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Anticoagulation in patients with heart failure: who, when, and why?
Ajith Nair1,
,
Brett Sealove1,,
Jonathan L. Halperin2,
Geoffrey Webber1 and
Valentin Fuster2,*
1 Mount Sinai Medical Center, New York, NY, USA
2 Zena and Michael A. Wiener Cardiovascular Institute, Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai Medical Center, New York, NY, USA
* Corresponding author. Tel: +1 212 241 7911; fax: +1 212 423 9488. E-mail address: valentin.fuster{at}mssm.edu
 |
Abstract
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The mortality rate associated with advanced heart failure (HF)
remains high. Although pharmacological and device therapy have
improved survival in patients with HF or depressed systolic
function, antithrombotic therapy is controversial. Autopsy studies
demonstrated a high incidence of arterial and venous thrombo-embolism
in patients with HF, but secondary analyses of clinical trials
have suggested lower rates of stroke and clinical thrombo-embolic
events, perhaps because a relatively high percentage of patients
had atrial fibrillation (AF) and were treated with anticoagulants.
Although anticoagulation is recommended for patients with AF
who have HF or reduced left ventricular ejection fraction (EF),
guidelines vary regarding antithrombotic therapy for patients
without AF. Those with ischaemic heart disease are typically
treated with a platelet inhibitor such as aspirin. Further studies
are needed to define the incidence of venous or right-sided
intracardiac source of thrombo-embolism in patients with HF
or reduced EF, as this may be an under-recognized cause of morbidity
and mortality. Ongoing studies will provide more insight into
the selection of optimum antithrombotic therapy and better assess
the net impact of such therapy on event-free survival in patients
with advanced HF.
Key Words: Heart failure • Anticoagulation • Aspirin • Thrombo-embolism • Atrial fibrillation
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Prevalence, aetiology, and mortality in patients with heart failure
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Heart failure (HF) is a growing epidemic affecting an estimated
five million Americans, and an even larger number have impaired
left ventricular (LV) ejection fraction (EF) without HF.
1 In
patients over 65 years old, HF is the most common reason for
hospital admissions,
2–4 and although the incidence of
HF has remained stable over 20 years, its prevalence is increasing
as the population ages. The aetiology of HF is varied, with
myocardial infarction (MI) and hypertension the most common
causes in developed countries and rheumatic heart disease, valvular
disease, and infections such as Chagas disease more prevalent
in developing countries. In the United States in 2001, over
57 000 patients died of complications of HF.
5 Despite optimal
pharmacological treatment and device therapy, the mortality
rate in patients with advanced HF remains high. In patients
enrolled in trials designed to evaluate the efficacy of implanted
automatic cardioverter-defibrillators (ICD), the average 2-year
mortality across all groups was 14.3% (vs. 17.3% with conventional
treatment).
6 Although many of these deaths were attributed to
progressive HF, the actual cause is often uncertain.
7 Older
autopsy studies found a high incidence of thrombo-embolism,
including cerebral, systemic, and pulmonary embolism, in patients
with HF.
8–11 In clinical studies, however, reported rates
of thrombo-embolic events in patients with HF have been lower,
ranging from 1.5 to 3.5 per 100 patient–years.
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Predisposition to thrombo-embolism
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According to the triad of factors predisposing to intravascular
thrombosis described by Rudolph Virchow more than 150 years
ago,
12 the risk of thrombo-embolism is elevated in patients
with HF. Stasis of blood in dilated, hypokinetic cardiac chambers
leads to formation of fibrin-rich thrombus (as opposed to platelet
thrombus). Endothelial dysfunction
13–15 is associated
with HF and elevated levels of prothrombotic markers suggests
that a hypercoaguable state may also exist in this population.
16–20 In a study of 25 patients with dilated cardiomyopathy, LV thrombus
was identified in 11 (44%) over a mean follow-up of 21.5 months,
and thrombus was more frequent in patients with fractional shortening
below 10%.
21
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Prevalence of thrombo-embolism in patients with HF
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The relatively high incidence of thrombo-embolism in patients
with HF reported in early case series may have reflected the
higher prevalence of rheumatic heart disease and under-treatment
of patients with atrial fibrillation (AF) with anticoagulant
drugs. In a 1958 study, 36 of 72 patients with idiopathic dilated
cardiomyopathy had evidence of cerebral or systemic embolism
at autopsy, and 34 had pulmonary embolism.
