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European Journal of Heart Failure 2006 8(4):428-432; doi:10.1016/j.ejheart.2006.02.012
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© 2006 European Society of Cardiology

Efficacy of antithrombotic therapy in chronic heart failure: The HELAS study

Dennis V. Cokkinosa,b,*, George C. Haralabopoulosb, John B. Kostisc, Pavlos K. Toutouzasa and for the HELAS investigators

a Cardiology Department, Hippokrateio Hospital, University of Athens Athens, Greece
b 1st Cardiology Department, Onassis Cardiac Surgery Center Athens, Greece
c UMDNJ-Robert Wood Johnson Medical School New Brunswick, USA

* Corresponding author. Cardiology Department, Hippokrateio Hospital, University of Athens, Athens, Greece.


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: It is not clear if long-term antithrombotic treatment has a beneficial effect on the incidence of thromboembolism in chronic heart failure (CHF). The HELAS study (Heart failure Long-term Antithrombotic Study) is a multicentre, randomised, double-blind, placebo-controlled trial to evaluate antithrombotic treatment in patients with CHF.

Methods: 197 HF patients (EF <35%) were enrolled. Patients with Ischaemic Heart Disease were randomised to receive either aspirin 325 mg or warfarin. Patients with Dilated Cardiomyopathy (DCM) were randomised to receive either warfarin or placebo.

Results: Analysis of the data from 312 patient years showed an incidence of 2.2 embolic events per 100 patient years, with no significant difference between groups. The incidence of myocardial infarction, hospitalisation, exacerbation of heart failure, death and haemorrhage were not different between the groups. No peripheral or pulmonary emboli were reported. Echocardiographic follow-up for 2 years showed an overall increase in left ventricular ejection fraction from 28.2±6 to 30.3±7 p<0.05, which was most obvious in patients with DCM taking warfarin (EF 26.8±5.3 at baseline, 30.7±10 at 2 years, p<0.05).

Conclusions: (1) Overall embolic events are rare in heart failure regardless of treatment. (2) Treatment does not seem to affect outcome.

Key Words: Heart failure treatment • Aspirin • Anti-thrombotic treatment • Anticoagulants

Received December 22, 2004; Revised July 22, 2005; Accepted February 27, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
It is uncertain whether antithrombotic treatment has a beneficial effect on the rate of thromboembolism in patients with chronic heart failure (CHF). Early studies showed a high incidence of thromboembolic events in patients dying from heart failure and a significant reduction in thromboembolism by oral anticoagulation [1]. However, subsequent studies suggested that thromboembolic events were much less common, ranging from 0.8% to 2.5% per 100 patient years [1-3].Retrospective analyses of observational data and studies designed to assess the effects of vasodilator and neuro-endocrine antagonists in heart failure have shown conflicting results, with some suggesting a benefit from antithrombotic agents [4,5] and others not [1,6]. Two randomised controlled trails have been reported. The WASH study (with about 600 patient years exposure) suggested that neither aspirin nor warfarin was superior to no antithrombotic treatment in terms of preventing death or vascular events [7]. The WATCH study similarly suggested no difference between aspirin, warfarin or clopidogrel [8]. Both studies suggested an increase in heart failure hospitalisation with aspirin compared to warfarin or, in the case of WASH, no treatment. Accordingly, ESC guidelines on heart failure suggest that in general there is little evidence to show that anti-thrombotic therapy modifies the risk of death or vascular events in patients with heart failure [9].

The HELAS study was initiated before either WASH or WATCH had been reported and was designed to compare anticoagulation (warfarin) to placebo and antiplatelet treatment in patients with heart failure in order to (A) identify whether antithrombotic therapy reduces the incidence of thromboembolic and other unfavourable events in patients with heart failure, and (B) establish the risk of haemorrhage with antithrombotic therapy [10].


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
This was an international (Greece, Cyprus, Yugoslavia, Romania, Bulgaria, Poland and Georgia), multicentre, randomised, double-blind, placebo-controlled trial with two treatment arms. Details have been reported previously [8]. In the first treatment arm, patients with CHF and a previous history of myocardial infarction were randomised to receive either aspirin (ASA) or warfarin (W). In the second treatment arm, patients with idiopathic dilated cardiomyopathy (DCM) were randomised to receive either W or placebo (P). The study was conducted in accordance with the principles outlined in the Declaration of Helsinki. Initially, this study was designed to include 6000 patients (approximately 1500 in each of the four treatment groups); however, enrolment of patients proved to be much slower than anticipated despite the fact that over 40 centres contributed to the patient pool. After an investigators' meeting in May 1999, it was decided that enrolment would be terminated in August 1999, and the study would be considered a pilot study. The study was monitored by an independent Data and Safety Monitoring Committee, which conducted interim analyses to determine whether continuation of any of the treatment arms might be detrimental to the patients.

