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Low-Molecular-Weight Heparins in the Treatment of Acute Coronary Syndromes
Alexander G. G. Turpie, MD;
Elliott M. Antman, MD
Arch Intern Med. 2001;161:1484-1490.
ABSTRACT
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Platelet aggregation and activation of coagulation are key events in
the development of acute coronary syndromes. Patients with an acute coronary
syndrome are at high risk of death or myocardial infarction, and hence there
is a strong rationale for the use of antithrombotic agents. Heparin has been
shown to reduce the risk of death or myocardial infarction in aspirin-treated
patients with acute coronary syndromes, but it has a number of limitations,
including the need for regular monitoring and the risk of hemorrhage and thrombocytopenia.
Low-molecular-weight heparins offer a number of practical and clinical advantages
over unfractionated heparin, such as higher bioavailability and administration
by subcutaneous injection. Several low-molecular-weight heparins are available
that differ in their biochemical and pharmacologic properties, and it is not
possible to predict their clinical efficacy from their pharmacologic profile.
The decision regarding the use of a specific low-molecular-weight heparin
should be based on the efficacy and safety data available for each product.
In clinical trials comparing low-molecular-weight heparin with heparin, only
enoxaparin sodium has been shown to reduce the risk of coronary events in
patients with non–ST segment elevation acute coronary ischemia.
INTRODUCTION
Clinical and pathologic studies have highlighted the importance of plaque
rupture and platelet aggregation in the pathogenesis of the acute coronary
syndromes (ACS) of Q wave myocardial infarction (MI), non–Q wave MI,
and unstable angina.1-2 Following
rupture of an atherosclerotic plaque, tissue factor in the lipid core is exposed
to circulating factor VIIa, resulting in the formation of a tissue factor–factor
VIIa complex and generation of factor Xa.3-4
This leads ultimately to the formation of large amounts of thrombin, resulting
in fibrin deposition and platelet activation.5-6
Electrocardiographic evidence of ST segment elevation indicates that the culprit
artery is completely occluded and that the patient will most likely subsequently
develop ST segment elevation MI. The absence of ST segment elevation in patients
with unstable angina and non–Q wave MI indicates that the culprit artery
is only partially or intermittently occluded or that a rich collateral circulation
exists. Nonocclusive intracoronary thrombi are present in 85% or more of patients
with non–ST segment elevation ACS,1 and
autopsy studies in such patients suggest that vascular occlusion that leads
to MI or sudden death results from repeated episodes of plaque fissure and
mural thrombosis.2, 7 Such lesions
are often not stabilized by therapy focused only on symptom relief, but continue
to progress and cause ischemic events throughout several months.8-9
As a result, patients with ACS are at increased risk of death and MI. Death
or MI occurs in 9% to 11% of patients with non–ST segment elevation
ACS within 4 to 6 weeks after the onset of symptoms,10-11
and recurrent angina occurs in up to 64% of patients who are hospitalized.12
The key roles of thrombin generation and platelet activation in the
pathogenesis of ACS create a strong rationale for the use of antithrombotic
agents in the management of these conditions. Current management guidelines13 recommend that patients with unstable angina should
receive aspirin, at doses between 75 and 325 mg, unless clear contraindications
are present. These guidelines are supported by a 1983 study14
in which the incidence of death or MI in men with unstable angina who were
treated with 325 mg/d of aspirin compared with placebo was reduced by 51%
(P = .0005). The risk of nonfatal MI was also significantly
lower in aspirin-treated patients than in the placebo group and mortality
was reduced, although not significantly. Subsequently, several large controlled
trials in patients with unstable angina treated with aspirin at daily doses
between 75 and 325 mg demonstrated a significant reduction in death, MI, or
both.15-18
Unfractionated heparin (UFH) has also been used, alone or in combination
with aspirin, in patients with unstable angina, since it inhibits thrombin-induced
platelet aggregation and fibrin formation and thus prevents propagation of
an established thrombus. Indeed, combination treatment with aspirin and UFH
has previously been recommended for patients with unstable angina or non–ST
segment elevation MI because of the accumulating trial evidence showing the
benefit of such treatment.13 In an early clinical
trial, treatment with UFH was associated with reduced incidences of MI and
refractory angina, compared with placebo, and UFH tended to reduce the incidence
of MI to a greater extent than aspirin.17 In
a subsequent extension of this study, the incidence of MI was significantly
lower in UFH-treated patients than in patients receiving aspirin (0.8% vs
3.7%; P = .035).19
A meta-analysis of published trials found that the risk of death or MI was
reduced by 33% in patients with unstable angina who received both aspirin
and UFH, compared with those who received aspirin alone, which suggests that
