Q J Med 2002; 95: 461-468
© 2002 Association of Physicians
Antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm: a Cochrane systematic review
From the Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK
Received 27 November 2001 and in revised form 24 January 2002
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Summary |
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Background: Heart failure predisposes to stroke and thromboembolism, which in turn contribute to the high mortality and morbidity in heart failure.
Objectives: To determine the effect of antiplatelet agents, compared to placebo or anticoagulant therapy, on death and/or major thromboembolic events in adults with heart failure who are in sinus rhythm.
Design: Systematic review of randomized parallel group placebo or controlled trials comparing oral antiplatelet therapy with control or anticoagulation therapy in adults with chronic heart failure in sinus rhythm.
Data sources: Reference lists of papers resulting from this search, electronic database searching (MEDLINE, EMBASE, DARE), and abstracts from national and international cardiovascular meetings were studied to identify unpublished studies. Relevant authors of these studies were contacted to obtain further data.
Selection criteria: These included duration of treatment of at least 1 month, and adults with heart failure due to any underlying cause. To assess any adverse effects, cohort study and non-randomized controlled studies were assessed. Inclusion decisions were duplicated, disagreement resolved by discussion or a third party. No meta-analyses were performed, as no data were available from randomized comparisons.
Results: One randomized controlled trial of warfarin vs. aspirin vs. no antithrombotic therapy was found, but no definitive data have yet been published. Three retrospective, non-randomized cohort studies from large trials examining the role of ACE inhibitors have examined the role of aspirin therapy with and without anticoagulant therapy in patients with heart failure and/or left ventricular systolic dysfunction were identified, but the results from these trials were conflicting. A possible interaction with ACE inhibitors may reduce the efficacy of aspirin, although this evidence is from retrospective analyses of trial cohorts.
Conclusions: At present there is no evidence from long term RCTs to recommend use of aspirin to prevent thromboembolism in patients with heart failure in sinus rhythm. There is also no evidence to indicate superior effects from oral anticoagulation, when compared to aspirin, in patients with heart failure in sinus rhythm.
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Introduction |
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Chronic heart failure is an increasing clinical and social problem, and a significant cause of morbidity and mortality, with >30% annual mortality rates in patients with severe (NYHA IV) symptoms.1 Pulmonary embolism and peripheral arterial embolism, and these thromboembolic events contribute to the high morbidity in heart failure.2–4 For example, mild-to-moderate heart failure is associated with an annual stroke risk of approximately 1.5%5-8 compared to the annual stroke risk in the general population of <0.5%, while the annual risk of stroke increases to almost 4% in severe heart failure.1,4,9 Indeed, the SAVE study reported an inverse relationship between stroke risk and the left ventricular ejection fraction, with an 18% increase in stroke risk for every 5% reduction in left ventricular ejection fraction.10
Antiplatelet therapy with aspirin is common in patients with heart failure who are in sinus rhythm. Its use is based upon its general efficacy as an antithrombotic agent, as it has been shown to reduce the incidence of myocardial infarction (MI) and death in men and women aged >50 years, in patients with unstable angina and MI, and in patients with atherosclerotic cerebrovascular disease,11 while the administration of aspirin improves the patency rates of saphenous-vein aorto-coronary bypass grafts.12,13 In addition, aspirin reduces the incidence of stroke and death in patients with recurrent episodes of cerebral ischaemia.14 The addition of low-dose aspirin to warfarin therapy in patients at high risk of embolism from prosthetic heart valves also significantly reduces the incidence of systemic embolism and mortality.15 Furthermore, aspirin has been shown to be moderately effective in reducing venous thrombosis and thromboembolism in patients undergoing hip surgery, and possibly in preventing these occurrences in general-surgical patients.11
Antiplatelet agents such as dipyridamole and clopidogrel have also been studied in cardiovascular disease. Dipyridamole reduces the incidence of thromboembolism, when added to warfarin in high-risk patients with prosthetic heart valves,11,13 and the risk of stroke when added to aspirin in patients with a history of cerebrovascular disease.11,16,17 However, dipyridamole appears to have little antithrombotic effect, and studies indicate 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 recent large ‘Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events’ (CAPRIE) trial, with evidence of a reduction in the composite endpoint of vascular death, ischaemic stroke and MI in patients with a history of cardiovascular disease.18
Prospective studies of antiplatelet-agents as in patients with heart failure in sinus rhythm have generally been limited, although information is available on the use of aspirin in certain subgroups of patients with heart failure, including those with atrial fibrillation and post-MI patients. There is also compelling evidence that aspirin reduces the risk of death in the acute and early post-MI phase, although the mortality benefits are less impressive during long-term treatment or following the late initiation of aspirin,11 and the magnitude of any potential long-term benefits are less well established.