In order to be enrolled in the study, the patients had to be aged between 20 and 75years with symptomatic HF, in NYHA class II-IV and an ejection fraction (EF)<35% measured echocardiographically by the area-length method or Simpson's rule, or by radionuclide or angiocardiographic ventriculography. The diagnosis of IHD was established by either a previous MI (>2months from date of enrolment) or by coronary arteriography. In the diagnosis of DCM, coronary artery disease was excluded by a negative history for angina or MI, a negative thallium scan or coronary arteriography. The study was approved by the Ethics Committee of the Onassis Cardiac Surgery Centre and by the Hellenic National Drug Administration. All patients gave written informed consent.

Exclusion criteria were evidence of reversible ischaemia, mitral valvular disease or hypertrophic cardiomyopathy, atrial fibrillation, LV thrombi on echocardiography, other severe life-threatening diseases that might limit survival and/or compliance with the 2-year study period, contraindication to ASA or W, uncontrolled hypertension (BP>160/100mm Hg) or pregnancy. Patients already on antiplatelet or anticoagulant therapy could be randomised into the study, provided that the responsible physician did not consider continuation of previous treatment to be clearly indicated.

All patients who met the inclusion criteria underwent screening prior to enrolment, consisting of a clinical assessment, 12-lead ECG, X-ray and echocardiographic study. Additional tests consisted of haematology and biochemistry profiles, prothrombin time expressed as INR and recording of medications. Computerised randomisation was conducted by fax or by phone to the Athens University Coordinating Centre. 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 [12].

Routine follow-up examinations were conducted at 2, 4, 6, 8, 14, 18, and 22months, consisting of a clinical examination and an assessment of concomitant medication and drug compliance. At 12 and 24months, an extensive follow-up was performed with echocardiography, X-ray, haematology and biochemistry. The occurrence of clinical endpoints-stroke or peripheral or pulmonary embolism, death, non-fatal myocardial infarction, (re)-hospitalisation for exacerbation of heart failure or any other reason (e.g., arrhythmia) and any invasive diagnostic or revascularization procedures required-was recorded.

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. Placebo (Uni-Pharma, Greece) tablets were given daily or according to sham adjustment. Study drug administration was initiated immediately following randomisation and continued for up to 2 years. Study drug administration could be terminated prematurely due to an adverse event, significant bleeding, or if cardiac surgery was performed and unblinding was considered necessary by the patient's attending physician. If, at any time, there was a conflict between continuing the trial protocol and providing optimal patient care, optimal patient care was considered the priority.

The primary endpoint was any of the following: non-fatal stroke, peripheral or pulmonary embolism, myocardial (re)infarction, re-hospitalisation, exacerbation of heart failure, or death from any cause. Secondary endpoints have been reported [8]. Safety was assessed by comparing the incidence of all cerebrovascular events ascribed to intracranial haemorrhage and bleeding while on study drug.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Between January 1998 and August 1999, 197 patients were enrolled in HELAS. During follow-up, atrial fibrillation occurred in three patients, 1 in the IHD-ASA group, and 2 in the DCM-P group. These patients were withdrawn from the study. None of these patients had events up to exclusion time. Thus, 114 patients were classified as IHD and 80 were categorized as DCM. In the IHD arm, 61 patients were randomised to receive ASA, and 53 were randomised to receive W. In the DCM arm, 37 patients were randomised to receive W and 43 patients were randomised to receive placebo.

The baseline characteristics of the patients enrolled in the study are shown in Table 1. Patients with DCM were younger, more likely to be women and had a lower ejection fraction (EF), and larger left ventricular end diastolic (LVED) and end systolic volume than patients with IHD. Baseline medication did not differ markedly between groups. Overall, approximately 60% of patients were receiving an ACE inhibitor (Table 1).


