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European Journal of Heart Failure 1999 1(4):419-423; doi:10.1016/S1388-9842(99)00055-0
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© 1999 European Society of Cardiology

Antithrombotic therapy in heart failure: a randomized comparison of warfarin vs. aspirin (HELAS)

Dennis V. Cokkinos* and Pavlos K. Toutouzas

Cardiology Department, Medical School, University of Athens Athens, Greece

* Corresponding author. Tel.: +30-1-940-6058; fax: +30-1-939-3336


   Abstract
Top
 Abstract
1. Introduction
 2. Study objectives
 3. Study synopsis
 4. Inclusion/exclusion criteria
 5. Primary efficacy endpoint
 6. Additional analyses
 7. Safety endpoints
 8. Statistical procedures and...
 9. Sample size
 10. Trial financing
 11. Endpoints
 References
 
It is uncertain whether anti-thrombotic treatment reduces the incidence of thrombo-embolism in patients with heart failure, so there is a need for a large scale controlled study to assess the effects of anti-thrombotic therapy in this setting. We report the design of a randomized controlled multicenter double blind trial examining the effects of aspirin, warfarin and placebo in patients with heart failure on the risk of thrombo-embolism. We planned to recruit 6000 patients with heart failure without contraindications to anticoagulants or antiplatelet agents and to follow them for a mean time of 2 years following randomization. The study was planned to determine the rate of thrombo-embolic and haemorrhagic events and death among patients randomized to aspirin, warfarin and placebo, stratified according to the presence or absence of underlying coronary disease. Ancillary studies parallel to the main study will attempt to identify clinical and echocardiographic risk factors for thrombo-embolism and will also examine whether hemostatic or neurohormonal mechanisms contribute to an increase in the risk of thrombo-embolism in patients with heart failure. We hoped that the results of the study would improve the clinical management and cost-effectiveness of treatment for patients with heart failure. However, the recruitment of patients proved more difficult than expected and a number of centers decided not to participate. To avoid a great delay it was decided by the principal investigators and submitted to the executive committee to terminate enrolment in this study when 300 patients had been enrolled, and accept that this is a pilot study.

Received June 10, 1999; Revised August 17, 1999; Accepted August 17, 1999


   1. Introduction
Top
 Abstract
 1. Introduction
2. Study objectives
 3. Study synopsis
 4. Inclusion/exclusion criteria
 5. Primary efficacy endpoint
 6. Additional analyses
 7. Safety endpoints
 8. Statistical procedures and...
 9. Sample size
 10. Trial financing
 11. Endpoints
 References
 
Former reports from autopsy studies conducted in the 1960s showed a high incidence of thrombo-embolic events in patients dying from heart failure [1–3]. In 1981 an article from Fuster et al. [4] from the Mayo Clinic strongly influenced clinical practice by reporting that the risk of thrombo-embolism in 104 patients with heart failure due to dilated cardiomyopathy was high, with a cumulative incidence of 18% or 3.5 events/100 patient-years of follow-up. That study also reported that oral anticoagulation diminished thrombo-embolism in the patients treated. A subsequent report in 1985 from Kyrle et al. [5] suggested that subsequent oral anticoagulation completely prevented recurrent thrombo-embolism among patients who had had a previous event. The authors of that study calculated the risk of thrombo-embolism without anticoagulation therapy as 45 events/100 patient-years.

All of these earlier studies provided strong support for the use of anticoagulation mainly in dilated cardiomyopathy. However, according to the results of recently conducted studies (V-HeFT I and II) [6] the incidence of thrombo-embolism in patients with heart failure (NYHA class II–III) was only 2.2–2.5 events/100 patient-years. Also in a study of 264 ambulatory patients with a mean left ventricular ejection fraction of 27%, Katz et al. [7] showed an incidence of stroke of 1.7 events/100 patient-years during 528 patient-years of follow-up. In SOLVD [8] only 21 of 2569 patients (0.8%) had a stroke recorded. A total of 15.8% patients were receiving anticoagulants, while 9.7% of patients were in atrial fibrillation. In the CONSENSUS trial [9] 33% were receiving anticoagulants, but approximately 50% were in atrial fibrillation. Only 3/253 patients (1.18%) suffered a stroke during the 12-month follow-up. It is clear that far larger studies are required to determine whether anti-thrombotic therapy reduces thrombo-embolic risk in heart failure.