Our objective was to perform a systematic review addressing the role of long-term oral antiplatelet agents compared to placebo or anticoagulant therapy on total deaths and/or major thromboembolic events in patients with heart failure in sinus rhythm, with the hypothesis that oral anticoagulation reduces total deaths, cardiovascular deaths and/or major thromboembolic events in patients with heart failure, when compared to placebo. The efficacy of antithrombotic therapy in atrial fibrillation (including those with heart failure) is the subject of another Cochrane review,19 and will not be addressed in the present review.
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Methods |
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Criteria for considering studies for this review
We considered randomized parallel-group placebo or controlled trials comparing antiplatelet therapy (e.g. non-steroidal anti-inflammatory agents, ticlopidine, clopidogrel, dipyridamole, aspirin) with control or anticoagulation, in adults with heart failure due to any underlying cause, with a duration of treatment at least 1 month. Patients with heart failure defined clinically and if possible, by more objective evidence (e.g. echocardiography, radionuclide ventriculography) of left ventricular systolic dysfunction. To assess any adverse effects, we also examined cohort studies and non-randomized controlled studies, as well as decision analysis studies. Data from the non-randomized studies have been included to provide additional information, to aid interpretation of data on the effectiveness of the therapy. Complications of active therapy (when compared to control) was also recorded.
Studies were excluded if only participants with atrial fibrillation only were studied, if no clinical events were recorded or available, or if the trial was of only short duration (<1 month). We also excluded studies if there were additional active treatments in the intervention arm (e.g. beta-blockers, ACE inhibitors), or if participants of various diagnoses and diagnostic sub-groups were not distinguished in analyses or not available from investigators.
We included the following outcome measures: all-cause deaths; cardiovascular deaths (stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism) and sudden deaths; non-fatal cardiovascular events (non-fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism); revascularization procedures (e.g. coronary angioplasty, embolectomy); and major bleeding events (fatal, non-fatal).
Analysis of data
We analysed data using the Review Manager (RevMan version 4.1) statistical software. The two reviewers (GYHL and CRG) independently selected suitable trials for inclusion in the review. There was a review of the inclusion criteria for each question; the search strategies; the methodology criteria; and methods for pooling the data. The data extracted includes information relating to the complexities of the topic area, such as patient characteristics and concomitant treatments, as well as data relating to study eligibility, quality, and outcomes. Non-randomized studies would not usually be helpful in a review of the effects of these drugs as any estimates of treatment effects are likely to be biased, but they have been included as they may help in assessing side-effects. Assessment of trial quality was made in accordance with guidelines in the Cochrane Handbook,20,21 including adequacy of randomization, degree of blinding and losses to follow-up for each trial.
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Results |
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We identified 1651 references from our search strategy (Figure 1
). From these, we excluded 1645 references after examining the title and abstract because they were not relevant. Full reprints of the remaining six references were obtained for more detailed examination (Table 1).
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One recent prospective study of 279 patients randomized to receive oral anticoagulation with warfarin (INR 2.5) vs. aspirin (300 mg) vs. no antithrombotic therapy was identified, although the data have not been formally published.22 However, this pilot randomized trial22 is limited by small numbers and short follow-up period.