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  		Table 1 Baseline characteristics of HELAS patients

 
3.1. Follow-up at 1 and 2years
There were 312 patient years of follow-up in the study. The average length of follow-up was 21.9months for the DCM-W group, 18.9months for the DCM-P group, 18.5months for the IHD-A group and 18.7months for the IHD-W group.

3.2. Endpoints
Due to the small number of patients enrolled, it was not possible to evaluate differences in efficacy between the treatment groups. A summary of the number of events per 100 patient years is shown in Table 2. Embolic events were relatively rare compared to death or hospitalisation for heart failure, occurring at a rate of approximately 2.2 events per 100 patient years. Only five strokes were recorded, there were no peripheral or pulmonary embolisms and two myocardial infarctions. The incidence of the primary endpoint, which was any of the following: non-fatal stroke, peripheral or pulmonary embolism, myocardial re-infarction, re-hospitalisation, exacerbation of heart failure, or death from any cause; was 14.9 events per 100 patient years for IHD-A, 15.7 events per 100 patient years for IHD-W, 8.9 events per 100 patient years for DCM-W and 14.8 events per 100 patient years for DCM-P patients. There were 9.6 deaths per 100 patient years for the entire population, predominantly due to worsening heart failure. Major haemorrhage only occurred in the warfarin groups, at a rate of 4.6 per 100 patient years and was usually due to over-anticoagulation but no case led to death.


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  		Table 2 Endpoint event occurrence per 100 patient years

 
3.3. Echocardiography
Echocardiographic follow-up at 1 and 2years showed no significant differences from baseline values in the measured variables apart from left ventricular ejection fraction (LVEF) (Table 3), which increased from 28.2±6 to 30.3±7 p<0.05, driven primarily by the increase in patients with DCM on warfarin (26.8±5.3 at baseline to 30.7±10 at 24months, p<0.05)). LVEF did not change in patients with IHD.


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  		Table 3 Comparison of ejection fraction (%) between study groups at baseline, 12 months and 24 months

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Our results are in accord with recent reviews that do not recommend anticoagulation in patients with heart failure due to the low incidence of embolic events. In a review of studies performed over the last 20years, Sirajuddin et al [6] report an incidence of thromboembolism of 1.5-3.2 events per 100 patient years. In WASH [17], which was very similar to the HELAS study, there were only four strokes in 627 patient years exposure (1.56/100 patient years, 27±1months follow-up). The investigators concluded that the benefits of warfarin for patients with heart failure in sinus rhythm have not been established.

We were very careful to exclude patients with atrial fibrillation from our study, as well as those with an intraventricular thrombus. However, data from two large studies did not identify atrial fibrillation as an independent risk factor of thromboembolism in heart failure [1]. Left ventricular mural thrombi may increase the risk of systemic embolization following myocardial infarction [1]; however, in chronic CHF, this concept may not apply as the pathophysiological substrate may differ [1]. Poor exercise capacity [1] and low LVEF [4,11] may indicate an increased risk of thromboembolic events.

The WASH and WATCH trials reported that aspirin resulted in a higher rate of heart failure hospitalisation [7,8]. Reservations on its use in heart failure have been raised previously [13,14] and are cited again in the ESC guidelines [9]. We could not identify a similar hazard in our study but the rate of use of ACE inhibitors was relatively low compared to previous studies. It is possible that doses of aspirin ≤100mg [12] may not show an adverse interaction with ACE inhibitors. Whether there is an important interaction between ACE inhibitors and aspirin or not remains controversial [15,16]. The wider use of clopidogrel in the future may circumvent this issue [1].

Another issue is the question of whether the administration of placebo is ethically justified in patients who have had a previous myocardial infarction. Several trials have shown that aspirin, clopidogrel and warfarin are effective when initiated shortly after an acute myocardial infarction. However, it is not clear whether these agents, especially aspirin, continue to exert benefit beyond the first few months of treatment [14]. In SOLVD [2], both anticoagulant and antithrombotic treatment seemed to improve survival in patients with heart failure. However, in the SOLVD meta-analysis [17], although total and cardiac mortality and deaths due to congestive heart failure and myocardial infarction decreased, the incidence of embolic complications did not decrease. Thus, the beneficial effects of anticoagulation remain to be explained.

