HIRSH
et al., AHA/ACC Expert Consensus Document on Warfarin Therapy
JACC 2003;41:1633-52
American
Heart Association/American College of Cardiology Foundation
Guide to Warfarin Therapy
Clinical
Applications of Oral Anticoagulant Therapy
The
clinical effectiveness of oral anticoagulants has been established
by well-designed clinical trials in a variety of disease conditions.
Oral anticoagulants are effective for primary and secondary
prevention of venous thromboembolism, for prevention of systemic
embolism in patients with prosthetic heart valves or atrial
fibrillation, for prevention of acute myocardial infarction
(AMI) in patients with peripheral arterial disease and in
men otherwise at high risk, and for prevention of stroke,
recurrent infarction, or death in patients with AMI (64).
Although effectiveness has not been proved by a randomized
trial, oral anticoagulants also are indicated for prevention
of systemic embolism in high-risk patients with mitral stenosis
and in patients with presumed systemic embolism, either cryptogenic
or in association with a patent foramen ovale. For most of
these indications, a moderate anticoagulant intensity (INR
2.0 to 3.0) is appropriate.
Although
anticoagulants are sometimes used for secondary prevention
of cerebral ischemia of presumed arterial origin when antiplatelet
agents have failed, the Stroke Prevention in Reversible Ischemia
Trial (SPIRIT) study found high-intensity oral anticoagulation
(INR 3.0 to 4.5) dangerous in such cases (121).
The trial was stopped at the first interim analysis of 1316
patients with a mean follow-up of 14 months because there
were 53 major bleeding complications during anticoagulant
therapy (27 intracranial, 17 fatal) versus 6 on aspirin (3
intracranial, 1 fatal). The authors concluded that oral anticoagulants
are not safe when adjusted to a targeted INR range of 3.0
to 4.5 in patients who have experienced cerebral ischemia
of presumed arterial origin. In a second study (the Warfarin
Aspirin Recurrent Stroke Study [WARSS]) (187a),
2206 patients with noncardioembolic ischemic stroke were randomly
assigned to receive either low-intensity warfarin (INR 1.4
to 2.8) or aspirin (325 mg/d). The primary end point of death
or recurrent ischemic stroke occurred 17.8 patients assigned
to warfarin and 16.0 assigned to aspirin (P-0.25). The rates
of major bleeding were 2.2% and 1.5% in the warfarin and aspirin
groups, respectively (not significant). Thus, low-intensity
warfarin and aspirin exhibit similar efficacy and safety in
patients with noncardioembolic ischemic stroke.
Prevention
of Venous Thromboembolism
Oral anticoagulants when given at a dose sufficient to maintain
an INR between 2.0 and 3.0 are effective for prevention of
venous thrombosis after hip surgery (188
–190) and major gynecologic surgery (191,192).
The risk of clinically important bleeding at this intensity
is modest. A very low fixed dose of warfarin (1 mg daily)
prevented subclavian vein thrombosis in patients with malignancy
who had indwelling catheters (193).
In contrast, 4 randomized trials found this dose of warfarin
ineffective for preventing postoperative venous thrombosis
in patients undergoing major orthopedic surgery (194
–197). Levine and associates (198)
reported that warfarin, 1 mg daily for 6 weeks followed by
adjustment to a targeted INR of 1.5, prevented thrombosis
in patients with stage 4 breast cancer receiving chemotherapy.
In general, when warfarin is used to prevent venous thromboembolism, the targeted INR should be 2.0 to 3.0.
Treatment
of Deep Venous Thrombosis or Pulmonary Embolism
The optimum duration of oral anticoagulant therapy is influenced
by the competing risks of bleeding and recurrent venous thromboembolism.
The risk of major bleeding during oral anticoagulant therapy
is 3% per year with an annual case fatality rate of 0.6%.
On the other hand, the case fatality rate from recurrent venous
thromboembolism is 5% to 7%, with the rate being higher in
patients with pulmonary embolism. Therefore, at an annual
recurrence rate of 12%, the risk of death from recurrent thromboembolism
is balanced by the risk of death from anticoagulant-related
bleeding. The risk of recurrent thromboembolism when anticoagulant
therapy is discontinued depends on whether thrombosis is unprovoked
(idiopathic) or is secondary to a reversible cause; a longer
course of therapy is warranted when thrombosis is idiopathic
or associated with a continuing risk factor (199).
