1. health and fitness
2. therapy

Antithrombotic Agents in
Coronary Artery Disease
Coronary atherosclerosis is the underlying abnormality in
John A. Cairns, MD, Chair; H. Daniel Lewis Jr, MD;
Thomas W. Meade, DM; George C. Sutton, MD; and
Pierre
Theroux, MD
chapter begins with
pathophysiology,
rds
followed by discussion of the clinical syndromes under
the
of
infarction
a
major headings
acute
section
on
myocardial
of coronary thrombosis.10 However, the
thrombus typically develops at a site of underlying coronary
artery stenosis of only mild to moderate severity as deter¬
mined by coronary angiography.1112 Recent progression of
coronary stenosis is a common feature of unstable angina,13'14
and careful analyses of these stenoses have shown char¬
acteristic morphologic features suggestive of atherosclerotic
plaque disruption,
partially lysed thrombus, or both.1516 The
of thrombosis is highest among those patients
prevalence
who undergo angiography within hours of the most recent
episode of chest pain. Angioscopic observations17 confirm
the angiographic impression of the development of plaque
and thrombosis. The angiographic observation of
damage
DeWood and colleagues18 that occlusive coronary thrombosis
is an early and important event in more than 80% of
transmural infarcts has been confirmed among thousands of
patients undergoing angiography in the early hours of AML
Falk19 has shown that patients experiencing sudden death
preceded by serial episodes of unstable angina may be found
at autopsy to have an occlusive thrombus composed of lay¬
ers of platelet thrombi in different stages of organization,
corresponding to the clinical episodes of ischemia. Platelet
emboli distal to the site of the occlusive thrombosis have also
been observed.19,20 Davies et al2122 have reported that
coronary thrombosis or plaque injury or both may be
demonstrated in 95% of sudden death victims.
The plaques most vulnerable to rupture are moderately
stenotic, relatively soft, have a central core rich in lipids, and
a fibrous cap poor in connective tissue and smooth muscle
cells, making them more prone to rupture under local stress
conditions.23 The site of rupture is usually rich in monocyteand lymphocytes.2425 Increasingly, athero¬
macrophages
sclerosis is seen as a chronic inflammatory process occurring
in response to a variety of injurious influences.26 Acute
exacerbation of this process, with the proliferation of inflam¬
matory cells and the release of lytic enzymes, may break
down connective tissue and lead to plaque fissuring and
rupture.27 The exposure of subendothelial collagen and the
release of tissue factor activates platelets and stimulates the
formation of thrombin. Eventually the platelets undergo a
"release reaction," with extrusion of active mediators of
thrombosis from cytoplasmic granules, leading to the enzy¬
matic liberation of arachidonic acid, the sequential evolution
of prostaglandins, and culminating in the synthesis of
thromboxane A2, an extremely potent vasoconstrictor and
plateletis aggregant. An irreversible stage of platelet aggre¬
gation reached, which may be accompanied or followed by
thrombin generation, the incorporation of fibrin and RBCs,
and the formation of a red thrombus.
A variety of markers of platelet activation (ie, (3thromboglobulins and thromboxane A2) and thrombin
generation (ie, fibrinopeptide A and prothrombin fragment
1 and 2) are elevated in concert with the clinical course of
unstable angina,2829 and new evidence indicates that sensitive
indicators of inflammation, such as C-reactive protein and
serum amyloid A protein, may be detected and are predictive
of poor outcomes.30 The observation of recurrent formation
and disruption of platelet occlusions in the canine coronary
stenosis model of Folts et al31 and the effects of various
interventions thereon3132 may be closely representative of
most instances
(AMI),
unstable angina, primary prevention, and stable angina. In
each section, the greatest weight is given to level I trials, of
which there are many. In addition, when formal overviews
have been published, they are referenced. Although the
overviews give a broad summary picture, they do not provide
the immediacy and more direct relevance of individual large,
well-designed clinical trials with unequivocal results.
details of the major trials are provided to give
Accordingly,
the reader a sense of the sorts of patients under study and
the potential generalizability of the results to the reader's
own patients. Greater emphasis is placed on the relatively
recent evidence. Although some of the details of individual
trials provided in earlier editions ofthis consensus conference
have been omitted, the summaries and recommendations
are based on all available evidence.
Pathophysiology
Endovascular thrombus formation is a critical factor in the
of acute myocardial infarction, unstable angina,
development
and thrombotic coronary occlusion during coronary
angioplasty. Herrick1 is generally credited with the first
clinical description of AMI, and his view of the causative role
of coronary thrombosis was widely accepted. As a result of
many subsequent observations,2"5 the concepts of evolving
coronary thrombosis underlying unstable angina and acute
occlusive thrombosis producing AMI became firmly
established. The first clinical trial of anticoagulation in AMI
was reported in 1948,6 and the American Heart Association
recommended that "anticoagulant therapy should be used in
all cases of coronary thrombosis with MI unless a definite
contraindication exists." Ry the 1950s, it appeared that patients
takingtheaspirin regularly had a reduced incidence of fatal ML7
By 1960s, the basis for the use of anticoagulant therapy
in unstable angina and AMI was being widely questioned.
The deficiencies in study designs were evident,8 the role of
coronary thrombosis in the pathogenesis of the acute
ischemic syndromes appeared less certain,9 and outcomes
following unstable angina and AMI had improved with other
advances in medical and surgical therapy. Subsequendy, a
evidence emerged to implicate platelet
huge body ofactivation
of the coagulation system, and
aggregation,
eventual coronary thrombosis in the pathophysiology of
unstable angina, AMI, and sudden coronary death. For
patients with acute and chronic manifestations of coronary
artery disease, there is now a strong rationale and extensive
evidence from clinical trials for therapies designed to prevent
and limit platelet aggregation and activation of the
coagulation cascade and to lyse coronary thrombi.
Reprint
requests: Dr. Cairns, McMaster University Medical Center,
1200 Main St W, Hamilton, ON L8N 3Z5, Canada
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Fourth ACCP Consensus Conference on Antithrombotic Therapy
Table
1.In-Hospital Mortality in AMI
Mortality
RR
Therapy,
Control,
Reduction
28
16.2
18.2
11
NS
Hospital stay
14.9
21.2
30
<0.005
28
9.6
11.2
14
NS
Duration
Study
MRC37
Bronx
Municipal38
Patients
1,427
1,136
of Therapy, d
Agent, Dose
Heparin .»
phenindione
(INR, 1.6-2.1)
vs placebo
Heparin .>
phenindione
Trial
Level
(INR >2-2.5)
vs
VA
Cooperative35
999
minimal
phenindione
Heparin .>
II
warfarin
(INR >2)
vs
placebo
the situation in human unstable angina.
Unstable angina results from compromised perfusion at
rest, while acute Q-wave infarction is associated with total
occlusion.33 Non-Q-wave infarction is intermediate, with
either subtotal obstruction or total obstruction with a degree
of collateral blood supply or recanalization. Unstable angina
is associated with no or minimal myocardial necrosis, but an
important risk of eventual coronary occlusion. The risk is
increased when the endothelium is not yet healed,
maintaining a stimulus to further thrombosis. The thrombus
itself is a strong thrombogenic stimulus, the entrapped
thrombin causing ongoing platelet and coagulation factor
activation. The healed endothelium and remodeled plaque
may constitute a progression of coronary artery stenosis and
may be associated with a risk of repeated plaque rupture.
Inappropriate increases in coronary tone, most often in
the region of an atherosclerotic plaque, are an important
component of the etiology of many episodes of acute
myocardial ischemia. On occasion, coronary spasm may
culminate in MI.34 Most often, however, the pathophysiologic
sequence appears to be one of atherosclerotic plaque
disruption, platelet activation, thrombin generation, and
partial or complete thrombotic occlusion.33 The acute and
late outcomes appear to be importandy related to the
completeness and persistence of the coronary occlusion.
Myocardial Infarction
Anticoagulant Therapy
Clinical Trials of Short-term Therapy Evaluating
Clinically Important Outcomes: Since 1948, there have been
more than 30 reports of the use of anticoagulants in AMI
(Tables 1 and 2).3536 However, only three of these trials were
of sufficient size to detect a modest but clinically important
One of these studies did find a
mortality.reduction
of mortality, while the other
statistically significant
two found statistically significant reductions in stroke and
pulmonary embolism.
The Medical Research Council Trial37 was a single-blind,
controlled trial in which 1,427 AMI patients of any age and
either sex were randomized to heparin (15,000 U IV bolus,
then 10,000 U IV every 6 h up to five doses) or no heparin
therapy. The heparin group
began phytonadione therapy
adjusted to maintain the thrombo test level
simultaneously,
between 20% and 10% (approximate international nor¬
malized ratio [INR], 1.6 to 2.1), while the no heparin group
received a minimal dose of phytonadione. The treatment
period was 28 days. Mean time to randomization was not
reported,
although the intent was the earliest possible entry.
More than 92% of randomized patients had definite or
probable MI. Among the high-dose anticoagulation group,
all-cause mortality fell from 18 to 16.2%, reinfarction from
13 to 9.7%, and the composite outcome of mortality or
reinfarction fell from 31 to 29.5% (risk reduction, 16%;
p=NS). There were statistically significant reductions in the
incidence of pulmonary embolism (5.6% vs 2.2%) and stroke
(2.5% vs 1.1%) (p<0.01 for all thromboembolism). Hemor¬
was more frequent in the anticoagulation group (1.3%
rhage
vs 5.1%), but none of these events was fatal.
The Bronx Municipal Hospital Center Trial38 randomized
1,136 AMI patients ofeither sex. Patients in the anticoagulant
group received heparin (5,000 U IV bolus, then 10,000 U
reduction of
Table 2.Incidence of Stroke and Pulmonary Embolism in AMI
Stroke
Study
MRC37
Municipal38
Cooperative39
Bronx
VA
Therapy,
Control,
1.1
2.5
2.3
3.8
1.7
0.8
Pulmonary Embolism
RR
Reduction
56
26
79
0.04
NS
0.001
Trial
Level
Therapy,
Control,
RR
%
Reduction
I
II
I
2.2
3.8
0.2
5.2
6.1
2.6
58
38
92
Trial
Level
<0.05
NS
0.005
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I
II
I
381S
hemorrhage was slightly increased (0.6% vs 0.4%, 2p<0.05),
was not different (1.3% vs 1.2%). Major
transfusion was definitely increased by
bleeding requiring
heparin (1.0% vs 0.8%, 2p<0.01). The SCATI study56
randomized 433 patients who had received IV SK within 6
h of onset of AMI to either heparin (2,000 U by IV bolus on
of SK; 12,500 U sc after 9 h, then 12,500 U sc
completion
every 12 h to hospital discharge) or no heparin. Aspirin
treatment was not permitted. Hospital mortality was reduced
to 4.5% from 8.8% (risk reduction=49%; p=0.05, level I),
recurrent ischemia was reduced to 14.2% from 19.6%
(p=0.08), although reinfarction was not, and the rate of mural
thrombosis was reduced. Bleeding was 4.4% among the
heparin-treated
patients vs 0.6% among the control patients.
A variety of smaller trials have focused on the surrogate
outcome of infarct-related artery patency (by coronary
angiography) in the attempt to assess the potential benefits
of adjuvant heparin therapy. The TAMI-3 study77 randomly
allocated 134 patients within 6 h of onset of AMI to IV rtPA
(infused over 3 h) plus heparin (10,000 U by IV bolus) or to
rtPA alone. Angiographic patency was assessed at 90 min
after onset of the rt-PA infusion and was found to be 79%
in each group. No aspirin was given until after angiography.
Bleich et al78 randomized 83 patients who had commenced
IV rtPA within 6 h of onset of AMI, to heparin, 5,000 U by
IV bolus plus 1,000 U/h after rtPA therapy was begun or no
heparin.
Angiographic patency was assessed at a mean of 57
h post-AM I onset, and was 71% in the heparin-treated group
and 44% in the no-heparin-treated group (p=0.04, level I).
Recurrent ischemia or reinfarction within 7 days was no less
frequent while receiving heparin, but bleeding rate was 64%
with heparin vs 36% with no heparin.
The HART study79 randomized 205 patients who had
commenced IV rtPA therapy within 6 h of the onset of AMI
to heparin (5,000 U by IV bolus plus 1,000 U/h after rtPA
therapy begun) or aspirin (80 mg orally, then once daily).
Angiographic
patency at a mean of 18 h post-AM I onset
showed 82% patency with heparin and 51% with aspirin
(p<0.0001). By 7 days, reocclusion had occurred in 12% of
heparin-treated
patients and 5% of aspirin-treated patients.