the addition of heparin provides further benefit in aspirin-treated patients.20 However, the use of UFH is associated with significant
disadvantages. The anticoagulant effect produced is unpredictable and doses
need to be continuously adjusted according to the activated partial thromboplastin
time, and even with adjustment dosing is often subtherapeutic, making long-term
treatment impractical.21 This is an important
issue because long-term treatment may be beneficial in patients with ACS:
the risk of ischemic events remains significant for several weeks after the
initial episode,21 and the coagulation system
can remain activated for several months.22-23
Furthermore, UFH treatment is associated with significant complications, including
hemorrhage,19 reactivation of the thrombotic
process within hours of discontinuing treatment,24
heparin-induced thrombocytopenia,25 and a rebound
increase in thrombotic activity and clinical events after discontinuation
of treatment.22, 26
Low-molecular-weight heparins (LMWHs) offer a number of potential advantages
over UFH in the management of ACS. They have a higher ratio of anti-Xa–anti-IIa
activity than UFH (thereby offering a potentially greater antithrombotic effect),
and as a result of the cascading nature of the coagulation system, inhibition
of a small quantity of factor Xa prevents the formation of considerably larger
amounts of thrombin.6 Other potential advantages
include a high bioavailability after subcutaneous administration; more predictable
anticoagulant effect, which avoids the need for therapeutic monitoring; and
decreased sensitivity to platelet factor 4.6
Although these features are common to all LMWHs, it is important to note that
LMWHs are a heterogeneous group of compounds that differ markedly in their
physical and pharmacologic properties. Thus, each LMWH must be tested in each
clinical indication and the results obtained with one LMWH do not apply to
another.
LMWHs IN ACS: PHARMACOLOGIC CONSIDERATIONS
The potency of LMWH is normally expressed in terms of the anti-Xa activity.27-28 However, with increasing understanding
of the mechanisms of action of LMWHs, it has become clear that a number of
other actions contribute to the antithrombotic effects of these agents. Indeed,
it is now recognized that up to 70% to 80% of the material contained in a
dose of LMWH acts via mechanisms that are independent of antithrombin.28-29 Such mechanisms include the following:
release of tissue factor pathway inhibitor (TFPI), interaction with heparin
cofactor II, inhibition of procoagulant effects of leukocytes, promotion of
fibrinolysis, protein binding, and effects on vascular endothelium (receptor
mediated and receptor independent). In particular, the effects of LMWHs on
TFPI have attracted increasing attention. Tissue factor pathway inhibitor
is a glycoprotein that inhibits the factor VIIa–tissue factor complex
by forming a quaternary complex with the factor VIIa–tissue factor complex
and factor Xa.30 In addition, it inhibits factor
Xa by binding at or near the active site30
and has a variety of other antithrombotic effects, which include the following:
inhibition of tissue factor–mediated activation of platelets and macrophages,
inhibition of factor Xa and elastase, multidomain inhibitor of protease generation,
interactions with low-density lipoproteins, interactions with vascular endothelium,
modulation of endogenous glycosaminoglycans, neutralization of endogenous
tissue factor, and possible regulatory functions.29
Both UFH and LMWHs release TFPI from the vascular endothelium.30-31
The LMWHs are prepared by a variety of chemical and enzymatic depolymerization
techniques, resulting in marked differences in their physical and biochemical
properties.27-28,32
Such variations in biological activity among LMWHs include the following:
variations in affinity for coagulation proteins (eg, antithrombin, platelet
factor 4, fibrinogen, protamine, factor VIII), differences in binding to endothelial
cells and blood cells, differences in protease inhibition, and differences
in bioavailability and pharmacokinetics. Typically, LMWHs have molecular weights
between 4000 and 8000 kd, but the available preparations differ in their molecular
weight distribution: some show a wide distribution of low- and high-molecular-weight
components, whereas with others the distribution is much narrower.32 Because the antithrombotic effects of LMWHs depend
on the relative distribution of medium (>9500 kd) and low (<3500 kd) molecular-weight
components,32 this variation has important
implications for the biological activity of LMWHs. Furthermore, chemical depolymerization
processes tend to reduce antithrombin binding activity, contributing to the
variation in anti-Xa activity among products.27-28
Differences in biological activity among LMWHs have been documented
in a series of studies.27-29
In anticoagulant assays, the specific activity ranges from 35 to 45 anti-IIa
U/mg or 80 to 120 anti-Xa U/mg,28 and the ratios
of anti-Xa to anti-IIa activities also differ; enoxaparin sodium and nadroparin
calcium, for example, have anti-Xa–anti-IIa ratios of approximately
3:1, whereas dalteparin sodium has a ratio of approximately 2:1.29
Similarly, the antithrombotic effect of different products varies markedly.