The reported risk of recurrence in patients with idiopathic
proximal vein thrombosis has been reported to be between 10%
and 27% when anticoagulants are discontinued after 3 months.
Extending therapy beyond 6 months seems to reduce the risk
of recurrence to 7% during the year after treatment is discontinued
(200).
Patients
should be treated with anticoagulants for a minimum of 3 months.
Moderate-intensity anticoagulation (INR 2.0 to 3.0) is as
effective as a more intense regimen (INR 3.0 to 4.5) but is
associated with less bleeding (166).
Treatment should be longer in patients with proximal vein
thrombosis than in those with distal thrombosis and in patients
with recurrent thrombosis versus those with an isolated episode.
Laboratory evidence of thrombophilia also may warrant a longer
duration of anticoagulant therapy, according to the nature
of the defect. Oral anticoagulant therapy is indicated for
>3 months in patients with proximal deep vein thrombosis
(201,202), for >6
months in those with proximal vein thrombosis in whom a reversible
cause cannot be identified and eliminated or in patients with
recurrent venous thrombosis, and for 6 to 12 weeks in patients
with symptomatic calf vein thrombosis (203–205).
Indefinite anticoagulant therapy should be considered in patients
with >1 episode of idiopathic proximal vein thrombosis,
thrombosis complicating malignancy, or idiopathic venous thrombosis
and homozygous factor V Leiden genotype, the antiphospholipid
antibody syndrome, or deficiencies of antithrombin III, protein
C, or protein S (206 –208).
Prospective cohort studies indicate that heterozygous factor
V Leiden or the G20210A prothrombin gene mutation in patients
with idiopathic venous thrombosis does not increase the risk
of recurrence (207,209).
These
recommendations are based on results of randomized trials
(207) that demonstrated that
oral anticoagulants effectively prevent recurrent venous thrombosis
(risk reduction >90%), that treatment for 6 months is more
effective than treatment for 6 weeks (206),
and that treatment for 2 years is more effective than treatment
for 3 months (208).
Primary
Prevention of Ischemic Coronary Events
The Thrombosis Prevention Trial (64)
evaluated warfarin (target INR 1.3 to 1.8), aspirin (75 mg/d),
both, or neither in 5499 men aged 45 to 69 years at risk of
a first myocardial infarction (MI). The primary outcome was
acute myocardial ischemia, defined as coronary death or nonfatal
MI. Although the anticoagulant intensity was low, the mean
warfarin dose was 4.1 mg/d. The annual incidence of coronary
events was 1.4% per year in the placebo group, whereas the
combination of warfarin and aspirin reduced the relative risk
by 34% (P-0.006). Given separately, neither warfarin nor aspirin
produced a significant reduction in acute ischemic events,
and the efficacy of the 2 drugs was similar (relative risk
reductions 22% and 23% with warfarin and aspirin, respectively).
The combined treatment, though most effective, was associated
with a small but significant increase in hemorrhagic stroke.
These results suggest that, in the primary prevention setting,
low-intensity warfarin anticoagulation targeting an INR of
1.3 to 1.8 is effective for prevention of acute ischemic events
(particularly fatal events) and that the combination of low-intensity
warfarin plus aspirin is more effective than either agent
alone, at the price of a small increase in bleeding.
Despite
its effectiveness, low-intensity warfarin is not preferred
over aspirin for primary prophylaxis in high-risk patients
because warfarin requires INR monitoring and is associated
with greater potential for bleeding.
The
effectiveness of the combination of low-intensity warfarin
plus aspirin in the Thrombosis Prevention Trial (64)
contrasts with the results of the Coumadin Aspirin Reinfarction
Study (CARS) (210), Stroke
Prevention in Atrial Fibrillation (SPAF) III trial (124),
and Post Coronary Artery Bypass Graft (Post-CABG) (211)
study, in which this type of combination therapy was ineffective.
In the Thrombosis Prevention Trial, the dose of warfarin was
adjusted between 0.5 and 12.5 mg/d (INR of 1.3 to 1.8), whereas
in the CARS and SPAF III studies, warfarin was given in fixed
doses. The reason for the contrasting effectiveness of low-intensity
warfarin in these primary and secondary prevention situations
is not clear.