Rates of recurrent ischemia and hemorrhage were no
different between the two
while all stroke
groups.
The ECSG-6 study80 recruited 652 patients to a regimen
of rtPA plus immediate ASA, followed by ASA, 75 to 125 mg
on alternate days, with subsequent randomization to IV
heparin (5,000 U stat IV, 1,000 U/h, no adjustment) or no
heparin. Angiography at a mean of 81 h showed slightly
improved
patency with heparin (83% vs 75%) (2p<0.01).
The National Heart Association of Australia Study81
evaluated 241 patients who had commenced IV rtPA therapy
within 4 h of onset of AMI and were all given IV heparin for
24 h. They were then randomized to ongoing IV heparin
therapy vs a daily regimen of oral ASA, 300 mg, plus
300 mg for 1 week. Angiographic patency was
dipyridamole,
79.8% in the heparin-treated group and 82% in the aspirin/
dipyridamole-treated group (p=NS). Death rate was 5% for
the heparin-treated group and 2% for the aspirin/
dipyridamole-treated group (p=NS), while reinfarction rates
were 5% for the heparin-treated group and 2% for the
aspirin/dipyridamole-treated group (p=NS). Rates of
recurrent pain and hemorrhage were no different between
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the two groups.
These angiographic trials, all conducted among patients
receiving rtPA, suggest that heparin therapy may improve
the rates of coronary patency in some patients receiving IV
thrombolytic therapy/However, the greatest benefit appears
in the Bleich et al7 trial in which the patients did not receive
aspirin, is less marked in the HART study79 in which a low
and possibly suboptimal dose of aspirin was administered,
and was least marked in the ECSG-6 trial80 in which
optimal-dose aspirin therapy was commenced immediately.
However, the angiographic assessment of patients in the
ECSG-6 trial was somewhat later than optimal for assessing
the benefit of heparin in achieving early patency. The
TAMI-3 study78 suggested that heparin therapy may not be
needed for at least 90 min after the initiation of rtPA therapy,
and the Australian study81 suggests that after 24 h, there may
be no benefit of heparin over aspirin/dipyridamole.
The APRICOT study82 randomized 300 AMI patients
who had received SK or anisoylated plasminogen SK
activator complex (APSAC) followed by IV heparin, and
whose infarct-related artery was angiographically patent less
than 48 h from treatment, to a regimen of ASA, 325 mg/d,
placebo, or ongoing IV heparin therapy until INR was 2.8 to
4.0 with warfarin. At repeated angiography at 3 months,
reocclusion rates were ASA 25%, warfarin 30%, and placebo
32%. The ASA-treated patients showed significantly greater
freedom from reinfarction, revascularization, and death than
the placebo-treated patients (93% vs 76%; p<0.01). This
study suggests that ASA is sufficient antithrombotic therapy
beyond 48 h. The optimal combination of thrombolytic
agent, aspirin, and heparin in terms of early angiographic
infarct-related artery patency has not been clearly delineated
by the studies reported to date.
To our knowledge, the only thrombolytic study demon¬
strating a statistically significant improvement by heparin of
the clinically important outcome of hospital mortality was the
SCATI study.5" However, this study employed no aspirin,
and the results are not generalizable to current practice.
The overview of the International tPA/SK Mortality Trial
and the ISIS-3 trial indicated only a modest benefit of
Several design features of these trials may have
heparin.76
resulted in less efficacy from heparin than might have been
achieved.83 Heparin therapy was begun relatively late in
these trials (first dose at 12 h in the International tPA/SK
Mortality Trial, and at over 4 h in ISIS-3). The subcutaneous
route of administration with a conservative dose of heparin
would likely have produced delayed onset of anticoagulation
and relatively minimal prolongation of activated partial
time (APTT) in many patients.83 The key to
thromboplastin
preventing recurrent venous thrombosis and pulmonary
embolism in studies of venous thromboembolism appears to
have been the administration of sufficient heparin to prolong
the APTT by 1.5 to 2 times control. When this goal was
achieved, the rate of recurrence was very low whether
was given IV or sc.84 It has been demonstrated that
heparin
a fixed dose of heparin of 15,000 U sc every 12 h produced
a subtherapeutic APTT response in the initial 24 h in more
than 63% of patients and led to a substantial risk of venous
thromboembolism.84 Studies of the time course of APTT
have shown that the peak level from a given
prolongation
dose of SC heparin occurs in about 4 h, and furthermore, that
Fourth ACCP Consensus Conference on Antithrombotic Therapy
therapy prolongs the INR to 2 to 3. Evidence of
anterior infarction should generally be sufficient to prompt
the use of heparin. The indication is strengthened in the
warfarin
presence of atrial fibrillation, congestive heart failure, dilated
LV, acute ventricular aneurysm, or mural thrombus detected
on
2D
echocardiography.
Thrombus is commonly associated with chronic LV
aneurysm (48 to 66% in surgical studies).5859 However,
systemic emboli are infrequent (4 to 5% by preoperative
history). In a retrospective study of 89 patients with LV
aneurysm, 20 were treated with anticoagulants for 40
patient-years and 69 were not so-treated for 288 patientyears.60 Onlyhadonea clinical
patient who was not receiving anti¬
embolic event, an incidence of
coagulants
0.35/100 patient-years. On the basis of this study, the
presence of a long-term LV aneurysm, even containing
thrombus, does not justify anticoagulant therapy.
Studies of Venous Thromboembolism: Venous thrombosis
results from blood stasis and low shear rates, leading to
activation of the coagulation system and the formation of
fibrin thrombi. The incidence of deep venous thrombosis in
patients with AMI is 17 to 38% within 72 h, and 50 to 60%
within 5 to 7 days. In those restricted to bed for 5 days, the
incidence is 63% in the absence of cardiac failure and 80%
when cardiac failure is present. Those younger than 50 years
have an incidence of 13% that rises to 70% in those 70 years
or older.61 The incidence of pulmonary embolism was
reduced in all three of the large randomized studies of
and AMI37"39 (Table 2). Although the clinical
anticoagulation
of pulmonary embolism is unreliable as carried out
diagnosis
in the studies, the findings are supported by autopsy data5462
and by the results of studies using full-dose heparin therapy
followed by oral anticoagulants demonstrating a significant
reduction in the incidence of venous thrombosis diagnosed
by 125I-fibrinogen
leg scanning.6364
Several studies have assessed the efficacy of low-dose
following AML Marks and Teather65
heparin therapy
the results of a level I study in which 81 post-MI
reported were
randomized to low-dose heparin therapy
patients
(7,500 U sc bid) or to control. Thrombi (detected by
fibrinogen leg scanning) occurred in 14 patients in the
control group and 2 in the low-dose heparin group (p<0.005).
Similar results were reported by Warlow et al.66 In contrast,
II study, randomized 50 patients to
Handley,67 in a Ulevel
sc every 12 h for 7 days) or to control
heparin (7,500
(detected by fibrinogen leg
therapy. Venous thrombosis
scanning) developed in 29% of controls and in 23% oftreated
patients (p=NS).
In the Antiplatelet Trialists' Overview,68 high-risk medical
patients receiving antiplatelet therapy had fewer episodes of
deep venous thrombosis and pulmonary embolus than did
those receiving placebo. However, there were rather few
events and there were very little data on patients with AMI,
so that the benefit of antiplatelet therapy among such
patients is uncertain.
Conjoint Use ofAnticoagulants With Thrombolytic Agents:
The efficacy of IV thrombolytic agents in the reduction of
of LV function in AMI is clear.
mortality and the preservation
However, following successful thrombolysis, there is a risk of
infarct-related artery reocclusion of 5 to 30% and a rate of
reinfarction of about 4% when acetylsalicylic acid (ASA) is
not used.69 The
to the generation
thrombolytic
agents may paradoxically lead
of increased amounts of thrombin.70
Hence, there is a good theoretic rationale for the conjoint use
of heparin.
In the large overview of thrombolytic therapy reported in
1985,71 there was no statistically significant benefit evident
from the addition oforal or IV anticoagulation to thrombolytic
therapy.
Accordingly, no anticoagulant therapy was
mandated in the GISSI-1 or ISIS-2 trials.72'73 Among those
patients in GISSI-1 who had received anticoagulation or
antiplatelet therapy, there was no evidence of additional
benefit. In the ISIS-2 trial, aspirin reduced the rate of
reinfarction by 50% in patients receiving SK and improved
the odds reduction of mortality by SK from 25 to 42%. Some
form of heparin was used in 65% of patients in ISIS-2, and
among the patients receiving both SK and ASA, there was
an increasing trend toward greater mortality reduction as the
intensity of planned heparin therapy increased (no heparin
12.9% down to 9.6%; subcutaneous heparin 13.5% down to
7.6%; and IV heparin 13.1% down to 6.4%). Major bleeding
rates increased as the intensity of heparin therapy increased.
Two large trials have attempted to delineate the value of
adjuvant heparin with thrombolytic therapy. The GISSI-2
trial74 randomized patients using a 2x2 factorial design to
either IV rtPA or SK, followed at 12 h postrandomization by
calcium heparin 12,500 U sc or no heparin and continued
every 12 h until hospital discharge. Eighty-seven percent of
patients received aspirin. The composite outcome of vascular
death or severe LV damage was not different between
(22.7%) and no heparin (22.9%), nor was the rate of
heparin
reinfarction or postinfarct angina significantly reduced by
With heparin treatment, the absolute
heparin treatment.
increased risk of bleeding was 4.7% and of major bleeding
it was 0.4%. The International tPA/SK Mortality Trial75
recruited 8,401 additional patients according to the GISSI-2
protocol, and among the entire 20,891 patients, there was no
difference in mortality between heparin (8.5%) and no
(8.9%), nor was there a difference in the rate of
heparin
reinfarction. The absolute risk of major bleeding was
increased 0.5% by heparin.
In ISIS-3,76 in addition to the random allocation to
fibrinolytic
therapy, the patients were randomized to heparin
or no heparin therapy in a factorial design (calcium heparin
U SC begun at 4 h after initiating throm¬
therapy, 12,500 and
infusion
continued every 12 h for 7 days). About
bolytic
80% of patients allocated to heparin therapy continued
treatment for 7 days, and about 17% of those allocated to no
some heparin and, therefore, the net
heparin received
difference in high-dose subcutaneous heparin use is
estimated to be about 70 to 75% ofthe theoretical difference.
At 35 days, the vascular mortality was 10.3% in the heparin
group and 10.6% in the no heparin group (p=NS). The
comparative mortalities during the 7-day treatment period
were 7.4% and 7.9% (2p=0.06). An overview76 of the results
from GISSI-2 and ISIS-3 calculated mortality at about 35
days to beand10% with heparin and 10.2% with no heparin
(p=NS), during the 7-day treatment period, mortality
was 6.8% with heparin and 7.3% with no heparin (2p<0.01).
In addition, in ISIS-3, there was a trend toward reduced
reinfarction with heparin (3.2% in hospital) compared with
no heparin (3.5% in hospital) (2p=0.09). Probable cerebral
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383S
hemorrhage was slightly increased (0.6% vs 0.4%, 2p<0.05),
was not different (1.3% vs 1.2%). Major
transfusion was definitely increased by
bleeding requiring
heparin (1.0% vs 0.8%, 2p<0.01). The SCATI study56
randomized 433 patients who had received IV SK within 6
h of onset of AMI to either heparin (2,000 U by IV bolus on
of SK; 12,500 U sc after 9 h, then 12,500 U sc
completion
every 12 h to hospital discharge) or no heparin. Aspirin
treatment was not permitted. Hospital mortality was reduced
to 4.5% from 8.8% (risk reduction=49%; p=0.05, level I),
recurrent ischemia was reduced to 14.2% from 19.6%
(p=0.08), although reinfarction was not, and the rate of mural
thrombosis was reduced. Bleeding was 4.4% among the
heparin-treated
patients vs 0.6% among the control patients.
A variety of smaller trials have focused on the surrogate
outcome of infarct-related artery patency (by coronary
angiography) in the attempt to assess the potential benefits
of adjuvant heparin therapy. The TAMI-3 study77 randomly
allocated 134 patients within 6 h of onset of AMI to IV rtPA
(infused over 3 h) plus heparin (10,000 U by IV bolus) or to
rtPA alone. Angiographic patency was assessed at 90 min
after onset of the rt-PA infusion and was found to be 79%
in each group. No aspirin was given until after angiography.
Bleich et al78 randomized 83 patients who had commenced
IV rtPA within 6 h of onset of AMI, to heparin, 5,000 U by
IV bolus plus 1,000 U/h after rtPA therapy was begun or no
heparin.
