 2B). Table 3 provides detailed information regarding the bleeding sites. The most frequent site of major bleeding was the gastrointestinal tract (2.0% in the P2Y12 inhibitor group and 2.4% in the aspirin group). The selected subgroup analyses were generally consistent with respect to the primary efficacy (online supplemental figure S1) and safety (online supplemental figure S2) end points.

Table 3

Bleeding site

The multivariate analysis—which was adjusted for age, sex, dyslipidaemia, history of stroke, peripheral artery disease, percutaneous coronary intervention/coronary artery bypass grafting and PPI use—revealed no significant differences in efficacy (HR 1.20; 95% CI 0.80 to 1.79; p=0.373) and safety (HR 0.76; 95% CI 0.40 to 1.42; p=0.382) outcomes between the P2Y12 inhibitor and aspirin groups (detailed data not shown). The Schoenfeld residuals indicated that the Cox proportional-hazard assumptions were not violated.

Discussion

In this study, we evaluated the efficacy and safety of oral anticoagulant therapy combined with P2Y12 inhibitors or aspirin in patients enrolled in the AFIRE trial. The findings of the present study are as follows: (1) there were no significant differences in the efficacy and safety outcomes between the aspirin and P2Y12 inhibitor groups and (2) this result was the same with the co-prescription of PPI.

Considering the balance between the risk of bleeding and prevention of thrombosis, the intensity of antithrombotic therapy is a clinical challenge when a patient with AF undergoes percutaneous coronary intervention. In the present subanalysis of the AFIRE trial,6 we assessed the efficacy and safety of P2Y12 inhibitors and aspirin in patients with stable CAD and AF undergoing oral anticoagulant therapy in the chronic phase.

For patients with AF in the chronic phase after percutaneous coronary intervention, guidelines recommend direct oral anticoagulant monotherapy,3–5 although there has not been robust evidence for its efficacy. The OAC-ALONE study9 was the first randomised clinical trial focused on this issue and was conducted to evaluate the efficacy and safety outcomes of oral anticoagulant monotherapy versus oral anticoagulant and single antiplatelet therapy in those patients. However, that study was statistically underpowered because patient enrolment was prematurely terminated. In the present subanalysis, we focused on patients who received direct oral anticoagulants plus single antiplatelet therapy in the AFIRE trial, a randomised clinical trial of patients with AF and stable CAD in which the efficacy and safety of single antiplatelet therapy with P2Y12 inhibitors and aspirin were assessed when combined with anticoagulant therapy.6 In this subanalysis, there were no significant differences in efficacy or safety between the P2Y12 inhibitor and aspirin groups, which may indicate that single antiplatelet therapy with aspirin is comparable to single antiplatelet therapy with P2Y12 inhibitors. It is conceivable that the rate of combination with PPI might have influenced the results; however, PPI administration rates were relatively high (approximately 60%) and did not differ between the two groups. In fact, the similarly high rates of PPI administration may have contributed to the similar incidence of bleeding events between the two groups.

In the WOEST (What is the Optimal antiplatElet & Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary StenTing) trial, researchers investigated the efficacy and safety of vitamin K antagonist plus single antiplatelet therapy with clopidogrel, as compared with triple therapy with vitamin K antagonist plus dual antiplatelet therapy, in patients with acute phase of percutaneous coronary intervention receiving oral anticoagulants and undergoing percutaneous coronary intervention. It revealed a significantly lower incidence of bleeding events in the vitamin K antagonist plus single antiplatelet therapy group, and no difference in the incidence of thrombotic events between groups.10 After the WOEST trial, it has become common practice to discontinue aspirin when switching from dual antiplatelet therapy to single antiplatelet therapy. In this study, the P2Y12 inhibitor group had a higher prevalence of a history of percutaneous coronary intervention than the aspirin group (82.2% vs 66.3% in table 1), which might have been due to the preceding WOEST trial. There have been recent investigations of the choice of antithrombotic therapy in patients with AF undergoing percutaneous coronary intervention compared with those receiving direct oral anticoagulants with P2Y12 inhibitors and triple therapy11–13 or direct oral anticoagulants with P2Y12 inhibitors and vitamin K antagonists with or without aspirin.14 Of note, in the PIONEER AF-PCI (A Study Exploring Two Strategies of Rivaroxaban and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention) trial,11 15 mg of rivaroxaban was selected with antiplatelets, the same dose as in the present study and lower than that of the global standard dose (20 mg). The results of recently published network meta-analyses of randomised controlled trials on this issue suggested that therapy with direct oral anticoagulants plus P2Y12 inhibitors is preferred over other regimens, including vitamin K antagonists or triple therapy.15–17 Moreover, the guidelines recommend P2Y12 inhibitors as antiplatelet agents in patients with AF who are on anticoagulant therapy.3–5 However, a higher incidence of stent thrombosis was observed in the less-intensive antithrombotic therapy group in a subanalysis of the AUGUSTUS (A Study of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombosis (Blood Clots) Due to Having Had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart) trial,7 which indicates that careful attention should be paid to patients at high risk of thrombotic events.

