6. Initial Recognition And
Management In The Emergency Department
A variety of treatment options (Figure
3) (24-40)
are available that can reduce mortality and morbidity in patients
with STEMI, but the effectiveness of these therapies diminishes
rapidly within the first several hours after symptoms onset (162,185).
The traditional ED evaluation of patients with chest pain relies
heavily on the patient’s history, physical examination, and
the ECG. This approach not infrequently fails to identify patients
who are actually suffering from STEMI, which results in an inappropriate
discharge home from the ED (186).
Such missed MI patients are at relatively high risk of death or
complications for the next 4 to 6 weeks after ED discharge (187-192).
In a large study on this subject, Pope et al. (188)
found that 889 of 10 689 patients who presented to 10 US hospital
EDs with chest pain or other symptoms that suggested acute cardiac
ischemia had STEMI; 19 patients (2.1%, 95% CI 1.1% to 3.1%) were
discharged from the ED. Patients with STEMI were more likely not
to be hospitalized if they were nonwhite (odds ratio [OR] for discharge
4.5; 95% CI 1.8 to 11.8) or had a normal or nondiagnostic ECG (OR
7.7; 95% CI 2.9 to 20.2). The risk-adjusted mortality ratio for
MI patients who were not hospitalized compared with those who were
hospitalized was 1.9 (95% CI 0.7 to 5.2).
6.1.
Optimal Strategies for Emergency Department Triage
Class I
Hospitals should establish multidisciplinary teams (including
primary care physicians, emergency medicine physicians, cardiologists,
nurses, and laboratorians) to develop guideline-based, institution-specific
written protocols for triaging and managing patients who are seen
in the prehospital setting or present to the ED with symptoms suggestive
of STEMI. (Level of Evidence: B)
The advent of highly effective, time-dependent treatment for STEMI
coupled with the need to reduce healthcare costs adds further incentive
for clinicians to get the right answer quickly and to reduce unnecessary
admissions and length of hospital stay. Investigators have tried
various diagnostic tools such as clinical decision algorithms, cardiac
biomarkers, echocardiography, and myocardial perfusion imaging in
an attempt to avoid missing patients with MI or unstable angina.
The most successful strategies to emerge thus far are designed to
identify MI patients and, when clinically appropriate, screen for
unstable angina and underlying coronary artery disease. Most strategies
use a combination of cardiac biomarkers, short-term observation,
diagnostic imaging, and provocative stress testing. An increasing
number of high-quality centers now use structured protocols, checklists,
or critical pathways to screen patients with suspected MI or unstable
angina (193-205).
It does not appear to matter whether the institution designates
itself a chest pain center. Rather, it is the multifaceted, structured
approach to the problem that appears to provide clinical, cost-effective
benefit (206,207).
One randomized trial has confirmed the safety, efficacy, and cost-effectiveness
of the structured decisionmaking approach compared with standard,
unstructured care (208).
6.2. Initial Patient Evaluation
Class I
1. The delay from patient contact with the healthcare system (arrival
at the ED or contact with paramedics) to initiation of fibrinolytic
therapy should be less than 30 minutes. Alternatively, if PCI is
chosen, the delay from patient contact with the healthcare system
(typically, arrival at the ED, or contact with paramedics) to balloon
inflation should be less than 90 minutes. (Level of Evidence: B)
2. The choice of initial STEMI treatment should be made by the emergency
medicine physician on duty based on a predetermined, institution-specific,
written protocol that is a collaborative effort of cardiologists
(both those involved in coronary care unit management and interventionalists),
emergency physicians, primary care physicians, nurses, and other
appropriate personnel. For cases in which the initial diagnosis
and treatment plan are unclear to the emergency physician
or are not covered directly by the agreedupon protocol, immediate
cardiology consultation is advisable. (Level of Evidence: C)
Regardless of the approach used, all patients presenting to the
ED with chest discomfort or other symptoms suggestive of STEMI or
unstable angina should be considered high-priority triage cases
and should be evaluated and treated on the basis of a predetermined,
institution-specific chest pain protocol. The protocol should include
several diagnostic possibilities (Figure
9) (4). The patient should be
placed on a cardiac monitor immediately, with emergency resuscitation
equipment, including a defibrillator, nearby. An ECG should be performed
and shown to an experienced emergency medicine physician within
10 minutes of ED arrival. If STEMI is present, the decision as to
whether the patient will be treated with fibrinolytic therapy or
primary PCI should be made within the next 10 minutes (Figure
7) (180). The goal for patients
with STEMI should be to achieve a door-to-needle time of within
30 minutes and a door-to-balloon time of within 90 minutes (Figure
6) (155). If the initial ECG
is not diagnostic, the patient remains symptomatic, and there is
a high clinical suspicion for STEMI, serial ECGs at 5- to 10-minute
intervals or continuous ST-segment monitoring should be performed.
Ideally, such decisions should be made by the emergency medicine
physician on duty in the ED based on a predetermined, institution-specific,
written protocol that has been developed with input from cardiologists
(both those involved in coronary care unit management and interventionalists),
emergency medicine physicians, primary care physicians, nurses,
and other appropriate personnel. For non-interventional hospitals,
this will usually require formal, written transfer agreements and
protocols that will permit expeditious transfer of patients who
require urgent mechanical revascularization
to the nearest appropriate interventional facility (Figure
6) (155). The protocol should
also include the level of training and certification of personnel
required to accompany the patient during transfer, the minimum equipment
requirements, and the type(s) of transport vehicles (e.g., standard
ground ambulance, mobile intensive care unit, helicopter, or fixed-wing
aircraft) that can be used on the basis of patient condition. For
cases in which the initial diagnosis and treatment plan are unclear
to the emergency medicine physician or are not covered directly
by the agreed-upon protocol, immediate cardiology consultation is
advisable.
6.2.1. History
Class I
The targeted history of STEMI patients taken in the ED should ascertain
whether the patient has had prior episodes of myocardial ischemia,
such as stable or unstable angina, MI, coronary bypass surgery,
or PCI. Evaluation of the patient’s complaints should focus
on chest discomfort, associated symptoms, sex and age-related differences
in presentation, hypertension, diabetes mellitus, possibility of
aortic dissection, risk of bleeding, and clinical cerebrovascular
disease (amaurosis fugax, face/limb weakness or clumsiness, face/limb
numbness or sensory loss, ataxia, or vertigo). (Level of Evidence:
C)
The history taken in the ED must be concise and detailed enough
to establish the probability of STEMI but should be obtained expeditiously
so as not to delay implementation of reperfusion therapy.
Chest Discomfort. The severity of discomfort varies and
is typically graded on a scale of 1 to 10, with 10 being the mostsevere
pain. It is important to keep in mind that many patients will not
admit having chest “pain” but will acknowledge the presence
of chest “discomfort,” because of their definition of
pain. The chest discomfort is often described as a crushing, vice-like
constriction, a feeling equivalent to an “elephant sitting
on the chest,” or heartburn. Usually, the discomfort is substernal
but may originate in or radiate to areas such as the neck, jaw,
interscapular area, upper extremities, and epigastrium. The duration
of the discomfort, which typically lasts longer than 30 minutes,
may wax and wane and may be remitting. It may be described as “indigestion
in the chest” and occasionally may be relieved with belching.
The possibility of precipitation of STEMI by use of illicit drugs
such as cocaine should be considered.
The targeted history of patients with STEMI taken in the ED should
ascertain whether the patient has had prior episodes of myocardial
ischemia such as stable or unstable angina, MI, coronary bypass
surgery, or PCI. Evaluation of the patient’s complaints should
focus on chest discomfort, associated symptoms, sex- and age-related
differences in presentation, hypertension, diabetes mellitus, possibility
of aortic dissection, risk of bleeding, and clinical cerebrovascular
disease (amaurosis fugax, face/limb weakness or clumsiness, face/limb
numbness or sensory loss, ataxia, or vertigo).
Associated Symptoms. Other symptoms to be aware of when
taking a patient’s history include nausea and vomiting. Diaphoresis
associated with a pale complexion may also appear, as well as weakness
or profound fatigue. Dizziness, lightheadedness, syncope, and paresthesia
may occur because of pain and hyperventilation.
Hypertension. Hypertension should be assessed, because chronic,
severe, poorly controlled hypertension or severe uncontrolled hypertension
on presentation is a relative contraindication to fibrinolytic therapy
(see Section 6.3.1.6.3.2).
Sex-
and Age-Related Differences in Presentation. It has been noted
in studies that women present with STEMI at an older age and later
after the onset of symptoms than men (53,210).
There must be an elevated index of suspicion during the evaluation
of women for STEMI. Although some variation exists, when large databases
of MI patients are examined, symptom profiles for STEMI by sex generally
appear more similar than different between men and women (211-215).
Elderly patients with STEMI are significantly less likely than younger
patients to complain of chest discomfort. However, elderly patients
with STEMI are more likely to complain of shortness of breath, as
well as other atypical symptoms such as syncope or unexplained nausea.
(181).
Diabetes Mellitus. Diabetics may have impaired angina (pain)
recognition, especially in the presence of autonomic neuropathy.
A diabetic may misinterpret dyspnea, nausea, vomiting, fatigue,
and diaphoresis as disturbance of diabetic control. Up to 50% of
diabetic individuals with type 2 diabetes for longer than 10 years
will have autonomic nervous system dysfunction manifested by impaired
heart rate variability.
Diabetics with STEMI should be evaluated for renal dysfunction (216).