Angiographic patency was assessed at a mean of 57
h post-AM I onset, and was 71% in the heparin-treated group
and 44% in the no-heparin-treated group (p=0.04, level I).
Recurrent ischemia or reinfarction within 7 days was no less
frequent while receiving heparin, but bleeding rate was 64%
with heparin vs 36% with no heparin.
The HART study79 randomized 205 patients who had
commenced IV rtPA therapy within 6 h of the onset of AMI
to heparin (5,000 U by IV bolus plus 1,000 U/h after rtPA
therapy begun) or aspirin (80 mg orally, then once daily).
Angiographic
patency at a mean of 18 h post-AM I onset
showed 82% patency with heparin and 51% with aspirin
(p<0.0001). By 7 days, reocclusion had occurred in 12% of
heparin-treated
patients and 5% of aspirin-treated patients.
Rates of recurrent ischemia and hemorrhage were no
different between the two
while all stroke
groups.
The ECSG-6 study80 recruited 652 patients to a regimen
of rtPA plus immediate ASA, followed by ASA, 75 to 125 mg
on alternate days, with subsequent randomization to IV
heparin (5,000 U stat IV, 1,000 U/h, no adjustment) or no
heparin. Angiography at a mean of 81 h showed slightly
improved
patency with heparin (83% vs 75%) (2p<0.01).
The National Heart Association of Australia Study81
evaluated 241 patients who had commenced IV rtPA therapy
within 4 h of onset of AMI and were all given IV heparin for
24 h. They were then randomized to ongoing IV heparin
therapy vs a daily regimen of oral ASA, 300 mg, plus
300 mg for 1 week. Angiographic patency was
dipyridamole,
79.8% in the heparin-treated group and 82% in the aspirin/
dipyridamole-treated group (p=NS). Death rate was 5% for
the heparin-treated group and 2% for the aspirin/
dipyridamole-treated group (p=NS), while reinfarction rates
were 5% for the heparin-treated group and 2% for the
aspirin/dipyridamole-treated group (p=NS). Rates of
recurrent pain and hemorrhage were no different between
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the two groups.
These angiographic trials, all conducted among patients
receiving rtPA, suggest that heparin therapy may improve
the rates of coronary patency in some patients receiving IV
thrombolytic therapy/However, the greatest benefit appears
in the Bleich et al7 trial in which the patients did not receive
aspirin, is less marked in the HART study79 in which a low
and possibly suboptimal dose of aspirin was administered,
and was least marked in the ECSG-6 trial80 in which
optimal-dose aspirin therapy was commenced immediately.
However, the angiographic assessment of patients in the
ECSG-6 trial was somewhat later than optimal for assessing
the benefit of heparin in achieving early patency. The
TAMI-3 study78 suggested that heparin therapy may not be
needed for at least 90 min after the initiation of rtPA therapy,
and the Australian study81 suggests that after 24 h, there may
be no benefit of heparin over aspirin/dipyridamole.
The APRICOT study82 randomized 300 AMI patients
who had received SK or anisoylated plasminogen SK
activator complex (APSAC) followed by IV heparin, and
whose infarct-related artery was angiographically patent less
than 48 h from treatment, to a regimen of ASA, 325 mg/d,
placebo, or ongoing IV heparin therapy until INR was 2.8 to
4.0 with warfarin. At repeated angiography at 3 months,
reocclusion rates were ASA 25%, warfarin 30%, and placebo
32%. The ASA-treated patients showed significantly greater
freedom from reinfarction, revascularization, and death than
the placebo-treated patients (93% vs 76%; p<0.01). This
study suggests that ASA is sufficient antithrombotic therapy
beyond 48 h. The optimal combination of thrombolytic
agent, aspirin, and heparin in terms of early angiographic
infarct-related artery patency has not been clearly delineated
by the studies reported to date.
To our knowledge, the only thrombolytic study demon¬
strating a statistically significant improvement by heparin of
the clinically important outcome of hospital mortality was the
SCATI study.5" However, this study employed no aspirin,
and the results are not generalizable to current practice.
The overview of the International tPA/SK Mortality Trial
and the ISIS-3 trial indicated only a modest benefit of
Several design features of these trials may have
heparin.76
resulted in less efficacy from heparin than might have been
achieved.83 Heparin therapy was begun relatively late in
these trials (first dose at 12 h in the International tPA/SK
Mortality Trial, and at over 4 h in ISIS-3). The subcutaneous
route of administration with a conservative dose of heparin
would likely have produced delayed onset of anticoagulation
and relatively minimal prolongation of activated partial
time (APTT) in many patients.83 The key to
thromboplastin
preventing recurrent venous thrombosis and pulmonary
embolism in studies of venous thromboembolism appears to
have been the administration of sufficient heparin to prolong
the APTT by 1.5 to 2 times control. When this goal was
achieved, the rate of recurrence was very low whether
was given IV or sc.84 It has been demonstrated that
heparin
a fixed dose of heparin of 15,000 U sc every 12 h produced
a subtherapeutic APTT response in the initial 24 h in more
than 63% of patients and led to a substantial risk of venous
thromboembolism.84 Studies of the time course of APTT
have shown that the peak level from a given
prolongation
dose of SC heparin occurs in about 4 h, and furthermore, that
Fourth ACCP Consensus Conference on Antithrombotic Therapy
Table 4.Mortality Following MI: Effect of Long-term Anticoagulation
Mortality
Duration of
Study, yr
MRC,88
Patients
1964
383
Agent, Dose
Therapy, yr
Phenindione
Therapy,
Reduction,
Control,
Level
14.8
21.2
30
NS
II
16
24
33
<0.01
I
40
12.2
42
10.4
5
17T
NS
NS
II
II
(INR 2-2.5) or
minidose
VA Cooperative,86'87
1969
1965,
747
phenindione
Warfarin
(INR 2-2.5)
placebo
Phenprocoumon
(INR 2.5-5.0)
vs ASA (1.5 g/d)
vs placebo
vs
German-Austrian
l,89 1980
946
the maximal APTT prolongation is achieved only after
several doses.83 The competing risk as the vigor of heparin
dosage regimens are increased is, of course, hemorrhage.
This risk was low in both the International tPA/SK Mortal¬
ity Trial75 and in ISIS-3.76
The GUSTO trial85 was designed to compare front-loaded
rtPA, a combination of rtPA and SK, and a standard dose of
SK. It was believed that vigorous anticoagulation should be
and accordingly the patients allocated rtPA
employed,
received IV heparin, commencing with a 5,000-U bolus
simultaneously, followed by a 1,000- to 1,200-U/h continuous
infusion for at least 48 h, attempting to maintain APTT at 60
to 85 s. The patients allocated SK also received heparin,
either according to a regimen identical to that of the rtPAtreated patients or a regimen identical to that used in ISIS-3
(12,500 U sc begun at 4 h after initiation of SK therapy and
repeated every 12 h for 7 days or until prior hospital dis¬
charge). In the SK groups, the 30-day mortality was 7.2%
with subcutaneous heparin and 7.4% with IV heparin
(p=NS). Furthermore, there were no statistically significant
differences in reinfarction, major hemorrhage, cerebral
infarct-related artery patency, or reocclusion in
hemorrhage,
relation to the heparin regimens. In conjunction with the
overview of the International tPA/SK Mortality Trial and
ISIS-3 results, the data from GUSTO suggest there is no
reason to routinely administer heparin along with SK. It
seems rational to reserve its use for those patients at high risk
of systemic embolization because of congestive heart failure,
large infarction, or atrial fibrillation, and then to commence
heparin therapy only when the APTT is within or below the
therapeutic range. To our knowledge, there has been no
study
among patients receiving rtPA that has assessed the
value of adjunctive heparin in relation to important patient
outcomes. However, the results from the angiographic trials,
together with the short half-life and lesser systemic fibrin¬
of rtPA, provide a rationale for adjunctive heparin
olytic effect
for about 48 h following the administration of rtPA.
therapy
Clinical Trials of Long-term Therapy: Table 4 summarizes
the results of three major randomized controlled trials of
long-term oral anticoagulation following AMI, based on
patients enrolled during the 1950s to 1970s. In the VA
study,8687 there was a statistically significant reduction of
mortality at 3 years, which was lost by 7 years. In the Medical
Research Council (MRC) trial,88 there was a favorable trend
at 3 years, whereas in the German-Austrian study,89 there
was no suggestion of a reduction of mortality at 2 years. A
large, statistically significant reduction in recurrent MI was
apparent in the MRC study, and there were favorable trends
in the other two. Unfortunately, the criteria for recurrent
AMI were not clearly described. For the combined end point
of mortality and recurrent infarction, there was a significant
reduction in the MRC study and minor trends in favor of
anticoagulations in the other two studies. The combined
outcome of pulmonary and systemic embolism was reduced
in all three studies, reaching statistical significance in two of
them.
In 1970, an International Anticoagulant Review Group90
attempted to overcome the problem of inadequate numbers
by
pooling data from nine controlled, long-term anticoagulant
trials involving 2,205 men and 282 women. Using the pooled
data, it was concluded that mortality was reduced by 20% in
men given long-term anticoagulants, but the benefit
appeared to be restricted to those with prolonged angina or
previous infarction on admission to the trial.
In 1980, the Sixty Plus Reinfarction Study91'92 (Table 5)
from the Netherlands revived the issue of the value of longterm anticoagulation for survivors of AML Ambulatory
patients older than 60 years (mean, 67.6 years) receiving
acenocoumarin or phenprocoumon following transmural MI
that had occurred at least 6 months earlier (mean, 6 years)
were randomly allocated double blind to continue oral
anticoagulant therapy (INR, 2.7 to 4.5) or matchingplacebo.
There were 878 patients randomized (85% men). The
principal outcome of total mortality fell from 15.7 to 11.6%
with anticoagulation (risk reduction, 23%; p=0.071; level II).
Recurrent MI was reduced from 15.2 to 6.9% (risk reduction,
55%; p=0.0005; level I), and the risk of an intracranial event
fell from 5.2 to 3.1% (risk reduction, 40%; p=0.16; level II),
with a predominance of nonhemorrhagic stroke in the
placebo-treated group and of hemorrhagic stroke in the
anticoagulant-treated group. Major and minor extracranial
more frequent in the
hemorrhages were considerably
anticoagulant-treated group, but transfusion was rare, and
there were no fatal hemorrhages. An efficacy analysis of
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385S
Table 5.More Recent Trials of Long-term Anticoagulation Following AMI
Trial
Level
RR
Study, yr
Sixty Plus,91 1980
Patients
Reinfarction
Stroke
WARIS,93 1990
Mortality
1,214
ASPECT,94 1994
3,404
Reinfarction
Stroke
Reinfarction
Stroke
Control,
11.6
6.9
3.1
15.7
15.2
5.2
40
0.071
0.0005
0.16
15
14
3.3
20
20
7.2
24
34
55
0.0267
0.0007
0.0015
10
6.7
2.1
11.1
14.2
3.6
10
53
42
878
Mortality
Mortality
Reduction,
Therapy,
patients adhering to study therapy showed still more marked
benefits.
During the interval from 1983 to 1986, the Warfarin
Reinfarction Study (WARIS)93 (Table 5) recruited 1,214
patients (78% men) who had sustained an AMI a mean of 27
days previously. They were randomized double blind to
warfarin (INR,2.8to4.8)or placebo. The groups were well
matched for major prognostic variables; 47% had anterior
MI, only 1% had received thrombolytic therapy, and 48%
receiving P-blockers on discharge. Patients were
not to take ASA. During a mean follow-up of 37
months, all-cause mortality fell from 20 to 15% with warfarin
(risk reduction, 24%; p=0.0267; level I); reinfarction fell
from about 20 to 14% (risk reduction, 34%; p=0.0007; level
I), and stroke fell from 7.2 to 3.3% (risk reduction, 55%;
p=0.0015; level I). An efficacy analysis, considering only
those patients who had not been off the study drug for more
than 28 days, revealed even more marked benefits. Venous
thromboembolism was rare while receiving placebo and did
not occur while receiving warfarin. There was one peripheral
arterial embolus in each group. There were five intracranial
hemorrhages with warfarin treatment, three of them fatal,
and there were eight episodes of major extracranial
were
advised
hemorrhage with warfarin treatment, for a combined
incidence of major bleeding of 0.6%/yr.