Acute
Myocardial Infarction
Initial evidence supporting use of oral anticoagulants in
patients with AMI dates to the 1960s and 1970s, when warfarin
given in moderate intensity (estimated INR of 1.5 to 2.5)
was found effective for prevention of stroke and pulmonary
embolism (212–216).
Of 3 randomized trials in which the effectiveness of oral
anticoagulants was evaluated in patients with AMI (213–215),
2 (213,215) showed a significant
reduction in stroke but no significant impact on mortality,
whereas there was a reduction in mortality in the third (214).
In all 3 studies, the incidence of clinically diagnosed pulmonary
embolism was reduced. Effectiveness of oral anticoagulants
in the long-term management of patients with AMI was supported
by the results of a meta-analysis of data pooled from 7 randomized
trials published between 1964 and 1980, which showed that
oral anticoagulants reduced the combined end points of mortality
and nonfatal reinfarction by 20% during treatment periods
of between 1 and 6 years (215–217).
Subsequently,
a higher INR was evaluated in several European studies. The
Sixty-Plus Re-infarction Study included patients >60 years
of age who had been treated with oral anticoagulants for >6
months; lower rates of reinfarction and stroke were observed
in patients randomized to continue anticoagulant therapy than
in those from whom anticoagulation was withdrawn (218).
As a treatment-interruption trial in a select age group, the
findings were of limited generalizability. In another study
with no age restriction (the WArfarin Re-Infarction Study
[WARIS]), Smith and associates (219) reported a 50% reduction
in the combined outcomes of recurrent infarction, stroke,
and mortality. Similarly, the Anticoagulants in the Secondary
Prevention of Events in Coronary Thrombosis (ASPECT) trial
(119), which also had no
age restriction, reported a 50% reduction in reinfarction
and a 40% reduction in stroke among survivors of MI. Each
of these studies (119,218,219)
used high-intensity warfarin regimens (INR 2.7 to 4.5 in the
Sixty-Plus Study and 2.8 to 4.8 in the WARIS and ASPECT studies);
each found the incidence of bleeding was increased with anticoagulants.
More
recently, several studies have evaluated different intensities
of anticoagulation, either alone or in combination with aspirin
(Tables 4 and 5). The ASPECT II study
compared warfarin alone (goal INR 3.0 to 4.0) with aspirin
(80 mg daily) and with the combination of aspirin (80 mg daily)
plus warfarin (INR 2.0 to 2.5) in 993 patients after an acute
coronary syndrome. The sponsor halted the study because of
slow recruitment when the composite end point of death, MI,
and stroke occurred in 9.0% of patients on aspirin alone,
5.0% of those on warfarin alone, and 5.0% of those on the
combined regimen. There was an excess of minor bleeding in
those on the combination of warfarin (INR 2.0 to 2.5) and
aspirin (220) In the Antithrombotics
in the Prevention of Reocclusion In COronary Thrombolysis
(APRICOT) II study (221)
of 308 patients with TIMI grade 3 coronary flow after thrombolysis
for ST segment– elevation MI, aspirin (160 mg initially
followed by 80 mg daily) was compared with aspirin in the
same dosage combined with warfarin (INR 2.0 to 3.0) to assess
the 3-month rate of angiographic reocclusion. Reocclusion
occurred in 30% of the group given aspirin alone compared
with 18% in those given aspirin plus warfarin (relative risk
0.60; 95% CI 0.39 to 0.93). There was an increase in minor
but not major bleeding in the combination group (221).
The WARIS II trial (222)
compared warfarin or aspirin or both in 3630 patients <75
years of age with AMI randomized at the time of hospital discharge
and followed up for 2 years for the first occurrence of the
composite of all-cause death, nonfatal reinfarction, or thromboembolic
stroke. This composite end point occurred in 20% of the patients
on aspirin alone (160 mg/d), 16.7% of those on warfarin alone
(mean INR 2.8), and 15% of those on the combination of both
drugs (mean INR 2.2; aspirin 75 mg/d). Odds ratios for the
combined end point were 0.71 for the combination of warfarin
plus aspirin versus aspirin alone (95% CI 0.58 to 0.86; P-0.0005),
0.81 for warfarin alone versus aspirin alone (95% CI 0.67
to 0.98; P-0.028), and 0.88 for the combination versus warfarin
alone (95% CI 0.72 to 1.07; P-0.20). The superiority of the
combination over aspirin was highly significant at P-0.0005,
but there was no significant difference between the 2 warfarin
groups. Major bleeding occurred at a rate of 0.15% per year
in the aspirin-alone group, 0.58% per year in the warfarin-alone
group, and 0.52% per year in the combination group (222).