With regard to the choice of antiplatelet agent to continue after dual antiplatelet therapy for patients after percutaneous coronary intervention, most researchers who investigated the benefits of shortening the duration of dual antiplatelet therapy examined the continuation of low-dose aspirin after the completion of dual antiplatelet therapy.18–20 Recent studies have been conducted to evaluate continuous treatment with P2Y12 inhibitors instead of aspirin after the completion of dual antiplatelet therapy, in terms of its ability to reduce the risks of gastrointestinal and intracranial bleeding complications associated with low-dose aspirin while simultaneously maintaining prevention of thrombotic events.21–23 Among patients with established atherosclerosis, single antiplatelet therapy with P2Y12 inhibitors compared with that with aspirin reduced the combined risk of ischaemic stroke, myocardial infarction and vascular death and was equivalent in terms of its safety profile.24 However, in a meta-analysis of randomised controlled trials comparing P2Y12 inhibitors and aspirin, researchers reported that P2Y12 inhibitors were associated with a lower risk of myocardial infarction and a similar risk of stroke compared with aspirin.25 Regarding the risk of bleeding posed by combination therapy with anticoagulants and antiplatelets, Schalekamp et al reported26 that patients receiving clopidogrel or aspirin with vitamin K antagonist exhibited a significantly higher risk of hospitalisation due to major bleeding (OR 2.9; 95% CI 1.2 to 6.9 and OR 1.6; 95% CI 1.3 to 1.9, respectively) compared with controls. Likewise, Lamberts et al reported that, in a nationwide cohort study with 8700 patients, the risk of bleeding increased on adding aspirin (HR 1.50; 95% CI 1.23 to 1.82) or clopidogrel (HR 1.84; 95% CI 1.11 to 3.06) to treatment with vitamin K antagonist.27 The risk of increased bleeding when adding either clopidogrel or aspirin to anticoagulant treatment was similar. Thus, the choice of antiplatelet agent is still considered controversial, and the optimal strategy of antithrombotic therapy may not be ‘one-size-fits-all’, especially in patients with AF undergoing percutaneous coronary intervention combined with anticoagulant therapy. However, the awaited results of an ongoing, large, randomised controlled trial, in which clopidogrel and aspirin are being directly compared as long-term antiplatelet agents beyond dual antiplatelet therapy after drug-eluting stent implantation, may shed further light on the matter.28

This study had several limitations. First, it was a subanalysis of the AFIRE trial and not itself a randomised controlled study. Second, this study was performed only in Japan, and the dose of rivaroxaban was set at the Japanese authorised dose,29 which is not consistent with global doses, although 15 mg of rivaroxaban was used in the PIONEER AF-PCI trial.11 Likewise, the main dose of aspirin in this study was 100 mg (94.5%), which is lower than the global dose. Third, almost all patients (94.6%) in the P2Y12 inhibitor group were taking clopidogrel; therefore, it was impossible to perform a subanalysis focusing on the type of P2Y12 inhibitor. Besides, a higher incidence of clopidogrel-related genetic polymorphisms has been reported,30 especially in the East Asian population, which may have affected the results in this study. However, the effects of such polymorphisms are expected to be less pronounced in patients in the chronic than in the acute phase. Taking these racial differences into account, caution should be exercised in applying these results to other populations. Third, regarding previous interventions undergone by patients (percutaneous coronary intervention or coronary artery bypass grafting), we did not have access to the data on whether they were performed for acute coronary syndrome; therefore, we could not determine the relationship between intervention and optimal antithrombotic strategy in the chronic phase.

Further prospective studies are necessary for evaluation of the inferior-to-superior relationship of antiplatelet agents under direct oral anticoagulant therapy for patients with AF and stable CAD.

