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New Approaches to Diagnosis and Management of Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction
Robert A. O'Rourke, MD;
Judith S. Hochman, MD;
Marc C. Cohen, MD;
Charles L. Lucore, MD;
Jeffrey J. Popma, MD;
Christopher P. Cannon, MD
Arch Intern Med. 2001;161:674-682.
ABSTRACT
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Recently, it has been demonstrated in multiple clinical research studies
that non–Q-wave myocardial infarction shares many of the features of
unstable angina pectoris and that both diseases initially are managed similarly.
Important new antiplatelet drugs (glycoprotein IIb-IIIa inhibitors) and antithrombin
agents (low-molecular-weight heparin) are currently recommended for patients
with unstable angina pectoris/non–ST-segment elevation MI who are at
high or intermediate risk on the basis of symptoms, electrocardiographic findings,
and the presence or absence of serum markers (eg, troponin I, troponin T,
and creatine kinase-MB). This review provides important information concerning
the results of clinical studies of glycoprotein IIb-IIIa inhibitors (tirofiban
hydrochloride and eptifibatide) when used with unfractionated heparin in patients
with this syndrome or with low-molecular weight heparin (enoxaparin sodium)
in similar patients. The Thrombolysis in Myocardial Infarction IIIB, Veterans
Affairs Non–Q-Wave Infarction Studies in Hospital, and Fast Revascularization
During Instability in Coronary Artery Disease II studies evaluating a conservative,
ischemia-guided approach vs an early aggressive approach to such patients
are presented, with a practical algorithm for treating such patients.
INTRODUCTION
In 1994, the Agency for Health Care Policy and Research sponsored the
development of an unstable angina guideline to "define diagnostic and management
strategies likely to maximize therapeutic benefit for patients with unstable
angina."1 Since then, greater understanding
of risk factors in the setting of unstable angina pectoris (UAP) has enhanced
our insight about how UAP should be managed. It is also now accepted that
patients with non–Q-wave myocardial infarction (NQMI) share many similarities
to patients with UAP, and thus, patients with non–ST-segment elevation
ischemia are approached as a single (if still heterogeneous) group in terms
of clinical management. A new guideline for the management of UAP and non–ST-segment
elevation MI (non-STEMI) was published by the American College of Cardiology/American
Heart Association in September 2000.2
Concurrent with this better understanding of UAP, important new agents
with effects on platelet aggregation and thrombosis have become available
and approved for the management of acute coronary syndromes (ACS). These include
several platelet glycoprotein (Gp)IIb-IIIa receptor antagonists—tirofiban
hydrochloride, eptifibatide, and abciximab—and a low-molecular-weight
(LMW) heparin, enoxaparin sodium.
This brief review is intended to provide the practicing physician with
practical information about how the UAP guidelines can be used by addressing
how new approaches to risk stratification can be used to refine management
strategies; it assesses the utility and role of therapies in UAP/non-STEMI
on the basis of levels of evidence derived from clinical trials. New treatment
algorithms are proposed that reflect improved understanding of contributors
to risk in UAP/non-STEMI and incorporate recently approved pharmacological
agents that have demonstrated efficacy in this clinical setting.
PATHOGENESIS OF ACS
Erosion, fissuring, or rupture of an atherosclerotic plaque is the signal
event in ACS. Immediately after plaque disruption, platelets adhere to the
site of injury by means of specific Gp receptors to collagen and von Willebrand
factor. This results in platelet activation, with a change in the platelets'
shape, the release of storage granules that contain platelet agonists such
as adenosine diphosphate and thromboxane A2, and a conformational
change in the platelet fibrinogen receptor GpIIb-IIIa.3-4
This adhesion molecule, present in large numbers on the platelet surface (approximately
40 000 per platelet to 80 000 per platelet), is a member of the
integrin family—a group of similar cell-surface receptors, each of which
is composed of noncovalently linked  and ß transmembrane subunits.
Plaque disruption also results in the release of tissue factor, a lipoprotein
produced by smooth muscle cells, macrophages, and endothelial cells into the
blood. Tissue factor activates the extrinsic pathway of the coagulation cascade
with the resultant generation of thrombin.5-6
Thrombin then acts on fibrinogen, initiating its conversion to fibrin, which
forms the scaffolding of the developing thrombus. In addition to its role
in coagulation, thrombin activates platelets, stimulating them to adhere to
and potentially seal the disrupted endothelial surface.