Possibility of Aortic Dissection. Severe tearing pain radiating
directly to the back associated with dyspnea or syncope and without
ECG changes indicative of STEMI should raise the suspicion for aortic
dissection, and appropriate studies should be undertaken. Clinicians
should have a heightened index of suspicion for aortic dissection
in elderly hypertensive patients. However, it must be kept in mind
that the dissection may extend to the pericardial sac and produce
cardiac tamponade or disrupt the origin of a coronary artery.
Risk of Bleeding. Patients should be questioned about
previous bleeding problems, e.g., during surgery or dental procedures,
history of ulcer disease, cerebral vascular accidents, unexplained
anemia, or melena. The use of antiplatelet, antithrombin, and fibrinolytic
agents as part of the treatment for STEMI will exacerbate any underlying
bleeding risks.
Clinical Cerebrovascular Disease. The patient with STEMI
frequently has medical conditions that are risk factors for both
MI and stroke. Evidence for prior episodes suggestive of clinical
cerebrovascular disease should be sought. For example, the patient
should be asked whether he/she has ever had symptoms of transient
retinal or cerebral ischemia such as amaurosis fugax, face/limb
weakness or clumsiness, face/limb numbness or sensory loss, ataxia,
or vertigo. Transient ischemic attacks (TIAs) typically last less
than 30 minutes, whereas symptoms that last more than 60 to 90 minutes
are more likely to indicate the presence of a stroke (217).
In addition, the patient should be asked whether he/she has ever
had an ischemic stroke, intracerebral hemorrhage [ICH], or subarachnoid
hemorrhage. A brief summary of the details for diagnosis of the
different stroke subtypes is available (218).
Finally, a history of cognitive decline/dementia may indicate the
presence of cerebral amyloid angiopathy and increased risk of ICH,
and information regarding head and facial trauma should be obtained.
6.2.2. Physical Examination
Class I
1. A physical examination should be performed to aid in
the diagnosis and assessment of the extent, location, and presence
of complications of STEMI. (Level of Evidence: C)
2. A brief, focused, and limited neurological examination to look
for evidence of prior stroke or cognitive deficits should be performed
on STEMI patients before administration of fibrinolytic therapy.
(Level of Evidence: C)
A brief physical examination may promote rapid triage (Table
5), whereas a more detailed physical examination aids in the
differential diagnosis and is useful for assessing the extent, location,
and presence of complications of STEMI (Tables
6 and 7) (219).
Evidence
of prior stroke or dementia may be suggested by the finding on examination
of focal neurological or cognitive deficits (Table
6). A brief but focused examination can identify focal neurological
or cognitive deficits.
6.2.2.1. Differential Diagnosis
The differential diagnosis of STEMI includes conditions that can
be exacerbated by fibrinolysis and anticoagulation (Table
8). The pain of aortic dissection is typically described as
searing, ripping, or tearing and frequently radiates to the back
or lower extremities. The pain is worse at onset and lasts for hours.
Major pulses may be absent, and a murmur of aortic regurgitation
may be present. A transesophageal echocardiogram, computed tomography
(CT) scan, or magnetic resonance imaging scan is useful for establishing
the diagnosis of aortic dissection. Active peptic ulcer disease
can be present with chest or epigastric pain, sometimes radiating
posteriorly, and may be associated with syncope, hematemesis, or
melena. Free subdiaphragmatic air may be seen on upright chest X-ray
in perforations. Acute pericarditis may show PR-segment depression
and ST-segment elevation on the ECG but without reciprocal ST-segment
depression (220). Pain from pericarditis
is usually pleuritic and can radiate to the shoulder and trapezius
ridge and is often relieved by sitting up and leaning forward, characteristics
not found in STEMI. A rub is often present. Pulmonary embolus, with
or without infarction, presents with dyspnea and knifelike pleuritic
pain, sometimes with hemoptysis. Pulmonary embolism can present
with chest pain similar to that of STEMI. Costochondral pain is
described as sharp or sticking, with associated localized tenderness.
Pneumothorax may present with acute dyspnea, pleuritic pain, and
differential decrease in breath sounds with hyperresonance over
1 lung field. Acute cholecystitis may mimic STEMI, and rightupper-
quadrant abdominal tenderness should be sought on physical examination.
6.2.3. Electrocardiogram
Class I
1. A 12-lead ECG should be performed and shown to an experienced
emergency physician within 10 minutes of ED arrival on all patients
with chest discomfort (or anginal
equivalent) or other symptoms suggestive of STEMI. (Level of
Evidence: C)
2. If the initial ECG is not diagnostic of STEMI but the patient
remains symptomatic, and there is a high clinical suspicion for
STEMI, serial ECGs at 5- to 10- minute intervals or continuous 12-lead
ST-segment monitoring should be performed to detect the potential
development of ST elevation. (Level of Evidence: C)
3. In patients with inferior STEMI, right-sided ECG leads should
be obtained to screen for ST elevation suggestive of RV infarction.
(See Section 7.6.6
and the ACC/AHA/ASE 2003 Guideline Update for the Clinical Application
of Echocardiography). (Level of Evidence: B)
The 12-lead ECG in the ED is at the center of the therapeutic decision
pathway because of the strong evidence that ST-segment elevation
identifies patients who benefit from reperfusion therapy (221).
Mortality increases with the number of ECG leads showing ST elevation.
Important predictors of mortality on the initial 12-lead ECG include
left bundle branch block (LBBB) and anterior location of infarction
(Figure 10) (222,223).
Diagnostic criteria of greater than 0.1 mV in leads V1 through V4
may have reduced specificity for STEMI in patients with early repolarization.
Some evidence exists to support the use of greater than or equal
to 0.2 mV anteroseptal elevation as a preferable threshold for diagnosing
STEMI, because a higher proportion of patients are correctly classified
as having STEMI than with a threshold of greater than 0.1 mV in
these leads (221).
In
the absence of ST elevation, there is no evidence of benefit of
fibrinolytic therapy for patients with normal ECG or nonspecific
changes, and there is some suggestion of harm (including increased
bleeding risk) for patients with ST-segment depression only (221,224).
Notwithstanding this, fibrinolytic therapy may be appropriate when
there is marked STsegment depression confined to leads V1 through
V4 and accompanied by tall R waves in the right precordial leads
and upright T waves indicative of a true posterior injury current
and circumflex coronary occlusion. In circumstances where there
is a suggestive clinical history and suggestive evidence of true
posterior infarction, confirmatory data from posterior leads (i.e.,
V7 and V8) as well as 2-dimensional echocardiography may be especially
helpful; this latter investigation has a high negative predictive
value (225,226).
Primary PCI is another reperfusion strategy that may be effective
in patients with true posterior MI (see Section
6.3.1.6.4.2).
Initial errors in ECG interpretation can result in up to 12% of
patients being categorized inappropriately, demonstrating a potential
benefit of accurate computer-interpreted electrocardiography and
fax transmission to an expert (227).
It is less likely that STEMI is present if the upward-directed STsegment
changes are concave rather than convex (228).
Because lethal ventricular arrhythmias may develop abruptly in patients
with STEMI, all patients should be monitored electrocardiographically
on arrival in the ED. It is important to examine serial tracings
approximately 5 to 10 minutes apart, or if symptoms recur, during
evaluation in the ED for development of ST elevation if the initial
ECG is nondiagnostic. ST elevation may also be detected by intermittent
visual inspection of the oscilloscope or auditory alarms in systems
with continuous ST-segment monitoring capability.
Although the Fibrinolytic Therapy Trialists’ (FTT) Collaborative
Group overview indicates that patients with new or presumably new
LBBB are at high risk when presenting with presumed MI, this ECG
presentation is a frequent cause of delay or lack of reperfusion
therapy because of the concern of the validity of the ECG criteria
for MI diagnosis and the risk of therapy. This is also a situation
in which direct PCI may be preferable to fibrinolytic therapy (156).
It has been suggested that patients with new or presumably new LBBB
coupled with a typical ischemic history be approached with a plan
to rule in MI using 1 of 3 ECG criteria that provide independent
diagnostic value. These consist of ST elevation greater than or
equal to 0.1 mV in leads with a positive QRS, ST depression greater
than or equal to 0.1 mV in V1 to V3, and ST elevation greater than
or equal to 0.5 mV in leads with a negative QRS (229,230).
6.2.4. Laboratory Examinations
Class I
Laboratory examinations should be performed as part of the management
of STEMI patients but should not delay the implementation of reperfusion
therapy. For specific laboratory examinations, see Table
9. (Level of Evidence: C)
In
addition to serum cardiac biomarkers for cardiac damage, several
routine evaluations have important implications for management of
patients with STEMI (Table 9). Although
these studies should be undertaken when the patient is first examined,
therapeutic decisions should not be delayed until results are obtained
because of the crucial role of time to therapy in STEMI.
6.2.5. Biomarkers of Cardiac Damage
Class I
1. Cardiac-specific troponins should be used as the optimum biomarkers
for the evaluation of patients with STEMI who have coexistent skeletal
muscle injury. (Level of Evidence: C)
2.
For patients with ST elevation on the 12-lead ECG and symptoms of
STEMI, reperfusion therapy should be initiated as soon as possible
and is not contingent on a biomarker assay. (Level of Evidence:
C)
Class
IIa
Serial biomarker measurements can be useful to provide supportive
noninvasive evidence of reperfusion of the infarct artery after
fibrinolytic therapy in patients not undergoing angiography within
the first 24 hours after fibrinolytic therapy. (Level of Evidence:
B)
Class III
Serial biomarker measurements should not be relied upon to diagnose
reinfarction within the first 18 hours after the onset of STEMI.