In a rabbit model of venous thrombosis, for example, enoxaparin and nadroparin
were found to be more effective than dalteparin and logiparin.27
Moreover, LMWHs also differ in their ability to release endogenous TFPI; following
intravenous administration of 100-U/kg doses in primates, circulating TFPI
concentrations ranged from 110 (dalteparin) to 150 ng/mL (logiparin).27
Such findings raise the question of whether differences in pharmacologic
properties among LMWHs are clinically relevant. In laboratory studies, the
antithrombotic and bleeding effects of a given LMWH depend on a number of
factors, including the animal model used and the route of administration32; thus, the clinical significance of such differences
is difficult to assess. Differences in efficacy and safety between LMWHs have
been considered to be small in clinical practice.28, 33
However, most comparisons between different agents have been made on the basis
of the clinical experience obtained with the low doses required for the prophylaxis
of deep vein thrombosis.28 Higher doses, where
any pharmacologic differences may be magnified, are required for the prevention
of ischemic events in patients with ACS, and thus differences in efficacy
and safety may become clinically evident in these situations. The efficacy
of a given LMWH in ACS depends on interactions between numerous biological
activities that are complex and not yet completely understood, including anti-Xa
and anti-IIa activities, release of TFPI, and effects on the vascular endothelium.
As a result, it is currently not possible to predict the clinical effect of
LMWHs from their pharmacologic profiles in laboratory studies. Hence, the
use of a given LMWH in ACS must be based on firm evidence from well-designed
clinical trials.
LMWHs IN ACS: A REVIEW OF THE CLINICAL EVIDENCE
A number of controlled clinical trials have investigated the use of
LMWHs in patients with ACS.11, 34-39
Details of these trials are summarized in Table 1.
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Clinical Trials With Low-Molecular-Weight Heparins in Patients With
Acute Coronary Syndromes*
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Placebo-Controlled Trials
The Fragmin during Instability in Coronary Artery Disease (FRISC) study,11 which was the only large placebo-controlled trial
we found, compared the effects of subcutaneous dalteparin and placebo in 1506
aspirin-treated patients with unstable angina or non–Q wave MI. During
the first 6 days, the incidence of death or MI was significantly lower in
dalteparin-treated patients than in the placebo group (1.8% vs 4.8%; P = .001). However, during long-term treatment for 35 to
45 days with a lower dosage of dalteparin (7500 IU/d), there was an apparent
reactivation of disease, and therefore the incidence of death or MI at 40
days did not differ significantly between the groups. In the subsequent FRISC
II study,34 patients received open-label dalteparin
for at least 5 days, they were then randomly assigned either invasive or noninvasive
treatment, and they were randomly allocated treatment with dalteparin or placebo
for 3 months. The risk of death or MI was reduced by 47% (P = .002) in dalteparin-treated patients at 30 days, but the observed
reduction was not statistically significant between the groups after 3 months.
The incidence of death or MI at 6 months was 13.3% in the dalteparin group
and 13.1% in the placebo group, and long-term dalteparin treatment was associated
with an increased risk of major bleeding complications, compared with that
in the placebo group (3.3% vs 1.5%, respectively).
