Antiplatelet versus anticoagulation treatment for people with heart failure in sinus rhythm

Monika Kozieł-Siołkowska; Eduard Shantsila; Alena Shantsila; Gregory YH Lip

doi:10.1002/14651858.CD003333.pub4

. 2025 Jun 11;2025(6):CD003333. doi: 10.1002/14651858.CD003333.pub4

Antiplatelet versus anticoagulation treatment for people with heart failure in sinus rhythm

Monika Kozieł-Siołkowska ^1,², Eduard Shantsila ^1,³, Alena Shantsila ¹, Gregory YH Lip ^4,^✉

Editor: Cochrane Central Editorial Service

PMCID: PMC12153039 PMID: 40497467

Abstract

Background

People with chronic heart failure have an increased risk of thrombotic complications, including stroke and thromboembolism, which in turn contribute to high mortality. Oral anticoagulants (e.g. warfarin) and antiplatelet agents (e.g. aspirin) are the principal oral antithrombotic agents. Many people with heart failure in sinus rhythm take aspirin because coronary artery disease is the leading cause of heart failure. Oral anticoagulation (OAC) has become a standard in the management of heart failure with atrial fibrillation. However, uncertainty regarding the appropriateness of OAC in heart failure with sinus rhythm remains. This is an update of a review previously published in 2016.

Objectives

To assess the effects of OAC versus antiplatelet agents for all‐cause mortality, non‐fatal cardiovascular events and risk of major bleeding in adults with heart failure (either with reduced or preserved ejection fraction) who are in sinus rhythm.

Search methods

In April 2025, we updated the searches of CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) portal. We searched the reference lists of papers and abstracts from cardiology meetings and contacted study authors for further information. We did not apply any language restrictions.

Selection criteria

We included randomised controlled trials (RCTs) comparing antiplatelet therapy versus OAC in adults with chronic heart failure in sinus rhythm. Treatment had to last for at least one month. We compared oral antiplatelets (aspirin, ticlopidine, clopidogrel, prasugrel, ticagrelor, dipyridamole) versus OAC (coumarins, warfarin, non‐vitamin K oral anticoagulants).

Data collection and analysis

Three review authors independently assessed trials for inclusion and assessed the benefits and harms of antiplatelet therapy versus OAC by calculating risk ratios (RRs) with 95% confidence intervals (CIs). We used GRADE criteria to assess the certainty of evidence.

Main results

This update did not identify additional studies for inclusion, so the evidence base remains unchanged since the previous review version (published in 2016). We included four RCTs with 4187 eligible participants. All studies compared warfarin with aspirin. One RCT additionally compared warfarin with clopidogrel. All included RCTs studied people with heart failure with reduced ejection fraction.

Analysis of all outcomes for warfarin versus aspirin was based on 3663 participants from four RCTs. Warfarin and aspirin probably both reduce all‐cause mortality, with little to no difference between their risks: 21.9% for warfarin, 21.9% for aspirin (RR 1.00, 95% CI 0.89 to 1.13; 4 studies, 3663 participants; moderate‐certainty evidence). OAC probably reduces the risk of non‐fatal cardiovascular events (6.6% for warfarin, 8.3% for aspirin), which included non‐fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism (RR 0.79, 95% CI 0.63 to 1.00; 4 studies, 3663 participants; moderate‐certainty evidence). Warfarin probably increases the risk of major bleeding events: 5.6% for warfarin, 2.8% for aspirin (RR 2.00, 95% CI 1.44 to 2.78; 4 studies, 3663 participants; moderate‐certainty evidence). We considered the risk of bias of the included studies to be low.

Analysis of warfarin versus clopidogrel was based on one RCT (N = 1064). With little to no difference between their risks, warfarin and clopidogrel may both reduce all‐cause mortality: 17.0% for warfarin, 18.3% for clopidogrel (RR 0.93, 95% CI 0.72 to 1.21; 1 study, 1064 participants; low‐certainty evidence) and non‐fatal cardiovascular events slightly, 4.6% for warfarin, 5.4% for clopidogrel (RR 0.85, 95% CI 0.50 to 1.45; 1 study, 1064 participants; low‐certainty evidence). Warfarin may increase the risk of major bleeding events slightly: 4.9% for warfarin, 2.0% for clopidogrel (RR 2.47, 95% CI 1.24 to 4.91; 1 study, 1064 participants; low‐certainty evidence). We considered the risk of bias for this to be low.

Authors' conclusions

There is some evidence from RCTs that OAC with warfarin compared to platelet inhibition with aspirin probably has little to no effect on mortality in people with systolic heart failure in sinus rhythm (moderate‐certainty evidence). Treatment with warfarin probably reduces non‐fatal cardiovascular events but probably increases the risk of major bleeding complications (moderate‐certainty evidence). We saw a similar pattern of results for the warfarin versus clopidogrel comparison (low‐certainty evidence). At present, there are no data on the role of OAC versus antiplatelet agents in heart failure with preserved ejection fraction in sinus rhythm. Also, there were no data from RCTs on the utility of non‐vitamin K antagonist oral anticoagulants compared to antiplatelet agents in heart failure with sinus rhythm.

Plain language summary

Are antiplatelet treatments or anticoagulation treatments better for people who have heart failure with a normal heart rhythm?

Key messages

– For people who have heart failure with a normal heart rhythm, there seems to be little to no advantage of warfarin (an anticoagulant: a medicine which prevents blood clotting by blocking proteins) over antiplatelet medicines like aspirin (which prevent blood clotting by blocking platelets).

– Treatment with warfarin leads to more bleeding problems than aspirin or clopidogrel.

How do anticoagulant and antiplatelet treatments help people with heart failure?

Some people with heart failure have an abnormal heart rhythm (known as atrial fibrillation) but some have a normal heart rhythm (known as sinus rhythm). People with heart failure might have slower blood flow in the heart, which puts them at risk of blood clots forming. Blood clots can be formed by clotting proteins (coagulation factors) and sticky blood cells (platelets).

Many people who have heart failure with normal rhythm have narrowed heart arteries, and doctors often give them aspirin, which is a medicine that can reduce clotting by blocking platelets. People with heart failure are also at risk of blood clots (thromboembolism) in the lungs, legs and brain (ischaemic stroke), which can lead to disability and death.

Oral anticoagulation (OAC) medicines like warfarin can block clotting proteins and help to prevent blood clots from forming. Warfarin is known to be better than aspirin for people with heart failure who have abnormal heart rhythm, so several studies have tried to find out whether all people with heart failure (including those with normal heart rhythm) should receive OAC.

What did we want to find out?

We wanted to find out whether there was any difference between the effects of anticoagulants and antiplatelets for people with heart failure and normal heart rhythm. In particular, we wanted to know if the type of medicine made any difference to the risk of dying, clotting complications (e.g. a heart attack or stroke), or serious bleeding problems.

What did we do?

We looked for studies that gave at least a month of antiplatelet or anticoagulant medicines to adults with heart failure in normal rhythm, with the type of treatment chosen at random. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We included four studies which treated a total of 4187 people.

We found that the risk of dying was almost identical whether people in the four studies took aspirin or warfarin. There was not enough evidence to prove the benefits of warfarin over aspirin to reduce the possibility of clotting complications, such as a heart attack or stroke. However, people receiving warfarin experienced serious bleeding twice as often as those taking aspirin. One medium‐sized study also compared warfarin with another antiplatelet drug, clopidogrel, and showed similar results: no difference in occurrence of death or clotting complications, but a higher chance of developing a serious bleed.

It is unlikely that further studies will change these conclusions unless new, more effective and safe drugs become available.

What are the limitations of the evidence?

We are only moderately confident in the evidence comparing warfarin with aspirin because there were few cases of clotting complications and bleeding, and because there were not enough studies to be certain about the risk of dying.

We have little confidence in the evidence comparing warfarin with clopidogrel because the evidence was based on only a few cases and there were not enough studies to be certain about the findings.

How up to date is this evidence?

This is an update of an earlier review. The evidence is current to April 2025.

Summary of findings

Summary of findings 1. Warfarin versus aspirin for heart failure in sinus rhythm.

Warfarin versus aspirin for heart failure in sinus rhythm
Patient or population: people with heart failure in sinus rhythm Settings: outpatient clinics Intervention: warfarin Comparison: aspirin
Outcomes	*Illustrative comparative risks (95% CI)^a**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Aspirin	Warfarin
All‐cause mortality Mean follow‐up: 18.5 – 42 months	219 per 1000	219 per 1000 (195 to 247)	RR 1.00 (0.89 to 1.13)	3663 (4 RCTs)	⊕⊕⊕⊝^b Moderate
Non‐fatal cardiovascular events (non‐fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism) Mean follow‐up: 18.5 – 42 months	83 per 1000	66 per 1000 (52 to 83)	RR 0.79 (0.63 to 1.00)	3663 (4 RCTs)	⊕⊕⊕⊝^c Moderate
Major bleeding events Mean follow‐up: 18.5 – 42 months	28 per 1000	56 per 1000 (40 to 78)	RR 2.00 (1.44 to 2.78)	3663 (4 RCTs)	⊕⊕⊕⊝^c Moderate
The corresponding risk* (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.

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^aAll results are presented for the whole‐population analyses. The assumed risk is provided based on the aspirin group as aspirin is often used in people with heart failure in sinus rhythm due to background ischaemic heart disease. ^bDowngraded by one level due to imprecision: the 95% CI crosses the line of no effect. ^cDowngraded by one level due to imprecision: low event rates.

Summary of findings 2. Warfarin versus clopidogrel for heart failure in sinus rhythm.

Warfarin versus clopidogrel for heart failure in sinus rhythm
Patient or population: people with heart failure in sinus rhythm Settings: outpatient clinics Intervention: warfarin Comparison: clopidogrel
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Clopidogrel	Warfarin
All‐cause mortality Mean follow‐up: 1.9 years	183 per 1000	170 per 1000 (132 to 221)	RR 0.93 (0.72 to 1.21)	1064 (1 RCT)	⊕⊕⊝⊝ Low^a
Non‐fatal cardiovascular events (non‐fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism) Mean follow‐up: 1.9 years	54 per 1000	46 per 1000 (27 to 78)	RR 0.85 (0.50 to 1.45)	1064 (1 RCT)	⊕⊕⊝⊝ Low^a
Major bleeding events Mean follow‐up: 1.9 years	20 per 1000	49 per 1000 (25 to 98)	RR 2.47 (1.24 to 4.91)	1064 (1 RCT)	⊕⊕⊝⊝ Low^a
* The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.

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^aDowngraded by two levels due to imprecision. The 95% confidence intervals crossed the line of no effect and the outcomes had low event rates.

Background

Description of the condition

Chronic heart failure is a major clinical and social problem, with an estimated prevalence of 1% to 2% of adults in developed countries. Its prevalence increases with age to more than 10% of those aged 70 years or over (McDonagh 2021).

According to the European Society of Cardiology (ESC) guidelines, heart failure consists of individuals with normal left ventricular ejection fraction (LVEF); heart failure with preserved ejection fraction (HFpEF), when ejection fraction is 50% or over; heart failure with mid‐range ejection fraction (HFmrEF), when ejection fraction equals 40% to 49%; and heart failure with reduced ejection fraction (HFrEF), when EF is less than 40% (McDonagh 2021).

Heart failure poses an increased risk of thrombotic complications, which occur in a third of people with the disease (Lip 2012). Mild to moderate heart failure with sinus rhythm is associated with an annual stroke risk of approximately 1.5% (Witt 2007), compared to less than 0.5% in the general population, while the annual risk of stroke increases to almost 4% in severe heart failure (Packer 1991). Indeed, the SAVE study reported an inverse relationship between stroke risk and LVEF, with an 18% increase in stroke risk for every 5% reduction in LVEF in severe heart failure (SAVE 1997). People with heart failure are also prone to developing venous thromboembolism (Khoury 2011; Piazza 2011). Pulmonary embolism and peripheral arterial embolism clearly contribute to the high morbidity in heart failure (Alberts 2010; Witt 2007). Multiple factors predispose people with heart failure to prothrombotic risk, including diastolic dysfunction, blood flow congestion and a hypercoagulable shift (Shantsila 2016a). For these reasons, people with heart failure could be expected to benefit from antithrombotic therapy, and it is essential to have evidence to support the best treatment options for prevention of thrombotic complications.

Description of the intervention

All people with heart failure who have atrial fibrillation have a CHA₂DS₂‐VASc score (a measure of stroke risk for people with AF) of 1 or more and benefit from oral anticoagulation (OAC) according to the current guidelines (Hindricks 2021). The choice of an antithrombotic agent in people with heart failure in sinus rhythm is more controversial, but antiplatelet therapy is common. Its use is based on its general efficacy as an antithrombotic agent, as it has been shown to reduce the incidence of myocardial infarction and death in men and women over the age of 50, in people with unstable angina and myocardial infarction, and in people with atherosclerotic cerebrovascular disease (APT Collab I 1994; ATT 2009), whilst the administration of aspirin improves the patency rates of saphenous‐vein aorto‐coronary bypass grafts (APT Collab I 1994; ATT 2009; Stein 1998). Aspirin also reduces the incidence of stroke and death in people with recurrent episodes of cerebral ischaemia (Sze 1988). Given that ischaemic cardiomyopathy is a major aetiological factor of heart failure, clinicians routinely use aspirin. Furthermore, research has shown aspirin to be moderately effective in reducing venous thrombosis and thromboembolism in people undergoing hip surgery and possibly in preventing these occurrences in general surgical patients (APT Collab I 1994).

