Received June 24,
2008; accepted January 12, 2009.
The role
of antithrombotic therapy in patients with chronic
heart failure has been a subject of debate for many years. Initial controlled
clinical trials in cardiac patients were conducted to determine whether
anticoagulation could reduce the high incidence of embolic events, particularly
strokes, observed in these patients.1–3These
trials found substantial clinical benefit from anticoagulation, including
reductions in embolic events and deaths. Because many patients in these trials had heart failure accompanied
by atrial fibrillation and valvular disease, their relevance to current
clinical practice for heart failure patients in sinus rhythm seems limited. Given that heart failure is associated with a hypercoagulable
state and that both sudden deaths and deaths resulting from progressive heart
failure may be caused by unrecognized atherothrombotic events, a clear
rationale for anticoagulation in chronic heart failure exists.4–6 Although a posthoc analysis
of the Studies of Left Ventricular Dysfunction (SOLVD) trial indicated that
warfarin therapy was associated with lower mortality and morbidity rates,7 no large prospective clinical
trial limited to heart failure patients in sinus rhythm has addressed this
question.8
Editorial
p 1559
Clinical
Perspective p 1624
Many patients
with chronic heart failure are treated with
aspirin. A posthoc analysis of SOLVD has suggested that patients receiving
aspirin may gain less benefit from angiotensin-converting enzyme (ACE)
inhibition in terms of survival or hospitalization for worsening of heart
failure.9 Meta-analyses of ACE
inhibitor trials in patients with heart failure and left ventricular
dysfunction after myocardial infarction (MI) have yielded mixed results but are
generally consistent with some weakening of ACE inhibitor benefit.10,11 Whether these findings should
affect the use of this agent remains controversial. More recently, a study of
279 patients randomized to open-label aspirin 300 mg QD, warfarin (target
international normalized ratio [INR] of 2.5 to 3.0), or no antithrombotic
therapy found an excess of heart failure hospitalizations in the aspirin group
compared with both warfarin and no antithrombotic agent patients.12 The finding that aspirin reduces
the benefit of ACE inhibitors could relate to known adverse effects of
prostaglandin inhibition in patients with heart failure.13 This may be more important in
patients treated with ACE inhibitors because the hemodynamic effects of these
agents are partially mediated by enhanced prostaglandin synthesis.14–18
The Warfarin
and Antiplatelet Therapy in Chronic Heart Failure
(WATCH) trial was undertaken to determine the optimal antithrombotic agent for
heart failure patients with reduced ejection fractions who are in sinus rhythm.4 Two primary hypotheses were
addressed: that anticoagulation with warfarin is superior to antiplatelet
therapy with aspirin in preventing major cardiovascular outcomes and that
clopidogrel, an antiplatelet agent with a prostaglandin-independent mechanism
of action, is superior to aspirin in this population. Aspirin was compared with
clopidogrel rather than a placebo because it was not judged feasible or ethical
to randomize heart failure patients with coronary artery disease to receive no
antithrombotic therapy.
The
WATCH trial design and baseline characteristics of enrolled patients have been
described previously4 and
are presented briefly here.
Patient Population
Patients were recruited between
October 1999 and June 2002 from
142 centers in the United States, Canada, and the United Kingdom. Patients ≥18
years of age were eligible if they had symptomatic heart failure (New York
Heart Association class II to IV) for >3 months before entry, had a left
ventricular ejection fraction ≤35% measured within 3 months by any standard
technique, were in sinus rhythm, and were treated with a diuretic and an ACE inhibitor for at least 60
days (unless not tolerated). For patients who could not tolerate an
ACE inhibitor, treatment with hydralazine plus long-acting nitrates or an
angiotensin II receptor antagonist was recommended. β-Blocker use was strongly
encouraged. Other heart failure treatments were at the discretion of the
investigators.
The primary exclusion criteria were
contraindications or
specific indications for any of the study medications, imminent procedures
necessitating withdrawal or use of the study medications, heart failure from
correctable causes, serious comorbid conditions expected to limit life
expectancy, or other conditions that would interfere with protocol adherence.