Two
studies, CARS (210) and the
Combined Hemotherapy And Mortality Prevention Study (CHAMP)
(223), compared aspirin alone
with the combination of aspirin and low-intensity warfarin
(lower limit of targeted INR <2.0). The CARS study in 8803
patients with AMI showed that low fixed-dose warfarin (1 or
3 mg/d) plus aspirin (80 mg) was no more effective than aspirin
alone (160 mg) for the long-term treatment of survivors of
MI (209). Thus, after a mean
of 14 months of follow-up, the incidence of death, recurrent
MI, or stroke was 8.6 in the aspirin group and 8.4 in the
combination of aspirin and warfarin (3 mg/d) group. Despite
the lack of increased efficacy, the combined aspirin and warfarin
(3 mg/d) group showed an increase in major bleeding. The CHAMP
study (223) was an open-label
trial that evaluated the relative efficacy and safety of aspirin
alone (162 mg/d) and the combination of warfarin (INR 1.5
to 2.5) and aspirin (81 mg/d) in 5059 patients with AMI. There
was no difference in total mortality (17.3% versus 17.3%),
in nonfatal MI (13.1% versus 13.3%), or in nonfatal stroke
(4.7% versus 4.2%). Despite lack of increased efficacy, major
bleeding was more common in the combined treatment group.
Indirect
support for the efficacy of oral anticoagulants in patients
with coronary artery disease also comes from a randomized
trial of patients with peripheral arterial disease (224).
A relatively high-intensity oral anticoagulant regimen (INR
2.6 to 4.5) produced a significant 51% reduction in mortality
(from 6.8% to 3.3% per year) compared with an untreated control
group (P<0.023).
A
meta-analysis of 31 randomized trials of oral anticoagulant
therapy published between 1960 and 1999 involving patients
with coronary artery disease treated for >3 months,
stratified by the intensities of anticoagulation and aspirin
therapy, is shown in Table 6. High-intensity (INR 2.8 to 4.8)
and moderate-intensity (INR 2 to 3) oral anticoagulation regimens
reduced the rates of MI and stroke but increased the risk
of bleeding 6.0-to 7.7-fold. When combined with aspirin, low-intensity
anticoagulation (INR <2.0) was not superior to aspirin
alone, whereas moderate-to high-intensity oral anticoagulation
and aspirin versus aspirin alone seemed promising. There was
a modest increase in the bleeding risk associated with the
combination (225).
Because
a rebound increase in ischemic events has been documented
after discontinuation of heparin (226)
and LMWH (227,228), the use
of oral anticoagulants to prevent reinfarction has been evaluated
in several studies. The ischemic event rate was reduced by
65% after 6 months in one study of 102 patients (P<0.05)
(229). In the Antithrombotic
Therapy in Acute Coronary Syndromes (ATACS) trial (230),
the combined rate of death, MI, and recurrent ischemia decreased
from 27.5% to 10.5% after 2 weeks with an INR of 2.0 to 2.5
in 214 patients (P-0.004), but most of the benefit accrued
during the earlier phase of heparin therapy. The Organization
to Assess Strategies for Ischemic Syndromes (OASIS) (231)
pilot study of hirudin versus heparin found a dose-adjusted
warfarin regimen (INR 2 to 2.5) superior to a fixed dose (3
mg daily) over 6 months in 506 patients, all of whom were
given aspirin concurrently. The 58% difference in the rate
of death, MI, or refractory angina was marginally significant,
but fewer patients were hospitalized for unstable angina (P-0.03).
From
the results of these clinical trials, conclusions can be drawn
about long-term treatment of patients with acute myocardial
ischemia: (1) High-intensity oral anticoagulation (INR 3.0
to 4.0) is more effective than aspirin but is associated with
more bleeding; (2) the combination of aspirin and moderate-intensity
warfarin (INR 2.0 to 3) is more effective than aspirin but
is associated with a greater risk of bleeding; (3) the combination
of aspirin and moderate-intensity warfarin (INR 2.0 to 3.0)
is as effective as high-intensity warfarin and is associated
with a similar risk of bleeding; (4) the contemporary trials
have not addressed the effectiveness of moderate-intensity
warfarin (INR 2.0 to 3.0), and in the absence of direct evidence,
it cannot be assumed that moderate-intensity warfarin is any
more effective than aspirin in preventing death or reinfarction;
and (5) there is no evidence that the combination of aspirin
and low-intensity warfarin (INR <2.0) is more effective
than aspirin alone, despite the fact that the combination
produces more bleeding.