On resting platelets, the GpIIb-IIIa receptor has a low affinity for
fibrinogen. However, on platelet activation, the affinity of the GpIIb-IIIa
receptor for fibrinogen increases. Each fibrinogen molecule is capable of
binding to the receptors on 2 different platelets simultaneously, forming
stable intercellular bridges. Platelets are thus linked to one another at
the site of injury by molecules of fibrinogen. The resulting platelet plug
is stabilized by strands of fibrin. Further adhesion of platelets to each
other results in propagation of a platelet-rich clot, leading eventually to
a reduced lumen and ischemia at rest or with minimal exertion. The critical
role of the GpIIb-IIIa receptor in the final common pathway of platelet aggregation
has led to the development of a number of specific and nonspecific GpIIb-IIIa
receptor antagonists.
PATIENT IDENTIFICATION AND RISK STRATIFICATION
Defining the most appropriate approach to therapy requires accurate
patient identification and careful stratification of risk (Table 1). When patients present with chest pain, initial electrocardiographic
(ECG) findings (ST-segment depression, ST-segment elevation, or T-wave inversion),
and laboratory test results (levels of creatine kinase [CK] and troponin)
can provide important information to assist in the risk stratification of
patients (Figure 1). In the Thrombolysis
in Myocardial Infarction III (TIMI-III) registry, ST-segment deviation of
at least 0.5 mm was found to be an independent predictor of death or MI at
1 year. In other previous studies, ST-segment elevation of at least 1.0 mm
was an independent risk factor. New or presumably new T-wave inversion on
admission electrocardiograms did not confer increased risk compared with no
ECG changes in the TIMI-III registry.7 However,
Savonitto et al8 studied 12 142 patients
in the Global Utilization of Streptokinase and Tissue Plasminogen Activator
for Occluded Arteries IIB trial and found that the ECG category and CK level
at admission remained highly predictive of death and MI after multivariate
adjustment for the significant baseline predictors of subsequent coronary
events. They showed that the ECG result and CK level on admission could identify
a difference in mortality between subjects with T-wave inversion and normal
CK level (1.7%) and subjects with ST-segment elevation or depression and elevated
CK level (14.4%).8 However, in a Thrombin Inhibition
in Myocardial Ischemia (TRIM) substudy, Holmvang and associates9
found an independent risk for subsequent MI or death in patients with UAP
and T-wave inversions in 5 or more leads. In a later publication, using continuous
ambulatory ECG recording, TRIM investigators reached a different conclusion.14 Although attempts have been made to find specific
ECG characteristics of acute coronary ischemia in patients with left bundle-branch
block, none has yet effectively stratified risk in this high-risk group.7, 10
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Table 1. Revised Risk Classification of Patients With UAP/Non-ST-Segment
Elevation MI*
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Figure 1. Algorithm for the assessment of
patients presenting with chest pain and suspected or definite coronary artery
disease. MI indicates myocardial infarction; ECG, electrocardiogram; CK-MB,
creatine kinase-MB fraction; SX, symptoms; CHD Pt, patients with coronary
heart disease; and ACS protocol, acute coronary syndrome protocol for patients
with unstable angina or non–ST-segment elevation myocardial infarction.
Stress testing indicates pharmacological stress testing (adenosine diphosphate
or dipyridamole) with myocardial perfusion imaging, or dobutamine echocardiography.
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Even with an initially normal ECG, further progression of symptoms of
UAP in patients with coronary heart disease or recurrent ischemia episodes
in the presence of signs or symptoms of congestive heart failure (eg, third
heart sound, mitral regurgitation, bibasilar rales) should be sufficient to
place a patient in the ACS protocol (Figure
1).
Improved understanding of the significance of troponin levels (in particular,
troponins I and T) allows for further refinement of the ACS paradigm.11-13,15 In
a recent analysis of data from the TIMI IIIB trial, troponin I levels provided
useful prognostic information and permitted the early identification of high-risk
patients.11 The mortality rate at 42 days was
significantly greater in patients with troponin I levels of at least 0.4 µg/L
compared with those with troponin I levels of less than 0.4 µg/L (3.7%
vs 1%; P<.001). The association between elevated
troponin I levels (highly sensitive for myocardial injury) and increased mortality
was evident even in those patients with normal CK-MB levels. In addition,
there were significant increases in mortality with increasing levels of troponin
I (P<.001). A similar relationship has also been
shown for troponin T.13
In the future, other biochemical markers such as C-reactive protein16-18 and fibrinogen19 may also play a useful role in the assessment of
risk for major cardiac events and death in the patient presenting with chest
pain.