All subjects provided written informed
consent. The study
protocol was approved by the Human Rights Committee of the Perry Point, Md,
Department of Veterans Affairs (VA) Cooperative Studies Program Coordinating
Center (CSPCC), by local regulatory authorities in Canada and the United
Kingdom, and by the Institutional Review Board or Ethics Committee at each
participating site.
Study Design
WATCH
was a multinational, prospective, randomized trial in which patients were
assigned to 1 of 3 treatment arms: aspirin 162 mg or clopidogrel 75 mg daily
provided in a double blind, double-dummy manner or open-label warfarin titrated
to a target INR of 2.5 to 3.0 with a designated acceptable range of 2.0 to 3.5.
There was no loading dose for either clopidogrel or aspirin. Warfarin therapy,
which was managed by either the investigative team or an anticoagulation
clinic, was initiated at 4 mg daily except in subjects ≥70 years of age or
taking amiodarone; they were started at 3 mg daily. INR was determined after 1
week, and dose was adjusted in increments of 1 mg as frequently as necessary to
achieve an INR of 2.5 to 3.0. The target INR range of 2.5 to 3.0 was chosen
because postinfarction trials achieving INR values in this range have shown
superiority of warfarin over aspirin, whereas those with lower INR targets and
values have not.19–22 Monitoring
visits were at the discretion of the responsible practitioners but maximally at
6-week intervals.
Patients were seen at 3-month intervals,
with interim telephone
contacts at 6-week intervals. These calls were scripted to identify changes in
clinical status, adverse events, study end points, and medication compliance.
Study End Points
The primary end point was the composite
of all-cause mortality,
nonfatal MI, and nonfatal stroke. Secondary end points included the 3
components of the primary end point and hospitalizations for heart failure. The primary safety end point was major
bleeding episodes, defined as bleeding episodes leading to death or disability
(including loss of neurological or special senses function), requiring surgical intervention,
or
associated with an acute decline of hemoglobin ≥2 gm/dL or transfusion of >1
U packed red cells or whole blood.
Study Management
An Executive Committee, consisting
of investigators, heart
failure researchers, and CSPCC and VA CSP Research Pharmacy Coordinating Center
representatives, served as the decision-making body for the study. Operational
aspects of the trial were overseen by the CSPCC, the study chairman’s office,
and coordinating offices in Canada and the United Kingdom. The VA CSP Research
Pharmacy Coordinating Center was responsible for obtaining, packaging, and
distributing the study drug supplies; working with the regulatory agencies of
the participating countries; and monitoring and reporting serious adverse
events. An independent Data and Safety Monitoring Board was responsible for
reviewing the study.
Randomization and
Blinding
The CSPCC generated a randomization
sequence for each site
separately using varying block sizes of 3 or 6. The site coordinator/site
investigator called the CSPCC to obtain a randomization number and treatment
allocation. Study medication was obtained from the local pharmacy or dispensing
unit on presentation of the signed consent form. Only patients randomized to
aspirin or clopidogrel were blinded to treatment received. In an emergency, the
blind could be broken by calling the VA CSP Research Pharmacy Coordinating
Center, the study chairman, the regional coordinating center, or the CSPCC. A
sealed envelope provided to the local pharmacy or dispensing unit could be
opened as a default strategy. No attempt was made to assess the adequacy of
blinding. The main outcome measures were adjudicated by an End Point Committee
made up of members blinded to treatment allocation, including INR results.
Sample Size and
Statistical Analyses
The
prespecified statistical analysis for the primary composite end point of death,
nonfatal MI, and nonfatal stroke was a log-rank test of the Kaplan–Meier
product limit estimator of time to first event based on intention-to-treat.23 The
original sample size of 1500 patients for each of the 3 groups was determined
using the method of Lakatos.24 This
was based on a planned enrollment period of 3 years, a mean follow-up period of
3.5 years, and an estimated 18% annual event rate, which would have 90% power
to detect a 20% between-group difference in annual event rates using a type I
error rate of 0.017 (adjusting for the 3 pair-wise comparisons).25 The
intent-to-treat log-rank test also was used to compare the effect of treatments
on total mortality. Intent-to-treat χ2 analyses were used to compare treatments on the dichotomous
secondary outcome measures.