Our patients were representative of patients included in the major heart failure trials as regards baseline characteristics and medications used, although β-blockers were underused, in accordance with prescribing practice at the time the study was initiated. ACE inhibitor use was suboptimal but was probably similar to that observed in clinical practice in the enrolling countries at that time. The uptake of both ACE inhibitors and β-blockers increased amongst participants during the course of the study In the recent EuroHeart Failure Survey Programme, β-blockers were given to only 36.9% of patients and ACE inhibitors to 61.8%, which is not very different from our study. However, a subgroup analysis of this study found that in patients with depressed left ventricular function ACE inhibitor usage was 82%.

We conclude that in patients with heart failure in sinus rhythm thromboembolic events are relatively uncommon and that there is no evidence, as yet, that the rate can be reduced by anticoagulant or antiplatelet treatment based on three randomised controlled trials. It is unclear, at present, whether the benefits outweigh the risks for any antithrombotic agent in patients with chronic heart failure in sinus rhythm.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Cleland J.G. Anticoagulant and antiplatelet therapy in heart failure. Curr Opin Cardiol (1997) 12:276–287.[Web of Science][Medline]
  2. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med (1991) 325:293–302.[Abstract]
  3. 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]
  4. Loh E., Sutton M.S.J., Wun C.C., et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med (1997) 336:251–257.[Abstract/Free Full Text]
  5. Cioffi G., Pozzoli M., Forni G., et al. Systemic thromboembolism in chronic heart failure. A prospective study in 406 patients. Eur Heart J (1996) 17:1381–1389.[Abstract/Free Full Text]
  6. Sirajuddin R.A., Miller A.B., Geraci S.A. Anticoagulation in patients with dilated cardiomyopathy and sinus rhythm: A critical literature review. J Card Fail (2002) 8:48–53.[CrossRef][Web of Science][Medline]
  7. Cleland J.G.F., Findlay I., Jafu S. The warfarin/aspirin study in heart failure (WASH): A randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J (2004) 148:157–164.[CrossRef][Web of Science][Medline]
  8. Cleland J.F.G., Ghosh J., Freemantle N., et al. Clinical trials update and cumulative meta-analyses from the American College of Cardiology: WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS-US, RIO LIPIDS and cardiac resynchronisation therapy in heart failure. Eur J Heart Fail (2004) 6:501–508.[Abstract/Free Full Text]
  9. The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). Eur Heart J (2005) 26:1115–1140.[Free Full Text]
  10. Cokkinos D.V., Toutouzas P.K. Antithrombotic therapy in heart failure: a randomized comparison of warfarin vs aspirin. Eur J Heart Fail (1999) 1:419–423.[Abstract/Free Full Text]
  11. Dries D.L., Rosenberg Y.D., Weclawin M.A., Domanski M.J. Ejection fraction and risk of thromboembolism events in patients with systolic dysfunction and sinus rhythm. Evidence for gender differences in the studies of left ventricular dysfunction trial. J Am Coll Cardiol (1997) 29:1074–1080.[Abstract]
  12. Guazzi M., Brambilla R., Reina G., et al. Aspirin-angiotensin converting enzyme inhibitor coadministration and mortality in patients with heart failure and dose-related adverse effects of aspirin. Arch Intern Med (2003) 163(13):1574–1579.[Abstract/Free Full Text]
  13. Cleland J.G., Bulpitt C.J., Falk R.H., et al. Is aspirin safe for patients with heart failure? Br Heart J (1995) 74:215–219.[Free Full Text]
  14. Cleland J.F.G. Is aspirin "the weakest link" in cardiovascular prophylaxis? The surprising lack of evidence supporting the use of aspirin for cardiovascular disease. Prog Cardiovasc Dis (2002) 44:275–292.[CrossRef][Web of Science][Medline]
  15. Teo K.K., et alfor the ACE Inhibitors Collaborative Group. Effects of long-term treatment with angiotensin converting enzyme inhibitors in the presence or absence of aspirin: a systematic review. Lancet (2002) 360:1037–1043.[CrossRef][Web of Science][Medline]
  16. Lapane K.L., Hume A.L., Barbour M.M., et al. Does aspirin attenuate the effect of angiotensin-converting enzyme inhibitors on health outcomes of very old patients with heart failure? J Am Geriatr Soc (2002) 50(7):1198–1204.[CrossRef][Web of Science][Medline]
  17. Al-Khadra A.S., Salem D.N., Rand W.M., et al. Warfarin anticoagulation and survival: a cohort analysis from the studies of left ventricular dysfunction. J Am Coll Cardiol (1998) 31:749–753.[Abstract/Free Full Text]

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