9 In a retrospective
analysis conducted in the early 1980s, Fuster
et al. reported
an 18% prevalence of systemic arterial embolism in patients
with idiopathic dilated cardiomyopathy who were not given anticoagulation
therapy (3.5%/year) and none in anticoagulated patients.
10 AF
was identified in 24 patients, 33% of whom developed thrombo-embolic
events (
Table 1). While two-thirds of patients with thrombo-embolism
had AF and were not treated with anticoagulation, one-third
of those who developed thrombo-embolism did not have documented
AF. Clinical or autopsy evidence of thrombo-embolism was found
in 60% of 131 patients with dilated cardiomyopathy in another
study; pulmonary embolism (with or without systemic embolism)
was found in 84% and right-sided intracardiac thrombus was identified
in 68% of these cases.
11
The incidence of clinical thrombo-embolic events in patients
with HF has been lower in more recent case series than in foregoing
studies. In an analysis of 224 patients awaiting cardiac transplantation
with mean EF 20±7%, thrombo-embolic events occurred in
six patients (3%) over a mean follow-up of 301±371 days
(3.2%/year); of these, four involved the central nervous system
and two were peripheral arterial emboli.
22 Eighty-two patients
were receiving warfarin for AF, LV mural thrombus, or prior
thrombo-embolism. One of the six patients who experienced embolic
episodes was receiving warfarin. The study did not evaluate
the occurrence of venous thrombo-embolism. In another group
of 164 patients awaiting transplantation with EF below 20% but
no documented AF or previous stroke, 34% had evidence of asymptomatic
infarction on brain imaging.
23 In a study of 264 ambulatory
patients with HF (mean EF 27%), the rate of stroke or transient
ischaemic attack was low (1.7%/year) over a mean of 24±9
years.
24 LV thrombus was identified in half the cases, and patients
with thrombus had a significantly higher rate of thrombo-embolism
(5.3%/year) than those without thrombus (
P=0.03). In a prospective
investigation of 406 consecutive patients with chronic HF (EF
23±8%), 11 patients (2.7%) developed thrombo-embolic
events over 16±11 months; seven of these occurred during
anticoagulant therapy.
25 Thrombo-embolic event rates were higher
in patients with AF, more severe haemodynamic impairment, and
impaired exercise capacity. Although these studies found lower
rates of thrombo-embolism (
1.5%/year in aggregate) than suggested
by earlier autopsy studies, anticoagulation was not randomized
and may have been influenced by the intrinsic risk of thrombo-embolism.
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Venous and right-sided intracardiac thrombo-embolism and sudden death in patients with HF
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Venous thrombo-embolism (VTE) remains an important cause of
morbidity and mortality, and HF has long been implicated as
a risk factor. In a series of 198 patients admitted to a coronary
care unit with decompensated HF, 9.1% had pulmonary embolism
(PE) despite therapy with enoxaparin in prophylactic dosage.
26 These data suggest that higher intensity anticoagulation may
be warranted for prevention of VTE in such high-risk patients.
In a retrospective analysis of an outpatient population, HF
was a predictor of VTE [odds ratio (OR) 2.6] and risk was inversely
related to LV function (greater in those with EF below 20%).
27 In another series, systemic embolism and PE were identified
in 45% of 38 patients with dilated cardiomyopathy.
28 Although
lower extremity venous thrombosis and the right ventricle have
not been a primary focus of study, both are potential sources
of thrombus formation in patients with HF.
Although most cases of sudden death in patients with HF are attributed to ventricular fibrillation, and this is the rationale for prophylactic ICD therapy in selected patients, intractable bradyarrhythmias or electromechanical dissociation (EMD) may be responsible for many of these deaths.27 Interrogation of ICDs from 1729 patients followed 6 years, during which 119 deaths (83 of cardiac aetiology) occurred, found no tachyarrhythmias within the hour prior to death in 46 (55%) patients.29 This implies that the deaths were more likely associated with bradyarrhythmias or EMD. Since autopsies were performed after only 15% of deaths, the attribution of 4.2% to pulmonary embolism may have been an underestimate. The results of a recent meta-analysis have similar implications. Half the deaths in a population of patients with HF were attributed to ‘pump failure’ (progressive cardiac dysfunction), whereas the remainder were sudden deaths ascribed to tachyarrhythmia.30 In patients without ischaemic heart disease, neither progressive myocardial dysfunction nor lethal ventricular arrhythmias are directly amenable to prevention by therapy with anticoagulant or platelet-inhibitor drugs, unless pulmonary embolism is more frequent than presently estimated.