Early Termination
Because of slow enrollment, the study
terminated prematurely in
January 2002. As a result, recruitment ended in June 2002 (4 months early), and
follow-up ceased 1 year later (16 months early). With the early termination,
1587 patients rather than 4500 were randomized. As a result, the difference in
annual event rate that the study was powered to detect with the original
parameters (power of 90% and a type I error rate of 0.017) increased from 20%
to 40%. Power to detect the original 20% difference dropped from 90% to 41%.
The authors had full access to and
take responsibility for the
integrity of the data. All authors have read and agree to the manuscript as
written.
Previous SectionNext Section
Enrollment
Of the 1587 patients enrolled, 937 patients
were from the United
States (590 patients in 44 VA sites and 347 in 41 other US sites), 332 were
from 28 Canadian sites, and 318 came from 29 sites in the United Kingdom.
Patient baseline characteristics are shown in Table 1. Although screening information was not
collected, [a suspicious gap in reporting that hides very possible
eliminating patients who might fare poorly on a vitamin K inhibitor] the
enrolled population was typical of trials involving patients with moderate to
severe systolic heart failure. Although patients were required to have heart
failure symptoms only for >3 months, Table 1 shows that 70% of the
patients had a heart failure diagnosis for ≥2 years. The patient
characteristics were well balanced among the 3 treatment groups. Among >70
baseline characteristics examined, the only intergroup difference that reached
statistical significance (P≤0.05) was the prevalence of diabetes, which was highest in the
warfarin group (38%) and lowest in the clopidogrel group (31%).
Follow-Up
and Protocol Adherence
The mean duration of follow-up was 1.9
years (median, 21
months), yielding 3073 patient-years of exposure. Figure 1 describes patient follow-up
experience and vital status at the end of the study. Of the 1587 patients
randomized, 523 received aspirin, 524 received clopidogrel, and 540 received
warfarin. The figure indicates that there were 282 deaths, 13 patients
terminated from the study because of a heart transplant, and 76 patients lost
to follow-up, including 31 at 3 terminated early because of site regulatory
issues. There were few differences between treatment groups. Of the 76 patients
lost to follow-up, 22 were determined to be alive as of March 1, 2003.
Figure 1 also shows the reasons that patients were
permanently discontinued from study drug. Although no difference existed
between treatment groups regarding overall drug discontinuation, warfarin was discontinued
by choice (32 patients) more frequently than aspirin (16 patients) or
clopidogrel (19 patients). Warfarin
patients also were more likely to have their study medication discontinued
because of hemorrhage and increased bleeding risk but were less likely to
have study medications stopped as a result of atrial fibrillation,
embolic/occlusive events, and cardiovascular events. In addition, 52 (9.9%) of
the aspirin patients, 48 (9.2%) of the clopidogrel patients, and 59 (10.9%) of
the warfarin patients had their medications stopped temporarily during the
study. For patients whose study medications were discontinued either
permanently or temporarily, 81 (26.8%) discontinued clopidogrel or aspirin
patients received nonstudy warfarin, 94 (55.6%) discontinued warfarin patients
received nonstudy aspirin, and 72 (48.0%) discontinued clopidogrel patients
received nonstudy aspirin.
On the basis of returned tablet counts,
80% of the prescribed double-blind aspirin and clopidogrel tablets were taken.
When documented periods of temporary or permanent discontinuations were
excluded, 93% of doses were used. After the initial 6-week titration phase, the
mean INR value in the warfarin arm was 2.6±0.9, with 70.4% of measurements
falling within the acceptable range (2.0 to 3.5), 20.3% falling below 2.0, and
9.3% falling above 3.5. The median INR was 2.5.
Primary and Secondary
End Points
Primary
Composite End Point and Its Components
Figure 2A shows the event curves of the primary composite end point of
all-cause mortality, nonfatal MI, or nonfatal stroke. For the warfarin versus
aspirin comparison, the unadjusted hazard ratio (HR) was 0.98 (95% CI, 0.86 to
1.12;P=0.77).