APPROACHES TO THERAPY
The goals of therapy in UAP/non-STEMI is to improve the balance etween
myocardial oxygen supply and demand, and to prevent patients from experiencing
further cardiac events related to their underlying disease and, in particular,
to the recently ruptured plaque and platelet aggregation (white thrombus).
A modification of existing therapeutic guidelines for the management of UAP
to reflect the availability of newer antiplatelet and antithrombin drugs,
including tirofiban, eptifibatide, and enoxaparin in UAP/non-STEMI is indicated
in Table 2. As in the past, aspirin, ß-blockers,
unfractionated heparin, and intravenous (IV) nitroglycerin are administered
to most patients with UAP. Angiotensin-converting enzyme inhibitors usually
are added for patients with depressed left ventricular function, congestive
heart failure, or diabetes. Long-acting calcium antagonists are sometimes
used for refractory chest pain. Guidelines concerning the usefulness of the
newer agents for particular patients, as well as for an early conservative
or early invasive approach to therapy, are provided. Indications for an early
invasive approach are as follows: (1) intermediate- and high-risk patients
with recurrent pain, despite intensive medical therapy, or with positive results
of testing for inducible ischemia; (2) intermediate- to high-risk angina in
patients with previous coronary angioplasty or coronary artery bypass surgery;
and (3) hemodynamic instability, congestive heart failure, and/or ejection
fraction of less than 0.40.1-2,9
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Table 2. Proposed Application of Antiplatelet and Antithrombin Therapy
in Treatment of Patients With UAP/Non-ST Segment Elevation MI*
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NEWER AGENTS IN UAP/NON-STEMI
Considering the role of platelet activation and thrombin generation
after plaque disruption in the pathogenesis of UAP/NQMI, a cornerstone of
therapy in this clinical setting has been altering or preventing these responses
to vascular injury with antiplatelet and antithrombin agents. The benefits
of aspirin and heparin, the prototype agents used in this setting, are well
established, and their use is currently standard in the management of UAP/non-STEMI;
however, aspirin and heparin have shortcomings.20
Recently, new agents with antithrombin or antiplatelet activity have become
available for use in the clinical setting of UAP/non-STEMI, as replacements
for, or as adjuncts to, standard therapies.
LIMITATIONS OF STANDARD THERAPIES
The antiplatelet agent aspirin irreversibly inhibits the enzyme cyclooxygenase,
thereby permanently preventing affected platelets from synthesizing thromboxane
A2, a potent vasoconstrictor and stimulator of platelet aggregation.
Although numerous clinical trials and a large meta-analysis support the use
of aspirin for the prevention and treatment of ACS,21
this agent has well-known limitations. These include little or no effect on
agonists of platelet aggregation other than thromboxane A2, failure
to prevent the initial adhesion of platelets to injured endothelium, inability
to prevent fibrinogen from binding to its receptor, and inhibition of prostacyclin
synthesis. Even low doses of aspirin can cause significant gastric irritation
and bleeding.22 Finally, in some patients,
platelets do not always respond to aspirin or may exhibit enhanced aggregation
with aspirin treatment; such patients who do not respond to aspirin (who may
represent 30%-40% of all patients who present with ACS) may be those who have
recurrent ischemic events despite aspirin therapy.23
The common antithrombin in clinical use is heparin.24
Heparin binds to antithrombin III, enhancing its ability to inactivate factor
Xa and thrombin and, to a lesser extent, clotting factors IXa, XIa, and XIIa.
By reducing the generation of thrombin and fibrin, this complex retards the
thrombotic process. Although the efficacy of heparin in the treatment of UAP/non-STEMI
has been established,25 it has several deficiencies
as a therapeutic agent. The primary limitation of heparin is the highly variable
dose-response relationship26; this necessitates
monitoring of the patient's coagulation status and may limit therapeutic effectiveness.