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HF and AF
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AF is common in patients with HF, especially among the elderly,
31 occurring in up to 25% of cases.
32,33 The concurrence of HF
and AF approximately doubles the risk of stroke and systemic
embolism associated with either condition alone,
34 and HF is
an independent risk factor for thrombo-embolism in patients
with AF.
33,35 There is little to suggest, however, that among
patients with AF the presence of HF or impaired LV function
contributes more to the overall risk of thrombo-embolism than
other common co-morbidities such as advanced age (>75 years),
hypertension, or diabetes mellitus, in the absence of a previous
thrombo-embolic event. Although in population-based studies
such as the Framingham Heart Study conducted more than a generation
ago, an increased risk of stroke was reported in association
with cardiac failure (OR 4.1 in men and 2.8 in women),
36 the
incidence of thrombo-embolism in patients with HF in the absence
of AF is not known.
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Anticoagulation in patients with HF
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The Survival and Ventricular Enlargement (SAVE) trial enrolled
patients after acute MI with EF below 40%.
37 Over 5 years, the
rate of stroke was 1.5%/year. LV function, older age, and non-use
of aspirin and/or anticoagulants were independent risk factors
for thrombo-embolism. For each 5% decrease in EF, there was
an 18% increase in stroke rate. When further stratified, patients
with EF <28% had a 5-year cumulative stroke risk of 8.1%
compared with 4.1% for those with EF >35% (
Figure 1).
15 Those treated with anticoagulation showed a reduction in the
rate of stroke by 81%, when compared with 56% for those who
were given antiplatelet therapy.
View larger version (10K):
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Figure 1 Kaplan–Meier estimate of the cumulative stroke rate among patients in the SAVE trial (from Loh et al.38).
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The Studies of LV Dysfunction (SOLVD) trial was designed to
assess the efficacy of enalapril on morbidity and mortality
in patients with systolic dysfunction. Enrolled patients had
an EF below 35%, regardless of aetiology, and patients with
AF were excluded from the analysis of thrombo-embolism. The
incidence of ischaemic stroke and systemic embolism was similar
to that in the SAVE trial, 2.4%/year among women and 1.8%/year
in men.
38 The annual risk of stroke was 1.5% in patients with
mild to moderate systolic dysfunction and 4% in those with severely
reduced EF, as compared with 0.5% in the general population.
39 The inverse relation between systolic function and risk of thrombo-embolism
was seen in women (in whom the incremental risk was 53% for
each 10% reduction in EF) but not in men. The risk of PE was
also greater in women than in men. A subsequent secondary analysis
of the SOLVD data found, after adjustment for baseline differences,
that anticoagulation therapy with warfarin was associated with
a relative risk reduction of 24% for all-cause mortality.
40 Therapy with a platelet inhibitor was associated with a 24%
reduction in SCD. With regard to thrombo-embolism, the risk
reduction was 53% among women (
P=0.03) and 23% in men (
P=0.06).
Antithrombotic therapy was not randomized in either the SAVE
or SOLVD trials, nor was the quality of anticoagulation systematically
monitored in patients given warfarin. Furthermore, the occurrence
of thrombo-embolic events was not a primary outcome. Thus, it
is not possible to draw firm conclusions about the safety and
efficacy of anticoagulation or antiplatelet therapy from the
available data.
In the first Veterans Affairs Vasodilator-HF Trial (V-HeFT I), the incidence of thrombo-embolic events (stroke, systemic embolism, and pulmonary embolism) without warfarin therapy was 2.7%/year over an average of 2.28 years in patients with HF. In V-HeFT II, the rate was 2.1%/year in males following an average of 2.56 years.41 There was no difference in the rate of thrombo-embolism in patients treated with warfarin or between patients with non-ischaemic vs. ischaemic aetiology of HF, but thrombo-embolism was more frequent in patients with lower peak exercise oxygen consumption. Warfarin therapy was not randomized (19.5% of patients in V-HeFT I and 21.4% of patients in V-HeFT II were receiving anticoagulation therapy at entry). During the trial, warfarin use was not associated with lower rates of thrombo-embolism in patients with HF. A criterion for entry into these trials was an EF less than 45%; patients with more severely impaired ventricular function might be at higher risk and benefit more from anticoagulation.
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Bleeding associated with anticoagulation
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Practitioners typically hesitate to prescribe anticoagulation
because of concerns about bleeding, especially among elderly
patients. Intracerebral haemorrhage (ICH) is the most feared
complication; warfarin (INR 2–3) doubles the risk, whereas
aspirin increases the risk by 40%.