Aspirin has been so far the most widely used antiplatelet drug and its efficacy has been established in the setting of acute myocardial infarction, unstable angina and also in patients with transient ischemic attacks where it has been demonstrated that aspirin reduces the risk of stroke and death [10]. Studies of the use of aspirin in patients with atrial fibrillation have given conflicting results. In the SPAF trial [11] aspirin at a dose of 325 mg/day reduced the risk of stroke and embolism by 42%, but it has been less effective than warfarin which produced a reduction at a level of 62%. Other studies of atrial fibrillation have failed to show an effect of aspirin on stroke rate [12–14].

There are no detailed prospective studies to examine the effects of aspirin in reduction of thrombo-embolism in heart failure patients. A number of studies have suggested the possibility of an adverse interaction between aspirin and ACE inhibitors [15,16].

The V-HeFT studies [6] examined many variables attempting to identify risk factors for thrombo-embolism in patients with heart failure. Only peak exercise oxygen consumption (VO2 max) was a significant predictor of events. Other measures of the severity of heart failure (cardiothoracic ratio from chest X-ray, left ventricular ejection fraction) showed weak association with thrombo-embolic risk. Surprisingly, most recent studies fail to show that atrial fibrillation is an independent risk factor of thrombo-embolism in heart failure [4,6]. Left ventricular mural thrombi increase the risk of systemic embolization following myocardial infarction [17] but it is not clear that these data can be extrapolated to chronic heart failure [7,18,19] or that warfarin is effective in preventing events [7,19]. A meta-analysis of the SAVE study [20] showed a strong inverse relationship between left ventricular ejection fraction and rate of thrombo-embolism.

In a recent analysis of the data from the SOLVD study the use of antiplatelet agents (including aspirin) was associated with a decrease in morbidity and improved survival in patients with left ventricular dysfunction. However, no mention was made of embolic episodes and antiplatelet agents appeared beneficial only in the ischemic group [16]. Warfarin use was associated with improved survival and a decrease in morbidity in the same trial [21]. However, in this study no reduction of fatal stroke, fatal pulmonary embolism or other vascular deaths was seen, the main reduction in fatal and non-fatal myocardial infarction [20]. Conclusions, however, cannot be drawn as to whether this benefit was truly related to the anticoagulant therapy as the baseline characteristics between the two groups were very different.

In order to address the lack of data we have organized a large scale randomized controlled trial to compare anticoagulation (warfarin) to placebo and antiplatelet agent treatment (ASA — aspirin) in patients with heart failure, in order to determine whether antithrombotic therapy safely reduces the incidence of thrombo-embolic events in patients with heart failure and, if so, whether aspirin or warfarin is more effective.

One important point that has been widely discussed is the question whether the administration of placebo is ethically justified for various categories of patients. We believe that the following aspects should weigh in the final decision:

The subgroup of post-infarction patients should not be left without antithrombotic treatment. Two major trials, WARIS [22] and ASPECT [23] have shown an increased incidence of reinfarction and cerebrovascular episodes without anticoagulation. In the EPSIM trial [24] the percentage of patients with heart failure was too low for meaningful conclusions. The beneficial effects of antiplatelet agents in heart failure of ischemic etiology and warfarin on myocardial infraction [21] in SOLVD have already been discussed. In this group aspirin and anticoagulants should be compared.

In patients with dilated cardiomyopathy no hard data exist that if left ventricular thrombi and atrial fibrillation are excluded anticoagulation is mandatory [6,7,17,18,22,27]. Baker and Wright [25], after reviewing all the English-language studies referenced from January 1966 to September 1993 concluded that ‘until adequate studies are performed, anticoagulation should be discouraged for patients with heart failure who are in sinus rhythm’. In a more recent review, Koniaris and Goldhaber state that evidence from published reports do not demonstrate convincingly that the benefits of anticoagulation exceeds the risks for patients with dilated cardiomyopathy [26].