A further complication may result from the nonspecific binding of heparin
to plasma proteins and endothelial cells, and inactivation by platelet factor
4. Furthermore, heparin can actually stimulate platelet aggregation, which
may exacerbate thrombus formation. Finally, its prolonged use for several
days can lead to thrombocytopenia in a small percentage of patients.
PLATELET GpIIb-IIIa RECEPTOR ANTAGONISTS
Table 3 describes the outcomes
of death or MI in patients in 4 clinical trials of platelet GpIIb-IIIa antagonists
in ACS.
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Table 3. Outcomes of Death or MI in 4 Clinical Trials of Platelet GpIIb-IIIa
Antagonists in Acute Coronary Syndromes Without PCI
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Tirofiban
Tirofiban (Aggrastat) is a nonpeptide tyrosine derivative whose structure
mimics the arginine-glycine-aspartic acid (RGC) by which fibrinogen binds
to the IIb-IIIa receptor, thereby competing with fibrinogen for binding sites.
Tirofiban inhibits platelet aggregation, depending on dose and serum concentration.
Usually, it leads to more than 90% inhibition within 30 minutes of initiation
of the recommended regimen. Inhibition of platelet aggregation by tirofiban
is rapidly reversible. The use of tirofiban in addition to aspirin and heparin
in the medical management of UAP/NQMI was examined in the Platelet Receptor
Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable
Signs and Symptoms (PRISM-PLUS) trial.27
The PRISM-PLUS trial examined the clinical efficacy of tirofiban vs
placebo in preventing acute ischemic events in 1915 high-risk patients with
UAP/NQMI.27 Patients were randomized to 1 of
the following 3 treatment arms: tirofiban, tirofiban plus unfractionated heparin,
or unfractionated heparin, all in the presence of aspirin, unless contraindicated.27-28 The tirofiban arm was discontinued
early because of an increased 7-day mortality at an interim analysis.28 However, when given in combination with weight-adjusted
heparin, tirofiban hydrochloride at a dose of 0.4 µg/kg per minute for
30 minutes followed by 0.1 µg/kg per minute reduced the 7-day composite
event rate of death, infarction, or refractory angina. The mean (±SD)
duration of infusion for the study drugs was 71.3 ± 20.0 hours; angiography
and angioplasty were performed, when clinically indicated, after 48 hours
of therapy.
In patients treated with tirofiban plus heparin, the composite primary
end point of death, MI, or refractory ischemia event rate was significantly
lower than in the heparin-alone group at 7 days (12.9% vs 17.9%; risk ratio,
0.68; 95% confidence interval [CI], 0.53-0.88; P
= .004). The incidence of the composite end point was also reduced significantly
(P = .03) in the tirofiban-plus-heparin group vs
the heparin-alone group at 30 days and 6 months. For the harder composite
end points of death or MI, the frequency of events was reduced significantly
at 7 (P = .006) and 30 days (P = .03). The benefits of tirofiban plus heparin vs heparin alone were
maintained across various subpopulations (eg, age, sex, and diagnostic status).
The benefits of tirofiban plus heparin vs heparin alone were seen in patients
treated medically, in patients undergoing coronary angioplasty (percutaneous
coronary intervention [PCI]), and in patients undergoing coronary artery bypass
graft (CABG) surgery.27
Bleeding complications and thrombocytopenia were rare, and there was
no incidence of intracranial bleeding. Major bleeding according to TIMI criteria
occurred in 0.8% of patients receiving heparin alone and in 1.4% of those
receiving tirofiban plus heparin (P>.05). There were
also no significant differences in the number of blood transfusions. Thrombocytopenia,
defined as a reduction in platelet count below 90 x 109/L,
was marginally higher in the tirofiban plus heparin group (1.9% vs 0.8% for
heparin-alone group; P = .07), but was rapidly reversible
on cessation of the infusion.
Eptifibatide
Eptifibatide (Integrilin) is a cyclic heptapeptide modeled after the
snake venom disintegrin barbourin. The key structural feature of eptifibatide
is a cyclic lysine-glycine-asparagine that targets the ligand-adhesions site
(ie, RGD-binding sequence) of GpIIb-IIIa with high affinity. The cyclic structure
of the compound helps provide stability and decrease enzymatic degradation.