During the interval 1986 to 1991, the Anticoagulation in
the Secondary Prevention of Events in Coronary Thrombosis
(ASPECT) Research Group94 recruited 3,404 patients who
had sustained an AMI within 6 weeks of hospital discharge
(80% male; mean age, 61 years) (Table 5). They were
randomized double blind to treatment with nicoumalone or
phenprocoumon (INR, 2.8 to 4.8) or placebo. Anterior MI
had occurred in 46%, 25% had received thrombolytic
therapy, and 51% were discharged from the hospital taking
a (3-blocker. During a mean follow-up of 37 months,
all-cause mortality fell from 3.6 to 3.2%/yr (risk reduction,
10%; p=NS; level II), reinfarction fell from 5.1 to 2.3%/yr
(risk reduction, 53%; CI, 41 to 62%; level I), and stroke fell
from 1.2 to 0.7%/yr (risk reduction, 40%; CI, 10 to 60%; level
I). There were 17 intracranial hemorrhages with oral
anticoagulation, 8 of them fatal, and 2 nonfatal intracranial
hemorrhages with placebo. The number of major extracranial
was 56 with oral anticoagulants and 17 with
hemorrhages
placebo, for a combined annual incidence of major bleeding
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26
55
NS
<0.001
<0.001
of 1.4%/yr with oral anticoagulants and 0.4%/yr with placebo.
Event-free survival, including deaths, nonfatal MI, nonfatal
cerebrovascular events, or major bleeding by 3 years of
follow-up was significantly higher in the anticoagulationtreated group than in the placebo-treated group (83% vs
76%; p<0.001). The efficacy analysis showed risk reductions
for all-cause mortality of 16% (p=NS), for reinfarction of
59% (CI, 47 to 68%), and for stroke of 43% (CI, 17 to 66%).
Oral anticoagulation has been compared directly to
aspirin in two randomized clinical trials with inconclusive
results. The German-Austrian trial89 randomized 942
patients within 30 to 42 days of AMI to aspirin, placebo, or
phenprocoumon. Over a 2-year follow-up, the aspirintreated patients had statistically insignificant reductions of
all-cause mortality by 26% and of coronary mortality by
46.3% in comparison to phenprocoumon. Aspirin showed a
favorable trend in comparison to placebo, but phen¬
procoumon did not. In the EPSIM trial,94a 1,303 patients
were randomized a mean of 11.4 days following AMI to
treatment with aspirin or one of several anticoagulants. Over
a mean follow-up of 29 months, all-cause mortality was
10.3% with anticoagulation and 11.1% with aspirin. The
treatment period was stopped early when it appeared that a
statistically significant lower mortality with aspirin would not
be found.
Neri Serneri et al95 recruited 728 patients who had
survived Q-wave MI 6 to 18 months (mean, 11 months)
trial to determine the effec¬
previously into a multicenter
tiveness of low-dose subcutaneous heparin therapy in the
prevention of MI. Patients were randomly allocated to cal¬
cium heparin (12,500 U sc once daily) or usual therapy.
During a mean follow-up of just under 2 years, the rate of
reinfarction was reduced from 3.56 to 1.38% with heparin
(risk reduction, 61%; p=0.05). All-cause mortality was
reduced from 6.3 to 4.13% (risk reduction, 34%; p=NS), and
cardiovascular mortality was reduced from 4.9 to 3.9% (risk
reduction, 20%; p=NS). Efficacy analysis provided stronger
evidence for a benefit of heparin. Stroke and pulmonary
embolism were uncommon (0.8%) among control subjects,
but did not occur in those receiving heparin. There were no
major hemorrhages, and there was no evidence of osteoporo¬
sis on bone density measurements. The studypopulation was
only 18.9% of those screened, and the therapy was not
blinded. Nevertheless, the results suggest that low-dose
Fourth ACCP Consensus Conference on Antithrombotic Therapy
subcutaneous heparin therapy is safe, well tolerated, and
effective for the prevention of ML
studies
heparin
Summary: The low-dose subcutaneous vein
calf
thrombosis
of
for
reduction
the
evidence
provide
among patients with MI. In conjunction with a large body of
evidence in patients with other conditions (elective abdom¬
inal surgery, elective hip surgery) that prevention of calf vein
thrombosis prevents the development of proximal vein
thrombosis and pulmonary embolism, these studies indicate
that analogous prevention of proximal venous thrombosis
and pulmonary embolism may be achieved in patients with
MI, using heparin 7,500 U sc bid for a minimum of 7 days
and until full ambulation.96 The overviews of the large trials
of heparin therapy followed by oral anticoagulation for ap¬
indicate that mortality may be reduced
proximately 1 month,
while
about
20%,
achieving a 50% reduction in the inci¬
by of
dence systemic and venous embolism. The 2D echocar¬
diographic studies indicate that the risk of systemic embo¬
lism is related to the presence of mural thrombus, and that
mural thrombosis occurs in up to 40% of transmural ante¬
rior MI, yet is very uncommon with inferior MI. Patients
with extensive LV dysfunction and congestive heart failure
(CHF), a history of previous embolism, and atrial fibrillation
are at particularly high risk. Accordingly, there is a strong
case among patients with transmural anterior MI, extensive
LV dysfunction and CHF, previous embolism, or atrial
fibrillation for early full-dose heparin therapy (bolus 75 U/kg
IV, initial maintenance 1,250 U/h IV) that should be
sustained throughout the hospital stay or replaced by
subcutaneous heparin (initial dose, 17,500 U every 12 h;
APTT 1.5 to 2 times control) or oral warfarin (INR, 2.5 to
3.5). The low-dose subcutaneous-heparin regimen (7,500 U
bid) may be reserved for patients with non-Q or inferior in¬
farction, who are free of CHF, previous embolism, and atrial
fibrillation.
The appropriate duration of anticoagulant therapy is un¬
certain. The early large trials of full-dose anticoagulation in
patients with AMI required oral anticoagulation for approx¬
imately 1 month following AMI. The risk of systemic
embolism following MI persists beyond the hospital stay but
appears to fall off after 2 to 3 months.40 Studies of the sub¬
sequent survival of patients discharged from the hospital
alive following AMI indicate that the mortality risk is high¬
est in the first few months following MI, falling to a much
lower rate by 1 year.9798 Three recent, well-designed clin¬
ical trials of long-term oral anticoagulation91'93'94 following
AMI have shown reductions of death, reinfarction, and
stroke with acceptable hemorrhagic risk, although the INR
target ranges were higher than is now recommended in most
antithrombotic regimens (Sixty Plus Reinfarction Study, 2.7
to 4.5; WARIS and ASPECT, 2.8 to 4.8).
These data argue for a period of oral anticoagulation ex¬
tending somewhat beyond the hospital stay for those patients
with transmural anterior MI or extensive LV
dysfunction and CHF. The data from recent studies of
nonrheumatic atrial fibrillation support permanent anti¬
for patients with atrial fibrillation following
coagulation
ML99 Despite the benefits of long-term warfarin therapy for
the reduction of vascular events among MI survivors, in the
absence of trials directly comparing warfarin with aspirin
post-MI, aspirin will probably continue to be the agent of
choice because of its simplicity, low cost, and safety.
However, indirect comparisons suggest that warfarin may be
more effective and its potential value should not therefore
be overlooked.for example, in patients who cannot tolerate
aspirin or who have recurrent episodes despite taking
aspirin. Several post-MI trials currently in progress will
provide direct comparisons of aspirin and warfarin and also
information about the balance between benefits and hazards
of combined treatment with both aspirin and warfarin.99a
When warfarin is considered necessary for a patient
specifically for the reduction of the risk of venous or systemic
embolism, aspirin need not be given concurrently and
treatment with it should be recommended only when the
warfarin therapy is discontinued.
The evidence suggests that patients who are to receive
rtPA should also receive heparin, as a 75-U/kg IV bolus at the
time of initiating the rtPA infusion, with an initial
maintenance infusion of 1,000 to 1,200 U/h to maintain
APTT at 1.5 to 2 times control. A 48-h infusion is likely to
be sufficient, if aspirin is being given, and high-dose heparin
should be sustained only if there appears to be a high
therapy
risk of systemic embolism (large anterior MI, CHF, previous
systemic embolus, atrial fibrillation). Otherwise, only lowdose heparin therapy (7,500 U sc every 12 h) is indicated for
venous thrombosis until the patient is
prophylaxis againstIf the
fully ambulatory.
patient has received SK or APSAC,
be administered only if there
should
high-dose heparin
appears to be a high risk of systemic embolism. In such
patients, the APTT should be evaluated at intervals beginning
about 4 h after the initiation of SK therapy, and the heparin
therapy should be initiated when the APTT falls into the
therapeutic range.
Antiplatelet Therapy
Rationale: The use of antiplatelet therapy is based on the
well-established pauSophysiology of die acute syndromes
of coronary artery disease: unstable angina, AMI, and sudden
death.34 Ruptured atherosclerotic plaque is associated with
platelet aggregation at the site of exposed collagen, which
leads to intracoronary thrombus formation. Coronary artery
spasm may be associated. The coronary artery model of Folts
et al31 in dogs shows that die process is reversible widi aspirin
before an occlusive fibrin thrombus forms.
Aspirin causes irreversible inhibition of platelet cyclooxygenase, thereby preventing formation of thromboxane
A2, a platelet aggregant and potent vasoconstrictor.100
Adverse effects of aspirin are primarily related to bleeding,
GL The latter is less common at the low dosage
particularly
needed for the platelet antiaggregatory effects of aspirin.
drugs
Although other nonsteroidal anti-inflammatory
and platelet
platelet cyclo-oxygenase
reversibly inhibit
aggregation, clinical trials have not been conducted to assess
their value specifically in patients with coronary artery
disease. A recent randomized study of indobufen vs place¬
bo was conducted in 196 patients with heart disease and at
risk for cardiogenic embolism.101 More than half of these
patients had atrial fibrillation and about 40% had previous
MI. The primary end points were stroke, transient ischemic
attack (TIA), systemic and pulmonary embolism, and fatal
MI. Over 2-^ years of follow-up, these events were reduced
from 17.3 to 6.1% with treatment, a reduction of 65% (CI,
now
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387S
Table 6.All-Cause Mortality in Clinical Trials of Aspirin and Aspirin/Dipyridamole Following MI
All-Cause
Mortality
r
Study, yr
Patients
Elwood et al,109 1974
CDPA,110 1976
1,239
1,529
ASA, 300
ASA, 972
Elwood and
1,682
ASA, 900
Sweetnam,112 1979
Breddin et al,111 1980
946
AMIS,113 1980
4,524
mg/d
Post-AMI
<6
mo
1
Follow-up, Therapy, Placebo, Reduction,
Agent, Dose,
(mean, 9.8 wk)
Weeks-years
(mean, 7 yr)
Days-weeks
mo
%
%
12
22
8.0
5.8
10.8
8.3
26
30
p Level
0.094 II
0.057 II
12
12.3
14.8
17
0.124
II
24
38
10.1
10.8
12.3
9.7
18
Til
0.43
0.20
II
II
0.98
0.226
0.289
II
II
II
0.842
II
(mean, 7 wk)
ASA, 1,500
ASA, 1,000
30-42 d
2-60 mo
adj.*
PARIS
I,114 1980
2,026
%
ASA, 972 or
SA, 972 plus
2-60
mo
41
10.5
10.5
10.7
10.0
12.8
12.8
23
7.1
7.3
T
5
18
16
dipyridamole,
PARIS
II,123 1986
3,128
225
ASA, 990 plus
1-6
mo
dipyridamole,
225
*adj=adjusted; T=increase.
11 to
86%). Indomethacin has been shown
to increase
myocardial ischemia.102is a nonsteroidal
anti-inflammatory
Sulfinpyrazone100
It reversibly inhibits cyclo-oxygenase, but its exact
drug.
mechanism of action as a platelet inhibitor remains unclear.
It also normalizes shortened platelet survival in patients with
prosthetic heart valves, and its benefits appear to be more
marked on prosthetic rather than natural surfaces. Adverse
effects of sulfinpyrazone include exacerbation of peptic ulcer
of the effects of
and elevation
disease, potentiation
of uric acid.
Dipyridamole's100
warfarin,
effects appear
to
be related
to
an
platelet cyclic adenosine monophosphate. Its
antithrombotic effects are more evident on prosthetic
surfaces. Dipyridamole prolongs shortened platelet survival.
In contrast to aspirin, it does not increase the risk of GI
combined with warfarin.
bleeding even when
is a platelet antiaggregatory agent known to
Ticlopidine100
inhibit the formation of arterial thrombi. It is chemically
unrelated to the other antiplatelet drugs and its mechanism
of action is not completely understood. It inhibits the
induction of platelet aggregation by adenosine diphosphate
(ADP) and other agonists, prolongs bleeding time, and
normalizes shortened platelet survival. It can be associated
with diarrhea (which is common), rash, reversible
neutropenia (about 1% of cases), thrombocytopenia, and
liver function abnormalities (rare).