A recent comprehensive overview of anti-thrombotic treatment in heart failure [29] shows the paucity of evidence for anti-thrombotic therapy in heart failure and questions its value for any patient in sinus rhythm regardless. Neither European Society nor North American guidelines currently recommend anti-thrombotic treatment for heart failure regardless of its aetiology [29]. Accordingly, we have set up a study designed to answer some of the important questions to which answers are required.


   2. Study objectives
Top
 Abstract
 1. Introduction
 2. Study objectives
3. Study synopsis
 4. Inclusion/exclusion criteria
 5. Primary efficacy endpoint
 6. Additional analyses
 7. Safety endpoints
 8. Statistical procedures and...
 9. Sample size
 10. Trial financing
 11. Endpoints
 References
 

  1. To determine whether in patients with heart failure caused by a previous myocardial infarction warfarin, with a targeted INR between 2.0 and 3.0 is equally effective to enteric coated aspirin in a dose of 325 mg/day in preventing a composite end-point of embolic cardiogenic stroke, peripheral or pulmonary embolism or death. Secondary outcomes will be cardiac and total mortality, myocardial infarction or re-infarction, and heart failure exacerbation, documented at hospitalization.
  2. To determine whether in patients with heart failure secondary to dilated cardiomyopathy or hypertensive heart disease, warfarin, with the aim of producing an INR of 2.0–3.0 is superior to placebo in preventing the same events.


   3. Study synopsis
Top
 Abstract
 1. Introduction
 2. Study objectives
 3. Study synopsis
4. Inclusion/exclusion criteria
 5. Primary efficacy endpoint
 6. Additional analyses
 7. Safety endpoints
 8. Statistical procedures and...
 9. Sample size
 10. Trial financing
 11. Endpoints
 References
 
This is a multicenter, randomized, double-blind placebo-controlled trial (HEart failure Long term Antithrombotic Study, HELAS) with two treatment arms:

  1. Patients with heart failure secondary to myocardial infarction.
  2. Patients with idiopathic dilated cardiomyopathy or hypertensive heart disease.

The aim is to recruit 6000 patients from approximately 80 centers. Informed consent will be obtained from patients meeting eligibility criteria prior to enrollment in the study. An interim evaluation of the study will occur after approximately 1000 patients (500 per group) have been enrolled, by the Data and Safety Monitoring Committee (DSMC), further details are given below.

Standard medical therapy such as digitalis preparations, diuretics, converting enzyme inhibitors, anti-arrhythmics may be administered at the discretion of the responsible physician. All patients will be followed for the occurrence of any primary or component of the secondary endpoints. Hospital or other appropriate source documents associated with the above will be prospectively collected/reviewed and clinical events will be adjudicated.

The diagnosis of embolic cardiogenic stroke, peripheral embolism or pulmonary embolism will be made according to standard criteria. All-cause mortality will be reported. Myocardial (re)infarction will be determined by clinical, electrocardiographic and enzymatic criteria. Heart failure or arrhythmia exacerbation will be evaluated only at hospitalization.


   4. Inclusion/exclusion criteria
Top
 Abstract
 1. Introduction
 2. Study objectives
 3. Study synopsis
 4. Inclusion/exclusion criteria
5. Primary efficacy endpoint
 6. Additional analyses
 7. Safety endpoints
 8. Statistical procedures and...
 9. Sample size
 10. Trial financing
 11. Endpoints
 References
 
Patients must be aged between 20 and 80 years old in NYHA class II–IV heart failure and with left ventricular systolic dysfunction as evidenced by an ejection fraction of ≤35% measured by echocardiography with the area–length method or Simpson’s rule [28] or by radionuclide or angiocardiographic ventriculography.

The diagnosis of ischemic heart disease will be established either by a prior hospital diagnosis of myocardial infarction or coronary arteriography. Patients are excluded from study within 2 months of myocardial infarction. The diagnosis of dilated cardiomyopathy depends upon the exclusion of the existence of coronary artery disease by a negative history of angina and/or myocardial infarction, by a negative stress thallium scan or by coronary arteriography.