Like tirofiban, eptifibatide inhibits platelet aggregation in a dose-dependent
and reversible manner. Eptifibatide was studied for the acute treatment of
patients with UAP/NQMI in the Platelet Glycoprotein IIb-IIIa in Unstable Angina:
Receptor Suppression Using Integrilin Therapy (PURSUIT) trial.29
In the PURSUIT trial,29 eptifibatide
was compared with placebo for the acute treatment in 10 948 patients
with UAP/NQMI as manifested by a short-term episode of ischemic chest pain
(verified by means of ECG findings or CK-MB levels) during the previous 24
hours. Patients were randomized into 1 of the following 3 groups: high-dose
eptifibatide (infusion of 180 µg/kg bolus plus 2.0 µg/kg per minute),
low-dose eptifibatide (180-µg/kg bolus plus infusion of 1.3 µg/kg
per minute), or placebo. Drug or placebo treatment was administered in a double-blind
manner until hospital discharge of CABG or for up to 72 hours (96 hours for
patients undergoing percutaneous transluminal coronary angioplasty). Patients
received aspirin and unfractionated heparin with a target activated partial
thromboplastin time of 55 to 75 seconds. The primary end point was a composite
of death or MI at 30 days.
By design, low-dose eptifibatide therapy was discontinued after a prespecified
interim analysis showed no significant excess in adverse events in the high-dose
eptifibatide group. The rate of death or MI at 30 days was significantly lower
in patients treated with high-dose eptifibatide compared with placebo (14.2%
vs 15.7%; relative risk reduction, 9.5%; P = .04).
The risk reduction was 19% (8.1% vs 10.0%; P = .001)
at 30 days and 10% (12.2% vs 13.6%; P = .02) at 6
months. After only 72 hours and while the patients were still undergoing infusion
with the study drug, a significant (P<.001) reduction
in the rate of death or MI events was observed in the eptifibatide group (5.9%)
compared with the placebo group (7.6%). A markedly reduced frequency of events
was observed in patients undergoing early PCI while still taking the study
drug within the first 72 hours, compared with the placebo group with a 38%
reduction in death or MI (9.0% vs 14.4%; P .03).
However, among patients treated medically with late PCI or CABG after the
infusion was finished, at 72 hours, there was no benefit from eptifibatide
therapy.
The frequency of thrombocytopenia and the occurrence of stroke were
not significantly different between groups. The incidence of minor bleeding
according to TIMI criteria was 13.1% in the eptifibatide group vs 7.6% in
the placebo group; the frequency of major bleeding was 10.8% (eptifibatide
group) vs 9.3% (placebo group) (P = .02). Red blood
cell transfusions were required in 11.6% of the patients treated with eptifibatide
compared with 9.2% of the patients treated with placebo.
LOW-MOLECULAR-WEIGHT HEPARIN
Enoxaparin is an LMW heparin with an average molecular weight of 4500
d. Heparin chains with molecular weight of less than 5400 d (corresponding
to <18 saccharides) cannot bind antithrombin and thrombin simultaneously,
and thus cannot inactivate thrombin. However, the ability of short chains
containing the critical pentasaccharide sequence to inhibit factor Xa is relatively
preserved; enoxaparin thus has an anti–factor Xa/IIa ratio of 3.9:1
compared with 1:1 for unfractionated heparin.
Unlike unfractionated heparin, enoxaparin exhibits little nonspecific
binding to plasma proteins. Its bioavailabilty following subcutaneous administration
is high (91%), and its dose-response profile is predictable. Enoxaparin is
also associated with a much lower incidence of heparin-induced thrombocytopenia
than unfractionated heparin.
The efficacy of enoxaparin in the short-term treatment of patients with
UAP and NQMI was studied in the Efficacy and Safety of Subcutaneous Enoxaparin
in Non–Q-Wave Coronary Events (ESSENCE) and TIMI 11B trials.31-32
The ESSENCE trial compared enoxaparin and unfractionated heparin in
the treatment of 3171 patients with UAP/NQMI.31
Patients were randomized to subcutaneous enoxaparin sodium (1 mg/kg every
12 hours) or unfractionated heparin to maintain an activated partial thromboplastin
time of 60 to 90 seconds. All patients received aspirin. Therapy was administered
for a minimum of 48 hours and a maximum of 8 days or until hospital discharge
(median duration, 2.6 days). The primary end point was a composite of death,
MI, or recurrent angina within 14 days of enrollment. Secondary end points
included the same composite of death, MI, or recurrent angina at 48 hours
and 30 days as well as a double composite of death or MI at 48 hours, 14 days,
and 30 days.