Comparisons With UFH
Dalteparin
In the Fragmin in Unstable Coronary Artery Disease (FRIC) study, 1482
patients received either dalteparin, 120 IU/kg twice daily, or adjusted doses
of UFH for 6 days, after which they were randomly assigned dalteparin, 7500
IU once daily, or placebo for a further 39 days.37
The incidence of death, MI, or recurrent angina during the first 6 days was
7.6% in patients receiving UFH and 9.3% in dalteparin-treated patients; during
the double-blind treatment period, the incidence of this composite end point
was 12.3% in both the placebo and dalteparin groups. Thus, treatment of ACS
with dalteparin did not show long-term benefits.
Nadroparin
In clinical trials of the LMWH nadroparin, inconsistent results have
been reported. For example, in the recent Fraxiparine in Ischemic Syndrome
(FRAXIS) study (N = 3468), the incidence of coronary events (death, MI, refractory
angina, or recurrence of unstable angina) in patients receiving nadroparin,
86 anti-Xa U/kg twice daily, for 5 to 7 days or for 14 days was comparable
with that in patients treated with UFH at doses adjusted according to the
activated partial thromboplastin time.35 By
contrast, in a previous smaller study of just 219 patients,36
the incidence of coronary events in patients receiving aspirin plus a high
dosage of nadroparin (214 Institut Choay units per kilogram twice daily) was
significantly lower than in patients treated with aspirin plus UFH or aspirin
alone.
Enoxaparin
Two recent studies with enoxaparin38-39
have independently shown that this agent is more effective than UFH in preventing
coronary events in patients with ACS. In the Efficacy and Safety of Subcutaneous
Enoxaparin in Non–Q Wave Coronary Events (ESSENCE) study,38
3171 patients with angina at rest or non–Q wave MI were randomly assigned
either enoxaparin, 1 mg/kg (100 anti-Xa U/mg) every 12 hours, or adjusted
doses of UFH for up to 8 days; in addition, all patients received oral aspirin
at daily doses between 100 and 325 mg. After 14 days, death, MI, or recurrent
angina had occurred in 19.8% of patients receiving UFH, compared with 16.6%
of patients in the enoxaparin group; this corresponds to a risk reduction
of 20% (P = .019). The reduction in the incidence
of the composite end point was maintained and was significantly lower in the
enoxaparin group at 30 days (19.8% vs 23.3%, respectively; P = .016). The proportion of patients requiring coronary revascularization
was also significantly lower in the enoxaparin group at this time (27% vs
32.2%; P = .001). Long-term follow-up showed that
the beneficial effect of enoxaparin was still evident after 1 year.40 There was no significant difference in the incidence
of serious hemorrhagic complications between the 2 groups, but there was an
increase in minor hemorrhage, largely ecchymosis at the injection sites.
The Thrombolysis in Myocardial Infarction (TIMI) 11B study39
(N = 3910) was similar in design to the ESSENCE study, except that enoxaparin
was given as an initial 30-mg intravenous bolus, followed by injections of
1 mg/kg every 12 hours, and the short-term treatment phase was followed by
a 5-week outpatient placebo comparison using a lower dose of enoxaparin. After
8 days, the composite end point of death, MI, or urgent revascularization
had occurred in 14.5% of patients receiving UFH and 12.4% of enoxaparin-treated
patients, which corresponds to a risk reduction of 17% (P = .048). The corresponding figures at 14 days for the same composite
end point were 16.7% and 14.2%, respectively (P =
.029). At the end of the outpatient phase on day 43, the beneficial effects
of enoxaparin seen during the short-term phase were maintained during 7 weeks
of long-term treatment (although continued treatment provided no additional
benefit); the composite end point had occurred in 19.7% of UFH-treated patients
and 17.3% of enoxaparin-treated patients (P = .048).
As in the ESSENCE study, there was no significant difference in the rates
of major bleeding complications during the initial hospitalization between
treatment groups. However, during the outpatient phase, major hemorrhages
occurred in 2.9% of enoxaparin-treated patients and 1.5% of placebo-treated
patients (P = .021).