Three large-scale retrospective, post hoc, non-randomized cohort analyses of antithrombotic therapy in heart failure and/or left ventricular systolic dysfunction were also reviewed.7,10,23–26 These trials were designed to test the value of ACE inhibitors, and not antithrombotic therapy use per se. The V-HeFT trials included patients with symptomatic heart failure with radiological, echocardiographic or radionuclide evidence of left ventricular systolic dysfunction.7 The SOLVD trials included patients with left ventricular systolic dysfunction (defined as a left ventricular ejection fraction 
0.35) who were symptomatic and enrolled into the treatment trial5 or asymptomatic and enrolled into the prevention trial.6 The SAVE study included patients post-myocardial infarction with a left ventricular ejection fraction 40% and no overt heart failure, that is, asymptomatic patients.10 Limited information from a retrospective analysis of one trial has been presented in abstract form only.26 No published prospective studies have specifically examined the role of antiplatelet agents such as dipyridamole or clopidogrel in heart failure patients.
The data from the non-randomized observational studies are potentially confounded by a number of factors, including confounding, selection and information biases, as well as the substantial and uncontrolled use of anticoagulation or antiplatelet therapy in these patients, and the influence of time on the risk of embolization following thrombus development, particularly post-MI.
In summary, we could distinguish two kinds of study investigating antiplatelet therapy for heart failure in sinus rhythm: (i) randomized controlled trials;22 and (ii) post hoc analyses of the effects of antiplatelet therapy in non-randomized comparisons in large treatment trials of heart failure.
Randomized controlled trials
The WASH study reported no significant difference in the composite endpoint of death/non-fatal MI or stroke in the aspirin, warfarin and no antithrombotic therapy arms (32%, 24% and 27%, respectively).22 There was an excess of all-cause hospitalizations in the aspirin group (p=0.05), due to exacerbations of heart failure. Preliminary information reports five haemorrhages in this study—one on aspirin and four on warfarin. The total number of serious adverse events in patients taking aspirin was 198, compared to 173 on warfarin and 178 on no antithrombotic therapy.
Post hoc analyses of the effects of warfarin in non-randomized comparisons
Three large scale retrospective post hoc non-randomised cohort analyses of oral antiplatelet therapy in heart failure or left ventricular systolic dysfunction from the V-HeFT, SOLVD and SAVE trials were reviewed.7,10,23–26 In these cohorts, warfarin and antiplatelet agents were non-randomized, and were administered at the discretion of individual investigators. In view of the differing study populations and methodologies of the non-randomized studies, no meta-analyses were performed. No information on bleeding complications was provided in these study reports.
Antiplatelet therapy vs. control
In V-HeFT I, 12.6% of patient-years follow-up, and in VHeFT II, 27.3% of patient-years follow-up, included treatment with antiplatelet agents (aspirin, dipyridamole, or both).7 In 184 patient-years of treatment with antiplatelet agents in V-HeFT I, the incidence of thromboembolism was 0.5 per 100 patient-years (one stroke, no peripheral or pulmonary embolism) compared with 2.7 events per 100 patient-years (p=0.07) in patients not receiving any form of antithrombotic therapy.7 This trend towards benefit was not reproduced in V-HeFT II,7 where the rate of thromboembolism during 562 patient-years of treatment with antiplatelet agents was 1.6 per 100 patient-years compared with 2.1 per 100 patient-years without treatment (p=0.48).
Similarly, post hoc analyses from SOLVD suggested that patients receiving antiplatelet agents had a lower risk of sudden cardiac death (RR 0.76; 95%CI 0.61–0.95) and thromboembolism, although the latter was only significant in women (RR 0.47, 95%CI 0.24–0.92, p=0.03) and borderline-significant in men (RR 0.77, 95%CI 0.59–1.00, p=0.06).24 A further analysis from the SOLVD cohort reported that antiplatelet therapy use (46.3% of patients) was associated with a reduced all-cause mortality (adjusted hazard ratio HR 0.82, 95%CI 0.73–0.92, p=0.0005) and reduced risk of death or hospitalization for heart failure (HR 0.81, 95%CI 0.74–0.89, p<0.0001), although this effect was substantially reduced in those receiving enalapril, raising the possibility of an interaction between aspirin and ACE inhibitor therapy.23
In the SAVE trial, patients receiving antiplatelet therapy were observed to have a 56% reduction in total stroke risk (RR 0.44, 95%CI 0.29–0.65).10
Antiplatelet therapy vs. anticoagulant therapy
In V-HeFT I, 14.2% of patient-years follow-up and in VHeFT II 12.0% of patient-years follow-up included treatment with anticoagulant therapy.7 The incidence of all thromboembolic events was 2.7/100 patient-years over 1068 patient-years without warfarin in V-HeFT I, and 2.1/100 patient-years over 1188 patient-years in V-HeFT II, and was not reduced in patients treated with warfarin (2.9/100 patient-years and 4.9/100 patient-years, respectively), but was significantly reduced in the patients receiving antiplatelet agents (0.53/100 patient-years, p=0.07, in V-HeFT I and 1.6/100 patient-years, p=0.01, in V-HeFT II).7 Although a direct comparison was not made between aspirin and warfarin, the figures suggest that aspirin was superior to warfarin in the prevention of thromboembolism in this cohort.