The HR for the clopidogrel versus aspirin comparison was 1.08 (95% CI, 0.83 to
1.40; P=0.57),
and the HR
for the warfarin versus clopidogrel comparison was 0.89 (95% CI, 0.68 to 1.16; P=0.39).
Figure 2B shows
the event curves for all-cause mortality. The HR for warfarin versus aspirin
was 0.98 (95% CI, 0.85 to 1.13; P=0.75); for
clopidogrel versus aspirin, 1.04 (95% CI, 0.78 to 1.38; P=0.80); and for warfarin versus clopidogrel,
0.92 (95% CI, 0.69
to 1.23; P=0.58).
The numbers of primary end points were
similar across treatment
groups (Table 2), as were the
numbers of deaths and nonfatal MIs. Although the numbers of nonfatal strokes
were small (9, 11, and 1 in the aspirin, clopidogrel, and warfarin groups,
respectively), both the aspirin-warfarin and the clopidogrel-warfarin
differences reached nominal statistical significance (P<0.01 in both
cases). Three of the nonfatal strokes (1 in each treatment group) were
classified by the End Point Committee as hemorrhagic conversion. All others
were nonhemorrhagic. There were 6 fatal strokes; 3, 1, and 2 in the aspirin,
clopidogrel, and warfarin groups, respectively. For all strokes (fatal and
nonfatal), the differences for the aspirin-warfarin and clopidogrel-warfarin
comparisons were not quite as significant (bothP=0.016) as for
nonfatal cases only (Table 2). However, when
central nervous system bleeding was added to all strokes (Table 2), no significant
differences were found for any of the treatment group comparisons.
When these primary analyses were
considered for each gender group and each racial group (white, black, other)
separately, similar results were seen. The only exception was for nonfatal
strokes in women, in whom there were only 2 nonfatal strokes (0.9% of women).
Heart
Failure
Hospitalizations
In the aspirin group,
116 patients (22.2%) were hospitalized at least once for worsening heart
failure compared with 89 patients (16.5%) in the warfarin arm (Table 2), a nominally significant increase (P=0.019).
The total
number of heart failure admissions also was greater with aspirin compared with
warfarin (218 versus 155; P<0.001).
When time to heart failure admission or death was considered, no differences were
found. The HRs and 95% CIs were as follows: for warfarin versus aspirin, 0.94
(95% CI, 0.84 to 1.04; P=0.22);
for clopidogrel versus aspirin, 0.97 (95% CI, 0.78 to 1.21; P=0.79); and for
warfarin versus clopidogrel, 0.90 (95% CI, 0.72 to 1.12; P=0.37).
Systemic
Embolisms
There were only 10
total systemic (peripheral arterial, abdominal, renal, pulmonary, and other)
embolisms (Table 2). Of these 10, 4 were pulmonary embolisms. There were no
significant differences between treatment groups. There was only 1 death, a
warfarin patient with a pulmonary embolism.
Bleeding
Events
Major bleeding
episodes (Table 2) were more frequent in warfarin patients compared with
clopidogrel (P<0.01) but not aspirin (P=0.22)
patients. Six patients had 7 central nervous system bleeding episodes on
warfarin compared with 3 patients on aspirin and 1 patient on clopidogrel.
There also were more patients with minor bleeding episodes in the warfarin
group than in the clopidogrel group (P=0.025) and a
similar trend in the aspirin group (P=0.054).
Atrial
Fibrillation and Gastrointestinal Intolerance
Atrial fibrillation
occurred in 10% of patients at some time during their follow-up. There were no
differences between treatment groups (10.3%, 10.3%, and 9.3% for aspirin,
clopidogrel, and warfarin, respectively). Patients were routinely questioned
about symptoms of gastrointestinal intolerance at each visit. There were 49.9%
who reported dyspepsia or epigastria discomfort at some time, 41.2% who
reported diarrhea, 29.2% who reported nausea or vomiting, and 22.5% who
reported other symptoms of gastrointestinal intolerance. Differences between
treatment groups were found only for diarrhea; fewer aspirin patients reported
diarrhea than either clopidogrel (35.4% versus 43.9; P=0.0048) or
warfarin (35.4% versus 44.4%; P=0.0025)
patients.