The data from the TIMI 11B and ESSENCE studies were combined in a prospectively
planned meta-analysis to provide statistically robust estimates of the effects
of enoxaparin on specific end points.41-42
This analysis showed that the incidence of death or MI was significantly reduced
in enoxaparin-treated patients from day 8 to day 43; similarly, the incidence
of death, MI, or urgent revascularization was consistently about 20% lower
in enoxaparin-treated patients than in patients treated with UFH from day
2 to day 43. The pooled incidence of major hemorrhagic complications during
short-term treatment was 1.3% in the enoxaparin group and 1.1% in the UFH
group (P = .35). The incidence of minor hemorrhages
during the short-term phase was 10.0% and 4.3%, respectively (P<.001). A recently published meta-analysis by Eikelboom et al43 commented that the pooled LMWH trial data did not
show a benefit of LMWH over UFH in unstable angina and non–ST segment
elevation MI. The article highlighted that in the TIMI 11B and ESSENCE studies,
at 72 hours (when the treatment durations of both UFH and enoxaparin were
equal in most patients) there was no real benefit of enoxaparin over UFH in
the "hard end point" of death and MI. Neither of these trials were powered
to examine differences in efficacy at just 72 hours; to do so would have necessitated
a much larger trial because of the low number of events at this early time
point. It is notable, however, that when the data from TIMI 11B and ESSENCE
are combined, there is a strong trend toward a benefit of enoxaparin for the
composite end point of death and MI (enoxaparin, 1.9%, vs UFH, 2.5%; odds
ratio, 0.77; 95% confidence interval, 0.56-1.01) and a significant benefit
in the composite end point of death, MI, and recurrent angina requiring urgent
revascularization (enoxaparin, 6.4%, vs UFH, 8.1%; odds ratio, 0.78; 95% confidence
interval, 0.65-0.94).
Economic analysis of the data from the ESSENCE trial has shown that
the added treatment benefits of enoxaparin and the reduction in hospital costs
due to the ease of use and lack of need for coagulation monitoring result
in cost benefits of using enoxaparin in place of UFH.44
VARIATION IN EFFICACY OF LMWHs IN ACS: FACT OR ARTIFACT?
Although the differing results obtained in clinical trials with different
LMWHs in ACS would be consistent with the heterogeneous nature of this group
of agents, it is necessary to consider the possibility that these discrepancies
are attributable to differences in study designs or study populations rather
than true differences in efficacy among the LMWHs.
Differences in Study Designs
The doses of LMWH and UFH used in these studies differed, as did the
duration of treatment and the timing of the first dose after the onset of
symptoms. In the study by Gurfinkel et al,36
the ESSENCE study,38 and the TIMI 11B study,39 for example, patients were allocated treatment within
24 hours of the onset of chest pain, whereas in the FRISC,11
FRISC II,34 and FRAXIS35
studies, patients were randomly assigned treatment up to 48 or 72 hours after
the onset of symptoms. Differences in the definitions of clinical end points
may also have contributed to the differences between individual trial results.45
Differences in Study Populations
Differences in the patient populations studied may have contributed
to the variation in outcome, since there is some evidence that patients at
the highest risk of coronary events derive even greater benefit from treatment
with LMWH compared with UFH therapy. In the FRISC II study, treatment with
dalteparin was associated with a reduced incidence of death or MI at 3 months
in patients with elevated troponin T concentrations at baseline, but not in
patients with normal troponin T concentrations.34
In the ESSENCE and TIMI 11B studies, for example, although there was a relative
reduction in coronary events achieved with enoxaparin in all patients compared
with UFH, the benefit was greater in patients with risk factors such as ST-segment
depression or electrocardiographic changes at baseline or a previous history
of aspirin use.38, 41 Similarly,
in trials with glycoprotein IIb/IIIa inhibitors, patients at highest risk
have derived the greatest treatment benefit.46
Differences in study designs, however, do not preclude genuine differences
in efficacy among LMWHs.
POTENTIAL BIOCHEMICAL BASIS FOR PRODUCT DIFFERENCES
The LMWHs show considerable variation in their biochemical properties,
and it is this variation that may underlie the differing results seen in clinical
trials focusing on ACS.