Short-term Therapy of AMI: In 1979, Elwood and
Williams103 reported the results of a randomized, placebocontrolled trial of a single dose of 300 mg of aspirin
administered on first contact by general practitioners to
patients thought to have MI. Of the 2,530 patients randomly
assigned to therapy, results were reported for the 1,705
patients with confirmed MI. Mortality rate at 28 days was not
significantly different between the two groups (19.2% with
aspirin, 19.6% with placebo).104
The ISIS-2 pilot study105 was a trial of 619 patients with
suspected AMI randomized to treatment with SK, 1.5
increase in
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megaunits (MU) IV over 1 h, or placebo; to aspirin, 325 mg,
alternate days for 28 days, or placebo; and to heparin,
1,000 U/h for 48 h, or no heparin. SK therapy was associated
with nonsignificant decreases of early and late mortality, an
increase ofnonfatal reinfarction, and a statistically significant
decrease in strokes. Aspirin treatment was associated with a
on
significant decrease in early mortality and a nonsignificant
decrease in reinfarctions and strokes. Heparin therapy was
associated with a nonsignificant decrease in nonfatal
infarctions and a nonsignificant increase in strokes. The
numbers studied, however, in this pilot study did not provide
reliable information about the effects of aspirin or heparin
following SK treatment for AML The excess of nonfatal
reinfarction seen with SK when used alone in the ISIS-2 pilot
study is consistent with the findings of marked platelet
activation after IV SK in patients with AMI.106
Verheught et al conducted a randomized trial of 49
patients to evaluate 100 mg/d of aspirin vs placebo for 3
months after IV SK therapy for anterior AML There was a
statistically significant reduction in the frequency of left
anterior descending coronary artery occlusion among the
patients receiving aspirin. This research group also showed
in the APRICOT trial82 that among survivors of thrombolytic
therapy for AMI with a patent infarct-related artery at about
48 h, aspirin was more effective than warfarin in the
prevention of revascularization, recurrent MI, and death,
with better maintenance of patency by 3 months.
The Second International Study of Infarct Survival73 was
a randomized, placebo-controlled, double-blind trial of
short-term therapy with IV SK, oral aspirin, 160 mg daily for
1 month, both, or neither among 17,187 patients with
suspected AMI. In addition to a 23% risk reduction in the
5-week vascular mortality among those given SK, there was
a 21% reduction among those given aspirin, and a 40%
reduction among those given a combination of SK and
aspirin, all highly significant (the original article reported
odds reductions of SK 25%, ASA 23%, and combination
42%). The early reduction in mortality with aspirin persisted
Fourth ACCP Consensus Conference on Antithrombotic Therapy
when the patients were followed up for a mean of 15 months.
Aspirin reduced the risk of nonfatal reinfarction by 49%
(odds reduction, 51%) and nonfatal stroke by 46% (odds
reduction, 47%). The increased rate of early nonfatal
reinfarction noted when SK was used alone resolved when
aspirin was added (3.8% vs 1.3%).
Aspirin added to the benefit of SK therapy in all groups
examined. In particular, among patients older than 70 years,
the combination markedly reduced mortality from 23.8 to
15.8% (p<0.001) without increasing the risk of hemorrhage
or stroke. Because of the poor prognosis in older patients
with AMI, the absolute number of lives saved with aspirin
and thrombolytic therapy increases dramatically with age:
2.5 per 100 patients treated younger than 60 years; 7 to 8 per
100 patients treated age 60 years and older.108
ISIS-2 showed that short-term aspirin therapy for AMI
decreases mortality and reinfarction, has added benefit to
that of SK, and prevents the increase in reinfarction that
occurs after thrombolytic therapy. Consequently, aspirin
therapy for AMI is not only desirable, but necessary when
thrombolytic therapy is used. These benefits were achieved
with an aspirin dose of 160 mg/d. Although associated with
an increased rate of minor bleeding from 1.9 to 2.5%, aspirin
was not associated with any significantly increased
therapy
risk of major bleeding, including hemorrhagic stroke. The
benefit of aspirin, in contrast to that of SK, was independent
of the time of onset of treatment. However, early admin¬
prudent.
Long-term Therapy for AMI: Three antiplatelet drugs
have been evaluated in post-MI patients: aspirin, sulfin¬
pyrazone, dipyridamole, and a combination of aspirin and
dipyridamole.
Aspirin
There have been six large randomized, double-blind
secondary trials of aspirin alone following AMI109"114 (Table
6). Five of them, using doses of 300 to 1,500 mg of aspirin
mortality
daily, showed trends for the reduction of all-cause
a trend against
by aspirin, while AMIS113 demonstrated
aspirin for mortality, although there was a nonsignificant
reduction of recurrent ML None of these studies recruited
sufficient patients to have an 80% chance of demonstrating
a 20% reduction in mortality and reinfarction, or in fatal
reinfarction at the 0.05 level of significance.
In 1994, the Antiplatelet Trialists' Collaboration updated
their meta-analysis to include 145 randomized trials of
vs control in 70,000 high-risk
prolongedwithantiplatelet therapy
patients primarily occlusive vascular disease and 30,000
low-risk subjects from the general population.115 Among the
high-risk patients, antiplatelet therapy reduced vascular
mortality (odds reduction, 18%; SD, 3%; 2p<0.00001),
nonfatal MI (odds reduction, 35%; SD, 4%; 2p<0.00001),
nonfatal stroke (odds reduction, 31%; SD, 5%; 2p<0.00001),
and vascular events (nonfatal MI, nonfatal stroke, and
vascular death) (odds reduction, 27%; SD, 2%; p<0.00001).
The risk reduction for vascular mortality was highest in AMI
trials (risk reduction, 22%; SD, 4%; 2p<0.00001) and
unstable angina trials, and similar in the prior MI (odds
reduction, 15%; SD, 5%; 2p<0.005) and cerebrovascular
trials (odds reduction, 14%; SD, 7%; 2p<0.05).
with
vascular events
istration
seems
Among about 20,000 patients
AMI,
occurred in 10.6% receiving antiplatelet therapy vs 14.4% on
control regimen (odds reduction, 29%; SD, 4%; 2p<0.00001).
This represented about 38 vascular events avoided per 1,000
patients treated for 1 month. Among 20,000 patients with a
events occurred in 13.5% receiving antiplatelet
history ofvsMI,
regimen (odds reduction, 25%;
therapy 17.1% on control
SD, 4%; 2p<0.00001). This represents a 2-year treatment
benefit of 36/1,000 patients treated. Among 11,000 patients
with prior stroke or TIA, events occurred in 18.4% receiving
antiplatelet therapy vs 22.2% on control regimen (odds
reduction, 22%; SD, 4%; 2p<0.00001) and a 3-year treatment
benefit of 38/1,000. The benefit was about 50 events avoided
per 1,000 patients for 6 months of treatment among 4,000
patients with unstable angina, and a 1-year benefit of
20/1,000 in 16,000 other high-risk patients (2p<0.00001).
The most widely used antiplatelet regimen in these trials
was aspirin. Similar effectiveness was demonstrated with
doses of 500 to 1,500 mg daily, 160 to 325 mg daily, and 75
to 150 mg daily. Other studies have demonstrated less GI
side effects with lower dosages.116 The time required to
maximal inhibition of platelet aggregation at lower doses
supports the use of an initial dose of 160 to 325 mg for
emergencies.117
After
aspirin, the most widely studied antiplatelet
regimens were aspirin plus dipyridamole, sulfinpyrazone
alone, and ticlopidine, all ofwhich showed benefit compared
with placebo, but there was no clear evidence of benefit
different from that of aspirin.
Sulfinpyrazone
The Anturane Reinfarction Trial Research
Group118
reported the initial findings of a trial in which 1,629 patients
(86% male) were randomly allocated to treatment with
sulfinpyrazone (200 mg qid) or placebo, 25 to 35 days after
MI. Recruitment was stopped early because of observed
efficacy, butto follow-up of the 1,558 eligible patients was
continued
a mean of 16 months. In their second
the authors reported an overall reduction of
publication,119
32% in cardiac mortality (p=0.058) and a 43% reduction in
sudden death (p=0.041). The benefits at 24 months were
almost entirely due to the 75% reduction in sudden death
over the first 6 months of treatment (p=0.03). No further
benefit of treatment could be deduced thereafter.
Concerns about the analysis of the Anturane Reinfarction
Trial were based on the exclusion of certain patients and
events from the principal analysis of efficacy ("ineligible"
patients and "nonanalyzable" events), ambiguity and incon¬
sistency in classification of causes of death, the multiple
examinations of the data, and change in the principal end
points. Had the analysis been conducted by intention-totreat, the differences would not have reached statistical
significance.
On the basis of an audit of one half of the cases, the FDA
recalculated outcome frequencies and concluded there was
for mortality and
only a weak trend favoring sulfinpyrazonedeath.120
of
sudden
the
Repeated
separate analysis
rejected
classification of deaths and analysis of results by an external
review group and by the policy committee of the study
did not differ markedly from the
yielded results thatmaterial.121
Nevertheless, the FDA did
originally
published
not approve the claim that sulfinpyrazone was effective in
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389S
preventing sudden death in the first 6 months after infarction.
The Second Anturane Reinfarction Trial was reported by
an Italian group.122 This was a study of 727 patients
randomized, double blind, to treatment with sulfinpyrazone
placebo. The design was similar to the Anturane Rein¬
farction Trial except that patients were withdrawn from the
study for the occurrence of any thromboembolic event,
defined as an MI, stroke, or TIA. Treatment with sulfin¬
pyrazone for a mean of 19 months did not significantly affect
the incidence of total mortality or sudden death, but it did
reduce the incidence of reinfarction and of all throm¬
boembolic events. It did not show the pattern of early benefit
reported in the Anturane Reinfarction Trial. Thus, although
the two trials of sulfinpyrazone showed beneficial effects,
these effects were not consistent.
or
Dipyridamole
In the
Persantine-Aspirin Reinfarction Study (PARIS I
trial),114 mortality and coronary incidence (coronary death or
nonfatal MI) were similar in the two active treatment groups
(aspirinplus dipyridamole and aspirin alone), and consistently
lower than in the placebo group, but the reductions were not
(Table 6). PARIS II123 (Table 6)
statisticallya significant
combination
of aspirin and dipyridamole with
compared
placebo and reported a statistically significant reduction in
the
outcome of
composite
coronary death or nonfatal
reinfarction. There was no comparison with aspirin alone.
These trials provide no evidence for a benefit of a combination
of aspirin and dipyridamole over aspirin alone.
Ticlopidine
In the Canadian American Ticlopidine
Study (CATS),124
randomly assigned
daily, vs placebo
ticlopidine, 250 mg twiceand
were
thromboembolic stroke,
24
The
months).
primary analysis
(average,
patients whose outcome events occurred while taking the
trial medication or within 28 days of stopping treatment with
it. This "efficacy" analysis showed a 30.2% (95% CI, 7.5 to
48.3%; p=0.006) reduction in relative risk of stroke, MI, or
vascular death with ticlopidine. On an intention-to-treat
the risk
in the
are
1,053 patients
were
basis, where all events
to treatment with
1 to 17 weeks after
followed for up to 3 years
was restricted to
patients
accounted,
reduction for the combination end point was 23.3% (95% CI,
1.0 to 40.5%; p=0.02), and for fatal or nonfatal stroke it was
20.5%.
In the Ticlopidine Aspirin Stroke Study (TASS),125 3,069
patients with TIA or minor stroke within 3 months were
500 mg
randomly assigned to treatment with ticlopidine,
1,300 mg daily, for up to 6 years. Death from
daily, or aspirin,
any cause or nonfatal stroke occurred in 20% of patients
to
assigned to receive ticlopidine and in 22.7% assigned
receive aspirin. Ticlopidine's apparent advantage was noted
at 1 year and persisted over 5 years (p=0.048). At 3 years,
death or nonfatal stroke was 12% lower and fatal or nonfatal
stroke was 21% lower among patients assigned to receive
assigned to receive
ticlopidine compared with thetopatients
aspirin. Ticlopidine appeared be as effective in women as
in
men.
The Swedish Ticlopidine Multicenter Study (STIMS)126
was a double-blind trial of 687 patients with intermittent
claudication randomlyassigned to treatment with ticlopidine,
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250 mg twice a day, vs placebo. AMI, stroke, or TIA was
11.4% less frequent in the ticlopidine group, 89 (25.7%) vs
99 (29%) (p=0.24). An "on treatment" analysis, excluding
end points that did not occur within 15 days of taking study
medication, revealed these events to be 38.4% lower in the
ticlopidine group: 47 (13.8%) patients vs 76 (22.4%) patients
fact that
(p=0.017). This difference is a reflectionandof the
patients 16.2% of the
ticlopidine-treated
were no longer taking their
placebo-treated patientsmedication.