Investigators have also studied antiplatelet agents such as dipyridamole and clopidogrel in cardiovascular disease. Studies have shown that dipyridamole reduces the incidence of thromboembolism when added to warfarin in high‐risk patients with prosthetic heart valves (APT Collab I 1994; Stein 1998), and others have reported that it reduces the risk of stroke when added to aspirin in people with a history of cerebrovascular disease (APT Collab I 1994; APT Collab II 1994; Klimt 1986). However, dipyridamole appears to have little antithrombotic effect, and studies have indicated that the addition of dipyridamole adds little to aspirin therapy alone in most cardiovascular diseases. In contrast, the newer platelet‐active agent clopidogrel has been studied in the large Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial, with evidence of a reduction in the composite outcome of vascular death, ischaemic stroke and myocardial infarction in people with a history of cardiovascular disease (CAPRIE 1996).

There have been few prospective studies of OAC or antiplatelet agents in people with heart failure in sinus rhythm. Given the evident prothrombotic state in such people, it is plausible that the use of OAC can be beneficial. The updated version of this Cochrane review was not able to conclude that OAC was better than antiplatelet therapy (Shantsila 2016b). A joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis in 2012, 'Thromboembolism and antithrombotic therapy for heart failure in sinus rhythm', concluded that "whilst there is the potential for a reduction in ischaemic stroke, there is currently no compelling reason to routinely use warfarin for these patients" (Lip 2012). We performed a new literature search for this Cochrane review update to reflect recent advances in the field.

How the intervention might work

The efficacy of antithrombotic therapy in atrial fibrillation (including in people with heart failure) and of OAC versus placebo for heart failure in sinus rhythm are the subjects of related Cochrane reviews (Aguilar 2005; Lip 2014), and we will not address these topics in the present review, which focuses on heart failure in sinus rhythm.

There is compelling evidence that aspirin reduces the short‐term risk of death after myocardial infarction, although the mortality benefits are less impressive during long‐term treatment or following the late initiation of aspirin (APT Collab I 1994; ATT 2009). This evidence supports the use of aspirin in heart failure patients with ischaemic heart disease, although many of these people have only a distant history of myocardial infarction, and the magnitude of any potential long‐term benefits is not conclusively established.

Antithrombotic agents (i.e. OACs or antiplatelet agents) might reduce thrombotic complications, such as myocardial infarction and stroke, and improve survival in heart failure with sinus rhythm. Bleeding complications are not uncommon with these agents, an important consideration during assessment of their overall benefits.

Why it is important to do this review

This review addresses an important problem, and it calls for the best evidence‐based antithrombotic therapy in heart failure without atrial fibrillation. Pharmacotherapy is the cornerstone of heart failure treatment. The studies available at the time of the previous version of the review produced conflicting results. The update was made to help health professionals manage patients with heart failure according to the best current evidence. This update did not find additional studies for inclusion.

Objectives

Methods

Criteria for considering studies for this review

Types of studies

We included RCTs that compared antiplatelet therapy with OAC. Quasi‐randomised studies (for example, those that allocated participants by alternation or day of the week) were not eligible. We excluded studies with a follow‐up duration of less than one month. A short follow‐up period may lead to bias in outcome assessment as the review focuses on a chronic condition and longer‐term outcomes. Short‐term outcomes are unlikely to allow sufficient sensitivity to the treatment effects.

Types of participants

We included participants aged 16 years or older with clinically defined heart failure and, if possible, with objective evidence of left ventricular systolic dysfunction, diastolic dysfunction (e.g. echocardiography, radionuclide ventriculography), or both. Participants with heart failure with reduced or preserved ejection fraction were eligible. We excluded studies of participants with atrial fibrillation only and studies that did not perform a separate analysis for a subgroup of participants with heart failure.

Types of interventions

The interventions of interest were orally administered antiplatelet agents (aspirin, ticlopidine, clopidogrel, prasugrel, ticagrelor or dipyridamole) compared with OAC (coumarins, warfarin, dabigatran, apixaban, edoxaban or rivaroxaban). We considered studies administering treatment for at least one month. We excluded studies with additional simultaneously tested active treatments in the intervention arm (e.g. beta‐blockers, angiotensin‐converting enzyme (ACE) inhibitors, etc.).

Types of outcome measures

We presented primary and secondary outcomes as the number of events per 1000 participants, separately for individual agents. The follow‐up period was presented in months or years (specified in tables). We were especially interested in a mean follow‐up duration of at least one year because the review focuses on longer‐term outcomes.

Primary outcomes

All‐cause mortality
Non‐fatal cardiovascular events (non‐fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism)

Secondary outcomes

Major bleeding events

Search methods for identification of studies

Electronic searches

This is an update of a Cochrane review previously published in 2016. Since the review was first published in 2001, we updated the search in August 2005 (Appendix 1), February 2010 (Appendix 2), June 2013 (Appendix 3), and September 2015 (Appendix 4). For the current update, we re‐executed the search in April 2025 for the databases below (Appendix 5).

Cochrane Central Register of Controlled Trials (CENTRAL; 2025, Issue 3) in the Cochrane Library (searched 3 April 2025)
MEDLINE (Ovid, 1946 to 3 April 2025)
Embase (Ovid, 1980 to 3 April 2025)

We also searched the following trials registries.

US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 4 April 2025)
World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch; searched 4 April 2025)

We used the Cochrane sensitivity‐maximising RCT filters to search MEDLINE and Embase (Lefebvre 2011), applying no language or date restrictions. We would have had relevant foreign language papers translated if necessary, and we handsearched the reference lists of papers.

Searching other resources

We searched the reference lists of papers and abstracts from cardiology meetings. We also searched for post‐publication amendments published on included or eligible studies. We planned to ask for studies available on request if necessary.

Data collection and analysis

Selection of studies

Three authors (MK‐S, ES, AS) independently selected suitable trials for inclusion in the review; disagreements were resolved by discussion.

Data extraction and management

Three review authors (MK‐S, ES, AS) screened the titles and abstracts of studies identified by the search for inclusion and retrieved all potentially relevant studies. The three authors independently reviewed the characteristics of the preselected studies to identify studies eligible for this review. They were not blinded to any aspect of the studies (for example, journal type, authors' names, institution). There was no disagreement regarding the selection of eligible studies. The same three authors extracted data on study populations, interventions, prespecified outcomes, and study methodology.

Assessment of risk of bias in included studies

Using the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), two authors (MK‐S, ES) independently assessed the six domains related to risk of bias using the Cochrane RoB 1 tool: randomisation sequence generation, allocation concealment, incomplete outcome data, selective reporting, blinding of participants and personnel, and blinding of outcome assessors (Higgins 2011). The two authors had similar judgements and thus there were no disagreements that had to be discussed and resolved. For future updates we will consider outlining how disagreements would be resolved.

Measures of treatment effect

We expressed dichotomous outcome data as Mantel‐Haenszel risk ratios (RRs) with 95% confidence intervals (CIs). For future updates, any time‐to‐event data would be presented as hazard ratios with 95% CI.

Unit of analysis issues

The review included RCTs with parallel design. Multi‐arm trials have many forms, often a combination of elements, including multiple active interventions, their combinations, different doses/regimens, different control group strategies, etc. They can be combined in different ways, resulting in numerous possible trial structures that may benefit finding a niche use of a drug, but deviate from finding a clear answer to a drug class effect, as in this review.

Studies with more than two groups may lead to bias regarding data analysis. For this reason, this systematic review excluded multi‐arm studies.

We would incorporate data from cluster‐RCTs into the review using an approach based on multiplying the standard error of the effect estimate (from an analysis ignoring clustering) by the square root of the design effect.

Dealing with missing data

For unpublished studies or where data were incomplete in published papers, we made attempts to contact authors or researchers to obtain further details. Where relevant, we contacted pharmaceutical companies to attempt to obtain unpublished trial data on newer antiplatelet drugs that may have been used in people with heart failure.

Assessment of heterogeneity

We assessed statistical heterogeneity appropriately in each meta‐analysis using the I² and Chi² statistics. We regarded heterogeneity as substantial if I² was greater than 50% or there was a low P value (less than 0.10) in the Chi² test for heterogeneity.

Assessment of reporting biases

If we were able to pool more than 10 trials, we would have created and examined a funnel plot to explore possible small study biases for the primary outcomes.

Data synthesis

We considered whether an overall summary was meaningful and used a fixed‐effects model to conduct meta‐analyses. Moreover, a possible method for synthesising studies without meta‐analysis could be that described in the Synthesis Without Meta‐analysis (SWiM) reporting guideline (Campbell 2020). The SWiM guideline includes nine reporting items to improve the transparent reporting of synthesis of intervention effects when the synthesis does not use meta‐analysis of standardised effect sizes.

Subgroup analysis and investigation of heterogeneity

Heterogeneity was low across the included studies. If it were high, we would have investigated it through subgroup analyses. We had planned to undertake the following subgroup analyses for all endpoints with potentially important heterogeneity (I² > 40%).

Aetiology of heart failure ‐ ischaemic versus non‐ischaemic heart failure;
Concomitant clinical comorbidities ‐ participants with heart failure and diabetes mellitus versus participants with heart failure without diabetes mellitus.

Sensitivity analysis

We would have conducted sensitivity analyses to explore the effect of trial quality for each comparison by restricting the analysis to those trials rated as being at low risk of bias for random sequence generation and allocation concealment. However, all included trials were of low risk of bias in these domains.

Summary of findings and assessment of the certainty of the evidence

We created a summary of findings table using the following outcomes: all‐cause mortality, non‐fatal cardiovascular events (non‐fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism) and major bleeding events. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it related to the studies that contributed data to the meta‐analyses for each important outcome. We used methods and recommendations described in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2020), and constructed the tables using GRADEpro software (GRADEPro GDT). We created two summary of findings tables for the two comparisons: warfarin versus aspirin, and warfarin versus clopidogrel. We justified all decisions to downgrade the quality of studies in footnotes, and made comments to aid the reader's understanding of the review, where necessary.

Two review authors (MK‐S, ES) independently made judgements about the quality of the evidence. They resolved disagreements through discussion, or by involving a third review author (GL). They justified and documented the judgements, incorporating them into the reports of the results for each outcome.

We extracted study data, formatted our comparisons in data tables, and prepared a summary of findings table before writing the results and conclusions of our review.

Results

Description of studies

Results of the search

The initial search in 2005 yielded 1647 records, of which we excluded 1631 after screening titles and abstracts. We assessed the full text of the remaining 16 records. WASH 2004 met our inclusion criteria. We excluded 12 studies, and the other three were ongoing at the time (HELAS 2006; Pullicino 2000; WATCH 2009).

The updated search in 2010 yielded 1219 new records, of which we excluded 1203 after screening the titles and abstracts. We assessed 16 full‐text records, excluded 14 full texts and included two previously ongoing studies (HELAS 2006; WATCH 2009).

The updated search in 2013 yielded 1460 new records, of which we excluded 1452 after screening the titles and abstracts; four records were abstracts reporting on two retrospective analyses. However, they did not specify the proportion of participants with atrial fibrillation and did not provide information on adverse outcomes, so these were also excluded. We reviewed full‐text reports for the remaining four records, one of which met the inclusion criteria (WARCEF 2012) and we excluded the other three full texts.

The updated search in 2015 yielded 975 new records; we excluded 971 after screening the titles and abstracts and examined four records in detail. Pullicino 2013 was a subanalysis of WARCEF 2012, looking at different types of stroke; the analysis did not add any new information relevant to this review update. The three remaining records were conference proceedings of two randomised studies (ASAP‐HF 2013; CACHE‐EHF 2014), which did not fully meet our inclusion criteria and were excluded at the full‐text screening stage.

Searches were repeated in March 2020; these yielded 4697 records in total, of which we excluded 4680 after screening the titles and abstracts. We assessed 17 full‐text records and excluded all of them.

The latest updated search in April 2025 yielded 5958 records in total, of which we excluded 5749 after screening the titles and abstracts. We assessed 209 new full‐text records and excluded all of them.

In total, this review update includes four studies (HELAS 2006; WARCEF 2012; WASH 2004; WATCH 2009). We have not identified any new eligible studies since the previous review version (Shantsila 2016b). We present the reasons for excluding studies that closely missed the inclusion criteria in Characteristics of excluded studies.

We show the flow of studies, combined for the 2020 and 2025 searches, in Figure.

Included studies

We included four RCTs that met the review criteria for assessing the effectiveness of antiplatelet therapy (HELAS 2006; WARCEF 2012; WASH 2004; WATCH 2009; see Characteristics of included studies).

All studies recruited participants with heart failure with reduced LVEF only. Atrial fibrillation was not an absolute exclusion criterion in WASH 2004, but 92% of the study participants had no history of it at the time of recruitment. Other studies only included participants in sinus rhythm. The range of ages for the trials was 18 years and older with a mean age of 61 years across the trials. Most participants were men (61% to 93% across trials). We analysed all outcomes based on the intention‐to‐treat principle.