The occurrence of the primary composite end point was reduced significantly
in the enoxaparin group compared with the unfractionated heparin group (16.6%
vs 19.8%; P = .02). At 30 days, the incidence of
the composite end point was still significantly lower in the enoxaparin group
(19.8% vs 23.3% for unfractionated heparin; P = .02).
Death or MI was also reduced by 16% (6.2% for enoxaparin vs 7.7% for unfractionated
heparin; P = .08). The rate of revascularization
procedures (PCI and CABG) was significantly reduced in the enoxaparin group
(27.0% vs 32.2% for unfractionated heparin; P = .001).
There was no difference in major bleeding complications between trial groups.
The 1-year follow-up of the ESSENCE trial showed that there was still
a significantly lower incidence of the triple end point in the enoxaparin
group (32.0% vs 35.7%; P = .02).33
The positive trend observed at 30 days for death or MI also persisted at 1
year (11.5% for enoxaparin vs 13.5% for unfractionated heparin; P = .08).
The TIMI 11B trial was similar in design to ESSENCE.32
Unlike ESSENCE, patients received 30 mg of enoxaparin sodium as an IV bolus,
followed by subcutaneous injection of 1 mg/kg twice daily or IV unfractionated
heparin until hospital discharge or day 8. Patients in the enoxaparin group
also received subcutaneous enoxaparin sodium, 1 mg/kg twice daily, or a placebo
during a long-term phase that lasted an additional 35 days. The primary end
point was a composite of death, MI, or severe recurrent ischemia requiring
urgent revascularization, evaluated at 14 days (for the short-term phase)
and at 43 days (for the long-term phase).
Preliminary results of the TIMI 11B have recently been reported.34 After 14 days, use of enoxaparin correlated significantly
with a reduction in this composite end point (16.6% for unfractionated heparin
vs 14.2% for enoxaparin; P = .03). During the outpatient
phase of the trial, the significant advantage of enoxaparin over unfractionated
heparin was maintained to day 43, but no additional benefit of continued treatment
was evident.
Importantly, there was no significant difference between the enoxaparin
and unfractionated heparin groups in the incidence of instrumented or spontaneous
major hemorrhage during the in-hospital phase. In contrast, long-term treatment
with enoxaparin during the outpatient phase led to a significant increase
in major hemorrhage events, when compared with placebo (2.9% with enoxaparin
vs 1.5% with placebo; P = .02).
INVASIVE VS CONSERVATIVE STRATEGIES
The relative role of an early-invasive strategy for patients with UAP/NQMI
(early cardiac catheterization with PCI or CABG [if appropriate]), compared
with an early conservative strategy (cardiac catheterization, PCI, and CABG
reserved for patients who fail to respond to medical therapy) remains a subject
of debate. Intermediate- to high-risk patients with recurrent pain despite
intensive medical therapy, or positive results of a test for inducible ischemia,
are likely to benefit from an early invasive approach. It also seems reasonable
to use an early invasive strategy in patients with previous angioplasty or
CABG. On the other hand, low-risk patients can probably be treated effectively
with an early conservative approach. The 2 published studies of patients in
which this question has been best examined are the TIMI IIIB35-36
and Veterans Affairs Non–Q-Wave Infarction Studies in Hospital (VANQWISH)
trials.37 The Fast Revascularization During
Instability in Coronary Artery Disease (FRISC) study, with randomization after
5 to 7 days of therapy with a LMW heparin, dalteparin sodium, is also relevant.37
In TIMI IIIB, there was no significant difference in the primary end
point (death, nonfatal MI, or unsatisfactory exercise test) at 42 days between
the early invasive and early conservative strategies in patients with UAP/NQMI
(16.2% vs 18.1%, respectively; P>.05).35
However, the number of patients rehospitalized within 6 weeks was significantly
greater (P<.001) in the early conservative group
(14.1% vs 7.8%). Also, the number of antianginal medications taken by patients
in the early conservative group was significantly greater (P = .02). Favoring the early conservative strategy, there were 35%
fewer cardiac catheterizations (P<.001), 30% fewer
angioplasties (P<.001), and 6% fewer CABG surgeries
(P = .49) in the early conservative strategy group
by 6 weeks. The incidence of death or nonfatal infarction did not differ after
1 year by strategy, but fewer patients in the early invasive strategy underwent
late repeated hospital admissions.36
In the VANQWISH study, 920 patients with NQMI confirmed by means of
a greater than 1.5-fold elevation in serum CK-MB fraction were randomly assigned
to an invasive (n = 462) or conservative strategy (n = 458) within 24 to 72
hours.37 The invasive strategy included coronary
angiography as the initial diagnostic test after randomization, with myocardial
revascularization performed at the discretion of the treating physician. In
the conservative approach, only patients with spontaneous ischemia or positive
stress test findings before discharge underwent coronary angiography.37 The primary end point for the trial was the composite
of death or nonfatal MI.