Therefore,
the choice for long-term management involves aspirin alone,
aspirin plus moderate-intensity warfarin (INR 2.0 to 3.0),
or high-intensity warfarin (INR 3.0 to 4.0). The latter 2
regimens are more effective than aspirin but are associated
with more bleeding and are much less convenient to administer.
Furthermore, in the absence of tight INR control, the high-intensity
regimen has the potential to cause unacceptable bleeding.
An alternative approach to long-term antithrombotic management
of patients with acute myocardial ischemia is to use a combination
of aspirin plus clopidogrel. Recommendations of the choice
among these competing approaches is beyond the scope of this
review on oral anticoagulants but should be addressed in future
recommendations for the management of patients with acute
myocardial ischemia.
Prosthetic
Heart Valves
The most convincing evidence that oral anticoagulants are
effective in patients with prosthetic heart valves comes from
a study of patients randomized to receive warfarin in uncertain
intensity versus either of 2 aspirin-containing platelet-in-hibitor
drug regimens for 6 months (232).
The incidence of thromboembolic complications in the group
that continued warfarin was significantly lower than that
of the groups that received antiplatelet drugs (relative risk
reduction 60% to 79%). The incidence of bleeding was highest
in the warfarin group. Three studies addressed the minimum
effective intensity of anticoagulant therapy. One study of
patients with bioprosthetic heart valves found a moderate
dose regimen (INR 2.0 to 2.25) as effective as a more intense
regimen (INR 2.5 to 4.0) but associated with less bleeding
(167). A second study (168),
involving patients with mechanical prosthetic heart valves,
found no difference in effectiveness between a very high-intensity
regimen (INR 7.4 to 10.8) and a lower-intensity regimen (INR
1.9 to 3.6), but the higher-intensity regimen produced more
bleeding. Another study (169) of patients with mechanical
prosthetic valves treated with aspirin and dipyridamole found
no difference in efficacy between moderate-intensity (INR
2.0 to 3.0) and high-intensity (INR 3.0 to 4.5) warfarin regimens,
but more bleeding occurred with the high-intensity regimen.
A more recent randomized trial showed that addition of aspirin
(100 mg/d) to warfarin (INR 3.0 to 4.5) improved efficacy
compared with warfarin alone (63).
This combination of low-dose aspirin and high-intensity warfarin
was associated with a reduction in all-cause mortality, cardiovascular
mortality, and stroke at the expense of increased minor bleeding;
the difference in major bleeding, including cerebral hemorrhage,
did not reach statistical significance. A retrospective
study of 16 081 patients with mechanical heart valves in the
Netherlands attending 4 regional anticoagulation clinics (target
INR 3.6 to 4.8) found a sharp rise in the incidence of embolic
events when the INR fell to <2.5, whereas bleeding increased
when the INR rose to >5.0 (120).
Guidelines
developed by the European Society of Cardiology (233)
called for anticoagulant intensity in proportion to the thromboembolic
risk associated with specific types of prosthetic heart valves.
For first-generation valves, an INR of 3.0 to 4.5 was recommended.
An INR of 3.0 to 3.5 was considered sensible for second-generation
valves in the mitral position, whereas an INR of 2.5 to 3.0
was deemed sufficient for second-generation valves in the
aortic position. The American College of Chest Physicians
guidelines (234) of 2001
recommended an INR of 2.5 to 3.5 for most patients with mechanical
prosthetic valves and of 2.0 to 3.0 for those with bioprosthetic
valves and low-risk patients with bileaflet mechanical valves
(such as the St Jude Medical device) in the aortic position.
Similar guidelines have been promulgated conjointly by the
American College of Cardiology and the American Heart Association
(235). In contrast, a higher
upper limit of the therapeutic range (INR 4.8 to 5.0) has
been recommended by some European investigators (118,236).
Management
of women with prosthetic heart valves during pregnancy and
the potential shortcomings of heparin and LMWH in such patients
have been discussed in the section on pregnancy.