In the SOLVD cohort, antiplatelet and anticoagulant monotherapy each remained independently associated with a reduction in the risk of sudden cardiac death, but no direct comparison between them was made.23 Similarly, in the SAVE trial, warfarin use was associated with a 81% reduction in stroke risk (RR 0.19, 95%CI 0.13–0.27), but no direct comparison against aspirin (56% reduction) was made.10
One retrospective analysis of limited data from the PROMISE trial27 found that aspirin was used in 573 patients (ejection fraction 35%), with no benefit in stroke prevention, while warfarin was used in 324 patients with a significant reduction in stroke only in those who had very severe heart failure (ejection fraction 20%, 0.6% vs. 3.3% in controls, p<0.05).
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Discussion |
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Data from the one small prospective pilot trial and the non-randomized cohort studies are conflicting and do not clearly support the routine use of aspirin or antiplatelet agents for the reduction of stroke and thromboembolism in patients with heart failure who are in sinus rhythm, nor is there any clear advantage of aspirin over anticoagulant therapy. There was a trend towards more re-hospitalizations for heart failure amongst those taking aspirin.
The data from the retrospective post hoc non-randomized cohort analyses of oral antiplatelet therapy in heart failure or left ventricular systolic dysfunction from the V-HeFT, SOLVD and SAVE trials also do not adequately report bleeding complications, and highlights the unsatisfactory nature of such post hoc analyses.7,10,23–26
Although aspirin is generally considered to be a safe and well-tolerated antiplatelet agent, chronic aspirin is not without adverse effects. Indeed, long-term aspirin use is associated with a four-fold increased risk of gastrointestinal haemorrhage, and aspirin accounts for up to 30% of gastrointestinal haemorrhages in elderly patients.14,28 Chronic aspirin use is frequently associated with dyspepsia, which often leads to prescription of H2 blockers and proton pump inhibitors, increasing the risk of non-compliance in heart failure patients. Chronic aspirin use also may cause renal dysfunction, which may be a particular problem in patients with advanced heart failure who are already receiving ACE inhibitors.
Although there have been no prospective trials of aspirin in heart failure or other patients receiving ACE inhibitors, post hoc analyses demonstrate a consistent pattern suggesting that the benefits of ACE inhibitors may be reduced in patients receiving aspirin. In the SOLVD treatment trial, mortality in patients not receiving aspirin was reduced from 44.3% on placebo to 35.2% in patients randomized to enalapril (21% relative risk reduction).23,29 while in patients taking aspirin, overall mortality rates were 30.7% on placebo and 34.8% on enalapril (a 13% relative risk increase, p=0.002). The same interaction was also observed in the combined SOLVD trials.30 Similarly, in CONSENSUS II, the patients on aspirin actually experienced a significant increase in mortality with enalapril treatment, whereas those not on aspirin showed no effect.29
However, pooling data from the combined SOLVD trials with the individual patient data from three post-MI studies in patients with heart failure and/or left ventricular systolic dysfunction (SAVE, TRACE, and AIRE), patients on aspirin at the time of randomization produces a 15% (OR 0.85, 95%CI 0.76–0.95) risk reduction for the endpoint of death, compared with a 25% (OR 0.75, 95%CI 0.67–0.85) relative risk reduction in those not taking aspirin (p=0.23 for interaction).30 For the combined endpoint of death/heart failure/reinfarction, patients on aspirin at the time of randomization had a 24% (OR 0.76, 95%CI 0.69–0.84) risk reduction for the endpoint of death, compared with a 32% (OR 0.68, 95%CI 0.60–0.76) relative risk reduction in those not taking aspirin (p=0.20 for interaction).30 The latter meta-analysis therefore suggests that the proportional benefits of ACE inhibitors were relatively similar whether or not patients were taking aspirin at baseline, although the analysis does not take into consideration interactions after randomization.