(Level of Evidence: C)
The nomenclature of acute coronary syndromes is illustrated
in Figure 2 (8-10).
The central position of the 12-lead ECG and initial triage of patients
are emphasized. Serum cardiac biomarkers (creatine kinase [CK],
CK-MB, cardiac-specific troponins, myoglobin) are useful for confirming
the diagnosis of MI and estimating infarct size. Serum cardiac biomarkers
also provide valuable prognostic informatin. For patients with ST-segment
elevation, the diagnosis of STEMI is secure; initiation of reperfusion
therapy should not be delayed while awaiting the results of a cardiac
biomarker assay (231,232)
(Table 10). Quantitative analysis
of cardiac biomarker measurements provides prognostic information
as well as a noninvasive assessment of the likelihood that the patient
has undergone successful reperfusion when fibrinolytic therapy is
administered (Figure 11) (233,234).
Because
there are differences in the clinical need for biomarke in STEMI
versus NSTEMI patients and differences in the characteristics of
the various cardiac biomarkers, preferential use of a particular
biomarker should be base on the clinical syndrome. CK-MB is found
in the skeletal muscle and blood of healthy subjects; therefore,
the cutoff value for an elevated CK-MB is typically set a few units
above the upper end of the reference (normal) range. In contrast,
because cardiac troponin I (cTnI) and cardiac troponin T (cTnT)
are not normally detected in the blood of healthy people, the definition
of an abnormally increased level is a value that exceeds that of
99% of a reference control group. Given the nearly absolute myocardial
tissue specificity and high sensitivity for even microscopic zones
of myocardial necrosis, the ACC and the European Society of Cardiology
subsequently declared cardiac troponins to be the preferred biomarker
for diagnosing MI (233). A single
cutoff point was recommended such that an MI would be diagnosed
if, as a result of myocardial ischemia, cTnI or cTnT were detected
at least once within 24 hours of the index clinical event at a level
exceeding the 99th percentile of the mean value measured in a normal
control population (233). The superior
sensitivity makes troponin the preferred marker for patients with
UA/NSTEMI. In contrast, patients with STEMI are recognized on the
basis of the 12-lead ECG, and in general, subsequent confirmation
of MI can be ascertained by measurement of any of the available
cardiac biomarkers. Occasionally, a very small infarct will be missed
by CK-MB; therefore, troponin should be measured for patients suspected
to have STEMI who have negative serial CK-MBs.
It
should be recognized that in patients with STEMI, cTnT and cTnI
may first begin to rise above the reference limit by 3 to 6 hours
from the onset of ischemic symptoms. Therefore, a significant number
of patients will present o the emergency room with negative biomarkers.
Myoglobin, a low-molecular-weight heme protein found in cardiac
and skeletal muscle, is not cardiac specific but is released more
rapidly from infarcted myocardium than CK-MB and may be detected
as early as 2 hours after STEMI.
In
some patients, cardiac-specific troponins may not be detectable
for up to 6 hours after onset of chest pain. Thus, when CK-MB, cTnI,
or cTnT levels are elevated in less than 6 hours after the onset
of discomfort in patients with STEMI, clinicians should suspect
that an antecedent episode of unstable angina was in fact MI and
the patient is exhibiting a stuttering course of occlusion and release
of the infarct artery. Data from the Global Utilization of Streptokinase
and TPA for Occluded Arteries (GUSTO) III Study suggest that patients
with STEMI who have elevated cTnT levels and who are less than 6
hours from the onset of discomfort have an increased mortality risk
(235).
CK-MB is the preferred, widely available cardiac biomarker for most
patients with STEMI, for whom the need to diagnose reinfarction
and noninvasively assess reperfusion is greater
than the need to make the diagnosis. By mapping the time course
of the rise and fall of a biomarker (typically CKMB), clinicians
can detect an interruption of the progressive fall of the biomarker
level to a point below the upper reference limit (Figure
11) (233,234).
Re-elevation of the biomarker level is evidence of myocardial reinfarction
(Figure 12). A more rapidly rising
and falling biomarker such as CKMB or myoglobin is superior for
diagnosing reinfarction. As a consequence of continuous release
from a degenerating contractile apparatus in necrotic myocytes,
elevations of cTnI may persist for 7 to 10 days after MI, and elevations
of cTnT may persist for up to 10 to 14 days. The more protracted
time course of kinetic release of cTnI and cTnT limits the ability
of clinicians to make the diagnosis of reinfarction within several
days after the index STEMI event. An algorithm illustrating the
decision making process that incorporates biomarker measurements,
ECG findings, clinical symptoms, and, if available, autopsy data
for making the diagnosis of reinfarction is shown in Figure
12.
In
addition to monitoring the patient for resolution of schemic-type
chest discomfort and regression of the magnitude of ST-segment elevation
on the ECG, clinicians can obtain serial measurements of serum cardiac
markers to buttress the noninvasive diagnosis of reperfusion of
the infarctrelated artery after fibrinolytic therapy (Figure
11) (233,234,236).
An early peak of CK-MB (12 to 18 hours) suggests reperfusion. Because
of its rapid-release kinetics, myoglobin is also an attractive marker
for the early diagnosis of reperfusion.
CK-MB
isoforms are another serum cardiac biomarker less frequently used
for evaluating patients with STEMI. CK-MB exists in only 1 form
in myocardial tissue but in different isoforms (or subforms) in
the plasma. An absolute level of CKMB2 greater than 1 U/L or a ratio
of CK-MB2 to CK-MB1 of 1.5 has improved sensitivity and specificity
for diagnosis of MI within the first 6 hours compared with conventional
assays for CK-MB (237).
6.2.5.1.
Bedside Testing for Serum Cardiac Biomarkers
Class I
1.
Although handheld bedside (point-of-care) assays may be used for
a qualitative assessment of the presence of an elevated level of
a serum cardiac biomarker, subsequent measurements of cardiac biomarker
levels should be done with a quantitative test. (Level of Evidence:
B)
2. For patients with ST elevation on the 12-lead ECG and symptoms
of STEMI, reperfusion therapy should be initiated as soon as possible
and is not contingent on a bedside biomarker assay. (Level of Evidence:
C)
Handheld rapid bedside assays are clinically available for measuring
cTnI, cTnT, myoglobin, and CK-MB, but in general, bedside assays
are less sensitive and less precise than quantitative assays. Small
desktop rapid analyzers are also available for the same purpose.
A rapid, high-voltage electrophoretic system is available for measuring
CK-MB isoforms. Monitoring the timing of the appearance of a positive
bedside assay result may provide clinicians with a tool for a semiquantitative
estimate of a serum cardiac biomarker level at the patient’s
bedside (238). A positive bedside
test should be confirmed by a conventional quantitative test. However,
reperfusion therapy should not be delayed while one awaits the results
of a quantitative assay.
6.2.6. Imaging
Class I
1. Patients with STEMI should have a portable chest X-ray, but this
should not delay implementation of reperfusion therapy (unless a
potential contraindication is suspected, such as aortic dissection).
(Level of Evidence: C)
2. Imaging studies such as a high-quality portable cest X-ray, transthoracic
and/or transesophageal echocardiography, and a contrast chest CT
scan or magnetic resonance imaging scan should be used for differentiating
STEMI from aortic dissection in patients for whom this distinction
is initially unclear. (Level of Evidence: B)
Class IIa
Portable echocardiography is reasonable to clarify the diagnosis
of STEMI and allow risk stratification of patients with chest pain
who present to the ED, especially if the diagnosis of STEMI is confounded
by LBBB or pacing or if there is suspicion of posterior STEMI with
anterior ST depressions. (See Section
7.6.7, Mechanical Causes of Heart Failure/Low-Output Syndrome.)
(Level of Evidence: B)
Class III
Single-photon emission CT (SPECT) radionuclide imaging should not
be performed to diagnose STEMI in
patients for whom the diagnosis of STEMI is evident on the ECG.
(Level of Evidence: B)
Various
forms of imaging are often used to evaluate patients with symptoms
that are suggestive of MI or acute coronary syndrome. Cardiac imaging
can be of value in further determining the cause of chest discomfort
in patients suspected of having an acute MI or unstable angina but
whose initial ECG is normal or nondiagnostic. The 2 most studied
techniques thus far have been echocardiography and radionuclide
imaging.
Bedside
echocardiography is useful for diagnosis and risk stratification
of chest pain patients in the ED (226).
A highquality portable chest X-ray, transthoracic and/or transesophageal
echocardiography, and a contrast chest CT scan can be useful for
differentiating acute MI from aortic dissection in patients for
whom this distinction is clinically unclear. SPECT radionuclide
imaging at rest is not routinely indicated to establish the diagnosis
of MI in patients with STEMI, although it can provide valuable,
accurate diagnostic and prognostic information in patients who present
to the ED with symptoms suggestive of acute cardiac ischemia and
a normal or nondiagnostic ECG (239).
During the recuperative phase of hospitalization for STEMI, SPECT
imaging can be used to study myocardial perfusion and to look for
segmental abnormalities of LV wall motion.
6.2.7. Global Risk Assessment Tools
Global risk assessment provides an opportunity to integrate various
patient characteristics into a single score that can convey an overall
estimate of a patient’s prognosis over a given period of time.
Beyond being informative about prognosis, the general value of these
risk assessment tools is that they can influence clinical strategies.
In general, the risk of the intervention should be commensurate
with the underlying risk of the patient without the intervention
and the expected benefit of the intervention. That is, a high-risk
intervention should usually not be used for a very low-risk patient.