The 29.1% lower total
study
randomly inassigned
the
(64
89; p=0.015) was
ticlopidine
group
mortality to ischemic heart disease.vsFatal
MI was 43%
primarily due
vs
30.6% of the
lower (15 26).
In summary, patients with cerebrovascular disease and
patients with peripheral vascular disease had decreased
vascular events, including coronary events, while taking
the effectiveness of ticlopidine
ticlopidine. Inbe TASS,125 than
that of aspirin. The use of
to
appeared must begreater
weighed against its greater cost compared
ticlopidine
with aspirin and greater incidence of adverse effects and
their seriousness. These include rash, diarrhea, and
or thrombocytopenia, which occurred in 2% of
leukopenia
the treated patients in STIMS.126
Summary: Antiplatelet therapy is effective in reducing
vascular events (nonfatal MI, nonfatal stroke, vascular death)
in patients with evidence of atherosclerotic disease (acute
MI, unstable angina, history of AMI, stroke, TIA, stable
angina, or peripheral vascular disease). Aspirin, 75 to 325
is as effective as any other regimen, with little risk of
mg/d,
adverse events such as GI or intracerebral hemorrhage. Its
benefits are seen regardless of age or sex. Aspirin therapy in
these high-risk patients reduces vascular events by about one
fourth, nonfatal MI by one third, nonfatal stroke by one third,
and vascular death by one sixth.
Unstable Angina
Clinical Trials of Antiplatelet Drugs
Study12'
of aspirin was conducted in
The VA Cooperative
12 VA Medical Centers between 1974 and 1981 (Table 7).
The target population was comprised of men hospitalized
with a clinical diagnosis of unstable angina beginning within
1 month before and still present within the week before
admission. Patients had to have a clinical history or
hospital
ECG evidence of coronary artery disease, and an unstable
angina pattern ofeither crescendo or prolonged pain, or pain
at rest. AMI was ruled out by ECG and enzymatic criteria.
Of those patients with clinical unstable angina, 27.6% met
the study criteria, and 18.3% entered the trial. Subsequently,
72 were found to have developed AMI and were excluded
from the primary analysis, leaving 1,266 patients (100%
male). Patients entered the study within 51 h of hospital¬
ization. They were randomly allocated to treatment with 324
mg of aspirin in an effervescent buffered powder (AlkaSeltzer) dissolved in water or placebo. Coronary angiography
was not performed routinely. The principal outcome was
death or nonfatal AMI which was reduced from 10.1 to 5.0%
(51% reduction; p=0.0005) over the 12-week follow-up
The other major outcomes were fatal or nonfatal
period.
AMI (55% reduction; p=0.001), nonfatal AMI (51%
reduction; p=0.005), and all-cause mortality (51% reduction;
p=0.054). An intention-to-treat analysis, including the
Fourth ACCP Consensus Conference on Antithrombotic Therapy
Table
7.Aspirin in Unstable Angina
All-Cause
Cardiac Death or Nonfatal MI
Mortality
RR
RR
ASA,
Study
Patients
Lewis etal127
Cairns et al128
Theroux et al136
RISC138
mg/d
1,338
324
555
479
796
1,300
Entry
Window
650
75
51 h
8d
24 h
72 h
ASA, Placebo, Reduction,
ASA, Placebo, Reduction,
Follow-up
%
1.6 3 mo 3.3
3.0
11.7
24 mo
0
1.7
6d
5d0.25
30 d
0.5
patients with AMI at entry, indicated reductions in death or
p=0.004) and all-cause
(34% reduction; p=0.17). Eighty-six percent of
mortalitywere
followed up to 1 year, with a reduction in
patients
in the aspirin-treated group, from 9.6 to
43%
of
mortality
5.5% (p=0.008).
The Canadian Multicenter Trial128 of aspirin or
sulfinpyrazone, or both, was conducted in seven centers
between 1979 and 1984. The target population consisted of
patients admitted to a coronary care unit with a clinical
of unstable angina. These
diagnosis
(nonangiographic)
to delineate clinical
underwent
a
detailed
interview
patients
or ECG evidence of myocardial ischemia, to define an
unstable pain pattern, either crescendo pain or prolonged
pain at rest, and to rule out AMI. The study criteria were
satisfied by 85% of the 817 patients interviewed after the
exclusion process, among whom 159 refused study entry,
(73% male) who entered the trial. Patients were
leaving 555allocated
to one of four treatment regimens:
randomly
four
times daily) or matching placebo, plus
(325
aspirin
mg
(200 mg four times daily) or matching
sulfinpyrazone
for a total of eight tablets daily to be taken with
placebo,
meals or milk. Coronary angiography was not a prerequisite
for study entry. The primary analysis was one of efficacy, with
outcomes to be assessed only among patients who met
certain criteria established at the inception of the study, and
without knowledge of treatment allocated or of
applied
clinical outcome. Patients in this analysis had to have been
at least some study medication within the preceding
taking
month. The
outcome event of cardiac death or
nonfatal AMI (41% reduction;
primary
nonfatal MI occurred in 36 patients not given aspirin and 17
taking
aspirin, and by 2 years, the life-table rate of these
events was 17% vs 8.6%, a risk reduction of 50.8% (p=0.008).
The outcome event of cardiac death alone was reduced from
11.7 to 3%, a risk reduction of 71% (p=0.004). All deaths
were cardiac in this analysis. In the intention-to-treat
analysis, counting all randomized patients and all outcomes,
the outcome of cardiac death or nonfatal MI was observed
in 70 patients, including 17 patients who had been excluded
from the primary analysis of efficacy. The risk reduction with
aspirin was 30% (p=0.072). For the outcomes of cardiac
death and death from any cause, the corresponding risk
reductions with aspirin were 56.3% (p=0.009) and 43.4%
(p=0.035), respectively. Sulfinpyrazone had no significant
effect or interaction with aspirin in any analysis.
The Studio della Ticlopidina NelTangina Instabile
Group129 conducted a randomized, multicenter trial of
ticlopidine vs placebo in Italian coronary care units between
Level
%
%
0.25
2.0
51
71
0
75
0.054
0.004
NS
NS
NS
5.0
8.6
3.3
2.5
4.3
10.1
17.0
12.0
5.8
13.4
51
0.0005
0.008
51
72
0.01
57
0.033
68
<0.0001
1986 and 1987. The target population included patients
admitted to the CCU during the preceding 48 h with a
clinical diagnosis of unstable angina of the crescendo or rest
pain type. Eligibility required the demonstration of
spontaneous or exercise test-induced evidence, while in the
randomization, of transient ischemic ST
hospital andor before
segment T-wave abnormalities, without elevation of
cardiac enzyme levels. All patients received intensive con¬
ventional therapy, but no aspirin was allowed. Of the 2,438
patients with suspected unstable angina who were screened,
a total of 652 (72% male) were eligible and randomized to
treatment with ticlopidine, 250 mg bid plus conventional
vs conventional therapy alone, in an open-label
therapy
manner. The principal outcome was a composite of vascular
death or nonfatal MI, while secondary outcomes were TIA,
nonfatal stroke, and peripheral vascular accident. During the
24-week follow-up period, an intention-to-treat analysis
demonstrated a reduction in the rate of vascular death or
nonfatal MI from 13.6 to 7.3% byticlopidine (risk reduction,
46.3%; p=0.009). There were also statistically significant
reductions of nonfatal MI (46.1%; p=0.039) and the
composite of fatal or nonfatal MI (53.2%; p=0.006). Analysis
ofonly the eligible patients showed still greater riskreductions
and levels of significance. Life-table analyses of the events
were consistent with the simple outcome analyses. During
the trial, 17.5% of patients withdrew (19.1% ticlopidine, 16%
conventional therapy) for a variety of reasons. Side effects
accounted for the withdrawal of 4.8% of the ticlopidinetreated patients, most commonly because of the GI or skin
reactions. Mild bleeding disorders in 1% of patients resolved
without stopping ticlopidine therapy, and no clinically im¬
portant abnormalities of blood cell counts were detected.
Clinical Trials of Anticoagulant Drugs
Support for the use of anticoagulants in patients with un¬
stable angina can be found in the early literature on unstable
angina in one level V130 and three level III studies.131"133
Wood132 performed an unblinded study with patients
allocated sequentially to treatment with anticoagulants or no
anticoagulants. Randomization was aborted in this study
after the first 40 patients had been enrolled because of
benefit observed in the anticoagulant-treated group; the
then continued as a cohort study with 100 treated
study wastotal
and 50 control subjects. After follow-up of 2
patients
months, MI had occurred in 3% and death in 2% of treated
patients compared with 22% and 16%, respectively, in the
control patients. In an observational study of 360 patients
described by Vakil,133 mortality at 3 months was 9.5% in
CHEST /108 / 4 / OCTOBER, 1995 / Supplement
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391S
125 Hass WK, Easton
JD, Adams HP, et al. A randomized trial
comparing ticlopidine hydrochloride with aspirin for the
presentation of stroke in high-risk patients. N Engl J Med 1989;
321:501-07
Janzon L, Bergqvist D, Boberg J, et al. Prevention of myocardial
infarction and stroke in patients with intermittent claudication;
effects of ticlopidine: results from STIMS, the Swedish
Ticlopidine Multicentre Study. J Intern Med 1990; 227:301-08
127 Lewis HD, Davis JW, Archibald DG, et al. Protective effects of
aspirin against acute myocardial infarction and death in men with
unstable angina: results ofa Veterans Administration Cooperative
Study. N Engl J Med 1983; 309:396-403
128 Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or
both, in unstable angina: results of a Canadian multicenter
clinical trial. N Engl J Med 1985; 313:1369-75
129 Balsano F, Rizzon P, Violi F, et al. Antiplatelet treatment with
ticlopidine in unstable angina: a controlled multicenter trial.
126
Circulation 1990; 82:17-26
Phillips WC, Casten GG. Virtue of prompt
anticoagulant therapy in impending myocardial infarction:
experiences with 318 patients during a 10-year period. Am
Intern Med 1959; 50:1158-73
131 Beamish RE, Storrie VM. Impending myocardial infarction:
recognition and management. Circulation 1960; 21:1107-15
132 Wood P. Acute and subacute coronary insufficiency. BMJ 1961;
1:1779-82
133 Vakil RJ. Preinfarction syndrome-management and follow-up.
Am J Cardiol 1964; 14:55-63
134 Telford AM, Wilson C. Trial of heparin versus atenolol in
prevention of myocardial infarction in intermediate coronary
syndrome. Lancet 1981; 1:1225-28
135 Williams DO, Kirby MG, McPherson K, et al. Anticoagulant
treatment in unstable angina. Br J Clin Pract 1986; 40:114-16
136 Theroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both
to treat acute unstable angina. N Engl J Med 1988; 319:1105-11
137 Theroux P, Waters D, Qui S, et al. Aspirin versus heparin to
prevent myocardial infarction during the acute phase of unstable
angina. Circulation 1993; 88(pt I):2045-48
138 The RISC Group. Risk of myocardial infarction and death
during treatment with low-dose aspirin and intravenous heparin
in men with unstable
130 Nichol ES,
coronary artery disease. Lancet 1990; 336:
139
827-30, 139.
Theroux P, Waters D,
J, et al.
Reactivation of unstable
angina following discontinuation of heparin. N Engl J Med 1992;
327:141-45
Lam
140 Cohen M, Adams PC, Parry G, et al. Combination antithrombotic
therapy in unstable rest angina and non-Q-wave infarction in
nonoption aspirin users: primary end point analysis from the
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ATACS trial. Circulation 1994; 89:81-8
Holdright D, Patel D, Cunningham D, et al. Comparison of the
effect of heparin and aspirin versus aspirin alone on transient
myocardial ischemia and in-hospital prognosis in patients with
unstable angina. J Am Coll Cardiol 1994; 24:39-45
142 Neri Serneri GG, Gensini GF, Poggesi L, et al. Effect of heparin,
aspirin, or alteplase in reduction of myocardial ischaemia in
refractory unstable angina. Lancet 1990; 335:615-18
143 Theroux P, White H, David D, et al. A heparin-controlled study
of MK-383 in unstable angina [abstract]. Circulation 1994;
141
90:1-231 90:1-231
144 Theroux P, Kouz S, Knudtson
M, et al. A randomized doubleblind controlled trial with the non-peptidic platelet GPIIb/IIIa
antagonist RO 44-9883 in unstable angina [abstract]. Circulation
1994; 90:1-231
Jan de Boer M, van den Brand MJBM, et al.
