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European Journal of Heart Failure 2002 4(5):647-654; doi:10.1016/S1388-9842(02)00028-4
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© 2002 European Society of Cardiology

Antithrombotic therapy is associated with better survival in patients with severe heart failure and left ventricular systolic dysfunction (EPICAL study){star}

M. Echemanna,b, F. Allaa,b, S. Briançona, Y. Juillièrec, J.M. Viriona,b, P.M. Mertèsc, J.P. Villemotc, F. Zannadb,c,d,*,e EPICAL Investigators

a Service d'Epidémiologie et d'Evaluation cliniques, Hôpital Marin CHU Nancy, France
b Centre d'Investigation Clinique (CIC-INSERM) CHU Nancy, France
c Services de Cardiologie et de Chirurgie Cardiaque CHU Nancy, France
d Thérapeutique-Faculté de Médecine, Université Henri Poincaré Nancy, France
e Participating Hospitals in Lorraine France

* Corresponding author. CIC-INSERM-CHU Co no. 34, 54035 Nancy Cedex, France. Tel.: +33-3-83-65-66-25; fax: +33-3-83-65-66-19. E-mail address: f.zannad{at}chu-nancy.fr


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: In patients with congestive heart failure (CHF), clinical trials have demonstrated the benefit of a number of drugs on morbidity and mortality. Nevertheless so far, there is no published controlled study of long-term antithrombotic therapy in patients with CHF. The aim of this work was to identify the relationship between cardiovascular drug use, especially antithrombotic therapy, and survival of CHF patients in current clinical practice, using an observational, population-based database.

Methods: The EPICAL study (Epidémiologie de l'Insuffisance Cardiaque Avancée en Lorraine) has identified prospectively all patients with severe CHF in the community of Lorraine. Inclusion criteria were age 20–80 years in 1994, at least one hospitalisation for cardiac decompensation, NYHA III/IV HF, ventricular ejection fraction ≤30% or cardiothoracic index ≥60% and arterial hypotension or peripheral and/or pulmonary oedema. A total of 417 consecutive patients surviving at hospital discharge were included in the database. The average follow-up period was 5 years. Univariate Cox models were used to test the relationship of baseline biological and clinical factors to survival. Cardiovascular drug prescriptions were tested in a multivariate Cox model adjusted by other known predictive factors.

Results: Duration of disease >1 year, renal failure, serum sodium ≥138 mmol/l, old age, serious comorbidity, previous decompensation, high doses of furosemide and vasodilators use were independently associated with poor prognosis at 1 and 5 years. Oral anticoagulants, aspirin, lipid lowering drugs and beta-blockers use were associated with better survival. There was no interaction between aspirin and angiotensin converting enzyme inhibitor use on survival.

Conclusion: Antithrombotic therapy was associated with a better long-term survival in our study population of severe CHF. These results together with other previously published circumstantial evidence urge for a prospective, controlled and randomised trial specifically designed to evaluate optimal oral anticoagulants and aspirin in patients with congestive heart failure.

Key Words: Severe heart failure • Antithrombotic treatment • Survival • Epidemiology

Received July 19, 2001; Revised October 5, 2001; Accepted December 17, 2001


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Despite significant advances in medical and surgical management, the prognosis of chronic heart failure (CHF) remains poor. It is associated with poor functional capacity, decreased quality of life, and increased morbidity and mortality risk [1–3]

In observational databases, mortality rates in CHF patients are high, averaging 30–50% in 1 year. In clinical practice the mortality rate is much higher than in clinical trials [2–6].

Heart failure is associated with an hypercoagulable state, platelet activation and endothelial dysfunction [7]. Thromboembolic events may contribute to disease progression, ischemic events and cardiac sudden death. In the Framingham Heart Study, approximately 50% of all deaths in those who developed heart failure were ‘sudden’, this rate was also reported in clinical trials of drug therapy [8]. There is a need to identify patients at risk of thromboembolism in heart failure. Estimates vary regarding the risk of arterial and venous thromboembolism among these patients. Currently, the use of oral anticoagulants is usually indicated in CHF patients with atrial fibrillation, a previous thromboembolic event or known left ventricular thrombus. It is accepted, but of uncertain efficacy, in those with severe left ventricular dysfunction or dilatation and not indicated in unselected CHF patients with sinus rhythm [9].