Thus, these data suggesting an aspirin-ACE inhibitor interaction are far from definitive, since they are derived from post hoc analyses of non-randomized treatment groups. Indeed, ACE inhibitors are well-validated for the treatment of heart failure, and significant haemodynamic, symptomatic and prognostic benefits by their use. If aspirin potentially reduced this benefit, this would be disadvantageous.
The use of warfarin anticoagulation in patients with heart failure or LV systolic dysfunction is controversial4 and clear prospective trial evidence to indicate superior effects from oral anticoagulation, compared to aspirin, is lacking in patients with heart failure. Cohort studies have not given clear direct comparisons between antiplatelet therapy and anticoagulant therapy, and given the different populations and study methodologies, conclusions are limited. The only reliable prospective data comparing antiplatelet agents vs. anticoagulant therapy in heart failure are from one pilot short term trial (WASH) which is yet to be fully published.22 The Veterans Administration is currently conducting the large Warfarin-Antiplatelet Trial in Chronic Heart Failure (WATCH) in 4500 patients with NYHA Class II–IV heart failure and ejection fraction <30%, who will be randomized to warfarin or antiplatelet therapy (blinded aspirin or clopidogrel) [http://www.cardiosource.com/trials]. The primary outcomes in WATCH will be all-cause mortality, non-fatal myocardial infarction and non-fatal stroke, in addition to ischaemic events and thromboembolism.
Implications for practice
The thromboprophylactic benefits of aspirin in patients with heart failure who are in sinus rhythm are not convincing, and may even be detrimental, in view of the possible reduction of ACE inhibitor benefit and other side-effects. It should be emphasized that the evidence for a potential interaction between ACE inhibitors and antiplatelet agents is based on non-randomized studies—in light of the quality of the studies from which the data are derived and the post hoc nature of the study analyses, the possible interaction should be interpreted with caution.
Implications for research
This review incorporates only one pilot randomized controlled trial, and is therefore important for setting the scene for future inclusion of robust intervention studies. A large-scale randomized controlled trial in ambulant patients with heart failure to evaluate the effectiveness of anticoagulant therapy and antiplatelet therapy is long overdue. Such a study would also examine the interaction, if any, between the ACE inhibitors and aspirin therapy.
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Conclusions |
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There is conflicting evidence to support the use of antiplatelet agents to reduce the incidence of thromboembolism in heart failure who are in sinus rhythm. Indeed, observational studies have suggested the possibility of a direct interaction between aspirin and ACE inhibitors, although prospective studies will attempt to clarify this issue, in addition to the broader role of long-term antiplatelet therapy in heart failure. There is also no evidence to indicate superior effects from oral anticoagulation, when compared to aspirin, in patients with heart failure.
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Acknowledgments |
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We acknowledge the support of the City Hospital NHS Trust Research and Development Programme for the Haemostasis Thrombosis and Vascular Biology Unit. Our unit is a centre for the WATCH study as well as other trials of antithrombotic therapy in cardiovascular disease and stroke.
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Address correspondence to Professor G.Y.H. Lip, Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH. e-mail: g.y.h.lip{at}bham.ac.uk
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1. Gibbs CR, Davis MK, Lip GYH. ABC of Heart Failure, BMJ Books, London, 2000.