Ischemic
Versus Nonischemic Group Comparisons
Patients were divided
into ischemic (definite or probable) and nonischemic groups, and analyses for
the primary outcome measure, its components, and bleeding events were conducted
for each group separately. For the ischemic patients, the only significant
differences were for strokes; warfarin did better than either aspirin (0.0%
versus 1.6%; P=0.01)
or clopidogrel (0.0% versus 2.7%; P=0.0009).
For the nonischemic patients, the only significant finding was for major
hemorrhage; clopidogrel patients (0.7%) had fewer major hemorrhages than
warfarin patients (6.3%) (P=0.0093). The
small sample sizes, especially for the nonischemic patients (total n=424
patients), most likely reduced the likelihood of finding other differences.
Previous SectionNext Section
Discussion
With >3000 patient-years of follow-up,
the WATCH trial is the largest randomized trial to date examining
antithrombotic therapies in patients with chronic heart failure. Although the
trial was discontinued prematurely, the WATCH results suggest that for the primary
composite end point and all-cause mortality, major differences between
anticoagulation with warfarin and antiplatelet therapy with either aspirin or
clopidogrel are unlikely. Although the 327 primary end points observed were
only 23% of the protocol-specified 1440 events, the 95% confidence limits
around these results exclude 20% differences between warfarin and aspirin for
both the primary composite end point and total mortality. Similarly, 90% CIs
exclude a 20% difference favoring clopidogrel over aspirin for these end
points. Therefore, these results do not support our 2 primary hypotheses that warfarin is superior to aspirin in
preventing major cardiovascular outcomes and that clopidogrel is superior to aspirin in this population;
indeed, our results exclude these hypotheses
with a high degree of
certainty.
For 2 prespecified secondary end points,
nonfatal stroke and hospitalizations for worsening heart failure, some support
is provided for the first hypothesis that warfarin may be superior to aspirin
in preventing cardiovascular outcomes. These differences are not small and are
potentially clinically important. Given the early study termination and the
number of potential analyses, our results should be interpreted with caution.
The trend for more minor bleeding in the warfarin group than the aspirin group
also needs to be taken into account when the use of warfarin is considered. We
find no support from the secondary analyses that clopidogrel is superior to
aspirin.
The relatively low
incidence of stroke among our patients is noteworthy. For patients not assigned
to warfarin, the incidence of stroke was only 1.0 event per 100 patient-years
of follow-up, a finding consistent with observations from other trials
conducted in the past 2 decades.26,27 Based on posthoc analyses of atrial
fibrillation trials,28 this is far lower than for heart failure
patients
in atrial fibrillation for whom anticoagulation is strongly recommended.
However, nonfatal strokes and all strokes were less frequent in the warfarin
arm than in the groups assigned to either antiplatelet agent. These findings,
which represent the first prospective, controlled data in patients required to
be in sinus rhythm at baseline, are consistent with many physicians’ belief
that anticoagulation may prevent stroke in patients with chronic systolic heart
failure. These results should be tempered by the findings of more bleeding
episodes with warfarin.
Compared with aspirin
patients, the warfarin group experienced a 26% relative reduction (5.7%
absolute decrease) in the proportion of patients hospitalized for heart
failure. Taking into account multiple hospitalizations, warfarin was associated
with a 40% reduction in heart failure admissions compared with aspirin (6.0
events per 100 patient-years follow-up). One possible mechanism for this
difference is that aspirin may interfere with the increase in prostaglandin
levels that occurs in heart failure that is further enhanced by ACE inhibitors.