Exclusion criteria are reversible myocardial ischemia, mitral valve disease, hypertrophic cardiomyopathy, atrial fibrillation and LV thrombi at echocardiography. Patients with other severe life threatening disease that might limit survival and/or compliance with in the 2 years of study treatment are also excluded. Patients with contraindications to aspirin or warfarin treatment including active peptic ulcer, active or recent bleeding from any site, uncontrolled hypertension (BP >160/100 mmHg) thrombocytopaenia (platelet count <100 000/mm3) or allergy to the above mentioned drugs are excluded. Patients who are or become pregnant while the study is ongoing will be withdrawn from therapy.

Patients already on antiplatelet of anticoagulant therapy can still be randomized in the study provided the responsible physician does not consider the continuation of such treatment clearly indicated.

After obtaining the patient’s written informed consent, the relevant medical history and a full physical examination will be recorded and repeated at intervals during the study at 2, 4, 6, 8, 12, 14, 18, 22 and 24 months. Chest X-ray, biochemistry, ECG, and a detailed echocardiographic study will be carried out after randomization. The X-ray and echocardiogram will be repeated at 12 and 24 months. Biochemical tests will be carried out at randomization, 1, 12 and 24 months. INR tests will be run monthly in a partially blinded fashion (see below).


   5. Primary efficacy endpoint
Top
 Abstract
 1. Introduction
 2. Study objectives
 3. Study synopsis
 4. Inclusion/exclusion criteria
 5. Primary efficacy endpoint
6. Additional analyses
 7. Safety endpoints
 8. Statistical procedures and...
 9. Sample size
 10. Trial financing
 11. Endpoints
 References
 
The primary endpoint will be the composite of non-fatal stroke, peripheral embolism or pulmonary embolism, myocardial (re)infarction, worsening of cardiac failure, or death from any cause.


   6. Additional analyses
Top
 Abstract
 1. Introduction
 2. Study objectives
 3. Study synopsis
 4. Inclusion/exclusion criteria
 5. Primary efficacy endpoint
 6. Additional analyses
7. Safety endpoints
 8. Statistical procedures and...
 9. Sample size
 10. Trial financing
 11. Endpoints
 References
 
Analysis of the primary endpoint by gender and by age.

Attempts at coronary revascularization and readmission for ischemic symptoms at 6 months after enrollment.


   7. Safety endpoints
Top
 Abstract
 1. Introduction
 2. Study objectives
 3. Study synopsis
 4. Inclusion/exclusion criteria
 5. Primary efficacy endpoint
 6. Additional analyses
 7. Safety endpoints
8. Statistical procedures and...
 9. Sample size
 10. Trial financing
 11. Endpoints
 References
 
Safety end-points include a comparison between aspirin and warfarin of all cerebrovascular events ascribed to intracranial hemorrhage, the incidence of bleeding while on study drug and differences in bleeding index while on study drug.

An analysis of safety endpoints by gender, age will be conducted.


   8. Statistical procedures and data analysis randomization
Top
 Abstract
 1. Introduction
 2. Study objectives
 3. Study synopsis
 4. Inclusion/exclusion criteria
 5. Primary efficacy endpoint
 6. Additional analyses
 7. Safety endpoints
 8. Statistical procedures and...
9. Sample size
 10. Trial financing
 11. Endpoints
 References
 
Until the first interim analysis, subjects will be randomly assigned to one of two treatment groups, each with two arms (warfarin, with an INR 2.0–3.0 as an aim, ASA 325 mg, or placebo) by a computer-generated block randomization schedule at the Athens University Coordinating Center in a 5:5 ratio, stratified by participating hospital. Subjects and investigators will remain triple blinded to group results and individual treatment assignments unless emergency identification (unblinding) is required as described below. In patients receiving warfarin partial blinding is ensured by a tiered therapy system as described in the CAFA study vs. aspirin or placebo [30]: the physician dealing directly with the patient informs the patient of the new dose. The anticoagulation supervising group will never contact the patient directly. For patients receiving placebo or ASA the dose of the study medication is periodically modified according to a series of sequential computer-produced sham prothrombin results, without actual blood collection or prothrombin time or INR measurement.