42 The concomitant use of
aspirin and warfarin is associated with an estimated two- to
three-fold increase in ICH when compared with warfarin alone.
43 The risk of intracranial haemorrhage is elevated among elderly
patients with AF when INR levels (>3.5)
44–46 and in
those with cerebrovascular disease or poorly controlled hypertension.
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Current guidelines for anticoagulation in patients with HF
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The American College of Chest Physicians (ACCP), European Society
of Cardiology (ESC), American College of Cardiology/American
Heart Association (ACC/AHA), and Heart Failure Society of America
(HFSA) have issued independent guidelines that address anticoagulation
in patients with chronic HF (
Table 2).
5,47–49 A recent
study from Madrid found considerable inconsistency in the implementation
of widely promulgated clinical stroke risk stratification schemes
for selection of patients presenting to a hospital emergency
department.
50 The EuroHeart survey found wide deviations from
recommended approaches in routine clinical practice as well,
with low utilization of antithrombotic therapy in patients over
70 years old.
51 Each guideline calls for anticoagulation of
patients with HF who have AF. Most patients with HF associated
with impaired systolic function do not have documented AF, and
guidelines for management of patients without AF are less consistent.
The Heart Failure Society of America recommends that anticoagulation
be considered in patients with EF below 35%, and addition of
aspirin for patients with concomitant coronary artery disease
(CAD).
52 The American College of Chest Physicians guidelines
for antithrombotic therapy for patients with CAD recommend against
routine use of aspirin or anticoagulants in patients with HF
due to a non-ischaemic aetiology, and when otherwise indicated
that patients receive aspirin whether or not they are treated
with angiotensin-converting enzyme (ACE)-inhibitor drugs.
53 The American College of Cardiology/American Heart Association
(ACC/AHA) guidelines recommend warfarin for patients with HF
who have survived MI with extensive regional LV wall motion
abnormalities and for others with LV dysfunction with or without
symptoms of HF.
Based primarily on data from the SAVE and SOLVD studies and
other evidence reviewed earlier, it seems reasonable to consider
warfarin therapy in selected patients with LVEF below 35%, although
assessment of the risks and benefits of anticoagulation must
be individualized. No adequately powered randomized trials have
yet been completed to provide clear clinical guidance, and only
data from secondary analysis of non-randomized studies suggesting
a mortality benefit from warfarin therapy in patients with HF
provide support for its use.
40
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Ongoing studies
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The incidence of cardio-embolic stroke during the first 4 weeks
after MI is
2%, but increases to 15% in patients with LV mural
thrombus formation.
54 The Warfarin Re-infarction Study (WARIS)
and the Anticoagulants in the Secondary Prevention of Events
in Coronary Thrombosis (ASPECT) trials compared the mortality
rate and incidence of stroke for 3 years after MI in patients
taking warfarin (INR 2.4–4.8) or placebo. Both trials
showed significant reductions in mortality (24% and 10%, respectively)
and stroke (RR 55% and 40%, respectively). However, neither
included specific information about EF, so the severity of cardiac
dysfunction and its relation to the potential benefit of anticoagulation
cannot be assessed.
37,55 A meta-analysis by the Antithrombotic
Trialists' Collaboration concluded that, among high-risk patients,
allocation to antiplatelet therapy reduced the combined outcome
of any serious vascular event by
25%, non-fatal myocardial infarction
by 30%, non-fatal stroke by 25%, and vascular mortality by 17%.
56 This assessment has lead to a broad recommendation that antiplatelet
agents be used for secondary prevention of myocardial infarction,
but the analysis included only two trials of 134 patients with
HF. In our view, the evidence supporting the routine use of
aspirin in patients with ischaemic cardiomyopathy is not sufficient
to justify a recommendation.