Anti-Xa Activity
Although the anti-Xa activity of a LMWH does not directly predict antithrombotic
activity,29 it is noteworthy that there were
marked variations in the anti-Xa activities and the anti-Xa–anti-IIa
ratios of the LMWHs used in different trials. Enoxaparin has a higher anti-Xa–anti-IIa
ratio than LMWHs, such as dalteparin, which have not shown consistently favorable
results in clinical trials, although the anti-Xa–anti-IIa ratio of nadroparin
is similar to enoxaparin and the clinical study results to date with nadroparin
have not shown a consistent treatment benefit.6, 35-36
Moreover, the trough anti-Xa activities reported with dalteparin in the FRIC
study37 (0.35-0.37 anti-Xa IU/mL) were lower
than those obtained with the enoxaparin dose used in the ESSENCE and TIMI
11B studies (0.5-0.6 anti-Xa IU/mL).47 The
finding in the FRIC study that long-term treatment with dalteparin did not
reduce the incidence of coronary events suggests that the dose of dalteparin
may have been too low or the interval between doses too long to provide effective
anticoagulant cover.37 Importantly, the higher
anti-Xa activities obtained with enoxaparin in ESSENCE and TIMI 11B were not
associated with an increased risk of major bleeding.
TFPI Release
A number of the effects of LMWHs are mediated via mechanisms that are
independent of antithrombin binding and anti-Xa activity. Release of TFPI
may contribute to the prolonged antithrombotic effect seen after subcutaneous
administration of LMWH, which is maintained after the disappearance of circulating
anti-Xa activity.29 Recently, Bendz et al48 have shown a differential effect of UFH and LMWHs
(enoxaparin and dalteparin) on TFPI release in a small group of patients (N
= 12). Repeated administration of UFH resulted in partial depletion of free
TFPI plasma levels, a phenomenon that was not observed in patients treated
with either enoxaparin or dalteparin. The differing action of UFH and LMWH
on TFPI release could be a potential biochemical basis for the different clinical
benefits of these compounds.
von Willebrand Factor
A recent substudy49 of the ESSENCE trial
has highlighted another potential mechanism by which enoxaparin may exert
its beneficial effect in ACS. This study showed that circulating concentrations
of von Willebrand factor (vWF) increased 48 hours after admission with ACS
and that the magnitude of this increase was predictive of a poor outcome.
In addition, vWF mediates platelet adhesion to the vascular endothelium and
thus plays a key role in thrombus formation. In enoxaparin-treated patients,
the increase in vWF concentrations was significantly attenuated (mean increase
of 8.7% compared with 93.9% in patients receiving UFH, P<.001).49 The reduction in vWF concentrations
seen in the ESSENCE substudy may therefore contribute to the antithrombotic
effect of enoxaparin. This reduction may be a result of the binding of enoxaparin
to the heparin-binding domain of vWF, resulting in impaired binding of vWF
to platelets, or to a decrease in thrombin-induced release of vWF.6 Recently, a small study50
of vWF in 154 patients with ACS revealed that patients treated with enoxaparin
or polyethylene glycol–hirudin had a significantly smaller increase
in vWF after 48 hours than those treated with UFH or dalteparin. At present,
the effects of other LMWHs on vWF concentrations are unknown.
CONCLUSIONS
Although its usefulness has been limited by an unpredictable anticoagulant
effect and a risk of complications, UFH has played an important role in the
short-term management of ACS. Currently, LMWHs offer a number of practical
and clinical advantages over UFH. The various LMWHs differ markedly in their
biochemical and pharmacologic properties and have been studied under many
different trial designs, which make direct comparisons of published studies
difficult. As a result, clinical decisions regarding the use of a given LMWH
should be based on the efficacy and safety data available for each specific
product. The LMWHs have been shown to be effective in reducing ischemic outcomes
in ACS.
The LMWH enoxaparin has been shown to reduce the risk of acute coronary
events and the need for revascularization in patients with ACS when compared
with UFH treatment. There are potential biochemical bases for differences
in efficacy among LMWHs, but direct comparisons among the LMWHs are required
to determine the superiority of one over another.
AUTHOR INFORMATION
Accepted for publication January 9, 2001.
This study was supported by a grant from Aventis Pharma, Parsippany,
NJ.
Corresponding author and reprints: Alexander G. G. Turpie, MD, HHSC-General
Division, 237 Barton St E, Hamilton, Ontario, Canada L8L 2X2 (e-mail: turpiea{at}mcmaster.ca).
From the Department of Medicine, McMaster University, Hamilton, Ontario
(Dr Turpie), and Cardiovascular Division, Department of Medicine, Brigham
and Women's Hospital, Boston, Mass (Dr Antman).
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