The expected increase in risk associated with the intervention would
very likely outweigh the expected benefit.
Several
risk assessment tools have been proposed for patients with STEMI
(240-243).
One such tool uses clinical and ECG characteristics to predict risk
of mortality for a patient if and if not treated with fibrinolytic
therapy, as well as the risk of intracranial hemorrhage and major
bleeding. This decision aid suggests that some patients with small
infarctions may not have a substantial benefit from fibrinolytic
therapy, particularly those who may have a risk factor for bleeding.
These estimates are based on trials and registries. The use of this
aid in clinical practice did not increase the use of fibrinolytic
therapy overall (244). Whether
the widespread application of these tools can improve decision making
is not clear. Nevertheless, they provide estimates of risk that
may be useful in the tailoring of therapy for individual patients.
In general, however, patients who present with STEMI require evaluation
for rapid reperfusion therapy and treatment with aspirin, beta-blockers,
and ACE inhibitors. Nevertheless, any patient with a risk from the
intervention that exceeds their STEMI risk reduction will, on average,
do better without that treatment. This group will generally include
patients with a higher risk from the intervention or a lower absolute
risk reduction (generally because of a low absolute STEMI risk).
This issue may be particularly important for younger patients, who
tend to have a lower absolute risk of mortality (245),
and for the elderly, who tend to have a higher risk from interventions,
particularly with respect to fibrinolytic therapy (246).
Precise estimates of risks and benefits are useful because the low
STEMI risk in younger patients is often accompanied by a lower risk
of interventions. In contrast, in the elderly, the higher intervention
risk is accompanied by a higher STEMI risk (and thus a larger absolute
reduction in risk with the intervention) (247).
The
use of any risk assessment tool should not contribute to any delay
in providing the time-sensitive assessment and treatment strategies
that patients with STEMI require. Further research is necessary
to determine how these tools may best contribute to optimizing patient
outcomes.
6.3. Management
6.3.1. Routine Measures
6.3.1.1. Oxygen
Class I
Supplemental oxygen should be administered to patients with arterial
oxygen desaturation (SaO2 less than 90%). (Level of Evidence:
B)
Class IIa
It is reasonable to administer supplemental oxygen to all patients
with uncomplicated STEMI during the first 6 hours. (Level of
Evidence: C)
It has become universal practice to administer oxygen, usually by
nasal prongs, to virtually all patients suspected of having acute
ischemic-type chest discomfort, although it is not known whether
this therapy limits myocardial damage or reduces morbidity or mortality.
If oxygen saturation monitoring is used, therapy with supplemental
oxygen is indicated if the saturation is less than 90%. Experimental
results indicate that breathing oxygen may limit ischemic myocardial
injury (248), and there is evidence
that oxygen administration reduces ST-segment elevation (249).
The rationale for use of oxygen is based on the observation that
even with uncomplicated MI, some patients are modestly hypoxemic
initially, presumably because of ventilation-perfusion mismatch
and excessive lung water (250).
In
patients with severe congestive heart failure, pulmonary edema,
or a mechanical complication of STEMI, significant hypoxemia may
not be corrected with supplemental oxygen alone. Continuous positive-pressure
breathing or endotracheal intubation and mechanical ventilation
may be required in such cases (251).
For
patients without complications, excess administration of oxygen
can lead to systemic vasoconstriction, and high flow rates can be
harmful to patients with chronic obstructive airway disease. In
the absence of compelling evidence for established benefit in uncomplicated
cases, and in view of its expense, there appears to be little justification
for continuing its routine use beyond 6 hours.
6.3.1.2. Nitroglycerin
Class I
1. Patients with ongoing ischemic discomfort should receive sublingual
nitroglycerin (0.4 mg) every 5 minutes for a total of 3 doses, after
which an assessment should be made about the need for intravenous
nitroglycerin. (Level of Evidence: C)
2. Intravenous nitroglycerin is indicated for relief of ongoing
ischemic discomfort, control of hypertension, or management of pulmonary
congestion. (Level of Evidence: C)
Class III
1. Nitrates should not be administered to patients with systolic
blood pressure less than 90 mm Hg or greater than or equal to 30
mm Hg below baseline, severe bradycardia (less than 50 beats per
minute [bpm]), tachycardia (more than 100 bpm), or suspected RV
infarction. (Level of Evidence: C)
2. Nitrates should not be administered to patients who have received
a phosphodiesterase inhibitor for erectile dysfunction within the
last 24 hours (48 hours for tadalafil). (Level of Evidence:
B)
The physiological effects of nitrates include reducing preload and
afterload through peripheral arterial and venous dilation, relaxation
of epicardial coronary arteries to improve coronary flow, and dilation
of collateral vessels, potentially creating a more favorable subendocardial
to epicardial flow ratio (252-254).
Vasodilation of the coronary arteries, especially at or adjacent
to sites of recent plaque disruption, may be particularly beneficial
for the patient with acute infarction. Nitrate-induced vasodilatation
may also have particular utility in those rare patients with coronary
spasm presenting as STEMI.
Clinical trial results have suggested only a modest benefit from
nitroglycerin used acutely in STEMI and continued subsequently.
A pooled analysis of more than 80 000 patients treated with nitrate-like
preparations intravenously or orally in 22 trials revealed a mortality
rate of 7.7% in the control group, which was reduced to 7.4% in
the nitrate group. These data are consistent with a possible small
treatment effect of nitrates on mortality such that 3 to 4 fewer
deaths would occur for every 1000 patients treated (152).
Nitroglycerin may be administered to relieve ischemic pain and is
clearly indicated as a vasodilator in patients with STEMI associated
with LV failure. Nitrates in all forms should be avoided in patients
with initial systolic blood pressures less than 90 mm Hg or greater
than or equal to 30 mm Hg below baseline, marked bradycardia or
tachycardia (256), or known or
suspected RV infarction. Patients with RV infarction are especially
dependent on adequate RV preload to maintain cardiac output and
may experience profound hypotension during administration of nitrates
(257). Phosphodiesterase inhibitors
potentiate the hypotensive effects of nitrates because of their
mechanism of action in releasing nitric oxide and increasing cyclic
guanosine monophosphate (258).
Therefore, it is useful clinical practice to ascertain whether such
agents have been used, and nitrates should not be administered to
patients who have received a phosphodiesterase inhibitor for erectile
dysfunction in the prior 24 hours (48 hours for tadalafil).
Nitroglycerin is commonly given sublingually at doses of 0.4 mg
when patients present with STEMI. Arterial pressure may decline
precipitously because of limited control of the initial dose and
rate of absorption. An intravenous infusion of nitroglycerin allows
clinicians to titrate the therapy in response to the patient’s
blood pressure. A useful intravenous nitroglycerin regimen employs
an initial infusion rate of 5 to 10 mcg per minute with increases
of 5 to 20 mcg per minute until symptoms are relieved or mean arterial
blood pressure is reduced by 10% of its baseline level in normotensive
patients and by up to 30% for hypertensive patients, but in no case
below a systolic pressure of 90 mm Hg or a drop greater than 30
mm Hg below baseline. In view of their marginal treatment benefits,
nitrates should not be used if hypotension limits the administration
of beta-blockers, which have more powerful salutary effects.
6.3.1.3. Analgesia
Class I
Morphine sulfate (2 to 4 mg IV with increments of 2 to 8 mg IV repeated
at 5- to 15-minute intervals) is the analgesic of choice for management
of pain associated with STEMI. (Level of Evidence: C)
Pain relief is an important element in the early management of the
patient with STEMI. There is a tendency to underdose patients with
STEMI because of the desire to assess the response to anti-ischemic
or reperfusion therapy. This should be avoided, because patients
with STEMI have a hyperadrenergic state particularly early after
the onset of coronary occlusion. Conversely, it should not be assumed
that resolution of discomfort after administration of analgesics
indicates reperfusion has occurred (see Section
6.3.1.6.3.7 for further discussion). Pain, which is commonly
severe in the acute phase of the event, contributes to increased
sympathetic activity.
Pain management should be directed toward acute relief of symptoms
of ongoing myocardial ischemia and necrosis and toward general relief
of anxiety and apprehension, the latter of which can heighten pain
perception. Surges of catecholamines have been implicated as having
a role in plaque fissuring and thrombus propagation and in reducing
the threshold for ventricular fibrillation (259).
Because the pain of STEMI is related to ongoing ischemia, interventions
that affect the oxygen supply-demand relationship (i.e., by either
increasing
supply or decreasing demand) may lessen the pain of STEMI (260).
Control of cardiac pain is typically accomplished with a combination
of nitrates, opiate analgesic agents, oxygen, and beta-adrenergic
blockers. Treatment with these agents extends from the ED to the
critical care unit. An important consideration when using intravenous
nitrates is not to lower blood pressure to a level that would preclude
adequate dosage of morphine sulfate for pain control. Morphine sulfate
remains the analgesic agent of choice for management of pain associated
with STEMI, except in documented cases of morphine sensitivity.
The dose required for adequate pain relief varies in relation to
age and body size, as well as blood pressure and heart rate. Anxiety
reduction secondary to morphine administration reduces the patient’s
restlessness and the activity of the autonomic nervous system, with
a consequent reduction of the heart’s metabolic demands. Morphine
administration for patients with pulmonary edema is clearly beneficial
and may promote peripheral arterial and venous dilation, reducing
the work of breathing and slowing the heart rate secondary to combined
withdrawal of sympathetic tone and augmentation of vagal tone (259,260).