The studies were international (involving the USA, the UK, countries in Western and Eastern Europe, Canada and Argentina). The pharmaceutical industry provided some funding and support to the studies. The WASH trial was partly supported by Bristol‐Myers Squibb, which manufactures warfarin in the USA. Bristol‐Myers Squibb, Sanofi‐Synthelabo, and Dupont pharmaceutical companies partly supported the WATCH trial through unrestricted grants and provision of the study drugs. HELAS 2006 did not specify sources of funding, but Greece‐based centres led and co‐ordinated the study, and Greece‐based companies manufactured all study agents.

WASH 2004 was a pilot study of 279 participants recruited from 17 centres in the UK and three centres in the USA. This review analysed only the 180 participants randomised to warfarin (target international normalised ratio (INR) 2.0 to 3.0) versus aspirin (300 mg once daily). The remaining participants were randomised to no antithrombotic therapy and thus were outside the scope of the analysis. Investigators recorded baseline data on all participants by telephone at the data centre before randomisation using prospectively constructed blocks of random numbers.

Participants had to have a clinical diagnosis of heart failure requiring treatment with diuretics and evidence of left ventricular systolic dysfunction on echocardiography within six months before entry (WASH 2004). Echocardiographic criteria of left ventricular dysfunction included an increased left ventricular end‐diastolic internal dimension (≥ 56 mm or ≥ 30 mm/m² body surface area) combined with a fractional shortening of at least 28% or LVEF of at least 35%. Investigators were encouraged to use warfarin in participants who developed atrial fibrillation and to reduce the dose of aspirin or use any appropriate antidyspeptic medication if dyspepsia occurred. This trial was limited by open‐label treatment with warfarin, small numbers and relatively short follow‐up (27 ± 1 months). Also, from the study manuscript, it is not clear whether any participants had incomplete outcome data.

HELAS 2006 recruited 197 participants in centres in Greece, Cyprus, Yugoslavia, Romania, Bulgaria, Poland and Georgia. We excluded the participants with dilated cardiomyopathy who were randomised to warfarin versus placebo, but we included participants with underlying ischaemic heart disease (n = 115) who were randomised to warfarin versus aspirin. The trial was double‐blinded and included participants with the New York Heart Association (NYHA) class II to IV and LVEF of more than 35% assessed by echocardiography, or by radionuclide or angiocardiographic ventriculography. The university co‐ordination centre conducted computerised randomisation by fax or telephone. Investigators were blinded to therapy, and warfarin doses were recommended according to sham results where appropriate. However, the study manuscript does not provide details on the sham procedures, and it is unclear how robust they were. The participants were regularly followed up with a recording of any clinical outcomes. As with WASH 2004, HELAS 2006 is limited by the small number of participants and short follow‐up period (mean follow‐up time of 18.5 months for those taking aspirin and 18.7 months for those taking warfarin). It is not clear whether there was an independent assessment of study outcomes.

WATCH 2009 included 1587 participants from 142 centres in the USA, Canada and the UK. Participants were eligible if they had NYHA class II to IV heart failure for more than three months, LVEF of less than 35%, were in sinus rhythm and on a diuretic and ACE inhibitor (unless not tolerated). Participants were randomised into three arms: aspirin 162 mg once daily, clopidogrel 75 mg once daily in a double‐blind, double‐dummy manner, or open‐label warfarin (target INR 2.5 to 3.0). The Cooperative Studies Program Coordinating Center (CSPCC) generated randomisation sequences for each site and allocated treatment. The main outcome measures were adjudicated by a blinded committee. The mean duration of follow‐up was 1.9 years, for a total of 3073 participant‐years of follow‐up. Due to slow enrolment, the study failed to recruit the prespecified target of 4500 participants. The study was limited by open‐label management of warfarin. Also, similar to WASH 2004, it is not clear whether any participants in WATCH 2009 had incomplete outcome data.

WARCEF 2012 was a large RCT conducted at 168 centres in 11 countries. The trial recruited 2305 participants with LVEF of 35% or less and sinus rhythm who were randomised to warfarin (target INR of 2.0 to 3.5) or aspirin (325 mg once daily). Investigators reported the primary outcomes of the first event in a composite endpoint of ischaemic stroke, intracerebral haemorrhage or death from any cause during a mean follow‐up period of 3.5 ± 1.8 years. Two independent core echocardiography laboratories, which were unaware of the study treatment, assessed the accuracy of LVEF measurement. An independent endpoint adjudication committee blinded to the treatment assignments adjudicated all primary and secondary outcomes and cases of major haemorrhage. The WARCEF trial was a well‐designed, adequately powered study with low risk of the assessed bias types.

Excluded studies

We excluded 41 references and present our reasons for excluding 10 studies that most closely missed the inclusion criteria in Characteristics of excluded studies.

Four RCTs of ACE inhibitors assessed the use of antithrombotic therapy in participants with heart failure and/or left ventricular systolic dysfunction (Al‐Khadra 1998a; SAVE 1997; SOLVD 1997; V‐HeFT II 1992). These analyses were done outside the randomisation scheme. V‐HeFT II 1992 included participants with symptomatic heart failure and radiological, echocardiographic or radionuclide evidence of left ventricular systolic dysfunction. The SOLVD trials included participants with left ventricular systolic dysfunction, defined as an LVEF of 35% or less, who were either symptomatic and enrolled into the treatment trial (SOLVD‐treatment 1991), or asymptomatic and enrolled into the prevention trial (SOLVD‐prevent 1992). SAVE 1997 included participants following myocardial infarction with an LVEF of 40% or more and no overt heart failure (i.e. asymptomatic participants). PROMISE 1993 presented limited information from a retrospective analysis of one trial in abstract form only.

In one recent retrospective, observational, non‐randomised study, investigators used aspirin in 32% of 417 participants (warfarin in 28%) with an average follow‐up of five years (EPICAL 2002). Treatment with antithrombotic agents (either aspirin, warfarin or both) was associated with better survival at five years (40.4% versus 31% with no antithrombotic treatment, P = 0.01). However, we excluded this study because 24% of the participants had concomitant atrial fibrillation, investigators reported only survival rates, and they did not report event rates separately for the sinus rhythm group or those treated was aspirin, warfarin or no therapy.

Two almost identical abstracts presented results of the randomised open‐label clopidogrel versus aspirin in chronic heart failure (CACHE‐EHF 2014) study that compared 75 mg daily doses of the two drugs in 87 participants with heart failure in sinus rhythm and an N‐terminal‐pro‐brain natriuretic peptide (NT‐proBNP) of 400 ng/L (mostly NYHA II). By six months, treatment with aspirin was associated with worse renal function and higher diastolic blood pressure compared with clopidogrel, but investigators did not report any major adverse outcomes. The study did not have a comparator other than another antiplatelet agent (i.e. placebo or oral anticoagulant), so we excluded it from the analysis.

No adequately powered prospective studies have specifically examined the role of the antiplatelet agent dipyridamole in people with heart failure. There was a small randomised pilot study of dipyridamole plus aspirin (aggrenox) versus placebo in 18 participants with congestive heart failure (NYHA class II to IV) and LVEF of less than 40%, presented as a conference abstract in 2013 (ASAP‐HF 2013). After six months of therapy, there were no reported changes in haemodynamic characteristics in either group. BNP levels were reduced in the treatment group, but not in the placebo group (the report did not include a between‐group comparison). More participants in the treatment group showed improvement in six‐minute walking distance than in the placebo group. We excluded the study because no clinical events were recorded (although investigators mentioned the absence of bleeding events in both groups). There were two active treatments in the intervention arms, and investigators provided no information on whether the participants were in atrial fibrillation or sinus rhythm.

The COMMANDER HF trial compared rivaroxaban versus placebo in participants with heart failure of ischaemic aetiology in sinus rhythm.

Diener 2019 compared dabigatran with aspirin in individuals who had experienced an embolic stroke of undetermined source. However, the group of participants with heart failure was not specified.

Risk of bias in included studies

We summarise the risk of bias assessment in Figure and Figure. Because there were only four studies and all had a low risk of selection bias, we did not perform a sensitivity analysis.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Allocation

All studies used central randomisation with low risk of bias in relation to random sequence generation and allocation concealment.

Blinding

For blinding of participants and personnel, we assessed two studies as being at high risk (WASH 2004; WATCH 2009), one study as being at low risk (WARCEF 2012), and one study as being at unclear risk of blinding of participants and personnel (HELAS 2006).

WASH 2004 had an open‐label study design. Warfarin dosing was open‐label in WATCH 2009. In HELAS 2006, the investigator‐supervisor was blinded to the study and adjusted the study medication dose according to the prothrombin time results. The dose was then administered to the participant by a second investigator. In the placebo arm, the supervisor regulated the dose according to sham results.

We considered HELAS 2006 to be at unclear risk of detection bias in relation to the blinding of outcome assessors, while the other three studies were at low risk (WARCEF 2012; WASH 2004; WATCH 2009).

Incomplete outcome data

Two studies were also at unclear risk of incomplete outcome bias (WASH 2004; WATCH 2009), while two studies were at low risk of bias in this domain (HELAS 2006; WARCEF 2012). In the WASH 2004 study, participants randomised to aspirin had significantly more hospitalisations for cardiovascular reasons (P = 0.04), especially worsening heart failure. Of the 1587 participants randomised to the WATCH 2009 study, 76 participants were lost to follow‐up. The total number of heart failure hospitalisations was higher with aspirin compared with warfarin (218 versus 155; P < 0.001).

Selective reporting

We deemed all four included studies to be at low risk of selective reporting bias.

Other potential sources of bias

In the WASH 2004 study, cross‐over rates were 25% at 12 months, which might have influenced the certainty of the results or the risk of bias.

Effects of interventions

See: Summary of findings 1 Warfarin versus aspirin for heart failure in sinus rhythm; Summary of findings 2 Warfarin versus clopidogrel for heart failure in sinus rhythm

1. Warfarin versus aspirin

All‐cause mortality

Four trials involving 3663 participants in total reported all‐cause mortality (HELAS 2006; WARCEF 2012; WASH 2004; WATCH 2009). There is probably little to no difference in all‐cause mortality between groups (219 events per 1000 for both groups; RR 1.00, 95% CI 0.89 to 1.13; I² = 0%; Analysis 1.1). Certainty of the evidence was moderate.

1.1 — Comparison 1: Warfarin versus aspirin for people with heart failure in sinus rhythm, Outcome 1: All‐cause mortality

Non‐fatal cardiovascular events

Four trials, with a total of 3663 participants, reported non‐fatal cardiovascular events (such as non‐fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism) (HELAS 2006; WARCEF 2012; WASH 2004; WATCH 2009). Warfarin probably results in a reduction in non‐fatal cardiovascular events (66 per 1000 for warfarin, 83 per 1000 for aspirin; RR 0.79, 95% CI 0.63 to 1.00; I² = 0%; Analysis 1.2). Certainty of the evidence was moderate.

1.2 — Comparison 1: Warfarin versus aspirin for people with heart failure in sinus rhythm, Outcome 2: Non‐fatal cardiovascular events (non‐fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism)

Major bleeding events

Four trials, with a total of 3663 participants, reported rates of major bleeding events (HELAS 2006; WARCEF 2012; WASH 2004; WATCH 2009). Warfarin use probably results in a two‐fold increase in the risk of major bleeding compared to aspirin (56 per 1000 for warfarin, 28 per 1000 for aspirin; RR 2.00, 95% CI 1.44 to 2.78; I² = 4%; Analysis 1.3). Certainty of the evidence was moderate.

1.3 — Comparison 1: Warfarin versus aspirin for people with heart failure in sinus rhythm, Outcome 3: Major bleeding events

2. Warfarin versus clopidogrel

All‐cause mortality

Only one trial (with 1064 participants) reported on all‐cause mortality (WATCH 2009). The evidence suggests that there is little to no difference between groups (RR 0.93, 95% CI 0.72 to 1.21; low‐certainty evidence; Analysis 2.1).

2.1 — Comparison 2: Warfarin versus clopidogrel for people with heart failure in sinus rhythm, Outcome 1: All‐cause mortality

Non‐fatal cardiovascular events

Only one trial (with 1064 participants) reported on non‐fatal cardiovascular events (WATCH 2009). The evidence suggests that there is little to no difference between groups and participants treated with warfarin or clopidogrel were at similar risk (46 per 1000 for warfarin, 54 per 1000 for aspirin; RR 0.85, 95% CI 0.50 to 1.45; Analysis 2.2). Certainty of the evidence was low.

2.2 — Comparison 2: Warfarin versus clopidogrel for people with heart failure in sinus rhythm, Outcome 2: Non‐fatal cardiovascular events (non‐fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism)

Major bleeding events

WATCH 2009 (with 1064 participants) reported major bleeding events. Warfarin may increase the rate of major bleeding events (49 per 1000 for warfarin, 20 per 1000 for aspirin; RR 2.47, 95% CI 1.24 to 4.91; Analysis 2.3). Certainty of the evidence was low.

2.3 — Comparison 2: Warfarin versus clopidogrel for people with heart failure in sinus rhythm, Outcome 3: Major bleeding events

3. Other comparisons

No data were found for any other comparisons of interest.