Atrial
Fibrillation
Five trials with relatively similar study designs have addressed
anticoagulant therapy for primary prevention of ischemic stroke
in patients with nonvalvular (nonrheumatic) atrial fibrillation.
The SPAF study (237), the
Boston Area Anticoagulation Trial for Atrial Fibrillation
(BAATAF) (238), and the Stroke
Prevention In Nonvalvular Atrial Fibrillation (SPINAF) trial
were carried out in the United States (239);
the Atrial Fibrillation, Aspirin, Anticoagulation study (AFASAK)
was carried out in Denmark (240);
and the Canadian Atrial Fibrillation Anticoagulation (CAFA)
study (241) was stopped before
completion because of convincing results in 3 of the other
trials (242). In the AFASAK
and SPAF trials, patients also were randomized to aspirin
therapy (238,241).
The results of all 5 studies were similar; pooled analysis
on an intention-to-treat basis showed a 69% risk reduction
and >80% risk reduction in patients who remained on treatment
with warfarin (efficacy analysis) (243).
There was little difference between rates of major or intracranial
hemorrhage in the warfarin and control groups, but minor bleeding
was  3%
per year more frequent in the warfarin-assigned groups (244).
Pooled results from 2 studies were consistent with a smaller
benefit from aspirin. In the AFASAK study, 75 mg daily did
not significantly reduce thromboembolism, whereas in the SPAF
trial, 325 mg per day was associated with a 44% stroke risk
reduction in younger patients.
A
secondary prevention trial in Europe (the European Atrial
Fibrillation Trial [EAFT]) (245)
compared anticoagulant therapy, aspirin, and placebo in patients
with atrial fibrillation who had sustained nondisabling stroke
or transient ischemic attack within 3 months. Compared with
placebo, there was a 68% reduction in stroke with warfarin
and an insignificant 16% stroke risk reduction with aspirin.
None of the patients in the anticoagulant group suffered intracranial
hemorrhage.
The
SPAF II (246) trial compared
the efficacy and safety of warfarin with aspirin in patients
with atrial fibrillation. Warfarin was more effective than
aspirin for preventing ischemic stroke, but this difference
was almost entirely offset by a higher rate of intracranial
hemorrhage with warfarin, particularly among patients >75
years of age, in whom the rate of intracranial hemorrhage
was 1.8% per year. The intensity of anticoagulation was greater
in the SPAF trials than in several of the other primary prevention
studies; in addition, the majority of intracranial hemorrhages
during these trials occurred when the estimated INR was >3.0.
In the SPAF III study (124),
warfarin (INR 2.0 to 3.0) was much more effective than a fixed-dose
combination of warfarin (1 to 3 mg/d; INR 1.2 to 1.5) plus
aspirin (325 mg/d) in high-risk patients with atrial fibrillation,
whereas aspirin alone was sufficient for patients at low intrinsic
risk of thromboembolism. Whether treatment targeted to the
lower end of the therapeutic INR range (near 2) provides much,
if not all, the benefit achieved remains to be evaluated in
a prospective trial (123).
In a Dutch general practice population without established
indications for warfarin, neither low-nor standard-intensity
anticoagulation was better than aspirin in preventing ischemic
events (247).
In
summary, the evidence indicates that both warfarin and aspirin
are effective for prevention of systemic embolism in patients
with nonvalvular atrial fibrillation. Warfarin is more effective
than aspirin but is associated with a higher rate of bleeding.
As might be expected, randomized trials involving high-risk
atrial fibrillation patients (stroke rates >6% per year)
show larger absolute risk reductions by adjusted-dose warfarin
relative to aspirin, whereas the absolute risk reductions
are consistently smaller in trials of atrial fibrillation
patients with lower stroke rates. Warfarin, adjusted to achieve
an INR of 2 to 3, is therefore most advantageous (from the
perspective of benefit versus risk) for patients at greatest
intrinsic risk. Subgroup analysis of the atrial fibrillation
studies identified the following high-risk features: prior
stroke or thromboembolism, age >65 years, hypertension,
diabetes mellitus, coronary arterial disease, and moderate
to severe left ventricular dysfunction by echocardiography
(Figure 2) (173).
© 2003 by the American Heart Association, Inc., and the
American College of Cardiology Foundation
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