Side effects of morphine administration such as hypotension can
be minimized by keeping the patient supine and elevating the lower
extremities if systolic pressure goes below 100 mmHg systolic, assuming
pulmonary edema is not present. The concomitant use of atropine
in 0.5- to 1.5-mg doses intravenously may be helpful in reducing
the excessive vagomimetic effects of morphine if significant bradycardia
or hypotension occurs. Although respiratory depression is relatively
uncommon, patients’ respirations should be monitored, particularly
as their cardiovascular status improves. The narcotic reversing
agent naloxone, 0.1 to 0.2 mg intravenously, can be given initially
if indicated and repeated after 15 minutes if necessary. Nausea
and vomiting as potential side effects of large doses of morphine
may be treated with a phenothiazine (260).
See “Hospital Management”
(Section 7.2.4) for additional discussion of analgesia.
6.3.1.4. Aspirin
Class I
Aspirin should be chewed by patients who have not taken aspirin
before presentation with STEMI. The initial dose should be: 162
mg (Level of Evidence: A) to 325 mg (Level of Evidence:
C). Although some trials have used enteric-coated aspirin for
initial dosing, more rapid buccal absorption occurs with non–enteric-coated
aspirin formulations.
At a dose of 162 mg or more, aspirin produces a rapid clinical
antithrombotic effect caused by immediate and near-total inhibition
of thromboxane A2 production. The Second International Study of
Infarct Survival (ISIS-2) has shown conclusively the efficacy of
aspirin alone for treatment of evolving acute MI, with an absolute
risk difference in 35-day mortality of 2.4% (relative risk reduction
[RRR] 23%) (261). When aspirin
was combined with streptokinase, the absolute risk difference in
mortality was 5.2% (RRR 42%). A metaanalysis demonstrated that aspirin
reduced coronary reocclusion and recurrent ischemic events after
fibrinolytic therapy with either streptokinase or alteplase (262).
Accordingly, aspirin now forms part of the early management of all
patients with suspected STEMI and should be given promptly, certainly
within the first 24 hours, at a dose between 162 and 325 mg and
continued indefinitely at a daily dose of 75 to 162 mg (263).
Although some trials have used entericcoated aspirin for initial
dosing, more rapid buccal absorption occurs with non–enteric-coated
formulations (264).
Unlike fibrinolytic agents, there is little evidence for a time-dependent
effect of aspirin on early mortality. However, data do support the
contention that a chewable aspirin is absorbed more quickly than
one swallowed in the early hours after infarction, particularly
after opiate therapy. The use of aspirin is contraindicated in those
with a hypersensitivity to salicylate. Aspirin suppositories (300
mg) can be used safely and are the recommended route of administration
for patients with severe nausea and vomiting or known upper-gastrointestinal
disorders. In patients with true aspirin allergy (hives, nasal polyps,
bronchospasm, or anaphylaxis), clopidogrel or ticlopidine may be
substituted.
6.3.1.5. Beta-Blockers
Class I
Oral beta-blocker therapy should be administered promptly to those
patients without a contraindication, irrespective of concomitant
fibrinolytic therapy or performance of primary PCI. (Level of
Evidence: A)
Class IIa
It is reasonable to administer IV beta-blockers promptly to STEMI
patients without contra-indications, especially if a tachyarrhythmia
or hypertension is present. (Level of Evidence: B)
During the first few hours after the onset of STEMI, betablocking
agents may diminish myocardial oxygen demand by reducing heart rate,
systemic arterial pressure, and myocardial contractility. In addition,
prolongation of diastole caused by a reduction in heart rate may
augment perfusion to ischemic myocardium, particularly the subendocardium.
As a result, immediate beta-blocker therapy appears to reduce 1)
the magnitude of infarction and incidence of associated complications
in subjects not receiving concomitant fibrinolytic therapy, 2) the
rate of reinfarction in patients receiving fibrinolytic therapy,
and 3) the frequency of life-threatening ventricular tachyarrhythmias.
In patients not receiving fibrinolytic therapy, intravenously administered
beta-blocking agents exert a modestly favorable influence on infarct
size (265). Large early trials
suggested a mortality benefit as well. In ISIS-1 (266),
more than 16 000 patients with suspected acute MI were enrolled
within 12 hours of onset of symptoms; immediate atenolol, 5 to 10
mg IV, followed by oral atenolol, 100 mg daily, reduced 7-day mortality
from 4.3% to 3.7% (p less than 0.02; 6 lives saved per 1000 treated).
The mortality difference between those receiving and not receiving
atenolol was evident by the end of day 1 and was sustained subsequently.
In the Metoprolol In Acute Myocardial Infarction (MIAMI) trial (267),
more than 5700 subjects with evolving MI were randomly assigned
to receive placebo or metoprolol, up to 15 mg IV in 3 divided doses
followed by 50 mg orally every 6 hours for 48 hours and then 100
mg twice per day thereafter. Fifteen-day mortality was reduced with
metoprolol from 4.9% to 4.3%. As in ISIS-1, the mortality difference
between those given placebo and those receiving metoprolol was evident
by the end of day 1, after which it was sustained.
In subjects receiving concomitant fibrinolytic therapy, intravenously
administered beta-blocking drugs diminish the incidence of subsequent
nonfatal reinfarction and recurrent ischemia. In addition, they
may reduce mortality if given particularly early (i.e., within 2
hours) after onset of symptoms. In the Thrombolysis In Myocardial
Infarction Phase II (TIMI-II) trial (268),
in which all patients received IV alteplase, those randomly assigned
to receive metoprolol, 15 mg IV, followed by oral metoprolol, 50
mg twice per day for 1 day and then 100 mg twice per day thereafter,
had a diminished incidence of subsequent nonfatal reinfarction and
recurrent ischemia compared with those begun on oral metoprolol
6 days after the acute event. Among those treated especially early
(i.e., within 2 hours of symptom onset), the composite end point,
death or reinfarction, occurred less often in those given immediate
IV metoprolol than in those who did not receive it.
The benefits of routine early IV use of beta-blockers in the fibrinolytic
era have been challenged by 2 later randomized trials of IV beta-blockade
(269,270)
and by a post hoc analysis of the use of atenolol in the GUSTO-I
trial (271). A subsequent systematic
review of early beta-blocker therapy in STEMI found no significant
reduction in mortality (67). Therefore,
data on the early use of intravenous beta-blockade in STEMI are
inconclusive, and patterns of use vary.
Beta-blockers should not be administered to patients with STEMI
precipitated by cocaine use because of the risk of exacerbating
coronary spasm (272). If IV beta-blockade
induces an untoward effect, such as atrioventricular (AV) block,
excessive bradycardia, or hypotension, the condition is quickly
reversed by infusion of a beta-adrenergic agonist (i.e., isoproterenol
1 to 5 mcg/min). The presence of moderate LV failure early in the
course of STEMI should preclude the use of early IV beta-blockade
until the heart failure has been compensated but is a strong indication
for the oral use of beta-blockade before discharge from the hospital.
The following are relative contraindications to beta-blocker therapy:
heart rate less than 60 bpm, systolic arterial pressure less than
100 mm Hg, moderate or severe LV failure, signs of peripheral hypoperfusion,
shock, PR interval greater than 0.24 second, second- or third-degree
AV block, active asthma, or reactive airway disease.
Randomized trials of beta-blocker therapy in patients with STEMI
undergoing PCI without fibrinolytic therapy have not been performed.
However, it seems reasonable pending further information to extrapolate
data from those receiving another form of revascularization, fibrinolytic
therapy, to the PCI population. The more contemporary CAPRICORN
(Carvedilol Post-infarct Survival Controlled Evaluation) trial (273),
which includes patients undergoing either form of revascularization,
confirms the benefits of beta-blocker therapy in patients with transient
or sustained postinfarction LV dysfunction.
6.3.1.6. Reperfusion
6.3.1.6.1. General Concepts
Class I
All STEMI patients should undergo rapid evaluation for reperfusion
therapy and have a reperfusion strategy implemented promptly after
contact with the medical system. (Level of Evidence: A)
Although rapid spontaneous reperfusion of the infarct artery may
occur, in the majority of patients there is persistent occlusion
of the infarct artery in the first 6 to 12 hours while the affected
myocardial zone is undergoing necrosis. Prompt and complete restoration
of flow in the infarct artery can be achieved by pharmacological
means (fibrinolysis), PCI (balloon angioplasty with or without deployment
of an intracoronary stent under the support of pharmacological measures
to prevent thrombosis), or surgical measures (Figure
3) (24-40).
Despite the extensive improvement in intraoperative preservation
with cardioplegia and hypothermia and in numerous surgical techniques,
it is not logistically possible to provide surgical reperfusion
in a timely fashion, and therefore patients with STEMI who are candidates
for reperfusion routinely receive either fibrinolysis or a catheter-based
treatment.
Evidence exists that expeditious restoration of flow in the obstructed
infarct artery after the onset of symptoms in patients with STEMI
is a key determinant of short- and longterm outcomes regardless
of whether reperfusion is accomplished by fibrinolysis or PCI (24,274,275).