Discussion

Summary of main results

The analysis of warfarin versus aspirin was based on four RCTs with 3663 participants. More than half of the participants were from the well‐designed, double‐blind WARCEF 2012 trial. Despite some limitations of other studies (e.g. open‐label treatment with warfarin in two trials), the analysis showed low heterogeneity in the outcomes, and we judged the certainty of the evidence to be moderate for all‐cause mortality, non‐fatal cardiovascular events and major bleeding events. Despite the availability of different OAC and antiplatelet agents, the main analysis is limited to the long‐established agents, warfarin and aspirin. The analysis did not provide evidence that either was better for all‐cause mortality.

The risk of non‐fatal cardiovascular events tended to be lower in the warfarin group, but this was offset by the two‐fold rise in the risk of major haemorrhage. The reduction in non‐fatal cardiovascular events is likely due to undiagnosed/silent atrial fibrillation and deep vein thrombosis in some participants.

Comparison of warfarin with clopidogrel was limited to a single trial with open‐label warfarin management (WATCH 2009). Slow recruitment restricted the statistical power, and as a result the trial was stopped early. The quality of the evidence for these analyses was low. However, the outcomes of these analyses were broadly similar to those of warfarin versus aspirin, with results that did not favour either drug for the primary outcome, but with 2.5 times higher major bleeding rates in the warfarin arm of the study.

The updated search did not identify post hoc analysis of data from the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) trial (Merkler 2021). The authors assessed whether anticoagulation is superior to aspirin in reducing recurrent stroke in people with embolic stroke of undetermined source and left ventricle dysfunction. The above‐mentioned study did not evaluate heart failure status, but was based on changes in LVEF and regional wall motion abnormalities. Rivaroxaban may reduce the risk of recurrent stroke or systemic embolism among NAVIGATE ESUS participants with left ventricle dysfunction when compared to individuals medicated with aspirin.

There have been no new completed or ongoing studies identified during the review update. The authors of this review update feel that the evidence base is stable enough to formally declare the review as stable.

Overall completeness and applicability of evidence

Non‐vitamin K antagonist oral anticoagulants (e.g. direct thrombin inhibitor, dabigatran, and factor Xa inhibitors, apixaban, edoxaban and rivaroxaban) have now been approved for clinical use by people with atrial fibrillation and venous thromboembolism. These agents show good efficacy and a favourable safety profile and may become a suitable alternative to warfarin to be tested in future trials in heart failure in sinus rhythm. No such data are available at present. The COMMANDER HF trial compares rivaroxaban versus placebo in participants with heart failure of ischaemic aetiology in sinus rhythm. The non‐vitamin K antagonist oral anticoagulants are used as fixed‐dose agents as opposed to warfarin, and this would facilitate easier concealment of the study treatments.

Given the fact that all four included RCTs focused on heart failure with reduced ejection fraction, it is not possible to extrapolate their conclusions to patients with heart failure with preserved ejection fraction. Admittedly, the specific prothrombotic risk in heart failure with preserved ejection fraction and sinus rhythm has not been firmly established, and further research would be essential in this field.

Certainty of the evidence

The four studies were RCTs, but there were some limitations in the certainty of the evidence.

For warfarin versus aspirin, we downgraded all‐cause mortality by one level for imprecision as the 95% confidence interval crossed the line of no effect. We also downgraded non‐fatal cardiovascular events and major bleeding events by one level for imprecision due to low event rates.

For warfarin versus clopidogrel, we downgraded all‐cause mortality, non‐fatal cardiovascular events, and major bleeding events by two levels for imprecision. The 95% confidence intervals crossed the line of no effect and the outcomes had low event rates.

Potential biases in the review process

The process of updating this review was done independently by two authors (MK‐S and ES). Potential bias in the review process might be related to the selection of outcomes. Moreover, cross‐over rates in the studies seem to be undesirable when evaluating therapeutic agents.

The review authors decided to exclude multi‐arm trials and studies with durations of less than one month. Multi‐arm trials may have many forms, often a combination of elements, including multiple active interventions, their combinations, different doses/regimens, different control group strategies, etc. They can be combined in different ways, resulting in numerous possible trial structures that may benefit finding a niche use of a drug, but deviate from finding a clear answer to a drug class effect, as in this review. Given the bias that this may introduce to data analysis, we decided to exclude multi‐arm studies from this review.

A short follow‐up period may lead to bias in outcome assessment as the review focusses on a chronic condition and longer‐term outcomes. Short‐term outcomes are unlikely to allow sufficient sensitivity to the treatment effects, so we excluded these from the review.

Agreements and disagreements with other studies or reviews

The current available evidence does not support the routine use of antiplatelet agents or OAC in people with heart failure and sinus rhythm.

Ntaios 2019 evaluated the effect of OAC versus antiplatelet or placebo for stroke prevention in people with heart failure and sinus rhythm. Ntaios 2019 included five studies (COMMANDER HF trial; HELAS 2006; WARCEF 2012; WASH 2004; WATCH 2009). They found that OAC is associated with a considerable reduction of stroke risk, which is offset by an increase in major bleeding risk. For every 1000 patients medicated with OAC rather than antiplatelet or no antithrombotic treatment for 2.21 years, 13 strokes are prevented, but 20 additional major haemorrhages occur, without any difference in death rates.

Authors' conclusions

Implications for practice.

There is moderate‐certainty evidence that there is probably no difference in all‐cause mortality between warfarin and aspirin in people with heart failure in sinus rhythm. Warfarin is probably associated with a slightly lower risk of non‐fatal cardiovascular events but a higher risk of major bleeding complications (moderate‐certainty evidence). We saw a similar pattern of results for the warfarin versus clopidogrel comparison (low‐certainty evidence). At the time of writing, there were no data on the role of oral anticoagulants versus antiplatelet agents in heart failure with preserved ejection fraction in sinus rhythm. Likewise, there were no data from randomised controlled trials on the utility of non‐vitamin K oral anticoagulants compared to antiplatelet agents in heart failure in sinus rhythm.

Implications for research.

Current evidence is based on four randomised controlled trials (HELAS 2006; WASH 2004; WATCH 2009, WARCEF 2012), and further similar studies are unlikely to change the conclusions regarding comparisons of warfarin with aspirin. Although the comparison of warfarin with clopidogrel is only based on a single, medium‐sized study, it generally agrees with the conclusions of the aspirin studies, and new studies are unlikely to lead to new clinically relevant conclusions.

Several non‐vitamin K antagonist oral anticoagulants have now been approved for clinical practice. They show good efficacy and a favourable safety profile in other clinical settings, including heart failure with atrial fibrillation. Future trials should establish the potential utility of these agents in patients with heart failure in sinus rhythm.

The role of antithrombotic agents in heart failure with preserved ejection fraction remains unclear. It would be important to obtain contemporary data on thrombotic risk specific to this condition and, if the risk is confirmed, high‐quality randomised controlled trials would be necessary to establish optimal management of people with heart failure with preserved ejection fraction.

Feedback

Cochrane Editorial Unit's report on feedback on anticoagulants reviews, 15 February 2011

Summary

Feedback received on this review, and other reviews and protocols on anticoagulants, is available on the Cochrane Editorial Unit website at www.editorial-unit.cochrane.org/anticoagulants-feedback.

Reply

Contributors

What's new

Date	Event	Description
11 June 2025	New search has been performed	Updated search, through April 3, 2025.
11 June 2025	New citation required but conclusions have not changed	No new studies identified and thus conclusions remain unchanged.

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History

Protocol first published: Issue 2, 2000 Review first published: Issue 4, 2001

Date	Event	Description
2 March 2020	Amended	Clarification message from the Co‐ordinating Editor added to the Declarations of interest Declarations of interest statement about the review’s compliance with the Cochrane conflict of interest policy, which includes the relevant parts of the Cochrane Commercial Sponsorship Policy.
3 May 2016	Amended	Cochrane Heart withdrew this review as the current author team is unable to progress to the final stage of the review update.
15 February 2011	Feedback has been incorporated	Added a link to the Cochrane Editorial Unit's report on feedback on anticoagulants reviews.
15 February 2011	New search has been performed	New author added. An updated search has been performed up until 11 February 2010 with the addition of two new studies to the previous review. However, the overall conclusion of the review remains unchanged.
11 February 2010	Amended	Error in dates: 'assessed as up‐to‐date' and 'date of search' from the RevMan conversion has been corrected.
22 May 2009	Amended	Author details error due to RevMan conversion has been corrected.
8 September 2008	Amended	Converted to new review format.
5 December 1999	New citation required and conclusions have changed	Substantive amendment

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Acknowledgements

We would like to acknowledge those who contributed to the current version of the review.

Cochrane Heart supported the authors in the development of this review update prior to its closure in March 2023. The following people conducted the editorial process for this update.

Sign‐off Editor (final editorial decision): Michael Brown, Michigan State University
Managing Editor (selected peer reviewers, collated peer‐reviewer comments, provided editorial comments/guidance to authors, edited the article): Joey Kwong and Jessica Thomas, Cochrane Central Editorial Service
Editorial Assistant (conducted editorial policy checks, collated peer‐reviewer comments, supported editorial team): Lisa Wydrzynski, Cochrane Central Editorial Service
Copy Editor (copy‐editing and production): Andrea Takeda, Cochrane Central Production Service
Peer‐reviewers (provided comments and recommended an editorial decision): James E Siegler, University of Chicago (clinical/content review); Jessica D'Urbano (consumer review); Nuala Livingstone, Cochrane Evidence Production & Methods Directorate (methods review); Jo Platt, Cochrane Evidence Production & Methods Directorate (search review)

Appendices

Appendix 1. Search strategies 2005

CENTRAL

1 HEART‐FAILURE‐CONGESTIVE*:ME 2 (CARDIAC near FAILURE) 3 (HEART near FAILURE) 4 ((#1 or #2) or #3) 5 ANTICOAGULANTS*:ME 6 ANTICOAGULANT* 7 ANTI‐COAGULANT* 8 ANTITHROMBINS*:ME 9 ANTITHROMB* 10 ANTI‐THROM* 11 COUMARINS*:ME 12 COUMARIN* 13 WARFARIN 14 WARFARIN*:ME 15 DICOUMAROL 15 (#5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15) 16 (#4 and #15)

MEDLINE

1 exp Heart Failure, Congestive/ 2 heart failure.tw. 3 cardiac failure.tw. 4 or/1‐3 5 exp ANTICOAGULANTS/ 6 exp Coumarins/ 7 warfarin.tw. 8 dicoumarol.tw. 9 coumarin$.tw. 10 or/5‐9 11 4 and 10 12 exp Platelet Aggregation Inhibitors/ 13 antiplatelet$.tw. 14 anti‐platelet$.tw. 15 ticlopidine.tw. 16 clopidogrel.tw. 17 dipyridamole.tw. 18 or/12‐17 19 18 and 4 20 11 or 19 21 randomized controlled trial.pt. 22 controlled clinical trial.pt. 23 Randomized controlled trials/ 24 random allocation.sh. 25 double blind method.sh. 26 single‐blind method.sh. 27 or/21‐26 28 (animal not human).sh. 29 27 not 28 30 clinical trial.pt. 31 exp Clinical trials/ 32 (clin$ adj25 trial$).ti,ab. 33 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ti,ab. 34 placebos.sh. 35 placebo$.ti,ab. 36 random$.ti,ab. 37 research design.sh. 38 or/30‐37 39 38 not 28 40 39 not 29 41 comparative study.sh. 42 exp evaluation studies/ 43 follow up studies.sh. 44 prospective studies.sh. 45 (control$ or prospectiv$ or volunteer$).ti,ab. 46 or/41‐45 47 46 not 28 48 47 not (29 or 40) 49 29 or 40 or 48 50 20 and 49

Embase

1 exp Heart Failure/ 2 heart failure.tw. 3 cardiac failure.tw. 4 or/1‐3 5 Anticoagulant Agent/ 6 exp Coumarin Anticoagulant/ 7 warfarin.tw. 8 dicoumarol.tw. 9 coumarin$.tw. 10 or/5‐9 11 4 and 10 12 exp Antithrombocytic Agent/ 13 antiplatelet$.tw. 14 anti‐platelet$.tw. 15 ticlopidine.tw. 16 clopidogrel.tw. 17 dipyridamole.tw. 18 or/12‐17 19 18 and 4 20 11 or 19 21 random$.ti,ab. 22 factorial$.ti,ab. 23 (crossover$ or cross over$ or cross‐over$).ti,ab. 24 placebo$.ti,ab. 25 (double$ adj blind$).ti,ab. 26 (singl$ adj blind$).ti,ab. 27 assign$.ti,ab. 28 allocat$.ti,ab. 29 volunteer$.ti,ab. 30 Crossover Procedure/ 31 Double Blind Procedure/ 32 Randomized Controlled Trial/ 33 Single Blind Procedure/ 34 or/21‐33 35 exp animal/ 36 nonhuman/ 37 exp animal experiment/ 38 or/35‐37 39 exp human/ 40 38 not 39 41 34 not 40 42 20 and 41

Appendix 2. Search strategies 2010

CENTRAL and DARE (the Cochrane Library)