The effects of long-term antiplatelet agents or oral anticoagulants (antithrombotic agents) on survival in patients with congestive heart failure have not been investigated in prospective controlled trials. Moreover, it has been suggested that the benefit of angiotensin converting enzyme inhibitor therapy may be decreased in CHF patients concomitantly treated with aspirin [10]. Epidemiological CHF studies carried out in the general population may be useful to analyse the relationship between cardiovascular drug use and patient survival. The EPICAL (Epidémiologie de l'Insuffisance Cardiaque Avancée en Lorraine) study afforded such an opportunity. The objectives of this study were to identify the social, demographic, laboratory, clinical, and therapeutic factors associated with long-term (5 year) survival of patients with severe heart failure due to left ventricular systolic dysfunction.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
The design and main results of the EPICAL study have been previously described [6]. Briefly, EPICAL was a prospective, observational, community-based epidemiological study undertaken to investigate the incidence, quality of life, prognosis and utilisation of healthcare resources associated with severe heart failure in a large regional community in France. Every private and public hospital in the Lorraine region, situated in the Northeast of France, participated in the study. During 1994, all patients presenting with severe heart failure and aged 20–80 years were systematically enrolled. The principal inclusion criteria included a left ventricular ejection fraction less than 30%, or a cardiothoracic ratio greater than or equal to 60% and hospitalisation for heart failure with dyspnea, stage III or IV of the NYHA classification, and arterial hypotension or peripheral and/or pulmonary oedema. In all, 2576 patients were registered, 499 of whom fulfilled all inclusion criteria and were included between January 1 and December 31, 1994. The present study concerned a subgroup of 417 patients surviving the index hospitalisation whose medical treatment records were complete (Fig. 1).


Figure 1
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  		Fig. 1 Selection process for patient enrolment.

 
2.1. Data collection
The following data were recorded during hospitalisation: administrative and social characteristics, medical history; as well as clinical and laboratory findings and drugs prescribed at discharge from the index hospitalisation (trade names, dosages and routes of administration). Data were collected on standardised forms with predefined items. The hospitalisation summary, contained in the discharge letter, was used for data capture after verification for coherence. One and 5 years after enrolment, survival status of all patients was recorded from administrative data and family doctors.

2.2. Data analysis
Bivariate statistical analysis (Pearson {chi}2-test or Fisher exact test) were applied to compare social, demographic, laboratory, clinical and therapeutic characteristics between patients taking or not taking antithrombotic therapy

Survival rates were estimated with Kaplan–Meier analysis. The average follow up period of patients was 5 years. An univariate analysis was performed to identify which variables had a significance level <0.20 (Mantel–Cox test). A forward stepwise multivariate Cox model was used to identify the influence of clinical and biological baseline characteristics on survival (age, gender, etiology, previous decompensation, interventional treatment, angioplasty and pace-maker, serious comorbidity, type I and II diabetes, cardiac rhythm, heart conduction disturbances, history of phlebothrombosis or lower limb arthritis, heart rate, ejection fraction, Quetelet index, history of renal failure and/or serum creatinine >180 µmol/l, duration of disease, alcohol habit, smoking, hyperlipidemia, serum potassium and sodium). Then, each therapeutic drug class was tested separately in the final multivariate Cox model. Finally, a last multivariate Cox model identified the relations between survival and cardiovascular drugs used at hospital discharge after adjusting for other predictive factors at 5 years. Results are reported as Relative Risk (RR) of death with 95% Confidence Interval (CI). The significance level for the variables retained in the multivariate models was set at 0.10 and BMDP software was used for statistical analysis [11].


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
The clinical features describing the study population are summarised in Table 1. Ninety-eight patients (23.4%) were hospitalised in an academic hospital. Cardiovascular drug prescriptions at hospital discharge are described in Table 2.


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  		Table 1 Clinical characteristics of patients surviving at hospital discharge

 


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  		Table 2 Cardiovascular drugs at hospital discharge

 
Angiotensin-converting enzyme inhibitors were used in 312 patients (74.8%), aspirin in 129 (30.9%) and oral anticoagulants in 118 (28.3%). Among patients receiving an oral anticoagulant, only 10 patients also took aspirin. Thus, antithrombotic therapy (oral anticoagulants or aspirin) was used in 237 patients (56.8%). We defined three dose levels for furosemide and two dose levels for angiotensin converting enzyme inhibitors according to the usual recommendations [19].

The social, demographic, laboratory, clinical and therapeutic factors significantly related to oral antithrombotic therapy prescription at the 0.05 significance level in univariate analysis are presented in Table 3.