2. Fuster V, Gersh BJ, Giuliani ER, Tajik AJ, Bradenburg RO, Frye RL. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol1981; 47:525–31.[ISI][Medline]
3. Kyrle PA, Korninger C, Gossinger H, Glogar D, Lechner K, Niessner H, et al. Prevention of arterial and pulmonary embolism by oral anticoagulants in patients with dilated cardiomyopathy. Thromb Haemost1985; 54:521–3.[ISI][Medline]
4. Lip GYH. Intracardiac thrombus formation in cardiac impairment: investigation and the role of anticoagulant therapy. Postgrad Med J1996; 72:731–8.[Abstract]
5. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med1991; 325:293–302.[Abstract]
6. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med1992; 327:685–91.[Abstract]
7. 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. Circulation1993; 87(Suppl. VI):VI94–101.
8. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Tristani F, Harston WE, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med1986; 314:1547–52.[Abstract]
9. 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. N Engl J Med1991; 325:1468–75.[Abstract]
10. Loh E, Sutton MS, Wun CC, Rouleau JL, Flaker GC, Gottlieb SS, Lamas GA, Moye LA, Goldhaber SZ, Pfeffer MA. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med1997; 336:251–7.
11. 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. Br Med J1994; 308:81–106.
12. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy: II. Maintenance of vascular graft or arterial patency by antiplatelet therapy. Br Med J1994; 308:159–68.
13. Stein PD, Dalen JE, Goldman S, Theroux P. Antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts. Chest1998; 114(Suppl. 5):658–65S.
14. Sze PC, Reitman D, Pincus MM, Sacks HS, Chalmers TC. Antiplatelet agents in the secondary prevention of stroke: meta-analysis of the randomized control trials. Stroke1988; 19:436–42.
15. Turpie AG, Gent M, Laupacis A, Latour Y, Gunstensen J, Basile F, Klimek M, Hirsh J. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med1993; 329:524–9.
16. Klimt CR, Knatterud GL, Stamler J, Meier P. Persantine-Aspirin Reinfarction Study: Part II. Secondary coronary prevention with persantine and aspirin. J Am Coll Cardiol1986; 7:251–69.[Abstract]
17. Forbes CD. Secondary stroke prevention with low-dose aspirin, sustained release dipyridamole alone and in combination: ESPS Investigators. European Stroke Prevention Study. Thromb Res1998; 92(Suppl. 1):S1–6.[ISI][Medline]
18. CAPRIE Steering Committee. A randomised blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet1996; 348:1329–39.[ISI][Medline]
19. Segal J. Anticoagulants versus antiplatelet drugs for preventing venous thromboembolism in atrial fibrillation [Cochrane review]. Cochrane Library 2001, 3. Oxford, Update Software.
20. Clarke M. Critical Appraisal of Studies: Cochrane Collaboration Reviewers' Handbook. Oxford, Cochrane Collaboration, 2000.
21. Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. Br Med J1994; 309:1286–91.
22. Jones CG, Cleland JGF Meeting report: the LIDO, HOPE, MOXCON and WASH studies. Eur J Heart Failure1999; 1:425–31.[Medline]
23. 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. J Am Coll Cardiol1998; 31:419–25.
24. Al-Khadra AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA. Warfarin anticoagulation and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction. J Am Coll Cardiol1998; 31:749–53.
25. Dries DL, Domanski MJ, Waclawiw MA, Gersh BJ. Effect of antithrombotic therapy on risk of sudden coronary death in patients with congestive heart failure. Am J Cardiol1997; 79:909–13.[ISI][Medline]
26. 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. J Am Coll Cardiol1997; 29:1074–80.[Abstract]
27. Falk RH, Pollak A, Tandon PK, Packer M. The effect of warfarin on prevalence of stroke in patients with severe heart failure. J Am Coll Cardiol1993; 21(Suppl):218A.
28. Faulkner G, Prichard P, Somerville K, Langman MJ. Aspirin and bleeding peptic ulcers in the elderly. Br Med J1988; 297:1311–13.[ISI][Medline]
29. Nguyen KN, Aursnes I, Kjekshus J. Interaction between enalapril and aspirin on mortality after acute myocardial infarction: subgroup analysis of the Cooperative New Scandinavian Enalapril Survival Study II. Am J Cardiol1997; 79:115–19.[ISI][Medline]
30. Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, Torp-Pedersen C, Ball S, Pogue J, Moye L, Braunwald E. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet2000; 355:1575–81.[ISI][Medline]
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