#1 MeSH descriptor heart failure explode all trees #2 heart next failure in All Text #3 cardiac next failure in All Text #4 (#1 or #2 or #3) #5 MeSH descriptor anticoagulants this term only #6 MeSH descriptor coumarins this term only #7 MeSH descriptor 4‐Hydroxycoumarins explode all trees #8 warfarin in All Text #9 dicoumarol in All Text #10 dicumarol in All Text #11 coumarin* in All Text #12 anticoagulant* in All Text #13 anti‐coagulant* in All Text #14 (#5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13) #15 MeSH descriptor platelet aggregation inhibitors explode all trees #16 antiplatelet* in All Text #17 anti‐platelet* in All Text #18 aspirin in All Text #19 ticlopidine in All Text #20 clopidogrel in All Text #21 dipyridamole in All Text #22 antithrombocytic in All Text #23 "acetyl salicylic acid" in All Text #24 acetylsalicylic in All Text #25 (#15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24) #26 (#14 or #25) #27 (#4 and #26)

MEDLINE Ovid

1 exp Heart Failure/ 2 heart failure.tw. 3 cardiac failure.tw. 4 or/1‐3 5 Anticoagulants/ 6 Coumarins/ 7 exp 4‐Hydroxycoumarins/ 8 warfarin.tw. 9 dicoumarol.tw. 10 dicumarol.tw. 11 coumarin$.tw. 12 or/5‐11 13 exp Platelet Aggregation Inhibitors/ 14 antiplatelet$.tw. 15 anti‐platelet$.tw. 16 aspirin.tw. 17 ticlopidine.tw. 18 clopidogrel.tw. 19 dipyridamole.tw. 20 or/13‐19 21 4 and (12 or 20) 22 randomized controlled trial.pt. 23 controlled clinical trial.pt. 24 randomized.ab. 25 placebo.ab. 26 exp Clinical Trials as Topic/ 27 randomly.ab. 28 trial.ti. 29 or/22‐28 30 exp animal/ not humans/ 31 29 not 30 32 21 and 31

Embase Ovid

1 exp Heart Failure/ 2 heart failure.tw. 3 cardiac failure.tw. 4 or/1‐3 5 anticoagulant agent/ 6 exp coumarin anticoagulant/ 7 warfarin.tw. 8 dicoumarol.tw. 9 dicumarol.tw. 10 coumarin$.tw. 11 or/5‐10 12 exp antithrombocytic agent/ 13 antiplatelet$.tw. 14 anti‐platelet$.tw. 15 aspirin.tw. 16 ticlopidine.tw. 17 clopidogrel.tw. 18 dipyridamole.tw. 19 or/12‐18 20 4 and (11 or 19) 21 random$.tw. 22 factorial$.tw. 23 (crossover$ or cross‐over$).tw. 24 placebo$.tw. 25 (doubl$ adj blind$).tw. 26 (singl$ adj blind$).tw. 27 assign$.tw. 28 allocat$.tw. 29 volunteer$.tw. 30 Crossover Procedure/ 31 Double‐blind Procedure/ 32 Randomized Controlled Trial/ 33 Single‐blind Procedure/ 34 or/21‐33 35 (animal/ or nonhuman/) not human/ 36 34 not 35 37 20 and 36

Appendix 3. Search strategies 2013

CENTRAL

#1MeSH descriptor: [Heart Failure] explode all trees #2heart near/2 failure* #3cardiac near/2 failure* #4myocardial near/2 failure* #5heart near/2 decompensat* #6#1 or #2 or #3 or #4 or #5 #7MeSH descriptor: [Anticoagulants] this term only #8MeSH descriptor: [Coumarins] this term only #9MeSH descriptor: [4‐Hydroxycoumarins] explode all trees #10warfarin #11dicoumarol #12dicumarol #13coumarin* #14anticoagulant* or anti‐coagulant* #15indirect next thrombin next inhibitor* #16benzopyron* or benzopyran* #17#7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 #18MeSH descriptor: [Platelet Aggregation Inhibitors] explode all trees #19antiplatelet* or anti‐platelet* #20antithrombocytic or "acetyl salicylic acid" or acetylsalicylic #21aspirin #22ticlopidine #23clopidogrel #24dipyridamole #25platelet near/2 (antagonist* or inhibit* or antiaggregant*) #26#18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 #27#17 or #26 #28#6 and #27

MEDLINE Ovid

1. exp Heart Failure/ 2. (heart adj2 failure*).tw. 3. (cardiac adj2 failure*).tw. 4. (myocardial adj2 failure*).tw. 5. (heart adj2 decompensat*).tw. 6. heart failure.tw. 7. cardiac failure.tw. 8. 1 or 6 or 7 9. 1 or 2 or 3 or 4 or 5 10. Anticoagulants/ 11. Coumarins/ 12. exp 4‐Hydroxycoumarins/ 13. warfarin.tw. 14. dicoumarol.tw. 15. dicumarol.tw. 16. coumarin$.tw. 17. anticoagulant*.tw. 18. indirect thrombin inhibitor*.tw. 19. benzopyr?n*.tw. 20. 10 or 11 or 12 or 13 or 14 or 15 or 16 21. 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 22. exp Platelet Aggregation Inhibitors/ 23. antiplatelet$.tw. 24. anti‐platelet$.tw. 25. aspirin.tw. 26. ticlopidine.tw. 27. clopidogrel.tw. 28. dipyridamole.tw. 29. (platelet adj2 (antagonist* or inhibit* or antiaggregant*)).tw. 30. 22 or 23 or 24 or 25 or 26 or 27 or 28 31. 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 32. 20 or 30 33. 21 or 31 34. 8 and 32 35. 9 and 33 36. randomized controlled trial.pt. 37. controlled clinical trial.pt. 38. randomized.ab. 39. placebo.ab. 40. drug therapy.fs. 41. randomly.ab. 42. trial.ab. 43. groups.ab. 44. 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 45. exp animals/ not humans.sh. 46. 44 not 45 47. 34 and 46 48. 35 and 46 49. ((2010* or 2011* or 2012* or 2013*) not 201001*).ed. 50. 47 and 49 51. 48 not 47 52. 50 or 51

Embase Ovid

1. exp heart failure/ 2. heart failure.tw. 3. cardiac failure.tw. 4. (heart adj2 failure*).tw. 5. (cardiac adj2 failure*).tw. 6. (myocardial adj2 failure*).tw. 7. (heart adj2 decompensat*).tw. 8. 1 or 2 or 3 9. 1 or 4 or 5 or 6 or 7 10. anticoagulant agent/ 11. exp coumarin anticoagulant/ 12. warfarin.tw. 13. dicoumarol.tw. 14. dicumarol.tw. 15. coumarin$.tw. 16. anticoagulant*.tw. 17. indirect thrombin inhibitor*.tw. 18. benzopyr?n*.tw. 19. 10 or 11 or 12 or 13 or 14 or 15 20. 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 21. exp antithrombocytic agent/ 22. antiplatelet$.tw. 23. anti‐platelet$.tw. 24. aspirin.tw. 25. ticlopidine.tw. 26. clopidogrel.tw. 27. dipyridamole.tw. 28. (platelet adj2 (antagonist* or inhibit* or antiaggregant*)).tw. 29. 21 or 22 or 23 or 24 or 25 or 26 or 27 30. 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 31. 19 or 29 32. 20 or 30 33. 8 and 31 34. 9 and 32 35. random$.tw. 36. factorial$.tw. 37. crossover$.tw. 38. cross over$.tw. 39. cross‐over$.tw. 40. placebo$.tw. 41. (doubl$ adj blind$).tw. 42. (singl$ adj blind$).tw. 43. assign$.tw. 44. allocat$.tw. 45. volunteer$.tw. 46. crossover procedure/ 47. double blind procedure/ 48. randomized controlled trial/ 49. single blind procedure/ 50. 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 51. (animal/ or nonhuman/) not human/ 52. 50 not 51 53. 33 and 52 54. 34 and 52 55. ((2010* or 2011* or 2012* or 2013*) not 201001*).dd. 56. 53 and 55 57. 54 not 53 58. 56 or 57

Appendix 4. Search strategies 2015

CENTRAL

MEDLINE Ovid

1. exp Heart Failure/ 2. (heart adj2 failure*).tw. 3. (cardiac adj2 failure*).tw. 4. (myocardial adj2 failure*).tw. 5. (heart adj2 decompensat*).tw. 6. heart failure.tw. 7. cardiac failure.tw. 8. 1 or 6 or 7 9. 1 or 2 or 3 or 4 or 5 10. Anticoagulants/ 11. Coumarins/ 12. exp 4‐Hydroxycoumarins/ 13. warfarin.tw. 14. dicoumarol.tw. 15. dicumarol.tw. 16. coumarin$.tw. 17. anticoagulant*.tw. 18. indirect thrombin inhibitor*.tw. 19. benzopyr?n*.tw. 20. 10 or 11 or 12 or 13 or 14 or 15 or 16 21. 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 22. exp Platelet Aggregation Inhibitors/ 23. antiplatelet$.tw. 24. anti‐platelet$.tw. 25. aspirin.tw. 26. ticlopidine.tw. 27. clopidogrel.tw. 28. dipyridamole.tw. 29. (platelet adj2 (antagonist* or inhibit* or antiaggregant*)).tw. 30. 22 or 23 or 24 or 25 or 26 or 27 or 28 31. 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 32. 20 or 30 33. 21 or 31 34. 8 and 32 35. 9 and 33 36. randomized controlled trial.pt. 37. controlled clinical trial.pt. 38. randomized.ab. 39. placebo.ab. 40. drug therapy.fs. 41. randomly.ab. 42. trial.ab. 43. groups.ab. 44. 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 45. exp animals/ not humans.sh. 46. 44 not 45 47. 34 and 46 48. 35 and 46 49. ((2010* or 2011* or 2012* or 2013* or 2014* or 2015*) not 201001*).ed. 50. 47 and 49 51. 48 not 47 52. 50 or 51

Embase Ovid

ClinicalTrials.gov (www.ClinicalTrials.gov)

(searched on 29 July 2016)

Key words:

heart failure AND warfarin (24 entries)

heart failure AND dabigatran (5 entries)

heart failure AND apixaban (4 entries)

heart failure AND edoxaban (1 entry)

heart failure AND rivaroxaban (9 entries)

cardiac failure AND warfarin (24 entries)

cardiac failure AND dabigatran (5 entries)

cardiac failure AND apixaban (4 entries)

cardiac failure AND edoxaban (1 entry)

cardiac failure AND rivaroxaban (9 entries)

The World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal (apps.who.int/trialsearch/)

(searched on 29 July 2016)

Key words

heart failure AND warfarin (4 entries)

heart failure AND dabigatran (1 entry)

heart failure AND apixaban (0 entries)

heart failure AND edoxaban (1 entry)

heart failure AND rivaroxaban (3 entries)

cardiac failure AND warfarin (4 entries)

cardiac failure AND dabigatran (1 entry)

cardiac failure AND apixaban (0 entries)

cardiac failure AND edoxaban (1 entry)

cardiac failure AND rivaroxaban (3 entries)