There was no significant difference (P = .35)
in the occurrence of death or nonfatal MI between patients treated with the
invasive (26.9%) or conservative strategy (29.9%) after an average follow-up
of 23 months (range, 12-44 months). In contrast, death or nonfatal MI was
significantly more prevalent in patients undergoing an invasive vs a conservative
strategy before hospital discharge (P = .004), at
hospital discharge (P = .007), at 1 month (P = .01), and at 1 year (P = .05).
Of the 21 deaths during the first 30 days after revascularization in the invasive
group, 11 followed CABG, indicating a 10.4% perioperative mortality. Of note,
in the invasive group, mortality 30 days after PCI occurred in none of 98
patients. There were 49% fewer cardiac catheterizations and 25% fewer revascularizations
(PCI and CABG) in the conservative strategy group. Of interest, the presence
of diabetes mellitus was an independent high risk factor for death or MI in
both strategies.
The results of the VANQWISH study do not favor an early invasive strategy
in managing most NQMI but rather an ischemia-guided conservative approach.
In fact, this study suggests that early invasive treatment with CABG of high-risk
patients may actually be harmful. A risk model for predicting mortality in
non–Q-wave myocardial infarction favored an invasive vs conservative
strategy in patients with previous MI, diabetes, peripheral vascular disease,
hypertension, anterior wall ST-segment depression, and a widened QRS duration.38
The FRISC II study, in which 3048 patients with ACS were treated with
dalteparin for 5 to 7 days, was reported more recently.39
Patients without acute problems who were not at high risk for revascularization
(eg, aged >75 years or previous CABG) were then randomized to continued dalteparin
therapy or placebo (double-blind) and to an invasive or noninvasive treatment
strategy. Only 54% to 57% had elevated troponin levels. Patients in the noninvasive
group underwent revascularization only for refractory or recurrent symptoms
despite maximal medical therapy, severe ischemia on symptom-limited exercise
testing, or acute MI. At 6 months, there were no differences in the death
or MI event rates between continued treatment with dalteparin and placebo.
However, death or MI occurred in 9.4% of patients assigned to the invasive
strategy and in 12.1% of those assigned to the noninvasive strategies (P<.03). At 1 year, the mortality rate in the invasive
strategy was 2.2% compared with 3.9% in the noninvasive strategy (P = .02). It may be concluded from the FRISC II study that patients
with UAP/non-STEMI who are not at very high risk for revascularization, and
who receive 5 to 10 days of treatment with LMW heparin, aspirin, nitrates,
and ß-blockers, have a better outcome with a routine invasive than a
routine conservative approach.
There are notable differences between these randomized trials. Baseline
patient characteristics indicate that risk was highest in the VANQWISH trial
and lowest in the FRISC II trial, which had the fewest smokers and less previous
MI, hypertension, diabetes, and non-STEMI. The FRISC II trial was further
biased toward lower risk by excluding those older than 75 years and patients
with previous CABG and by treating all patients with LMW heparin for a median
of 6 days before initiating the invasive strategy. The TIMI-IIIB populations
seemed intermediate in risk, but again, the subgroup with NQMI had a much
higher risk for death or reinfarction than subjects with UAP.
Unpublished data from the recently completed Treat Angina with Aggrastat
(Tirofiban) and Determine Cost of Therapy with an Invasive or Conservative
Strategy (TACTICS-TIMI) study18 suggest that
high-risk patients treated within the first 48 hours after hospitalization
with a GpIIb-IIIa inhibitor do better with a subsequent early aggressive therapy
rather than with a conservative approach.
TREATMENT ALGORITHMS
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