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  		Table 3 Characteristics of patients with antithrombotic therapy

 
There were no differences for age (≤60 years, 57.3%; [60–70] years, 57.1%; [70–80] years, 56.1%; P=0.97), history of phlebo-thrombosis (P=0.47) or heart conduction disturbances (normal, 54.3%; disorders, 57.8%; P=0.22) in antithrombotic therapy users compared to non-users. Nevertheless, there were some expected differences between patients with and without antithrombotic therapy in univariate analysis. For example, patients on oral anticoagulants had more frequently atrial arrhythmias and ischemic heart disease etiology.

Overall, 1- and 5-year survival rates were, respectively, 75% (105 deaths), and 36% (257 deaths) in the studied cohort. The use of antithrombotic therapy was significantly associated with a better survival (Fig. 2).


Figure 2
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  		Fig. 2 Kaplan–Meier survival of patients taking or not taking antithrombotic therapy (oral anticoagulants or aspirin) at 5 years.

 
The influence between survival, cardiovascular drugs, clinical and biological baseline characteristics in multivariate analysis are described in Table 4. Recent diagnosis of heart failure (<1 year), age below 70 and over 60 years, serum sodium ≥138 mmol/l and absence of renal impairment, serious comorbidity or no previous decompensation were associated with better survival.


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  		Table 4 Relationship between cardiovascular drugs use and survival after adjustment for biological and clinical mortality risk factors (multivariate analysis)

 
Use of aspirin, oral anticoagulants, lipid lowering drugs and beta blockers were independently associated with better survival at 5 years after adjustment for other known factors. No significant interaction between aspirin and ACE inhibitor therapy on survival was found.


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
There are few available pragmatic, community-based and observational epidemiological studies reporting full data on cardiovascular drug prescriptions. The EPICAL study covers a wide geographical area and diverse hospital types. To our knowledge, our study is the only one, which reports at 5 years, the relation between survival and cardiovascular drug use, with special reference to antithrombotic therapy use at hospital discharge, in patients with advanced heart failure.

Although there has never been a randomised trial of aspirin for thromboembolism risk reduction, the efficacy of aspirin as an antithrombotic agent is well established. Moreover, aspirin can cause bleeding complications but this occurs less frequently than with anticoagulant agents. In our study, only a few patients received concomitant aspirin and an oral anticoagulant: 8% in our study as compared with 18% in the SOLVD trial [12]. Whether oral anticoagulants should be preferred to aspirin in patients with CHF is still an open question [13].

Due to the observational design of the study, patients were not randomised to receive antithrombotic therapy. As a consequence, significant differences in baseline characteristics were inevitable and patients taking antithrombotic agents were probably at lower risk as can be judged from their baseline clinical and biological factors. Therefore, using multivariate Cox models, we studied associations between drug treatment and survival after adjustment for other classical biological and clinical prognostic factors such as age, renal function, serum sodium level, and the duration of the disease [6,8,14,15].

As could be expected, high doses of furosemide were associated with poor prognosis, reflecting the fact that higher doses are used in severe patients. Alternatively, diuretic therapy could have contributed to the progression of the disease by activating neuroendocrine systems [14]. Even though in 1994 only a few heart failure patients took beta blockers, they were associated with a lower mortality in our study, in agreement with recent randomised trials [16]. These results underline the usefulness of observational studies such as EPICAL. Moreover, oral anticoagulants, aspirin and lipid lowering drugs were associated with better survival in patients with advanced heart failure in our observational study.

Oral anticoagulants and aspirin were each independently associated with better long-term survival estimated as a two-fold increase at 5 years. Our results extend the findings of the SOLVD clinical trial subgroup analyses [warfarin RR=0.76 (0.65–0.89)] and antiplatelet agents [RR=0.82 (0.73–0.92)] at an average 3 years follow-up [12,17]. In the SAVE trial which included post-myocardial infarction patients with left ventricular dysfunction ≤40% [18], patients receiving warfarin or aspirin had a reduced stroke relative risk (81 and 56%, respectively) as compared to patients receiving no antithrombotic therapy. Our results suggest that the benefit of antithrombotic therapy may be even greater in ‘real world’ patients compared to patients selected in clinical trials.

Angiotensin converting enzyme inhibitors were associated with a better survival in univariate analysis, but not in the multivariate Cox model because of the negative correlation between angiotensin converting enzyme inhibitor use and renal failure. Indeed, we have previously demonstrated in the same EPICAL cohort that renal failure was associated with a higher rate of non-prescription of angiotensin converting enzyme inhibitors [19]. The interaction between aspirin and angiotensin-converting enzyme inhibitors is controversial. Clinical trials have suggested a lower benefit of ACE inhibitors in patients treated with aspirin [10,12]. In our study no interaction was identified.

