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European Journal of Heart Failure 2001 3(3):265-269; doi:10.1016/S1388-9842(01)00140-4
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© 2001 European Society of Cardiology

Thromboembolism in heart failure, old ideas and new challenges

Richard Isnard* and Michel Komajda

Cardiology Department, Hôpital Pitié-Salpêtrière 47 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France

* Corresponding author. IFR 14 ‘Muscles, cœur, vaisseaux’. Tel.: +33-142176727; fax: +33-142176719 E-mail address: richard.isnard{at}psl.ap-hop-paris.fr ((R. Isnard).


   Abstract
Top
 Abstract
1. Introduction
 2. Thromboembolism in heart...
 3. Thromboembolism in heart...
 References
 
Until now, the administration of antithrombotic therapy in patients with congestive heart failure has not been well codified. The incidence of thromboembolic complication, such as stroke, peripheral or pulmonary embolism, is regarded as too low to justify the use of anticoagulation in non-selected patients. However, other thrombotic complications may occur especially in patients with ischemic heart failure and represent potential targets for antithrombotic therapy. The objective of this paper is to review the available evidence in the absence of the results of large ongoing trials.

Key Words: Congestive heart failure • Anticoagulation • Antithrombotic therapy

Received August 2, 2000; Revised December 22, 2000; Accepted February 12, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Thromboembolism in heart...
 3. Thromboembolism in heart...
 References
 
It is well recognized that patients with heart failure (HF) have an increased risk of thromboembolic complications. For prevention purposes, some patients receive warfarin, others receive antiplatelet agents or no antithrombotic therapy. Anticoagulation with warfarin is mandatory in patients with heart failure and atrial fibrillation in the absence of contraindications. However, the decision whether to give antithrombotic therapy to patients with heart failure in sinus rhythm, essentially depends on the physician's experience and his own evaluation of the thromboembolic risk of each patient. Unfortunately, until now neither randomized nor controlled studies have been available to guide the physician's prescription. The objective of this paper is to review the available evidence in the absence of the results of large ongoing trials.


   2. Thromboembolism in heart failure: old ideas
Top
 Abstract
 1. Introduction
 2. Thromboembolism in heart...
3. Thromboembolism in heart...
 References
 
When considering thromboembolism in heart failure, the first idea which occurs is the risk of thrombus formation in the cardiac chambers and the risk of thrombus migration in the systemic or pulmonary circulation. Intra-cardiac thrombi were first demonstrated by autopsy studies, then during cardiac surgery and finally by cardiac imaging, especially echocardiography. The risk of thromboembolism in HF is multifactorial: low cardiac output through dilated cavities of poor contractility; regional wall motion abnormalities; and atrial fibrillation are the main factors. Abnormal endocardial surface after myocardial infarction or in inflammatory or infiltrative cardiomyopathy may also favour the formation of clots. It has also been suggested recently that patients with HF may be in a hypercoagulable state [1,2]. Furthermore, venous stasis due to circulatory slowing and reduced activity may result in pulmonary embolism.

Therefore, thromboembolism in HF has usually been defined as the occurrence of stroke, peripheral embolism or pulmonary embolism.

In autopsy studies, the incidence is very high; Roberts reported a frequency of 37% in 152 patients with dilated cardiomyopathy [3]. However, it is difficult to extrapolate from these studies if death is related to a thromboembolic complication or if the presence of thrombus in the cardiovascular system is only a marker of end-stage heart failure. On the opposite, several small clinical studies [4–7] have reported a relatively low incidence of clinical thromboembolic complications, ranging from 1.7 to 3.5% a year (Table 1). A metaanalysis reported an incidence of stroke and peripheral arterial embolism of 1.9% in patients not receiving anticoagulant therapy [8].


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  		Table 1 Incidence and type of TE events in small studies (>100 patients)

 
Large scale therapeutic trials provided the opportunity to follow for several years large cohorts of patients with heart failure or asymptomatic left ventricular systolic dysfunction following or not myocardial infarction [9–12]: even if there were some slight differences in the methodology (some studies reported only strokes or fatal strokes, others reported all the events including pulmonary events) it is noteworthy that the incidence is very close to the previous values (approx. 2% a year) (Table 2). This incidence is not significantly different according to whether patients received warfarin, which does not mean that warfarin is not efficient, as we can guess that patients receiving warfarin have the higher risk of thromboembolism. Information about the proportion of the different types of thromboembolic events is available from VHeF-T and SOLVD trials [10,11]: stroke represents 60–80% of these events whereas peripheral and pulmonary embolism only 10–20% each. Therefore, the annual incidence of stroke is less than 2% and not all of the cases are related to cardioembolic events, especially in patients with ischemic heart disease in whom associated cerebrovascular atherosclerosis may sometimes be the cause of the events.