As discussed previously (Section
4.1), efforts should be made to shorten the time from recognition
of symptoms by the patient to contact with the medical system. All
healthcare providers caring for patients with STEMI from the point
of entry into the medical system must recognize the need for rapid
triage and implementation of care in a fashion analogous to the
handling of trauma patients. When considering recommendations for
timely reperfusion of patients with STEMI, the Writing Committee
reviewed data from clinical trials, focusing particular attention
on enrollment criteria for selection of patients for randomization,
actual times reported in the trial report rather than simply the
allowable window specified in the trial protocol, treatment effect
of the reperfusion strategy on individual components of a composite
primary end point (e.g., mortality, recurrent nonfatal infarction),
ancillary therapies (e.g., antithrombin and antiplatelet agents),
and the interface between fibrinolysis and referral for angiography
and revascularization. When available, data from registries were
also reviewed to assess the generalizability of observations from
clinical trials of reperfusion to routine practice. Despite the
wealth of reports on reperfusion for STEMI, it is not possible to
produce a simple algorithm given the heterogeneity of patient profiles
and availability of resources in various clinical settings at various
times of day. This section introduces the recommendations for an
aggressive attempt to minimize the time from entry into the medical
system to implementation of a reperfusion strategy using the concept
of medical system goals. More detailed discussion of these goals
and the issues to be considered in selecting the type of reperfusion
therapy may be found in Section 6.3.1.6.2,
followed by a discussion of available resources in Section
6.3.1.6.2.1.
The medical system goal is to facilitate rapid recognition and treatment
of patients with STEMI such that door-to-needle (or medical contact–to-needle)
time for initiation of fibrinolytic therapy can be achieved within
30 minutes or that door-to-balloon (or medical contact–to-balloon)
time for PCI can be kept under 90 minutes. These goals may not be
relevant for patients with an appropriate reason for delay, such
as uncertainty about the diagnosis (particularly for the use of
fibrinolytic therapy), need for evaluation and treatment of other
life-threatening conditions (e.g., respiratory failure), or delays
associated with the patient’s informed choice to have more
time to consider the decision. In the absence of such types of circumstances,
the emphasis is on having a system in place such that when a patient
with STEMI presents for medical care, reperfusion therapy can be
provided as soon as possible within these time periods. Because
there is not considered to be a threshold effect for the benefit
of shorter timesto reperfusion, these goals should not be understood
as “ideal” times but rather the longest times that should
be considered acceptable. Systems that are able to achieve even
more rapid times for patients should be encouraged. Also, this goal
should not be perceived as an average performance standard but as
a goal that an early treatment system in every hospital should seek
for every appropriate patient.
A critically important goal of reperfusion is to restore flow in
the infarct artery as quickly and as completely as possible, but
the ultimate goal of reperfusion in STEMI is to improve myocardial
perfusion in the infarct zone. Despite adequate restoration of flow
in the epicardial infarct artery, perfusion of the infarct zone
may still be compromised by a combination of microvascular damage
and reperfusion injury (276-278).
Microvascular damage occurs as a consequence of downstream embolization
of platelet microemboli and thrombi followed by the release of substances
from activated platelets that promote occlusion or spasm in the
microvasculature. Reperfusion injury results in cellular edema,
free radical formation, calcium overload, and acceleration of the
apoptotic process. Cytokine activation in the infarct zone leads
to neutrophil accumulation and inflammatory mediators that contribute
to tissue injury.
Thus, construction of an ideal reperfusion regimen in patients with
STEMI not only should focus on the primary means of restoring flow
in the epicardial infarct artery (pharmacological or catheter-based)
but should also include adjunctive and ancillary treatments that
minimize the amount of microvascular damage and protect the jeopardized
myocardial infarct zone that contains cells in various stages of
ischemia, necrosis, and apoptosis (279,280).
The Writing Committee endorses further research to identify the
optimum strategies for achieving these goals.
6.3.1.6.2. Selection Of Reperfusion
Strategy
The literature provides very strong evidence that among patients
with suspected STEMI and without contraindications, the prompt use
of reperfusion therapy is associated with improved survival (156).
Despite such strong evidence, studies continue to indicate that
reperfusion therapy is underutilized and often not administered
soon after presentation (281-283).
Indecision about the choice of reperfusion therapy should not deter
physicians from using these strategies or delay them in administering
therapy.
There is controversy about which form of reperfusion therapy is
superior in various clinical settings. Part of the uncertainty derives
from the continual introduction of new agents, devices, and strategies,
which quickly make previous studies less relevant to contemporary
practice. With pharmacological reperfusion therapies, there are
new agents, dosing regimens, adjunctive treatments, and combined
strategies with procedures that are in a continual process of refinement
and evaluation. Similarly, with catheter-based approaches, there
are new devices, adjunctive therapies, technologies, and combined
strategies with medications that are being introduced and evaluated.
As a result, the evidence base regarding the best approach to reperfusion
therapy is quite dynamic.
Several issues should be considered in selecting the type of reperfusion
therapy, as discussed below.
Time From Onset of Symptoms. Time from onset of symptoms to
fibrinolytic therapy is an important predictor of MI size and patient
outcome (284). The efficacy of
fibrinolytic agents in lysing thrombus diminishes with the passage
of time (279). Fibrinolytic therapy
administered within the first 2 hours (especially the first hour)
can occasionally abort MI and dramatically reduces mortality (Figure
13) (156,159).
The National Heart Attack Alert Working Group (179)
recommends that EDs strive to achieve a 30-minute door-toneedle
time to minimize treatment delays. Prehospital fibrinolysis reduces
treatment delays by up to 1 hour and reduces mortality by 17% (285).
The amount of myocardium at risk, presence of collateral blood flow,
and duration of coronary occlusion are major determinants of myocardial
infarct size (286-289).
In animal models (18), occlusions
persisting greater than 30 minutes produce myonecrosis. Reperfusion
at 90 minutes salvages approximately half of the myocardium at risk.
Myocardial salvage is minimal after 4 to 6 hours of ischemia unless
ischemic preconditioning and/or collateral flow have modified the
wave front of necrosis.
A time-dependent decrease in efficacy of fibrinolytic therapy may
also contribute to the higher mortality rate in patients with longer
symptom duration (279). In contrast,
the ability to produce a patent infarct artery is much less dependent
on symptom duration in patients undergoing PCI. Several reports
claim no influence of time delay on mortality rates when PCI is
performed after 2 to 3 hours of symptom duration (290,291).
One study suggests that time to PCI is only important for patients
presenting with shock (292). Another
showed that time was associated with outcome in higher-risk but
not lower-risk patients (293).
Conversely, others have reported increasing mortality rates with
increasing door-to-balloon times (294,295).
Importantly, after adjustment for baseline characteristics, time
from symptom onset to balloon inflation is significantly correlated
with 1- year mortality in patients undergoing primary PCI for STEMI
(relative risk [RR] equals 1.08 for each 30 minute delay from symptom
onset to balloon inflation, p equals 0.04) (275,275a).
Interestingly, although the CAPTIM (173)
and PRAGUE-2 (177) studies reached
different conclusions about the overall superiority of PCI over
fibrinolysis, important observations were made in the subset of
patients presenting very early after the onset of symptoms. In the
subset of patients presenting within 3 hours of the onset of symptoms
in PRAGUE-2, mortality was equivalent in those treated with streptokinase
and those transferred with PCI (177). Patients
treated within 2 hours of symptom onset in CAPTIM had improved outcomes
with prehospital tissue plasminogen activator (tPA) versus transfer
for PCI (176). (See Section
6.3.1.6.2.1.)
It is also possible that time-to-treatment analyses have been confounded
by other variables (293, 296).
First, higherrisk patients report later to the hospital and may
respond better to PCI than to fibrinolytic agents. Second, shorter
doorto- balloon times may be a surrogate for better quality of care
and adherence to treatment guidelines. The Task Force on the Management
of Acute Myocardial Infarction of the European Society of Cardiology
(297) and this Committee both recommend
a target medical contact– or door-to-balloon time of less
than 90 minutes.
Risk of STEMI. Several models have been developed that
assist clinicians in estimating the risk of mortality in patients
with STEMI (240-242,298,299).
Although these models vary somewhat in the factors loaded into the
risk prediction tool and also vary with respect to statistical measures
of their discriminative power (e.g., C statistic), all the models
provide clinicians with a means to assess the continuum of risk
from STEMI. None of the models have been tested prospectively by
randomizing patients to a reperfusion strategy based on estimated
mortality at presentation. Retrospective analyses do suggest that
the absolute difference in mortality at 30 days between PCI and
fibrinolysis increases in favor of PCI as the estimated risk of
mortality with fibrinolysis increases (300).
Conversely, as the estimated mortality benefit with fibrinolysis
decreases, the absolute mortality benefit of PCI decreases, with
equipoise appearing (i.e., similar 30-day mortality rates) when
the estimated mortality with fibrinolysis is approximately 2% to
3% (300).
When the estimated mortality with fibrinolysis is extremely high,
as is the case in patients with cardiogenic shock, compelling evidence
exists that favors a PCI strategy. The SHOCK trial (SHould we emergently
revascularize Occluded Coronaries for cardiogenic shocK?) demonstrated
that patients with cardiogenic shock have a better 1-year survival
if they have undergone early coronary revascularization (184).
At 1 year, patients in the early revascularization group had a mortality
rate of 53% compared with 66% for the group that had initial medical
stabilization followed by no or late revascularization (184,301).
Observational data from NRMI suggest superiority of PCI over fibrinolysis
for patients with Killip class greater than or equal to II (302).
Risk
of Bleeding. Choice of reperfusion therapy is also affected
by the patient’s risk of bleeding. When both types of reperfusion
are available, the higher the patient’s risk of bleeding with
fibrinolytic therapy, the more strongly the decision should favor
PCI. If PCI is unavailable, then the
benefit of pharmacological reperfusion therapy should be balanced
against the risk. A decision analysis suggested that fibrinolytic
therapy should be favored against no reperfusion treatment until
the risk of a life-threatening bleed exceeds 4% in older patients
who have a risk profile similar to those in the classic randomized
trials of fibrinolytic therapy (247).