Randomized trial of a GPIIb/IIIa platelet receptor blocker in
refractory unstable angina. Circulation 1994; 89:596-603
146 The EPIC Investigators. Use of a monoclonal antibody directed
against the platelet glycoprotein Ilb/IIIa receptor in high-risk
coronary angioplasty. N Engl J Med 1994; 330:956-61
147 The Steering Committee of the Physicians' Health Study
Research Group. Final report on the aspirin component of the
ongoing Physicians' Health Study. N Engl J Med 1989; 321:
145 Simoons M,
129-35
148 Peto R, Gray R, Collins R, et al. Randomized trial of prophylactic
daily aspirin in British male doctors. BMJ 1988; 296:313-16
149 Hennekens CH, Buring JE, Sandercock P, et al. Aspirin and
other antiplatelet agents in the secondary and primaryprevention
of cardiovascular disease. Circulation 1989; 80:749-56
150 Manson JE, Stampfer J, Colditz GA, et al. A prospective study
of aspirin use and primary prevention in cardiovascular disease
JAMA 1991; 266:521-27
BuringJE, Hennekens CH, for Women's Health Study Research
Group. The women's health study: summary ofthe studydesign.
J Myocardial Ischemia 1992; 4:27-9
Ridker PM, Manson JAE, Gaziano JM, et al. Low-dose aspirin
therapy for chronic stable angina: a randomized, placeboin women.
151
152
controlled clinical trial. Ann Intern Med 1991; 114:835-39
153
Juul-Moller S, Edvardsson N, Jahnmatz B, et al. Double-blind
trial of aspirin in primary prevention of myocardial infarction in
patients with stable chronic angina pectoris.
Lancet
1992;
340:1421-25
154 Komrad MS, Coffey CE, Coffey KS, et al. Myocardial infarction
and stroke. Neurology 1984; 34:1403-09
155 Turpie AGG, Gent M, Laupacis A, et al. Comparison of aspirin
with placebo in patients treated with warfarin after heart-valve
replacement. N Engl J Med 1993; 329:524-29
Fourth ACCP Consensus Conference on Antithrombotic Therapy
after hospital admission, 9.5 h after an episode of chest pain,
the administration of aspirin alone, 162.5 mg/d, or the
combination of aspirin, 162.5 mg/d, plus heparin (APTT two
times control) until adequate oral anticoagulation with
warfarin was achieved. At 14 days, there was a significant
reduction in the combined end point of death, MI, and
recurrent ischemia in the combination group vs aspirin alone
(10.5% vs 27%; p=0.004). Again, the survival curves diverged
mainly
during the first few days of treatment. This study can
be considered to provide level II evidence. A meta-analysis
by these authors ofthe three studies comparing combination
with aspirin alone136138140 showed a 56% reduction
therapy
in the incidence of the hard end points of fatal and nonfatal
MI with the combination therapy. Another open-label trial
285 patients compared aspirin alone, 150 mg/d,
involving
with the combination with heparin (APTT, 1.5 to 2.5) for 24
h.141 The primary end point ofthe trial, transient ST segment
to
depression on continuous ECG monitoring, was not signifi¬
modified by the combination therapy, although the
cantly
total duration of ST segment shift was 2,111 min compared
with 4,908 min with aspirin alone. The in-hospital incidence
of MI infarction and ofdeath was unusuallyhigh in this study
at 29%. These events were equally distributed in the two
treatment groups.
In a previous trial by Neri Serneri et al,142 97 patients with
recurrent ischemia during the first 24 h of hospitalization
were randomized to treatment with IV heparin administered
by infusion, titrated to the APTT or by intermittent bolus or
to aspirin and in a modified protocol to heparin infusion or
to tissue plasminogen activator. Only the IV infusion of
was effective to reduce the number and duration of
heparin
ischemic episodes, as assessed over 3 days by anginal attacks
and transient ST segment depression on ECG monitoring.
In the 3-month follow-up of patients in the RISC study,
however, the low-dose aspirin therapy, 75 mg daily, decreased
the need for coronary angiography because of severe angina
135
by 44%""
New Trials of Antiplatelet Drugs
A novel approach to antiplatelet therapy is the inhibition
of the integrin platelet membrane receptor GPIIb/IIIa,
targeting the final and obligatory pathway to platelet
aggregation. The pilot studies with these agents have
suggested that they could reduce by an additional 50 to 75%
the event rates associated with unstable angina.143"145 One
level I study146 of 2,099 patients at high-risk coronary
defined by AMI, unstable and earlypostinfarction
angioplasty
or
angina, complex anatomy documented a 35% reduction
in the risk of thrombotic complications ofthe procedure with
the use of c7E3, a monoclonal antibody to the receptor. A
bolus was administered 10 min before the procedure,
followed by an infusion for 12 h. The bolus alone was
ineffective. A nonprespecified subanalysis from this study
suggests that patients with unstable angina were more likely
to benefit.146 The rate of bleeding was significantiy increased
with treatment: 14% compared with 7% with placebo.
Modalities of application to reduce the bleeding risk are now
under study. When available, the drug will be useful to
reduce complications in high-risk angioplasty.
Summary: Four large trials using aspirin in patients
with unstable angina have shown marked
hospitalized
reductions of AMI and cardiac death.127'128136138 The
benefits were present with low-dose aspirin in the acute
and were maintained long term. Two of these trials
phasealso
evaluated heparin and the combination136138 and
have
one directly compared heparin with aspirin.137 Full-dose
therapy tended to be more effective than aspirin
heparin
alone during the acute phase and for approximately 48 h
(level II evidence). Because of potential additive effects of
the combination of aspirin and heparin, and more
because of the loss of the initial gain following
importantly,
the discontinuation of heparin used as single therapy, the
combination is recommended. An exception could be
patients in whom bypass surgery is planned in the short term
in whom the avoidance of aspirin will minimize the
perioperative blood loss. All patients should be receiving
aspirin at the time of angioplasty, and in high-risk situations,
the use of a bolus and infusion of c7E3 could be considered.
Long-term aspirin therapy is indicated in all patients.
can be used as an alternative treatment in
Ticlopidine
intolerant
of or allergic to aspirin. The full benefit
patients
of ticlopidine does not occur until up to 10 days after starting
treatment with the drug.
Primary Prevention
There have been two large trials of ASA administration to
patients free of a history of previous major vascular events
(MI or stroke).147148 The results do not lead directly to
recommendations for therapy and require careful evaluation.
The Physicians' Health Study147 (Table 9) was a doubleblind, placebo-controlled, randomized trial that was designed
to test two primary prevention hypotheses in a population of
free of MI, stroke, TIA, cancer, and current liver
physicians
or renal disease, peptic ulcer, or gout. It was postulated that
ASA might decrease mortality from cardiovascular disease
and 3-carotene might decrease cancer incidence. Between
1983 and 1988, 22,071 male US physicians, aged 40 to 80
years, were randomly allocated to low-dose ASA (as Bufferin,
Bristol-Myers Products, 325 mg every other day) or placebo,
plus (^-carotene (50 mg every other day), or placebo
according to a 2x2 factorial design. The ASA component was
terminated in 1988 at the recommendation of the data
monitoring board because of a clear reduction of MI, the low
likelihood of detecting a benefit of ASA on cardiovascular
mortality before the year 2000 or later, and the high
prevalence of ASA use among participants following the
occurrence of a nonfatal vascular event.
The principal outcome of cardiovascular death occurred
at a rate of only 15% of that expected for a general population
of white men with the same age distribution over a similar
events,
period, andandwas not different between ASA (124
events, 0.24%/yr). Total death
0.23%/yr)not placebo (133 217
was also
different (ASA,
events, 0.40%/yr; placebo,
227 events, 0.42%/yr). There was a striking reduction in the
rates of MI with ASA (139 events, 0.26%/yr) vs placebo (239
events, 0.44%/yr) (risk reduction, 44%; p<0.00001). A
for both fatal
statistically significant difference was observedstroke
rate was
and nonfatal infarction. The observed overall
vs
with
higher aspirin (119 events, In0.22%/yr)
placebo (98
the subgroup with
events, 0.18%/yr) (p=0.15).
hemorrhagic strokes, there was an increased rate with ASA
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393S
Table
9.Primary Prevention of Coronary Artery Disease With Aspirin.
British Doctors' Study1"
Physicians' Health Study1'
Reduction
Outcome
ASA*
Nonfatal
Fatal
0.18
2.36
Placebo*
*
(Increase)
Reduction'
ASA
Placebo*
(Increase)
MI
Total2.55
0.48
3.90
4.40
0.3
1.5
1.9
0.007 4.73
4.96
<0.00001
4.25
<0.00001
8.98
4.33
9.29
0.2NS
0.1 NS
0.3 NS
Stroke
Fatal
0.16
Nonfatal
2.02
Total
2.18
0.11
1.68
1.79
0.42
0.22
Hemorrhagic
Ischemic
1.67
1.50
Cardiovascular death 2.27
2.43
Total
death3.97
4.15
vascular
events
5.62
6.77
Important
2.6
Upper GI ulcer 3.0
2.8 Peptic ulcer 2.4
54.0
40.8
Bleeding
Transfusion
0.81
0.5
*Rate per 1,000 subjects per year.
* Absolute
reduction or increase per 1,000
(0.05)
(0.34)
(0.4)
(0.2)
(0.17)
(0.2)
(0.2)
NS
1.6
1.27
NS
(0.3)
NS
2.8
3.2 (0.4)
NS
NS
4.84.07
NS
(0.7)
NS
0.69
0.63
NS
(0.06)
NS 4.15
3.49
NS
(0.66)
NS
7.86
8.35
NS0.5
NS 16.0
14.4
1.6NS
1.10.01
15.3
15.5
0.2
NS
0.08(0.4)
(0.4)
(13.2)
0.02(0.3)
NS 4.682.96
<0.05
(1.7)
<0.00001
1.06
0.74
NS
(0.3)
subjects per year as a result of ASA therapy. Numbers in parentheses indicate increases.
(23 events, 0.04%/yr) vs placebo (12 events, 0.02%/yr)
(p=0.06). The combined outcome of "important vascular
events" (nonfatal MI, nonfatal stroke, and death from a
cardiovascular cause) was significantly reduced in the ASA
group (307 events, 0.56%/yr) vs the placebo group (370
events, 0.68%/yr) (risk reduction, 18%; p=0.01).
The British Doctors' Study148 was an open-label, randomly
allocated trial of ASA, 500 mg daily, vs aspirin avoidance (2:1
ratio of ASA vs avoidance), conducted among British male
who had no history of stroke, definite MI, or
physicians
ulcer.
Between 1978 and 1984,5,139 male physicians
peptic
were recruited and followed for up to 6 years. Vascular death
rates, including sudden death from unknown cause, and
peptic ulcer and gastric hemorrhage, were less frequent with
ASA (ASA, 0.79%/yr; no ASA, 0.84%/yr; risk reduction, 6%;
p=NS). Total mortality was somewhat less with ASA (ASA,
1.44%/yr; no ASA, 1.6%/yr; p=NS). There was only a trend
toward reduced confirmed MI (ASA, 0.9%/yr; no ASA,
0.93%/yr; risk reduction, 3%; p=NS). Although there were
significantlynofewer confirmed TIAs in the ASA group (ASA,
0.16%/yr; ASA, 0.28%/yr; 2p<0.05), there were more
confirmed strokes in the ASA group (ASA, 0.32%/yr; no ASA,
0.29%/yr; p=NS), and considerably more disabling strokes in
the ASA group (ASA, 0.19%/yr; no ASA, 0.07%/yr; risk ratio,
2.58; 2p<0.05).
When the results of these two trials are evaluated using
methods, the observation of reduced frequency
of nonfatal AMI by ASA is sustained (risk reduction, 32%;
p<0.0001), although a statistical test for heterogeneity sug¬
gests that the observations are heterogeneous (p=0.035).149
The composite outcome of "any vascular event" is
significantly reduced (risk reduction, 13%; p<0.05), and a
trend toward increased nonfatal stroke is observed (risk
increase, 18%; p=NS). The absence of any reduction in total
cardiovascular death and all-cause mortality noted in each
overview
study separately persists.
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The appropriate therapeutic conclusions to be drawn from
these two trials are not obvious. Although there is a
significant decrease of fatal and nonfatal MI, there is a trend
toward increased stroke and particularly hemorrhagic stroke.