The Wafarin/Aspirin Study in Heart Failure (WASH) trial was an open-label, randomized pilot study comparing placebo, aspirin (300 mg/day), and warfarin (goal INR 2.5) in patients with HF associated with LV systolic dysfunction and sinus rhythm. Only 297 patients were randomized and there were no significant differences in the primary outcome (death, non-fatal MI, or non-fatal stroke) between the three groups over 23 months.57 The Warfarin Anti-platelet Trial in Chronic Heart Failure (WATCH) trial compared aspirin, clopidogrel, and warfarin in patients with HF and EF below 30%.58 Unfortunately, the trial was terminated because of slow recruitment after enrollment of 1587 patients and was underpowered to identify differences in rates of the primary outcome (death, MI, or stroke). A retrospective analysis showed a lower incidence of stroke in patients assigned to warfarin (0.7%) compared with aspirin (2.1%, P=0.06) or clopidogrel (2.4%, P<0.05). When the incidence of stroke in the warfarin group was compared with that in the aspirin and clopidogrel, the difference became more significant (P=0.001).59 [Massie (2004), unpublished results].60 The WARCEF trial is an ongoing double-blind study in patients with EF <35% in NYHA class I–III HF, randomized to aspirin (325 mg/day) or warfarin (target INR 2.75). The composite endpoint is stroke and death over 5 years, and secondary endpoints include all-cause mortality, stroke, and MI balanced against ICH.61 The results may provide valuable information about the relative safety and efficacy of aspirin and warfarin in patients with reduced EF, but may not be sufficiently powered with respect to the endpoint of clinical thrombo-embolism (stroke and systemic embolism). When the population of the WARCEF trial is combined with patients followed in the aborted WATCH trial, it may be possible to draw inference about the role of anticoagulation in patients with HF.
A confounding issue is the role of aspirin in patient with chronic HF. Aspirin use is associated with a 39% reduction for stroke among patients with prior MI,56 but the effect of aspirin on stroke in patients with HF has not been sufficiently investigated. In the WASH and WATCH trials, hospitalizations for HF were more frequent among patients receiving aspirin.62 One proposed mechanism for this apparent adverse effect is haemodynamic deterioration due to prostagalandin inhibition. Aspirin might reduce the efficacy of concurrently administered ACE-inhibitor medication, as a retrospective analysis of the SOLVD trial data suggested that the benefit of enalapril was attenuated in patients receiving aspirin. Patients receiving antiplatelet agents also showed a trend towards higher all-cause mortality (hazard ratio 1.10) compared with those given ACE-inhibitor therapy without antiplatelet agents (hazard ratio 0.77).63 The optimal antithrombotic management of warfarin-dependent patients undergoing percutaneous coronary intervention (PCI) is another controversial issue. Such patients require platelet inhibitor therapy (typically aspirin plus clopidogrel) for 1–4 weeks following intervention followed by long-term therapy with warfarin and clopidogrel. Given the paucity of evidence supporting one form of antithrombotic therapy over another, for patients with HF in sinus rhythm, we recommend that those who have had PCI be treated with antiplatelet therapy as recommended for patients without HF or AF (Figure 2).61
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Conclusions
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Present guidelines are aligned that patients with HF who have
AF, prior thrombo-embolism, or mobile or protruding intracardiac
thrombus should be treated with oral anticoagulation. Data from
secondary analyses of the SOLVD and SAVE trials support the
view that patients with low EF are at elevated risk of thrombo-embolism
when compared with patients with higher EF, and anticoagulation
decreases the risk. Although the WASH and WATCH studies were
underpowered to show differences in the primary outcome constellations
that included mortality, MI, or stroke, the number of strokes
and hospital admissions were lower in patients taking warfarin
than in those not anticoagulated. Decisions regarding optimum
antithrombotic therapy (anticoagulant vs. antiplatelet medication)
for patients with HF who do not have AF, a mechanical heart
valve, recent MI or LV mural thrombus must be based on scant
prospective data (level ‘C’ evidence). In fact,
whether patients with reduced cardiac function should be treated
with warfarin or aspirin remains unanswered. On one side, warfarin
is a difficult drug to manage because of the risk of haemorrhage,
yet on the other are questions about the efficacy of aspirin
and its safety when used concomitantly with ACE-inhibitor medication.
The WATCH trial attempted to address both these important issues,
but stopped prematurely because of poor enrolment. Results from
the ongoing WARCEF trial are expected to provide important additional
insight into the relative merits of therapy with warfarin or
aspirin, but may not be sufficient to address the matter of
thrombo-embolism unless combined with data from other studies.
Until this data become available, the information available
supports the use of aspirin or warfarin in patients with EF
<35% with or without clinical HF, but selection of individual
patients for anticoagulation on firm grounds is limited to a
few subsets. Strategies to decrease the risk of haemorrhage
in older patients during anticoagulant therapy including self-management,
specialized clinics, or alternate antithrombotic agents may
improve the risk-to-benefit ratio.
Conflict of interest: J.L.H. has received consulting fees from a number of pharmaceutical firms developing novel anticoagulants, none of which are presently marketed for clinical use.
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Footnotes
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These authors contributed equally to this work.
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Abstract
Prevalence, aetiology, and...