Risk
scores for bleeding after fibrinolytic therapy allow for the calculation
of this risk (246). Because they are
derived from less restricted populations, the scores that are most
generalizable are those derived from observational studies (246).
Time Required for Transport to Skilled PCI Laboratory.
The availability of interventional cardiology facilities is a key
determinant of whether PCI can be provided. For facilities that
can offer PCI, the literature suggests that this approach is superior
to pharmacological reperfusion (303).
The trials comparing pharmacological and PCI strategies, however,
were conducted before the advent of more recent pharmacological
and PCI strategies. When a composite end point of death, nonfatal
recurrent MI, or stroke is analyzed, much of the superiority of
a PCI strategy is driven by a reduction in the rate of nonfatal
recurrent MI (Figure 14) (40).
The rate of nonfatal recurrent MI can be influenced both by the
adjunctive therapy used (Figure 3)
(24-40)
and by the proportion of patients who are referred for PCI when
the initial attempt at fibrinolysis fails or myocardial ischemia
recurs after initially successful pharmacological reperfusion (Figure
14) (155).
The experience and location of the PCI laboratory also plays a role
in the choice of therapy. The trials were performed in centers with
highly experienced teams, and their results may not be generalizable
to all PCI laboratories throughout the country. Not all laboratories
can provide prompt, high-quality primary PCI. Even centers with
interventional cardiology facilities may not be able to provide
the staffing required for 24-hour coverage of the catheterization
laboratory. Despite staffing availability, the volume of cases in
the laboratory may be insufficient for the team to acquire and maintain
skills required for rapid PCI reperfusion strategies. A study from
NRMI investigated the effect of volume on the outcomes of patients
treated with PCI versus pharmacological reperfusion strategies (303).
They studied 446 acute-care hospitals, with 112 classified as low-volume
(fewer than or equal to 16 procedures), 223 as intermediatevolume
(17 to 48 procedures), and 111 as high-volume (49 or more procedures)
based on their annual primary angioplasty volume. They reported
that patients hospitalized at intermediate- and high-volume centers
had lower mortality with PCI reperfusion, whereas in the low-volume
centers, there was no significant difference between the 2 reperfusion
strategies. In another article from the NRMI investigators, the
volume of primary PCI procedures, but not pharmacological treatment,
was inversely associated with the mortality rate for patients with
STEMI (304).
A decision must be made when a STEMI patient presents to a center
without interventional cardiology facilities. Fibrinolytic therapy
can generally be provided sooner than primary PCI (Figure
7) (180). As the time delay
for performing PCI increases, the mortality benefit associated with
expeditiously performed primary PCI over fibrinolysis decreases
(305). Compared with a fibrin-specific
lytic agent, a PCI strategy may not reduce mortality when a delay
greater than 60 minutes is anticipated versus immediate administration
of a lytic (Figure 15) (305).
The
balance of risk/benefit between the transfer of patients for PCI
and more immediate treatment with fibrinolytic therapy remains uncertain.
The DANAMI-2 trial (DANish trial in Acute Myocardial Infarction),
conducted in Denmark, found that patients treated at facilities
without interventional cardiology capabilities had better composite
outcomes with transfer for PCI within 2 hours of presentation than
with pharmacological reperfusion treatment at the local hospital
(306). Whether these results could
be replicated elsewhere is not known. An alternative to transfer
is for hospitals without on-site cardiac surgery to develop the
capability to provide primary mechanical reperfusion therapy. A
study by Aversano and colleagues with 11 hospitals in Massachusetts
and Maryland suggested that this approach may improve outcomes (307).
It can be expected, however, that only a limited number of hospitals
could develop such a program, and it has yet to be determined whether
a certain volume of cases would be necessary to maintain the effectiveness
of the service. The economic implications of expansion of the number
of PCI-capable centers that are able to maintain an inventory of
the necessary catheters and other devices and provide 24-hour coverage,
7 days per week, deserve further evaluation from the perspectives
of individual institutions and the global healthcare delivery system.
See additional discussion in Section 6.3.1.6.2.1.
Given the current literature, it is not possible to say definitively
that a particular reperfusion approach is superior for all patients,
in all clinical settings, at all times of day (173,176,177)
(Danchin N; oral presentation, American Heart Association 2003 Annual
Scientific Sessions, Orlando, FL, November 2003). The main point
is that some type of reperfusion therapy should be selected for
all appropriate patients with suspected STEMI. The appropriate and
timely use of some reperfusion therapy is likely more important
than the choice of therapy, given the current literature and the
expanding array of options. Clinical circumstances in which fibrinolytic
therapy is generally preferred or an invasive strategy is generally
preferred are shown in Table 11.
6.3.1.6.2.1. Available Resources
Class I
STEMI patients presenting to a facility without the capability for
expert, prompt intervention with primary PCI within 90 minutes of
first medical contact should undergo fibrinolysis unless contraindicated.
(Level of Evidence: A)
The preferred reperfusion therapy for STEMI must take into account
the location of the patient, the response time and expertise of
the paramedical/ambulance personnel, their relationship to the regional
healthcare facility(s), and the availability, capability, and expertise
of the medical personnel at the facility. The most recent NRMI data
continue to support advantages of primary PCI versus fibrinolysis
in high-PCI–volume hospitals but not among those institutions
with low volume (fewer than or equal to 16 procedures per year)
(303). Approximately 20% of US
hospitals have cardiac catheterization laboratories; and less than
that number have the capacity for primary PCI. The C-PORT study
(Atlantic Cardiovascular Patient Outcomes Research Team), which
randomized 451 fibrinolysis-eligible patients with STEMI treated
in 11 community hospitals with diagnostic catheterization but not
onsite PCI facilities, is of interest. Patients were randomized
within 12 hours of symptom onset to an accelerated alteplase regimen
(median door-to-lytic time was 46 minutes) versus primary PCI (median
door-to-balloon time 101.5 minutes). At 6 months, the incidence
of death, re-MI, and stroke was 12.4% for PCI and 19.9% for fibrinolytic
therapy (p equals 0.03). Because only 18% of the intended sample
size was actually enrolled, this study is significantly underpowered,
and its conclusion can only be hypothesis-generating rather than
definitive (307). Importantly,
most C-PORT patients were randomized between 0800 and 1600 hours,
an experience consistent with NRMI data. The NRMI report also demonstrated
a substantially longer door-to-balloon time when patients with STEMI
undergo direct PCI outside of daylight hours (308).
The Zwolle group evaluated 1702 consecutive patients and found that
the 47% of patients who presented outside “routine duty hours”
(i.e., 1800 to 0800 hours) had a higher rate of both PCI failure
and 30-day mortality than those within the 0800 to 1800 period (6.9%
and 4.2% versus 3.8% and 1.9%, respectively; p less than 0.01) (309).
The reasons for these differences are unclear but could relate to
both patient and process-of-care factors, including variations in
both cognitive function and manual dexterity in sleep-deprived healthcare
providers (308,310).
Two studies germane to STEMI care and resource utilization are noteworthy.
The first, CAPTIM, a comparison of angioplasty and prehospital fibrinolysis
(accelerated alteplase) in STEMI, fell short of its planned 1200-patient
enrollment, and hence was underpowered (173).
Eight hundred forty patients were randomized to prehospital fibrinolysis
versus primary PCI. The primary end point was the composite of all-cause
mortality, nonfatal recurrent MI, and nonfatal disabling stroke
at 30 days, which occurred in 8.2% of patients assigned fibrinolytic
therapy and 6.2% of patients assigned to PCI (p not significant
[NS]). The components for death, reinfarction, and disabling stroke
were 3.8%, 3.7%, and 1.0% for fibrinolytic therapy and 4.8%, 1.7%,
and 0% for PCI. Unlike C-PORT, this trial liberally used rescue
angioplasty (28%), which probably accounts for the relatively low
reinfarction rate in the lytic-treated group. A subsequent analysis
from CAPTIM of the 55% of patients treated within 2 hours of symptom
onset revealed a mortality trend in favor of prehospital fibrinolysis
versus primary PCI (2.2% versus 5.7%, p equals 0.058), whereas those
patients treated beyond 2 hours had a 5.9% versus 3.7% (p equals
0.47) 30-day mortality rate, respectively (176).
Interestingly, there was a significant reduction in the frequency
of cardiogenic shock for patients treated within 2 hours with prehospital
fibrinolysis (1.3% versus 5.3%, p equals 0.032), whereas the frequency
of this event after 2 hours was similar (i.e., 3.9% versus 4.4%,
respectively) (176).
The
DANAMI-2 study, which compared primary PCI versus accelerated alteplase,
enrolled 1572 patients versus the 2000 patients planned (306).
Patients were eligible if they had a sum of greater than 0.4 mV
of ST elevation in 2 contiguous leads on their presenting ECG within
12 hours of symptom onset; however, patient enrollment consisted
of 37% of those screened, and patients deemed to be at high risk
during ambulance transport were excluded (306).