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  		Table 2 Incidence and type of TE events in large scale therapeutic trials

 
To summarize, there is agreement in all the published studies for the expected incidence of clinical TE events to be approximately 2% a year. However, the annual incidence of major haemorrhages during anticoagulant therapy reported in recent studies ranges from 2.3 in the randomized controlled study in which patients are highly selected, to 5.3% in population-based studies and 6.8% in elderly patients [13–16]. Therefore, given the low incidence of thromboembolic events in unselected patients and the risk of major bleedings with the anticoagulant, it is generally admitted that anticoagulation must be reserved for patients with HF with a very high risk of thromboembolism. In this setting, atrial fibrillation, mobile thrombus in the cardiac chambers and previous cardioembolic events are factors that predispose to TE events. The incidence of atrial fibrillation in HF grows with the stage of the disease and the age of the patient, ranging from 10% in the SOLVD study (mild to moderate HF, mean age 60) [17], to 30% in the ELITE II study (mild to moderate heart failure, mean age 73) [18], and to 50% in the CONSENSUS study (severe HF, mean age 70) [9]. Other risk factors, such as low left ventricular ejection fraction or low peak oxygen consumption, have also been identified, suggesting that patients with severe left ventricular systolic dysfunction or heart failure, are considered as being at high risk for thromboembolism, but there is no clear cut-off values for identifying high-risk subgroups.


   3. Thromboembolism in heart failure: new challenges
Top
 Abstract
 1. Introduction
 2. Thromboembolism in heart...
 3. Thromboembolism in heart...
References
 
As a matter of fact, we must be very cautious with a too simplistic interpretation of the previous results. Firstly, some thromboembolic events may have been underestimated or misdiagnosed. This is probably the case for pulmonary embolism, as this diagnosis is often difficult in clinical practice. This is particularly true in patients with heart failure, in whom episodes of acute heart failure may be triggered by pulmonary embolism and sudden death may result from massive pulmonary embolism. This is borne out by the necropsic data from Roberts showing that unlike the findings from clinical studies, pulmonary embolism is more frequent than systemic embolism [3]. The same might be true for stroke as it has been shown using brain nuclear imaging that clinically silent strokes are more frequent in patients with dilated cardiomyopathy than in controls [19].

Secondly, the relevant target for antithrombotic therapy might be not limited to the previously defined thromboembolic events. To date, ischemic heart disease is still the leading cause of HF. In these patients, acute coronary events such as unstable angina or myocardial infarction may occur and represent a common and severe thrombotic complication [20]. Conversely, some sudden deaths whether arrhythmic or not, are related to coronary thrombosis or to massive pulmonary embolism. This has been clearly shown in patients who experienced a cardiac arrest without previous known cardiovascular disease, in whom significant coronary artery disease is found in 40–60% with a high proportion of coronary thrombosis [21,22]. As regards mechanisms of sudden death in heart failure, data are scarce: Stevenson reported 29 cardiac arrests in hospitalized but stable patients with HF: myocardial ischemia is reported as the trigger in approximately 20% of the cases [23]. Recently, Urestsky et al. reported a 33% prevalence of acute coronary findings at autopsy in 171 patients from the ATLAS study. This prevalence was 54% in patients with ischemic heart failure who died suddenly [24]. These observations raise an interesting hypothesis: if we assume that thrombosis is involved not only in acute coronary events but also in sudden deaths in patients with ischemic heart disease, the challenge of antithrombotic therapy in heart failure is therefore not limited to classical thromboembolic complications.

In the WARIS study, warfarin anticoagulation when started within 4 weeks after acute myocardial infarction reduces mortality, fatal and non-fatal coronary events, pulmonary embolism and stroke [25]. Other studies also demonstrated a reduction of recurrent myocardial infarction achieved with anticoagulant given after acute myocardial infarction. Recent cohort post-hoc analysis from SOLVD suggested that warfarin prescription at baseline was associated with a decrease in sudden death, fatal myocardial, and hospital admissions for non-fatal MI [26]. Similar results were observed with aspirin [27].

What is the incidence of acute coronary events and sudden death in heart failure? In the SOLVD trial, in which almost 75% of patients had ischemic heart disease, the annual incidence of unstable angina and total myocardial infarction was approximately 5 and 3%, respectively, including 1% of fatal myocardial infarction [20]. Comparable rates of fatal myocardial infarction (0.8–1.3% a year) have been reported in other recent heart failure studies [18,28,29]. The incidence of sudden death ranges between 3 and 6% a year in CHF in the same recent studies including those with betablockers [18,28,29]. If we assume that 20–50% of these sudden deaths are triggered by a thrombotic event, 0.6–3% of sudden death per year could be prevented by antithrombic therapy. Thus, when adding the incidence of classical thromboembolic events to the incidence of coronary events and sudden death presumably related to coronary thrombosis, the estimated incidence of thromboembolic events could reach 12% a year (Table 3), a quite high incidence that represents a real challenge for antithrombotic therapy.


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  		Table 3 Estimated incidence of all thromboembolic events in patients with ischemic heart failure

 
Which antithrombotic therapy should we prefer in this perspective? Antiplatelet agents have the advantage of being efficient in coronary and cerebrovascular disease and do not increase the risk of bleeding complications too much. However, they are less efficient than warfarin for preventing thrombus formation in the cardiac chambers and a potential negative interaction between aspirin and angiotensin converting enzyme inhibitors has been shown, even if its real clinical relevance in terms of morbidity and mortality remains unknown. We hope that results of the on going WATCH trial will provide definitive answers to all these questions.


   References
Top
 Abstract
 1. Introduction
 2. Thromboembolism in heart...
 3. Thromboembolism in heart...
 References
 

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