Appendix 5. Search strategies 2025

Source	Search strategy
1. CENTRAL	#1 MeSH descriptor: [Heart Failure] explode all trees 14728 #2 heart near/2 failure* 40503 #3 cardiac near/2 failure* 2993 #4 myocardial near/2 failure* 1263 #5 heart near/2 decompensat* 1488 #6 {OR #1‐#5} 41519 #7 MeSH descriptor: [Anticoagulants] this term only 6289 #8 MeSH descriptor: [Coumarins] this term only 188 #9 MeSH descriptor: [4‐Hydroxycoumarins] explode all trees 2515 #10 warfarin 5704 #11 dicoumarol 53 #12 dicumarol 57 #13 coumarin* 430 #14 anticoagulant* or anti‐coagulant* 14303 #15 indirect next thrombin next inhibitor* 10 #16 benzopyron* or benzopyran* 362 #17 {OR #7‐#16} 17494 #18 MeSH descriptor: [Platelet Aggregation Inhibitors] explode all trees 5793 #19 antiplatelet* or anti‐platelet* 8754 #20 aspirin 17287 #21 ticlopidine 2719 #22 clopidogrel 6429 #23 dipyridamole 1453 #24 platelet near/2 (antagonist* or inhibit* or antiaggregant*) 8041 #25 {OR #18‐#24} 27465 #26 #6 and #17 and #25 390 Date added to CENTRAL trials database 1 September 2015 to 4 April 2025
2. Medline	1 exp Heart Failure/ (159164)  2 (heart adj2 failure).tw. (232965)  3 (cardiac adj2 failure).tw. (17390)  4 (myocardial adj2 failure).tw. (4132)  5 (heart adj2 decompensat).tw. (5982)  6 or/1‐5 (287145)  7 Anticoagulants/ (93494)  8 Coumarins/ (16282)  9 exp 4‐Hydroxycoumarins/ (27115)  10 warfarin.tw. (28331)  11 dicoumarol.tw. (726)  12 dicumarol.tw. (1050)  13 coumarin.tw. (17689)  14 anticoagulant.tw. (79860)  15 indirect thrombin inhibitor.tw. (43)  16 benzopyr?n.tw. (3545)  17 or/7‐16 (176369)  18 exp Platelet Aggregation Inhibitors/ (140845)  19 antiplatelet.tw. (37025)  20 anti‐platelet.tw. (5548)  21 aspirin.tw. (57097)  22 ticlopidine.tw. (2564)  23 clopidogrel.tw. (15263)  24 dipyridamole.tw. (8202)  25 (platelet adj2 (antagonist* or inhibit* or antiaggregant*)).tw. (18105)  26 or/18‐25 (193892)  27 6 and 17 and 26 (1184)  28 exp randomized controlled trial/ (636888)  29 controlled clinical trial.pt. (95687)  30 randomized.ab. (685529)  31 placebo.ab. (257200)  32 drug therapy.fs. (2797641)  33 randomly.ab. (456507)  34 trial.ab. (745546)  35 groups.ab. (2830278)  36 or/28‐35 (6248068)  37 exp animals/ not humans.sh. (5324046)  38 36 not 37 (5475162)  39 27 and 38 (730)  40 limit 39 to ed=20150901‐20250404 (272)
3. Embase	1 exp heart failure/ (724342)  2 (heart adj2 failure).tw. (393693)  3 (cardiac adj2 failure).tw. (26539)  4 (myocardial adj2 failure).tw. (6243)  5 (heart adj2 decompensat).tw. (12393)  6 or/1‐5 (790683)  7 anticoagulant agent/ (150668)  8 coumarin derivative/ (16679)  9 exp 4 hydroxycoumarin derivative/ (555)  10 warfarin.tw. (48197)  11 dicoumarol.tw. (681)  12 dicumarol.tw. (537)  13 coumarin.tw. (21902)  14 anticoagulant.tw. (121943)  15 indirect thrombin inhibitor.tw. (54)  16 benzopyr?n.tw. (4476)  17 or/7‐16 (270748)  18 exp antithrombocytic agent/ (437637)  19 antiplatelet.tw. (62562)  20 anti‐platelet.tw. (11255)  21 aspirin.tw. (133471)  22 ticlopidine.tw. (3453)  23 clopidogrel.tw. (29103)  24 dipyridamole.tw. (10601)  25 (platelet adj2 (antagonist* or inhibit* or antiaggregant*)).tw. (24901)  26 or/18‐25 (479636)  27 6 and 17 and 26 (9132)  28 random$.tw. (2189322)  29 factorial$.tw. (51680)  30 crossover$.tw. (97782)  31 cross over$.tw. (39971)  32 cross‐over$.tw. (39971)  33 placebo$.tw. (393144)  34 (doubl$ adj blind$).tw. (260654)  35 (singl$ adj blind$).tw. (35130)  36 assign$.tw. (538699)  37 allocat$.tw. (228031)  38 volunteer$.tw. (310726)  39 crossover procedure/ (81831)  40 double blind procedure/ (230495)  41 randomized controlled trial/ (874848)  42 single blind procedure/ (58790)  43 or/28‐42 (3207450)  44 (animal/ or nonhuman/) not human/ (6888689)  45 43 not 44 (2856845)  46 27 and 45 (1426)  47 limit 46 to dd=20150901‐20250404 (735)  48 limit 46 to rd=20150901‐20250404 (263)  49 47 or 48 (744)
4. ClinicalTrials.gov	Heart Failure \| Antiplatelet Agents \| Interventional studies \| First posted from 9 January2015 to 4 April2025 Heart Failure \| Anticoagulation Agents \| Interventional studies \| First posted from 9 January 2015 to 4 April 2025
5. WHO ICTRP	Advanced search Condition: Heart Failure Intervention: Antiplatelet (with synonyms) Recruitment status: All Date of registration is between: 9 January 2015 and 4 April 2025 Condition: Heart Failure Intervention: Anticoagulant (with synonyms) Recruitment status: All Date of registration is between: 9 January 2015 and 4 April 2025

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Data and analyses

Comparison 1. Warfarin versus aspirin for people with heart failure in sinus rhythm.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 All‐cause mortality	4	3663	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.89, 1.13]
1.2 Non‐fatal cardiovascular events (non‐fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism)	4	3663	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.63, 1.00]
1.3 Major bleeding events	4	3663	Risk Ratio (M‐H, Fixed, 95% CI)	2.00 [1.44, 2.78]

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Comparison 2. Warfarin versus clopidogrel for people with heart failure in sinus rhythm.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 All‐cause mortality	1	1064	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.72, 1.21]
2.2 Non‐fatal cardiovascular events (non‐fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism)	1	1064	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.50, 1.45]
2.3 Major bleeding events	1	1064	Risk Ratio (M‐H, Fixed, 95% CI)	2.47 [1.24, 4.91]

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

HELAS 2006.

*Study characteristics*
Methods	Randomised controlled trial Multicentre trial: centres in Greece, Cyprus, Yugoslavia, Romania, Bulgaria, Poland and Georgia Setting: outpatient clinics Period of trial: between January 1998 and August 1999
Participants	Heart failure, sinus rhythm Entire cohort was 197 participants, of whom 115 had ischaemic aetiology of heart failure and were randomised to warfarin or aspirin. These 115 participants were included in the present analysis (aspirin group: n = 61, age 61.0 ± 8.9 years, 93% men; warfarin group: n = 54, age 62.3 ± 9.7 years, 85% men). The remaining 82 participants had dilated cardiomyopathy and they were randomised to warfarin vs placebo (not included in this review). Among the 61 participants in the aspirin group, 1 developed atrial fibrillation and was withdrawn and excluded from the final analysis. Inclusion criteria Aged 20–75 years Symptomatic heart failure (NYHA class II–IV) LVEF < 35% by echocardiographically by the area–length method or Simpson's rule, or by radionuclide or angiocardiographic ventriculography Ischaemic heart disease established as previous myocardial infarction (> 2 months from date of enrolment) or by coronary arteriography, to be eligible for warfarin vs aspirin randomisation and analysis Exclusion criteria: Evidence of reversible ischaemia Mitral valvular disease Hypertrophic cardiomyopathy Atrial fibrillation Left ventricular thrombi on echocardiography Other severe life‐threatening diseases that might limit survival or compliance with the 2‐year study period Contraindication to aspirin or warfarin Uncontrolled hypertension (> 160/100 mm Hg) Pregnancy
Interventions	Warfarin (target INR 2.0‐3.0) vs aspirin 325 mg once daily (ischaemic aetiology of heart failure); Warfarin vs placebo (idiopathic dilated cardiomyopathy) Only the warfarin vs aspirin trial arm was used in this review.
Outcomes	Primary outcome: composite of non‐fatal stroke, peripheral or pulmonary embolism, myocardial (re)infarction, re‐hospitalisation, exacerbation of heart failure, or death from any cause Safety endpoints: major haemorrhage
Follow‐up duration	Mean duration: 18.5 months in the aspirin group; 18.7 months in the warfarin group
Funding source	Not reported
Declarations of interest	Not reported
Notes	Planned as a definite trial to recruit 6000 participants but stopped early due to actual recruitment being < 5% of the target recruitment; reported as a pilot trial
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Computerised randomization was conducted by fax or by phone to the Athens University Coordinating Centre"
Allocation concealment (selection bias)	Low risk	"Computerised randomization was conducted by fax or by phone to the Athens University Coordinating Centre"
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants were included in the follow‐up analysis, and an independent data committee conducted interim analyses.
Selective reporting (reporting bias)	Low risk	Predefined primary and secondary outcomes were used.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	"The investigator–supervisor was blinded to the study in the same manner as in the CAFA study and regulated the study medication dose according to the prothrombin time results to maintain an INR of 2–3. The dose was then administered to the patient by a second physician. In the placebo arm, the supervisor recommended the dose according to sham results." and further, "Warfarin (Panwarfin, Abbot, Greece) was supplied as 5‐mg tablets. The daily dose was 2.5–10mg, with a target INR of 2–3. ASA (Salospir A, Uni‐Pharma, Greece) was supplied as 325‐mg tablets and was given once daily or according to sham adjustment." Comment: The study used sham medications to conceal the study drug, but it is not clear how robust the system was. The provided reference refers to a study not related to warfarin.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	"The occurrence of clinical endpoints [end‐points listed] was recorded."

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WARCEF 2012.

*Study characteristics*
Methods	Randomised double‐blind double‐dummy controlled trial Multicentre trial: 168 centres in 11 countries Setting: outpatient clinics Period of trial: recruitment between October 2002 and January 2010 with a minimum follow‐up of 1 year
Participants	Heart failure, sinus rhythm Randomised 2305: warfarin group n = 1142, mean age 61 ± 11.6 years, 79.3% men; aspirin group n = 1163, mean age 61 ± 11.1 years, 80.7% men. 34 participants (1.5%) withdrew consent, and 35 (1.5%) were lost to follow‐up. All 2305 randomised patiens were included in the analysis. Inclusion criteria Age ≥ 18 years Sinus rhythm No contraindication to warfarin therapy LVEF ≤ 35% by echocardiography (or a wall‐motion index of ≤ 1.2) or as assessed by radionuclide or contrast ventriculography within 3 months before randomisation. Participants in any NYHA functional class were eligible, but participants in NYHA class I could account for no more than 20% of the total number of participants undergoing randomisation. Additional eligibility criteria A modified Rankin score of ≤ 4 Planned treatment with a beta‐blocker, an angiotensin‐converting–enzyme inhibitor, or hydralazine and nitrates Exclusion criteria A clear indication for warfarin or aspirin A condition with a high risk of cardiac embolism (e.g. arterial fibrillation, a mechanical cardiac valve, endocarditis, or an intracardiac mobile or pedunculated thrombus)
Interventions	Warfarin (target INR 2.0‐3.5) vs aspirin 325 mg once daily
Outcomes	Primary outcome: composite of ischaemic stroke, intracerebral haemorrhage, or death from any cause. Secondary outcome: composite of the primary outcome, myocardial infarction or hospitalisation for heart failure
Follow‐up duration	Mean 3.5 ± 1.8 years
Funding source	Supported by grants (U01‐NS‐043975 (to Dr Homma) and U01‐NS‐039143 (to Dr Thompson)) from the National Institute of Neurological Disorders and Stroke
Declarations of interest	Dr Homma reports receiving payment from AGA Medical (now St. Jude Medical) for his work as a member of a data and safety monitoring board and consulting fees from Boehringer Ingelheim; Dr Levin received consulting fees from United Healthcare; Dr Teerlink, received consulting fees from Amgen and grant support from Amgen, Cytokinetics, and Novartis on behalf of himself and from NovaCardia/Merck on behalf of himself and his institution; Dr. Graham, owning stock in March Pharmaceuticals, Medtronic, and Pfizer; Dr Labovitz received grant support from Boehringer Ingelheim on behalf of his institution, lecture fees from Boehringer Ingelheim, and fees for the development of educational presentations from the American College of Cardiology; Dr Anker received consulting fees from Amgen, Bosch Healthcare, GlaxoSmithKline, Helsinn, LoneStar Heart, Novartis, Professional Dietetics, PsiOxus, Relypsa, SHL Telemedicine, and Thermo Fisher, grant support from Vifor Pharma, and lecture fees from Novartis, holding patents with Brahms AG and Charit Berlin, and royalties from Imperial College; Dr Ponikowski received consulting fees from Bayer, Boehringer Ingelheim, Coridea, Corthera, Johnson & Johnson, Pfizer, Respicardia, and Vifor Pharma, grant support from Vifor Pharma on behalf of himself and his institution, and lecture fees from Abbott, Boehringer Ingelheim, Merck Serono, Pfizer, Respicardia, Sanofi‐Aventis, Servier, and Vifor Pharma; and Dr Lip received consulting fees from Astellas, AstraZeneca, Bayer, Biotronik, Boehringer Inhelheim, Bristol‐Myers Squibb, Pfizer, Merck, Portola, and Sanofi‐Aventis, speakers bureau fees from Bayer, Bristol‐Myers Squibb, Pfizer, Boehringer Ingelheim, and Sanofi‐Aventis, and payment for the development of educational presentations from Bayer, Boehringer Ingelheim, and Merck. Authors did not report any other potential conflict of interest relevant to this article.
Notes	—
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were (randomly) assigned to. . ."; the study protocol specifies that randomisation occurred centrally
Allocation concealment (selection bias)	Low risk	Quote: "Patients were (randomly) assigned to. . ."; the study protocol specifies that randomisation occurred centrally
Incomplete outcome data (attrition bias) All outcomes	Low risk	Survival status available for 97% of the participants
Selective reporting (reporting bias)	Low risk	Predefined primary and secondary outcomes were used.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"In the double‐blind, double‐dummy design, patients who were assigned to active warfarin received warfarin and placebo aspirin, and patients assigned to active aspirin received aspirin and placebo warfarin."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"An independent end‐point adjudication committee, whose members were unaware of the treatment assignments, adjudicated all primary and secondary outcomes and major hemorrhages."

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WASH 2004.