In recent heart failure trials, the rate of stroke was relatively low, ranging from 1.3 to 3.5% per year, and was not related to the severity of heart failure [20], although there is some evidence that the rate of stroke was inversely proportional to the ejection fraction [18,21]. The incidence of stroke and thromboembolism is significantly higher in the presence of atrial and left ventricular dilatation, particularly in severe left ventricular dysfunction. Thus, it may be postulated that oral anticoagulants may be useful, at least in patients at highest risk for thromboembolism (e.g. those with atrial fibrillation, mechanical valve replacement, or known thrombus). Unfortunately, oral anticoagulant use exposes patients to an increased risk of major bleeds and requires supervision of treatment in order to avoid potential hazardous drug interactions.

To date, it is not advisable to treat all severe heart failure patients with ventricular dysfunction with oral anticoagulants, because neither the decision to initiate anticoagulation nor the intensity of anticoagulation has been specified or controlled as part of any study protocol for CHF patients.

The combination of atrial fibrillation and heart failure is associated with a particularly high risk of thromboembolism, which is reduced by long-term treatment with warfarin. Nevertheless, there is conflicting evidence of benefit from routine antithrombotic treatment in patients with heart failure in sinus rhythm although anticoagulation should be considered in the presence of a mobile ventricular thrombus, atrial fibrillation, and severe left ventricular dilatation.

Large scale, prospective randomised controlled trials of antithrombotic treatment in heart failure are in progress, such as the WATCH (Warfarin and Antiplatelet Therapy in Chronic Heart failure) study and HELAS (HEart failure Long term Antithrombotic Study) [22]; the full results are awaited with interest [20,23].


   5. Conclusion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
Although EPICAL is an observational study, our results suggest that antithrombotic therapy (oral anticoagulants and aspirin) may be useful as part of the treatment of patients with advanced heart failure. These results support the conduct of a clinical trial investigating the effects of long-term antithrombotic therapy in patients with heart failure. The results of such trials will determine which antithrombotic therapy, if any, should be indicated in the routine management of patients with heart failure.


   Acknowledgements
 
The EPICAL study was supported by a grant from the Hospital Program for Clinical Research (PHRC 1993) of the French Ministry of Health and from l'Association de Recherche et d'Information Scientifique en Cardiologie (ARISC).


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
{star} Steering committee: Prof. E. Aliot (Nancy), Dr Ch. Breton (St Max), Prof. S. Briançon (Nancy), Prof. Y. Juillière (Vandoeuvre), Dr K. KhalifÈ (Metz), Dr P.M. Mertès (Vandoeuvre), Dr J.L. Neimann (Metz), Prof. J.P. Villemot (Vandoeuvre), and Dr F. Zannad (Nancy). Investigators committee: Dr S. Allam (Verdun), Dr Ph. Admant (Epinal), Dr N. Baille (Metz), Dr Ph. Bellanger (Chaumont), Dr R. D'Hôtel (Remiremont), Dr P. Dambrine (Freyming Merlebach), Dr J.F. Dodet (Nancy), Dr M. Graille (Nancy), Prof. M. Kessler (Nancy), Dr J.L. Neimann (Metz), Dr G. Rebeix (St Dizier), Dr Royer (Saint Avold), Dr J.P. Saulnier (Epinal), Dr J.Y. Thisse (Thionville), Dr B. Trutt (Strasbourg), Dr Ph. Vidal (Bar le Duc), M. Ch. Vuillemin (Nancy) Scientific Advisory Board: Prof. F. Delahaye (Lyon), Prof. P. Ducimetière (Paris), Dr F. Fagnani (Cachan), and Prof. L. Guize (Paris). Investigating participating centers: CHU (teaching hospitals) de Nancy: Hôpital Jeanne d'Arc, Hôpital Central, Hôpitaux de Brabois; Hôpitaux (community hospitals) de: Bar le Duc, Boulay, Briey, Creutzwald, Epinal, Forbach, Lunéville, Metz (Bon Secours, Saint Andre, Sainte Blandine, Hôpital d'instruction des Armées Legouest), Mont Saint Martin, Neufchâteau, Pont-à-Mousson, Rambervillers, Remiremont, Saint Avold, Saint Dié, Saint-Dizier, Sarrebourg, Sarreguemines, Saverne, Thionville, Verdun, Vittel; Cliniques (private hospitals): C. Bernard, Metz, Essey, Peupliers, Villerupt, Notre Dame, Saint-Dié; Centres de réadaptation d'Abreschviller et de Niderviller. Back


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

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