There is a rather high incidence of GI side effects, even at
the low doses of ASA employed. Among men aged 40 to 49
years, the annual risk of MI was only 0.1 %/yr (l/yr/1,000
whereas among men aged 60 to 69 years, the
subjects),
annual rate of MI was about 0.82%/yr (8.2/yr/l,000 subjects).
Among the older men, the absolute risk reduction with
aspirin was about 4.4 infarcts per year per 1,000 men treated,
and the benefit of aspirin probably outweighs the excess of
stroke and bleeding caused by aspirin. Evaluation of potential
absolute reductions of cardiovascular events in relation to
patient age and risk factor status and consideration of the
potential risk of aspirin side effects should help physicians
decide whether aspirin therapy is warranted in individuals
with no history of AMI, stroke, or transient cerebral ischemic
attack.
The primary prevention trials of aspirin have not included
women. The only available data were from a large prospective
cohort study of 87,678 US registered nurses aged 34 to 65
years, free of diagnosed coronary artery disease, stroke, and
cancer at baseline.150 Regular aspirin usage was carefully
documented at baseline and during follow-up from 1980 to
1986. Among women taking one to six aspirins per week, the
age-adjusted relative risk of a first MI was 0.68 (p=0.005).
This benefit was confined to women age 50 years or older
(relative risk [RR], 0.61; p=0.002). There were trends toward
less cardiovascular death (RR, 0.89; p=0.56) and important
vascular events (RR, 0.85; p=0.12), but there was no
difference for stroke (RR, 0.99). No benefits were observed
among women taking more than six aspirin per week. As in
any cohort trial, there are concerns about unanticipated and
undocumented confounders that may bias the conclusions.
Such factors might explain the failure to observe benefit
Fourth ACCP Consensus Conference on Antithrombotic Therapy
among the women taking more than six aspirins per week,
also be possible. Overall, the
might
although a (3 error
the
those
of
Physicians' Health Study in
findings support
men. New data should come from the Women's Health
Study.151
In other
settings of vascular disease, there are now trials
that indicate that women benefit from aspirin therapy when
the underlying problem is unstable angina128 or AMI.73
However, the lower age-matched risk of cardiac events for
women compared with men suggests that absolute benefits
at a given age may be less among women. It is likely that
women older than 50 years, free of a history of MI or stroke,
benefit from regular aspirin administration.
Stable Angina
Of the 22,071 male physicians without history of MI,
stroke, or transient cerebral ischemia enrolled in the
333 had a history of exertional
Study,months
Physicians' Health 60.2
of follow-up, 27 men had
During
angina.152
confirmed MI: 7 of 178 randomly assigned to receive ASA
and 20 of 155 who received placebo (risk reduction, 70%;
controlling for other cardiovascular risk
p=0.003). When
factors, there was an 87% risk reduction (p<0.001).
The Swedish Angina Pectoris Trial (SAPAT) Group153
2,035 patients with stable angina randomly
recendy described
to receive aspirin, 75 mg daily, or placebo for a
assigned
median of 15 months.145 All patients received sotalol for
control of angina. There was a 34% reduction ofthe primary
outcome of MI and sudden death (CI, 24 to 49%; p=0.003).
Other vascular events and mortality were reduced by 22 to
32%. Contrary to the title of the article, this was a secondary
prevention study with angina serving as a marker for
coronary artery disease, just as do prior MI, stroke, or TIA.
Recommendations
Acute Myocardial Infarction
It is strongly recommended that all pa¬
Anticoagulation:
considered for anticoagulant therapy.
AMI
be
tients with
1. It is strongly recommended that every patient with
AMI receive not less than low-dose heparin therapy (7,500
U sc every 12 h) and until fully ambulatory unless there is
a specific contraindication. This grade B recommendation is
based on the results of two level I studies6566 using heparin,
15,000 U/d sc, and demonstrating reduced calf vein thrombo¬
sis, and evidence from echocardiographic trials.40'41'43
2. It is strongly recommended that patients at increased
risk of systemic or pulmonary embolism because of anterior
Q-wave infarction, severe LV dysfunction, CHF, history of
echo evidence of
systemic or pulmonary embolism, 2Dreceive
mural thrombosis, or atrial fibrillation
therapeuticdose heparin (about 75 U/kg bolus IV, initial maintenance
1,250 U/h IV, APTT 1.5 to 2 times control), followed by
warfarin (INR, 2.5 to 3.5) for up to 3 months. Warfarin
be maintained long term for atrial fibrillation
therapy2.0should
(INR, to 3.0). This grade A recommendation is based on
three studies providing level I and II evidence for reduction
of mortality and embolism,37"39 an overview of randomized
trials of early anticoagulation,35 evidence from echocardio¬
studies reporting a markedly increased frequency
graphic
of mural thrombosis in anterior vs inferior MI,4041'43'53
and three level I trials of long-term anticoagulation
The recommendation for patients with atrial
therapy.91'94
fibrillation is further supported by five level I trials and one
level II trial.
3. It is recommended that all patients who have received
rtPA should receive heparin according to the following reg¬
imen: (a) about 75 U/kg IV bolus at initiation rtPA infusion,
initial maintenance 1,000 to 1,200 U/h IV, APTT 1.5 to 2
times control, maintained for 48 h; (b) maintenance of the
APTT at 1.5 to 2 times control beyond 48 h should be un¬
dertaken only in the presence of determinants of high risk
of systemic or venous thromboembolism (anterior AMI,
CHF, previous embolus, atrial fibrillation). In such cases, the
IV regimen may be sustained or consideration may be given
to subcutaneous administration (initial dose approximately
17,500 U every 12 h, to maintain APTT at 1.5 to 2 times
control), or to conversion to warfarin therapy.
4. It is recommended that patients who have received SK
or APSAC should receive IV heparin only in the presence of
determinants of high risk of systemic or venous thromboem¬
bolism (anterior AMI, CHF, previous embolus, atrial fibril¬
lation), and then according to the following regimen: mea¬
sure APTT when the indication emerges but not less than 4
h after beginning SK or APSAC infusion. If more than two
times control, repeat APTT as appropriate, and commence
infusion of heparin when APTT less than two times control
and maintain APTT in 1.5 to 2.0 times control range as long
as risk of thromboembolism is considered to be high. After
48 h, consideration may be given to subcutaneous adminis¬
tration (initial dose approximately 17,500 U every 12 h, to
maintain APTT at 1.5 to 2 times control), or to conversion
to warfarin therapy.
Antiplatelet Therapy: 1. It is strongly recommended that
all patients with AMI receive nonenteric-coated aspirin, 160
to 325 mg (2 to 4 children's tablets, or & to 1 adult tablet)
to chew and swallow as soon as possible after the clinical
impression of evolving AMI is formed, and whether or not
is to be given. The dose should be
thrombolytic therapymouth
indefinitely. This is a grade A
daily by
repeated
recommendation for the initial month, based on the results
of one level I trial73 and a grade B recommendation for the
based on an overview of aspirin trials (level
long-term use,AMI.115
The enteric-coated form will result in
II) following
fewer gastric side effects in long-term therapy.
Ifthe patient is to receive heparin, aspirin should be given
if warfarin therapy is commenced, the
conjointly. However,
be discontinued until the planned
should
aspirin therapy
course ofwarfarin is complete. Aspirin therapy should then
be restarted and maintained indefinitely. It is recommended
that aspirin not be given concurrendy with warfarin except
in situations of very high embolic risk or previous failure of
either therapy alone.
2. Aspirin is recommended for long-term therapy in
to warfarin because of its simplicity, safety, and
preference
low cost. Long-term warfarin therapy is recommended in
clinical settings of increased embolic risk (duration 1 to 3
months following AMI or AMI complicated by severe LV
CHF, previous emboli, or 2D echocardiographic
dysfunction,
duration indefinite with atrial
evidence of mural
thrombosis;
fibrillation).
Patients who have contraindications to aspirin should be
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395S
considered for long-term therapy with warfarin (INR, 2.5 to
3.5). The increased complexity, risk, and cost of such therapy
are concerns.
However, most aspirin-intolerant patients at
higher risk of reinfarction and cardiac death should receive
warfarin at least during the first 1 to 2 years following AMI.
This grade A recommendation is based on the results ofthree
level I trials.91"94
Some patients with recurrent ischemic episodes following
AMI may benefit from a combination of warfarin and aspirin.
Clinical trials are evaluating combinations of low-dose and
warfarin and low-dose aspirin (80 mg). This
low-intensity
is based on expert advice derived
C
recommendation
grade
from the results of level I trials for oral anticoagulation alone,
overviews of aspirin trials among patients following AMI, and
a trial of combination warfarin and aspirin among patients
with prosthetic valves.155
3. Sulfinpyrazone is not recommended for survivors of
AMI. There are two level II trials119122 that suggest a benefit
of sulfinpyrazone, but the recommendation against it is made
because of the evidence for benefit of aspirin, a less ex¬
pensive agent with a simpler dose regimen, and more exten¬
sive evidence supporting its efficacy.
4. Dipyridamole (either alone or in combination with
aspirin) is not recommended for survivors of AML There are
two level II studies, one showing no difference between a
combination of dipyridamole with aspirin vs aspirin alone114
and the other showing a trend favoring the combination of
dipyridamole and aspirin over placebo.123
Unstable Angina
Antiplatelet
Agents: It is strongly recommended that
with
unstable
patients
angina should be treated with aspirin,
(160 to 325 mg^d) commencing as soon as possible after the
clinical impression of unstable angina is formed and
continued indefinitely. This grade A recommendation is
based on the results of four level I studies.127,128*136,138
It is strongly recommended that patients
Anticoagulants:
with unstable angina should, in addition to
hospitalized
aspirin, commence IV heparin therapy (about 75 U/kg IV
bolus, initial maintenance 1,250 U/h IV, APTT 1.5 to 2.0
times control). The heparin therapy should be maintained
for 3 to 4 days, or until the unstable pain pattern resolves.
This grade B recommendation is based on the results of two
level I
trials.136'138-139
Other Alternatives: It is recommended that patients with
unstable angina, who have aspirin allergy, be considered for
therapy with ticlopidine (250 mg bid). This grade A
recommendation is based on the results of only one level I
trial.129
It is recommended that patients with unstable angina,
who have contraindications to aspirin or ticlopidine, receive
followed by warfarin (INR, 2.5 to 3.5) for a period
heparin,
ofseveral months. This grade C recommendation is based on
level III and IV trials130"133 arid on expert advice (level V).
The use of sulfinpyrazone is not recommended for
patients with unstable angina. This grade A recommendation
is based on the negative results of one level I trial.128
Stable Angina and Chronic Coronary Artery
Disease
L It is recommended that all patients with stable angina
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receive oral aspirin (160 to 325 mg^d)
indefinitely. This grade
the results of one level I
trial153 and the analysis of a subgroup of patients with stable
angina from a large level I clinical trial.147152
2. It is recommended that all patients with clinical or
laboratory evidence of coronary artery disease receive oral
aspirin (160 to 325 mg/d) indefinitely. This grade C
recommendation is based on expert advice derived from the
results oflevel I clinical trials,147153 analysis of a subgroup of
patients with stable angina,1^2 and the Antiplatelet Trialists'
A recommendation is based
on
overview. 115
Primary Prevention
1. The routine use of aspirin for primary prevention of
coronary artery disease in individuals free of a history of
AMI, stroke, or transient cerebral ischemic attack, and
younger than 50 years, is not recommended. This grade B
recommendation is based on a subgroup analysis of a large
level I trial147 indicating no benefit among patients younger
than 50 years, and overall an increased rate of duodenal
ulcer, bleeding, and transfusion, and a trend toward more
stroke.
hemorrhagic
2. It is recommended that aspirin (160 to 325 mg/d) be
considered for individuals older than 50 years who have at
least one additional major risk factor for coronary artery
disease and who are free of contraindications to aspirin. This
is a grade A recommendation for men, based on the results
of a large level I trial147 indicating reduced MI and important
vascular events overall, and that the benefits are confined to
patients older than 50 years. In that trial, the absolute
benefits increased with advancing age, and with the presence
of diabetes mellitus, systolic or diastolic hypertension,
cigarette smoking, and lack of exercise.147
This is a grade C recommendation for women, based on
the results of a large prospective cohort study (level III)150
reduced MI and that the benefits are confined to
indicatingolder
than 50 years. In that study, the absolute
patients
benefits increased with cigarette smoking, hypertension,
diabetes mellitus, high cholesterol levels, and history of
parental infarction.
ACKNOWLEDGMENT: The authors are grateful to Susan Crook
for handling the extensive communications necessary for the
development of this consensus and for typing the manuscript and
tables.
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