Conclusions

There were no statistically significant differences in cardiovascular and bleeding events in patients with AF and stable CAD taking rivaroxaban with either P2Y12 inhibitors or aspirin in the chronic phase.

Key messages

What is already known on this subject?

  • It remains unclear which antiplatelet agents—that is, P2Y12 inhibitors or aspirin—should be co-prescribed with oral anticoagulants for patients who are not suited for oral anticoagulant monotherapy because of a higher thromboembolic risk.

What might this study add?

  • Patients taking rivaroxaban in the chronic phase treated with P2Y12 inhibitors or aspirin did not significantly differ in their incidence of cardiovascular and bleeding events.

How might this impact on clinical practice?

  • The choice of antiplatelet agents remains controversial and there may not be an optimal, ‘one-size-fits-all’ therapeutic antithrombotic strategy, especially for patients with atrial fibrillation undergoing percutaneous coronary intervention combined with anticoagulant therapy.

  • Further prospective studies are necessary to evaluate the inferior-to-superior relationship of those antiplatelet agents under direct oral anticoagulant therapy for patients with atrial fibrillation and stable coronary artery disease.

Data availability statement

Data are available on reasonable request.

Ethics statements

Patient consent for publication

Ethics approval

The trial was conducted according to the Declaration of Helsinki and approved by the institutional review board of the National Cerebral and Cardiovascular Center, Japan, along with the institutional review boards of all participating institutions.

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • Twitter @HidehiraFukaya

  • Contributors HF, JA, SY and HO contributed to the study conception and design, data acquisition and data analysis and interpretation. All authors contributed to the drafting and critical revision of the manuscript for important intellectual content and approved the final version of the manuscript for publication.

  • Funding The study was funded by Japan Cardiovascular Research Foundation and Bayer Yakuhin

  • Competing interests HF reports personal fees from Nippon Boehringer Ingelheim and Daiichi Sankyo. JA reports personal fees from Bayer Yakuhin and Sanofi, and grants and personal fees from Daiichi Sankyo. SY reports grants from Takeda Pharmaceutical, Abbott and Boston Scientific, and personal fees from Daiichi Sankyo and Bristol-Meyers. KKa reports Grants-in-Aid for Scientific Research (20K08451) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and grants and personal fees from Bayer Yakuhin and Daiichi Sankyo. MA reports grants from the Japan Agency for Medical Research and Development (AMED), personal fees from Bristol-Myers Squibb and Nippon Boehringer Ingelheim, and grants and personal fees from Bayer Yakuhin and Daiichi Sankyo. TM reports grants from the Japan Cardiovascular Research Foundation and personal fees from Nippon Boehringer Ingelheim, Daiichi Sankyo, AstraZeneca and Bayer Yakuhin. MN reports grants and personal fees from Bayer Yakuhin, Daiichi Sankyo and Sanofi, and personal fees from Bristol-Myers Squibb and Nippon Boehringer Ingelheim. KMi reports personal fees from Amgen Astellas BioPharma, Astellas Pharma, MSD, Bayer Yakuhin, Sanofi, Takeda Pharmaceutical, Daiichi Sankyo, Nippon Boehringer Ingelheim and Bristol-Myers Squibb. NH reports grants and personal fees from Bayer Yakuhin, grants from Nippon Boehringer Ingelheim and personal fees from Bristol-Myers Squibb. KKi reports grants from the Japan Cardiovascular Research Foundation; grants and personal fees from Bayer Yakuhin, Daiichi Sankyo, Sanofi, MSD and AstraZeneca; and personal fees from Bristol-Myers Squibb and Nippon Boehringer Ingelheim. AH reports grants and personal fees from Boston Scientific Japan, Otsuka Pharmaceutical, Sanofi, Astellas Pharma, Bristol-Myers Squibb, Daiichi Sankyo and Bayer Yakuhin; grants from Fukuda Denshi, Abbott Japan, Japan Lifeline, Takeda Pharmaceutical and Sumitomo Dainippon Pharma; and personal fees from Toa Eiyo, Nippon Boehringer Ingelheim, Amgen Astellas BioPharma and AstraZeneca. HO reports personal fees from Towa Pharmaceutical, Bristol-Meyers Squibb, Pfizer, Toa Eiyo, Bayer Yakuhin and Novartis Pharma. All other authors declare no financial relationships relevant to the contents of this paper.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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