*Study characteristics*
Methods	Randomised open‐label controlled trial Multicentre trial: 17 centres in the UK and 3 centres in the USA. Setting: outpatient clinics Period of trial: recruitment between November 1995 and September 1998
Participants	Heart failure (sinus rhythm in 94% of the participants) Randomised 279 participants (180 participants eligible for this review, another 99 participants were randomised for no antithrombotic therapy): warfarin group n = 89, mean age 62 years, 76% men; aspirin group n = 91, mean age 65 years, 75% men Analysed: 180 participants randomised for warfarin vs. aspirin Inclusion criteria Clinical diagnosis of heart failure requiring treatment with diuretics Left ventricular systolic dysfunction on echocardiography performed within the 6 months prior to entry: end‐diastolic internal dimension (≥ 56 mm or ≥30 mm/m² body surface area) plus a fractional shortening of ≤ 28% or ejection fraction ≤ 35%. Exclusion criteria Definite indication for or contraindication to aspirin and warfarin (included mitral stenosis or mechanical valve prosthesis, increased risk of haemorrhage due to defects in haemostasis, deranged liver function, active peptic ulcer, and vascular malformation) Uncontrolled hypertension Evidence of poor drug compliance Alcohol abuse History of frequent falls
Interventions	Warfarin (target INR 2.0‐3.0) vs aspirin (300 mg once daily) vs no antithrombotic therapy Only the warfarin vs aspirin arm was used in this review.
Outcomes	Primary outcome: composite of all‐cause death, non‐fatal myocardial infarction and non‐fatal stroke Secondary outcomes: death or cardiovascular hospitalisation (including worsening heart failure, myocardial infarction, stroke, other thromboembolic events, and major haemorrhage); death or all‐cause hospitalisation, total number of hospitalisations; the composite of death, cardiovascular hospitalisation, and increase in diuretic therapy for worsening heart failure
Follow‐up duration	Mean 27 ± 1 months (for all trial participants)
Funding source	Supported in part by the NHS R&D Cardiovascular Disease and Stroke Programme Executive and Bristol‐Myers Squibb, who manufacture warfarin in the USA
Declarations of interest	Not reported in the trial manuscript
Notes	Arterial fibrillation was not an absolute exclusion criterion, but 92% of participants had no history of it at the time of recruitment.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Data on patients recorded by telephone at data centre before randomisation using prospectively constructed blocks of random numbers"
Allocation concealment (selection bias)	Low risk	"Data on patients recorded by telephone at data centre before randomisation using prospectively constructed blocks of random numbers"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No information provided on the presence of incomplete outcome data
Selective reporting (reporting bias)	Low risk	Predefined primary and secondary outcomes were used.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label design
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinded endpoint design

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WATCH 2009.

*Study characteristics*
Methods	Randomised controlled trial Aspirin and clopidogrel given in a double‐blind, double‐dummy manner; open‐label warfarin Multicentre trial: 142 centres in the United States, Canada, and the United Kingdom Setting: outpatient clinics Period of trial: between October 1999 and June 2003
Participants	Heart failure, sinus rhythm Randomised 1587 participants: warfarin group n = 540, mean age 63 ± 11 years, 85% male; aspirin group n = 523, aged 63 ± 11 years, 85% men; clopidogrel group n = 524, aged 62 ± 11 years, 86% men. Loss to follow‐up in warfarin group n = 35; aspirin group n = 24; clopidogrel n = 30; Analysed: 1585 patiens: 1063 participants for the warfarin vs aspirin comparison and 1064 patiens for the warfarin vs clopidogrel comparison: Inclusion criteria Age ≥ 18 years Symptomatic heart failure (NYHA class II to IV) for > 3 months before entry LVEF ≤ 35% measured within 3 months by any standard technique Sinus rhythm Treated with a diuretic and an ACE inhibitor for ≥ 60 days (unless not tolerated) Principle exclusion criteria: Contraindications or specific indications for any of the study medications Imminent procedures necessitating withdrawal or use of the study medications Heart failure from correctable causes Serious comorbid conditions expected to limit life expectancy Other conditions that would interfere with protocol adherence
Interventions	Warfarin (target INR 2.5‐3.0) vs aspirin 162 mg once daily or clopidogrel 75 mg once daily
Outcomes	Primary outcome: composite of all‐cause death, non‐fatal myocardial infarction and non‐fatal stroke. Secondary outcomes: all‐cause mortality; non‐fatal myocardial infarction; non‐fatal stroke; hospitalisations for heart failure Primary safety outcome: major bleeding episodes
Follow‐up duration	Mean 1.9 years, median 21 months
Funding source	This trial was supported and administered by the Cooperative Studies Program of the Office of Research and Development, Department of Veterans Affairs. Study drugs and unrestricted grants were provided by Bristol Myers Squibb, Sanofi‐Synthelabo, and Dupont pharmaceutical companies.
Declarations of interest	Dr Massie received research grants from Bristol‐Myers Squibb and Sanofi‐Aventis. Dr Schulman received research grants from Bristol‐Myers Squibb, and Sanofi‐Aventis and does consulting for Sanofi‐Aventis. Dr Ezekowitz served as a consultant to Bristol‐Myers Squibb and Sanofi‐Aventis. The other authors of the reporting manuscript reported no conflicts of interest.
Notes	Terminated early due to slow recruitment, 4500 participants planned for randomisation, 1587 participants randomised.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The Cooperative Studies Program Coordinating Center generated a randomization sequence for each site separately using varying block sizes of 3 or 6. The site coordinator/site investigator called the Cooperative Studies Program Coordinating Center to obtain a randomization number and treatment allocation." Comment: Central randomisation
Allocation concealment (selection bias)	Low risk	"The Cooperative Studies Program Coordinating Center generated a randomization sequence for each site separately using varying block sizes of 3 or 6. The site coordinator/site investigator called the Cooperative Studies Program Coordinating Center to obtain a randomization number and treatment allocation." Comment: Central randomisation
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No information provided
Selective reporting (reporting bias)	Low risk	Predefined primary and secondary outcomes were used All results were reported, including negative results
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants assigned to aspirin or clopidogrel were blinded, although those receiving warfarin were unblinded, which may lead to some performance bias.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The endpoint committee reviewed outcomes and were blinded to the therapies.

Open in a new tab

ACE: angiotensin converting enzyme; CAFA: Canadian Atrial Fibrillation Anticoagulation [study]; INR: international normalised ratio; LVEF: left ventricular ejection fraction; NYHA: New York Heart Association.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Al‐Khadra 1998a	Post hoc retrospective, non‐randomised analysis of ACE inhibitor trial
ASAP‐HF 2013	This is a study of a dipyridamole plus aspirin vs placebo. Oral anticoagulants have not been tested in the study.
CACHE‐EHF 2014	Comparator not of interest (a study of two antiplatelet agents)
COMMANDER HF trial	Rivaroxaban was compared to placebo
Diener 2019	Group of patients with HF not identified.
EPICAL 2002	Retrospective, observational, non‐randomised study
Merkler 2021	Study did not evaluate HF status, but was based on changes in LVEF and regional wall motion abnormalities.
PROMISE 1993	Post hoc retrospective, non‐randomised analysis of inotrope trial
SAVE 1997	Post hoc retrospective, non‐randomised analysis of ACE inhibitor trial
SOLVD 1997	Post hoc retrospective, non‐randomised analysis of ACE inhibitor trial
V‐HeFT II 1992	Post hoc retrospective, non‐randomised analysis of ACE inhibitor trial

Open in a new tab

ACE: angiotensin‐converting enzyme; HF: heart failure; LVEF: left ventricular ejection fraction

Differences between protocol and review

An exclusion criterion was added for the 2024 review update. Studies with follow‐up of less than one month were excluded. A short follow‐up period may lead to bias in outcome assessment as the review focusses on a chronic condition and longer‐term outcomes. Short‐term outcomes are unlikely to allow sufficient sensitivity to the treatment effects.

Changes were made to subgroup analyses: subgroup analyses would be conducted for all endpoints where heterogeneity is considered of potential importance (I² > 40%), and subgroups will include the following.

Aetiology of heart failure:
1. ischaemic versus non‐ischaemic heart failure,
Concomitant clinical comorbidities:
1. participants with heart failure and diabetes mellitus versus participants with heart failure without diabetes mellitus.

The title of the 2024 review update was changed from ‘Antiplatelet versus anticoagulation treatment for patients with heart failure in sinus rhythm’ to ‘Antiplatelet versus anticoagulation treatment for people with heart failure in sinus rhythm’. This change was made to reflect Cochrane style preferences.

Contributions of authors

Prof GYH Lip: conceived the review; helped to interpret data and provided a methodological, policy and clinical perspective on the data; participated in writing the original review and the current update. For purposes of dual data collection, screened papers for inclusion or exclusion and extracted data from papers that were included. Co‐ordinated the review process. He is the guarantor of the review.

Dr M Kozieł‐Siołkowska and Dr E Shantsila: revised and updated the current version of the review. For purposes of dual data collection, screened papers for inclusion or exclusion and extracted data from papers that were included.

Dr A Shantsila screened papers for inclusion or exclusion.

Sources of support

Internal sources

None, Other

No internal source of support.

External sources

None, Other

No external sources of support

Declarations of interest

G Lip: BMS, Pfizer, Boehringer Ingelheim, Daiichi‐Sankyo, Anthos Therapeutics (consultant; fees not received personally); University of Liverpool (employment); works as Consultant Cardiologist at the Liverpool Heart and Chest Hospital; investigator of the AFFIRMO Project ‐ funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 899871.

M Koziel‐Siolkowska: none known.

A Shantsila: none known.

E Shantsila: none known.

New search for studies and content updated (no change to conclusions)

References

References to studies included in this review

HELAS 2006 {published data only}

Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK. Efficacy of antithrombotic therapy in chronic heart failure: The HELAS study. European Journal of Heart Failure 2006;8:428-2. [DOI] [PubMed] [Google Scholar]

WARCEF 2012 {published data only}

Homma S, Thompson JL, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. New England Journal of Medicine 2012;366:1859-69. [DOI] [PMC free article] [PubMed] [Google Scholar]

WASH 2004 {published data only}

Cleland JG, Findlay I, Jafri S et al. The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. American Heart Journal 2004;148:157-64. [DOI] [PubMed] [Google Scholar]

WATCH 2009 {published data only}

Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JGF, Ezekowitz M, et al. Randomized trial of warfarin, aspirin and clopidogrel in patients with chronic heart failure. The warfarin and antiplatelet therapy in chronic heart failure (WATCH) trial. Circulation 2009;119:1616-24. [DOI] [PubMed] [Google Scholar]

References to studies excluded from this review

Al‐Khadra 1998a {published data only}

Al-Khadra AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA. Antiplatelet agents and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) trial. Journal of the American College of Cardiology 1998;31:419-25. [DOI] [PubMed] [Google Scholar]

ASAP‐HF 2013 {published data only}

Liu PY, Li YH, Chen JH, Tsai LM, Liao JK. A double-blind randomized placebo pilot study comparing aggrenox versus placebo in heart failure patients (ASAP-HF trial). In: European Journal of Heart Failure. Vol. 12. 2013:S74.

CACHE‐EHF 2014 {published data only}

Parsons S, Rigby AS, Gittus C, McDonagh T, McMurray JJ, Squire IB, et al. A randomized controlled trial of aspirin compared to clopidogrel in patients with heart failure. European Heart Journal 2014;35:159. [Google Scholar]
Parsons S, Rigby AS, Gittus C, McDonagh TA, McMurray JJ, Squite IB, et al. The clopidogrel or aspirin in chronic heart failure (CACHE) study. European Journal of Heart Failure 2014;16:267-8. [Google Scholar]

COMMANDER HF trial {published data only}

Zannad F, Anker SD, Byra WM, Cleland JG, Fu M, Gheorghiade M, et al, COMMANDER HF Investigators. Rivaroxaban in patients with heart failure, sinus rhythm, and coronary disease. New England Journal of Medicine 2018;379:1332-42. [DOI] [PubMed] [Google Scholar]

Diener 2019 {published data only}

Diener HC, Sacco RL, Easton JD, Granger CB, Bernstein RA, Uchiyama S, et al, RE-SPECT ESUS Steering Committee and Investigators. Dabigatran for prevention of stroke after embolic stroke of undetermined source. New England Journal of Medicine 2019;380:1906-17. [DOI] [PubMed] [Google Scholar]

EPICAL 2002 {published data only}

Echemann M, Alla F, Briancon S, Juilliere Y, Virion JM, Mertes PM, et al. Antithrombotic therapy is associated with better survival in patients with severe heart failure and left ventricular systolic dysfunction severe heart failure and left ventricular systolic dysfunction (EPICAL study). European Journal of Heart Failure 2002;4(5):647-54. [DOI] [PubMed] [Google Scholar]

Merkler 2021 {published data only}

Merkler AE, Pearce LA, Kasner SE, Shoamanesh A, Birnbaum LA, Kamel H, et al. Left ventricular dysfunction among patients with embolic stroke of undetermined source and the effect of rivaroxaban vs aspirin: a subgroup analysis of the NAVIGATE ESUS randomized clinical trial. JAMA Neurology 2021;78(12):1454-60. [DOI] [PMC free article] [PubMed] [Google Scholar]

PROMISE 1993 {published data only}

Falk RH, Pollak A, Tandon PK, Packer M. The effect of warfarin on prevalence of stroke in patients with severe heart failure. Journal of the American College of Cardiology 1993;21(Suppl 2):218A. [Google Scholar]

SAVE 1997 {published data only}

Loh E, Sutton MS, Wun CC, Rouleau JL, Flaker GC, Gottlieb SS, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. New England Journal of Medicine 1997;336:251-7. [DOI] [PubMed] [Google Scholar]