Prostaglandins such as prostacyclin and prostaglandin E1 have vasodilator,
natriuretic, and
antiaggregatory activity, which appears to play a compensatory role in patients
with heart failure. Although these data cannot be considered definitive, the
magnitude of reduction potentially achievable by avoiding aspirin is similar to
that observed with the most effective pharmacological therapies for heart
failure such as ACE inhibitors and β-blockers.29–32 Moreover, the relative and absolute
differences between warfarin and aspirin are similar to those observed in the
Warfarin and Aspirin Study in Heart Failure.12 It should be kept in mind, however, that
when an analysis of the time to first hospitalization or death was conducted,
the differences disappeared.
Many physicians and
patients are appropriately concerned about the safety of anticoagulation in
heart failure patients because they usually are older, generally are taking
multiple medications, and may have significant fluctuations in liver function,
food intake, and drug absorption related to congestion.19,33,34 In that regard, warfarin treatment in our
trial was associated with more frequent bleeding episodes compared with
clopidogrel and a nonsignificant excess of bleeding compared with aspirin.
However, warfarin-associated bleeding complications occurred at a frequency
similar to that observed in anticoagulation trials in post-MI and atrial
fibrillation patients. Although warfarin was related to a lower incidence of
stroke compared with the other 2 drugs, when central nervous system bleeding
and stroke were combined, these differences disappeared. Thus, the elevated
risks for bleeding (major, minor, and central nervous system) versus the lower
risk for stroke must be considered when warfarin is begun, especially given the
low rates of embolic events.
Several limitations
could have affected our results. The higher number of diabetic patients in the
warfarin group, with their higher risks, could have underestimated the ability
of warfarin to reduce thromboembolic events. However, the warfarin group had
few such events in our study. Another concern is that patients with symptoms
for only >3 months were enrolled. This may have resulted in a healthier
subset of patients with lower event rates (eg, ejection fraction may have
improved after continuation of heart failure treatment), although 70% of our
patients had been diagnosed for at least 2 years. An indication that our sample
may have been a healthier subset of the patient population is the
lower-than-expected event rate. Although our event rate was estimated to be 18%
annually for our sample size estimates, as seen in Figure 2A, it took almost 2 years to reach an 18% event rate. On the
other hand, our study may be a truer reflection of heart failure patients in
general. The early termination of the study, which reduced follow-up time by 16
months and reduced the number of events, made finding treatment differences
more difficult as a result of low statistical power. Future studies with a
longer follow-up time may be needed to find treatment differences. Finally, the
target INR range of 2.5 to 3.0 for warfarin is relatively narrow and may limit
generalizability to everyday practice. However, our medium INR was 2.5, and 70%
of the actual INRs were between 2.0 and 3.5.
Given the absence of
significant differences in the primary end point or in survival, this study
does not justify a systematic avoidance of aspirin in patients with chronic
heart failure in sinus rhythm. The WATCH results also do not provide supportive
data to reinforce the recent recommendations of the Seventh Consensus
Conference on Antithrombotic Therapy to avoid aspirin in patients with
nonischemic dilated cardiomyopathy and in other heart failure patients with no
evidence of or major risk factors for vascular disease.11 These results also provide no evidence to
support the use of aspirin. Although the use of warfarin rather than aspirin or
clopidogrel may have resulted in reduced strokes in our population, this
benefit may be offset by increased risk from bleeding. Overall, our primary
outcome measure and mortality results do not support our 2 primary hypotheses
that anticoagulation with warfarin is superior to antiplatelet therapy with
aspirin in preventing major cardiovascular outcomes and that clopidogrel is
superior to aspirin in this population.
Previous SectionNext Section
Acknowledgments
Sources
of Funding
This trial was supported and administered
by the Cooperative Studies Program of the Office of Research and Development,
Department of Veterans Affairs. Study drugs and unrestricted grants were
provided by Bristol Myers Squibb, Sanofi-Synthelabo, and Dupont pharmaceutical
companies.
Disclosures
Dr Massie has received research grants
from Bristol-Myers Squibb and Sanofi-Aventis. Dr Schulman has received research
grants from Bristol-Myers Squibb, and Sanofi-Aventis and does consulting for
Sanofi-Aventis. Dr Ezekowitz has served as a consultant to Bristol-Myers Squibb
and Sanofi-Aventis. The other authors report no conflicts.