   9. Sample size
Top
 Abstract
 1. Introduction
 2. Study objectives
 3. Study synopsis
 4. Inclusion/exclusion criteria
 5. Primary efficacy endpoint
 6. Additional analyses
 7. Safety endpoints
 8. Statistical procedures and...
 9. Sample size
10. Trial financing
 11. Endpoints
 References
 
Based on a pooled analysis of randomized trials, the incidence of embolic episodes is estimated to be two per 100 patient-years in patients with cardiac failure. The maximum sample size is 1500 patients (total 6000) in each treatment group. This will provide 90% of power to detect difference between the control group event incidence of 2.0% and active treatment incidence of 1.0, a relative reduction of 50% (two-sided alpha 0.05, power 90%). These assumptions do not take into account the possibility that anti-thrombotic therapy may reduce the risk of death, the rate of which is likely to be several times that for thrombo-embolic events. The recent results from SAVE [19] and Cioffi et al. [27] corroborate these assumptions. Statistic evaluation will be carried out by the UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ (Dr John Kostis).

At the first analysis, after 500 patients in each group have been analyzed, the Data Safety Monitoring Committee will determine whether the initially prescribed therapy will be continued for the duration of the trial.

9.1. Protocol amendment
The recruitment of patients proved more difficult than expected and a number of centers did not finally participate. To avoid a great delay it was decided by the principal investigators and submitted to the executive committee to terminate enrollment in this when 300 patients had been enrolled, and continue this as a pilot study.


   10. Trial financing
Top
 Abstract
 1. Introduction
 2. Study objectives
 3. Study synopsis
 4. Inclusion/exclusion criteria
 5. Primary efficacy endpoint
 6. Additional analyses
 7. Safety endpoints
 8. Statistical procedures and...
 9. Sample size
 10. Trial financing
11. Endpoints
 References
 
This trial is not sponsored by any major sponsor in the form of organization or company. Participating physicians are not receiving any remuneration. Participating centers will cover costs through their own resources. Running costs are being donated by companies and organizations in the form of donations in money, offers of personal and secretarial services and of printing or correspondence facilities and material. Study drug supplies have been donated. The trial participants have no financial interest pertaining to the results.

10.1. Committees
The following committees are in charge of this study, which is organized by the Cardiology Department of the Medical School of the University of Athens: — Executive Committee, Clinical Events Committee, Data and Safety monitoring Committee, Design Committee, Recruitment and Operation Committee, Ethical Committee, Publication Committee.

10.2. Preliminary findings
To date 290 patients have been enrolled in HELAS. The following table is a preliminary analysis of the baseline characteristics of the first 223 patients enrolled.
Ischemic Dilated Patient total
Distribution (n) 124 99 223
Age  62±9 56±11  59±10
EF  28±8 27±6  28±7


   11. Endpoints
Top
 Abstract
 1. Introduction
 2. Study objectives
 3. Study synopsis
 4. Inclusion/exclusion criteria
 5. Primary efficacy endpoint
 6. Additional analyses
 7. Safety endpoints
 8. Statistical procedures and...
 9. Sample size
 10. Trial financing
 11. Endpoints
References
 
Approximately 50% of the patients have completed a 1-year follow-up and the following events have been recorded. One embolic stroke (IHD group), One MI (IHD group), five deaths (four IHD group+one DCM group), three haemorrhagic episodes, seven drop-outs/discontinuations.


   References
Top
 Abstract
 1. Introduction
 2. Study objectives
 3. Study synopsis
 4. Inclusion/exclusion criteria
 5. Primary efficacy endpoint
 6. Additional analyses
 7. Safety endpoints
 8. Statistical procedures and...
 9. Sample size
 10. Trial financing
 11. Endpoints
 References
 

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  6. Dunkman WB, Johnson GR, Carson PE et al. For the V-HeFT VA cooperative studies group. Incidence of thromboembolic events in congestive heart failure. Circulation 1993;87 Suppl VI:VI-94–VI-101.
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  9. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med (1987) 316:1429–1435.[Abstract]
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D. V. Cokkinos, G. C. Haralabopoulos, J. B. Kostis, P. K. Toutouzas, and for the HELAS investigators
Efficacy of antithrombotic therapy in chronic heart failure: The HELAS study
Eur J Heart Fail, June 1, 2006; 8(4): 428 - 432.
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