SOLVD 1997 {published data only}

Dries DL, Domanski MJ, Waclawiw MA, Gersh BJ. Effect of antithrombotic therapy on risk of sudden coronary death in patients with congestive heart failure. American Journal of Cardiology 1997;79:909-13. [DOI] [PubMed] [Google Scholar]
Dries DL, Rosenberg YD, Waclawiw MA, Domanski MJ. Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular dysfunction trials. Journal of the American College of Cardiology 1997;29:1074-80. [DOI] [PubMed] [Google Scholar]

V‐HeFT II 1992 {published data only}

Dunkman WB, Johnson GR, Carson PE, Bhat G, Farrell L, Cohn JN, for the V-HeFT VA Cooperative Studies Group. Incidence of thromboembolic events in congestive heart failure. Circulation 1993;87(Suppl 6):VI194-VI101. [PubMed] [Google Scholar]

Additional references

Aguilar 2005

Aguilar MI, Hart R. Antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No: CD001925. [DOI: 10.1002/14651858.CD001925.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]

Alberts 2010

Alberts VP, Bos MJ, Koudstaal PJ, Hofman A, Witteman JC, Stricker BH, Breteler MM. Heart failure and the risk of stroke: the Rotterdam Study. European Journal of Epidemiology 2010;25:807-12. [DOI] [PMC free article] [PubMed] [Google Scholar]

APT Collab I 1994

Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy - I. Prevention of death, myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81-106. [PMC free article] [PubMed] [Google Scholar]

APT Collab II 1994

Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy - II:Maintenance of vascular graft or arterial patency by antiplatelet therapy. BMJ 1994;308:159-68. [PMC free article] [PubMed] [Google Scholar]

ATT 2009

Antithrombotic Trialists' Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373(9678):1849-60. [DOI] [PMC free article] [PubMed] [Google Scholar]

Campbell 2020

Campbell M, McKenzie JE, Sowden A, Katikireddi SV, Brennan SE, Ellis S, et al. Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline. BMJ 2020;368:l6890. [DOI: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

CAPRIE 1996

CAPRIE Steering Committee. A randomised blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39. [DOI] [PubMed] [Google Scholar]

GRADEPro GDT [Computer program]

GRADEpro GDT. Version accessed in November 2020. Hamilton (ON): McMaster University (developed by Evidence Prime), 2020. Available at https://www.gradepro.org.

Higgins 2011

Higgins JP, Green S, editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from https://training.cochrane.org/handbook/archive/v5.1/.

Hindricks 2021

Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. European Heart Journal 2021;42(5):373-498. [DOI] [PubMed] [Google Scholar]

Khoury 2011

Khoury H, Welner S, Kubin M, Folkerts K, Haas S. Disease burden and unmet needs for prevention of venous thromboembolism in medically ill patients in Europe show underutilisation of preventive therapies. Thrombosis and Haemostasis 2011;106:600-8. [DOI] [PubMed] [Google Scholar]

Klimt 1986

Klimt CR, Knatterud GL, Stamler J, Meier P. Persantine-Aspirin Reinfarction Study. Part II. Secondary coronary preventionwith persantine and aspirin. Journal of the American College of Cardiology 1986;7:251-69. [DOI] [PubMed] [Google Scholar]

Lefebvre 2011

Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from https://training.cochrane.org/handbook/archive/v5.1/.

Lip 2012

Lip GY, Piotrponikowski P, Andreotti F, Anker SD, Filippatos G, Homma S, et al, Heart Failure Association (EHFA) of the European Society of Cardiology (ESC) and the ESC Working Group on Thrombosis. Thromboembolism and antithrombotic therapy for heart failure in sinus rhythm: an executive summary of a joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis. Thrombosis and Haemostasis 2012;108:1009-22. [DOI] [PubMed] [Google Scholar]

Lip 2014

Lip GY, Shantsila E. Anticoagulation versus placebo for heart failure in sinus rhythm. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No: CD003336. [DOI: 10.1002/14651858.CD003336.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]

McDonagh 2021

McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal 2021;42(36):3599-726. [Google Scholar]

Ntaios 2019

Ntaios G, Vemmos K, Lip G. Oral anticoagulation versus antiplatelet or placebo for stroke prevention in patients with heart failure and sinus rhythm: systematic review and meta-analysis of randomized controlled trials. International Journal of Stroke 2019;14(9):856-61. [DOI] [PubMed] [Google Scholar]

Packer 1991

Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, et al. Effects of oral milrinone on mortality in severe chronic heart failure. New England Journal of Medicine 1991;325:1468-75. [DOI] [PubMed] [Google Scholar]

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References to other published versions of this review

Lip 2000

Lip GYH, Wrigley BJ, Pisters R. Antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm. Cochrane Database of Systematic Reviews 2000, Issue 2. Art. No: CD003333. [DOI: 10.1002/14651858.CD003333] [DOI] [PubMed] [Google Scholar]

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Lip GYH, Wrigley BJ, Pisters R. Antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No: CD003333. [DOI: 10.1002/14651858.CD003333.pub2] [DOI] [PubMed] [Google Scholar]

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Shantsila E, Lip GYH. Antiplatelet versus anticoagulation treatment for patients with heart failure in sinus rhythm. Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No: CD003333. [DOI: 10.1002/14651858.CD003333.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]

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[CD003333-bib-0002] Homma S, Thompson JL, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. New England Journal of Medicine 2012;366:1859-69. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD003333-bib-0003] Cleland JG, Findlay I, Jafri S et al. The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. American Heart Journal 2004;148:157-64. [DOI] [PubMed] [Google Scholar]

[CD003333-bib-0004] Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JGF, Ezekowitz M, et al. Randomized trial of warfarin, aspirin and clopidogrel in patients with chronic heart failure. The warfarin and antiplatelet therapy in chronic heart failure (WATCH) trial. Circulation 2009;119:1616-24. [DOI] [PubMed] [Google Scholar]

[CD003333-bib-0005] Al-Khadra AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA. Antiplatelet agents and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) trial. Journal of the American College of Cardiology 1998;31:419-25. [DOI] [PubMed] [Google Scholar]

[CD003333-bib-0006] Liu PY, Li YH, Chen JH, Tsai LM, Liao JK. A double-blind randomized placebo pilot study comparing aggrenox versus placebo in heart failure patients (ASAP-HF trial). In: European Journal of Heart Failure. Vol. 12. 2013:S74.

[CD003333-bib-0007] Parsons S, Rigby AS, Gittus C, McDonagh T, McMurray JJ, Squire IB, et al. A randomized controlled trial of aspirin compared to clopidogrel in patients with heart failure. European Heart Journal 2014;35:159. [Google Scholar]

[CD003333-bib-0008] Parsons S, Rigby AS, Gittus C, McDonagh TA, McMurray JJ, Squite IB, et al. The clopidogrel or aspirin in chronic heart failure (CACHE) study. European Journal of Heart Failure 2014;16:267-8. [Google Scholar]

[CD003333-bib-0009] Zannad F, Anker SD, Byra WM, Cleland JG, Fu M, Gheorghiade M, et al, COMMANDER HF Investigators. Rivaroxaban in patients with heart failure, sinus rhythm, and coronary disease. New England Journal of Medicine 2018;379:1332-42. [DOI] [PubMed] [Google Scholar]

[CD003333-bib-0010] Diener HC, Sacco RL, Easton JD, Granger CB, Bernstein RA, Uchiyama S, et al, RE-SPECT ESUS Steering Committee and Investigators. Dabigatran for prevention of stroke after embolic stroke of undetermined source. New England Journal of Medicine 2019;380:1906-17. [DOI] [PubMed] [Google Scholar]

[CD003333-bib-0011] Echemann M, Alla F, Briancon S, Juilliere Y, Virion JM, Mertes PM, et al. Antithrombotic therapy is associated with better survival in patients with severe heart failure and left ventricular systolic dysfunction severe heart failure and left ventricular systolic dysfunction (EPICAL study). European Journal of Heart Failure 2002;4(5):647-54. [DOI] [PubMed] [Google Scholar]

[CD003333-bib-0012] Merkler AE, Pearce LA, Kasner SE, Shoamanesh A, Birnbaum LA, Kamel H, et al. Left ventricular dysfunction among patients with embolic stroke of undetermined source and the effect of rivaroxaban vs aspirin: a subgroup analysis of the NAVIGATE ESUS randomized clinical trial. JAMA Neurology 2021;78(12):1454-60. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD003333-bib-0013] Falk RH, Pollak A, Tandon PK, Packer M. The effect of warfarin on prevalence of stroke in patients with severe heart failure. Journal of the American College of Cardiology 1993;21(Suppl 2):218A. [Google Scholar]

[CD003333-bib-0014] Loh E, Sutton MS, Wun CC, Rouleau JL, Flaker GC, Gottlieb SS, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. New England Journal of Medicine 1997;336:251-7. [DOI] [PubMed] [Google Scholar]

[CD003333-bib-0015] Dries DL, Domanski MJ, Waclawiw MA, Gersh BJ. Effect of antithrombotic therapy on risk of sudden coronary death in patients with congestive heart failure. American Journal of Cardiology 1997;79:909-13. [DOI] [PubMed] [Google Scholar]

[CD003333-bib-0016] Dries DL, Rosenberg YD, Waclawiw MA, Domanski MJ. Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular dysfunction trials. Journal of the American College of Cardiology 1997;29:1074-80. [DOI] [PubMed] [Google Scholar]

[CD003333-bib-0017] Dunkman WB, Johnson GR, Carson PE, Bhat G, Farrell L, Cohn JN, for the V-HeFT VA Cooperative Studies Group. Incidence of thromboembolic events in congestive heart failure. Circulation 1993;87(Suppl 6):VI194-VI101. [PubMed] [Google Scholar]

[CD003333-bib-0018] Aguilar MI, Hart R. Antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No: CD001925. [DOI: 10.1002/14651858.CD001925.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD003333-bib-0019] Alberts VP, Bos MJ, Koudstaal PJ, Hofman A, Witteman JC, Stricker BH, Breteler MM. Heart failure and the risk of stroke: the Rotterdam Study. European Journal of Epidemiology 2010;25:807-12. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD003333-bib-0020] Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy - I. Prevention of death, myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81-106. [PMC free article] [PubMed] [Google Scholar]

[CD003333-bib-0021] Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy - II:Maintenance of vascular graft or arterial patency by antiplatelet therapy. BMJ 1994;308:159-68. [PMC free article] [PubMed] [Google Scholar]

[CD003333-bib-0022] Antithrombotic Trialists' Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373(9678):1849-60. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD003333-bib-0023] Campbell M, McKenzie JE, Sowden A, Katikireddi SV, Brennan SE, Ellis S, et al. Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline. BMJ 2020;368:l6890. [DOI: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD003333-bib-0024] CAPRIE Steering Committee. A randomised blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39. [DOI] [PubMed] [Google Scholar]

[CD003333-bib-0025] GRADEpro GDT. Version accessed in November 2020. Hamilton (ON): McMaster University (developed by Evidence Prime), 2020. Available at https://www.gradepro.org.

[CD003333-bib-0026] Higgins JP, Green S, editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from https://training.cochrane.org/handbook/archive/v5.1/.

[CD003333-bib-0027] Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. European Heart Journal 2021;42(5):373-498. [DOI] [PubMed] [Google Scholar]

[CD003333-bib-0028] Khoury H, Welner S, Kubin M, Folkerts K, Haas S. Disease burden and unmet needs for prevention of venous thromboembolism in medically ill patients in Europe show underutilisation of preventive therapies. Thrombosis and Haemostasis 2011;106:600-8. [DOI] [PubMed] [Google Scholar]

[CD003333-bib-0029] Klimt CR, Knatterud GL, Stamler J, Meier P. Persantine-Aspirin Reinfarction Study. Part II. Secondary coronary preventionwith persantine and aspirin. Journal of the American College of Cardiology 1986;7:251-69. [DOI] [PubMed] [Google Scholar]

[CD003333-bib-0030] Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from https://training.cochrane.org/handbook/archive/v5.1/.

[CD003333-bib-0031] Lip GY, Piotrponikowski P, Andreotti F, Anker SD, Filippatos G, Homma S, et al, Heart Failure Association (EHFA) of the European Society of Cardiology (ESC) and the ESC Working Group on Thrombosis. Thromboembolism and antithrombotic therapy for heart failure in sinus rhythm: an executive summary of a joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis. Thrombosis and Haemostasis 2012;108:1009-22. [DOI] [PubMed] [Google Scholar]

[CD003333-bib-0032] Lip GY, Shantsila E. Anticoagulation versus placebo for heart failure in sinus rhythm. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No: CD003336. [DOI: 10.1002/14651858.CD003336.pub3] [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Antiplatelet versus anticoagulation treatment for people with heart failure in sinus rhythm

Monika Kozieł-Siołkowska

Eduard Shantsila

Alena Shantsila

Gregory YH Lip

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. Warfarin versus aspirin for heart failure in sinus rhythm.

Summary of findings 2. Warfarin versus clopidogrel for heart failure in sinus rhythm.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

1. Warfarin versus aspirin

All‐cause mortality

1.1. Analysis.

Non‐fatal cardiovascular events

1.2. Analysis.

Major bleeding events

1.3. Analysis.

2. Warfarin versus clopidogrel

All‐cause mortality

2.1. Analysis.

Non‐fatal cardiovascular events

2.2. Analysis.

Major bleeding events

2.3. Analysis.

3. Other comparisons

Discussion

Summary of main results