Twentynine hospitals, of which 5 conducted primary PCI and were
located a mean of 35 miles from referring hospitals (maximum 95
miles), participated. The median door-to-needle time for patients
randomized to fibrinolysis was approximately 50 minutes for patients
presenting either to a community (referral) hospital or an invasive
center. For patients who presented to a community hospital (where
1129 patients were enrolled), the time from initial presentation
to balloon inflation at an invasive center was 108 minutes; the
door-toballoon time was 93 minutes for patients presenting to an
invasive center and randomized to PCI. The primary composite end
point of death, reinfarction, and stroke through 30 days occurred
in 14.2% of the fibrinolysis-treated patients and 8.5% of the PCI-treated
patients (p less than 0.001). The individual end-point components
of death, reinfarction, and stroke occurred in 7.8%, 6.3%, and 2.0%
of the fibrinolysistreated patients and 6.6%, 1.6%, and 1.1% of
the PCI-treated patients, respectively. In addition to the exclusion
of highrisk patients for transport, some caveats in DANAMI-2 are
noteworthy: 1) The antithrombotic dosing regimen was in excess of
ACC/AHA guidelines. 2) The protocol specified that repeat fibrinolysis
was to be used for failed reperfusion, reinfarction, and recurrent
ST-elevation ischemia; this strategy was used in 26 patients within
12 hours after randomization, and only 1.9% underwent rescue PCI.
3) Patients with prior stroke were included, and an imbalance in
this baseline characteristic was present, (i.e., 4.0% for fibrinolysis
versus 2.7% for PCI ([1-sided p equals 0.06]). 4) The difference
in reinfarction rates between the 2 groups was likely exaggerated
by the exclusion of those patients associated with invasive procedures
(311).
Hence, on the basis of the data, patients with STEMI presenting
to a facility without the capability for expert, prompt intervention
with primary PCI within 90 minutes of first medical contact should
undergo fibrinolysis unless contraindicated. (See Sections
6.3.1.6.4.2, Primary PCI, and 6.3.1.6.4.2.4,
Interhospital Transfer for Primary PCI.)
6.3.1.6.3. Pharmacological Reprefusion.
Rationale For Fibrinolytic Therapy. Although the clinical
features of coronary obstruction were described nearly a century
ago (312,313),
thrombotic obstruction of the infarct artery as a cause of STEMI
was not proven until 1980 (20).
The benefits of fibrinolytic therapy are maximal when there is prompt,
adequate restoration of flow in the epicardial infarct artery and
perfusion of the myocardium in the infarct zone. Controlled clinical
trials have demonstrated the potential forfunctional, clinical,
and mortality benefits only if fibrinolytic therapy is given within
12 hours. (See additional discussion on the use of antithrombins
and antiplatelet agents as ancillary therapy in Sections
6.3.1.6.8.1 and 6.3.1.6.8.2.)
The
reduction in mortality with fibrinolytic therapy is present regardless
of sex, presence of diabetes, blood pressure (if less than 180 mm
Hg systolic) (246,314), heart rate,
or history of previous MI (156).
The mortality benefit is greater in the setting of anterior STEMI,
diabetes, low blood pressure, (less than 100 mm Hg systolic) or
high heart rate (greater than 100 bpm) (Figure
13) (156). The earlier therapy
begins, the better the outcome, with the greatest benefit decidedly
occurring when therapy is given within the first 3 hours. Benefit
occurs, however, up to at least 12 hours from the onset of symptoms.
The absolute benefit is less with inferior STEMI, except for the
subgroup with associated RV infarction or anterior ST-segment depression
indicative of a greater territory at risk (Figure
16) (156).
6.3.1.6.3.1.
Indications for Fibrinolytic Therapy
Class I
1. In the absence of contraindications, fibrinolytic therapy should
be administered to STEMI patients with symptom onset within the
prior 12 hours and ST elevation greater than 0.1 mV in at least
2 contiguous precordial leads or at least 2 adjacent limb leads.
(Level of Evidence: A)
2.
In the absence of contraindications, fibrinolytic therapy should
be administered to STEMI patients with symptom onset within the
prior 12 hours and new or presumably new LBBB. (Level of Evidence:
A)
Class IIa
1. In the absence of contraindications, it is reasonable to administer
fibrinolytic therapy to STEMI patients with symptom onset within
the prior 12 hours and 12-lead ECG findings consistent with a true
posterior MI. (Level of Evidence: C)
2. In the absence of contraindications, it is reasonable to administer
fibrinolytic therapy to patients with symptoms of STEMI beginning
within the prior 12 to 24 hours who have continuing ischemic symptoms
and ST elevation greater than 0.1 mV in at least 2 contiguous
precordial leads or at least 2 adjacent limb leads. (Level of
Evidence: B)
Class III
1. Fibrinolytic therapy should not be administered to asymptomatic
patients whose initial symptoms of STEMI began more than 24 hours
earlier. (Level of Evidence: C)
2. Fibrinolytic therapy should not be administered to patients whose
12-lead ECG shows only ST-segment depression except if a true posterior
MI is suspected. (Level of Evidence: A)
Because
the benefit of fibrinolytic therapy is directly related to the time
from symptom onset, treatment benefit is maximized by the earliest
possible application of therapy. The constellation of clinical features
that must be present (although not necessarily at the same time)
to serve as an indication for fibrinolysis includes symptoms of
myocardial ischemia and ST elevation greater than 0.1 mV, in 2 contiguous
leads, or new or presumably new LBBB on the presenting ECG (156,315).
In the very early phase of STEMI, giant hyperacute T waves may precede
ST elevation (316). True posterior
MI may be manifested by tall R waves in the right precordial leads
and ST-segment depression in leads V1 through V4, especially when
T waves are upright (317). Repeat
ECGs and incorporation of additional leads such as V7 through V9
are more specific for the detection of posterior infarction (225).
Patients with LBBB or anterior ST elevation are at greater inherent
risk from MI and achieve greater benefit with fibrinolytic therapy.
Additional valuable information may be garnered from concurrent
echocardiography to identify the location and extent of regional
wallmotion abnormalities. Patients with inferior MI and ST elevation
in V1, V4R, or both are more likely to have concomitant
RV infarction (318). Attainment
of additional ECG leads (right sided and/or posterior) or an echocardiogram
may help clarify the location and extent of infarction and anticipated
risk of complications, but it is important that acquisition of such
ancillary information not interfere with the strategy of providing
timely reperfusion in patients with STEMI (319).
6.3.1.6.3.2. Contraindications/Cautions
Class I
1. Healthcare providers should ascertain whether the patient has
neurological contraindications to fibrinolytic therapy, including:
any history of intracranial hemorrhage or significant closed head
or facial trauma within the past 3 months, uncontrolled hypertension,
or ischemic stroke within the past 3 months. (See Table
12 for a comprehensive list.) (Level of Evidence: A)
2. STEMI patients at substantial (greater than or equal to 4%) risk
of ICH should be treated with PCI rather than with fibrinolytic
therapy. (See Table 11 for further
management considerations.) (Level of Evidence: A)
A detailed list of contraindications and cautions for the use of
fibrinolytic therapy is shown in Table
12. Specific neurological considerations are addressed below.
Hemorrhage represents the most important risk of fibrinolytic therapy,
especially ICH, which may be fatal in half to two thirds of patients.
There is both legitimate concern and confusion surrounding the issue
of whether fibrinolytic therapy should be contraindicated in patients
with a history of prior cerebrovascular disease (2,320-322).
The 1996 ACC/AHA Guidelines for the Management of Acute Myocardial
Infarction (2) stated that “Previous
hemorrhagic stroke at any time; other strokes or cerebrovascular
events within 1 year” was a contraindication to use of thrombolytic
therapy and that “...history of prior cerebrovascular accident
or known intracerebral pathology not covered in contraindications”
was a caution/relative contraindication. After the first 627 patients
were enrolled in TIMI-II (320),
a number of protocol changes were made: the dose of tPA was reduced
from 150 to 100 mg, use of 80 mg of aspirin was postponed for 24
hours, patients who had a history of stroke or intermittent cerebral
ischemic attacks were excluded, and patients with blood pressures
greater than or equal to 180 mm Hg systolic or greater than or equal
to 110 mm Hg diastolic were excluded. The reduction of ICH frequency
by the exclusion of patients with any history of cerebrovascular
disease was likely confounded by the influence of the other 3 protocol
changes. The basis for the 1996 recommendation for a time frame
of 1 year for ischemic stroke as a contraindication to coronary
fibrinolysis was a consensus opinion without specific supporting
data.
In subsequent trials (26-31,33,323,324),
the use of prior TIA or stroke as an exclusion criterion has varied:
stroke within 2 years (30), stroke
within 6 months (323), TIA within
6 months/any history of stroke (33),
any stroke (26,27,324),
and any history of prior TIA or stroke (28,29,31)
have each been used as exclusion criteria. In some studies, the
frequency of ICH in patients older than 75 years ranged from 0.5%
with streptokinase and heparin (33)
to 2.5% with reteplase (26). Giugliano
et al. (325) showed that the higher
ICH frequencies with lanoteplase or tenecteplase may be explained
in part by the effect of the UFH (InTIME-2 [Intravenous NPA for
the Treatment of Infarcting Myocardium Early] equals 1.12%, InTIME-IIb
equals 0.50%) and dose of the UFH infusion (ASSENT-1 and TIMI-10B:
higher heparin dose equals 1.83%, lower heparin dose equals 0.74%).
(See discussion on the use of LMWH in the elderly in Section
6.3.1.6.8.1.2.) In the Maximal Individual Therapy in Acute Myocardial
Infarction (MITRA) registry (326),
previous stroke within 3 months was the strongest predictor of stroke
(OR equals 9.3, 95% CI 6.0 to 14.2) after STEMI. On the basis of
these data, it appears that the effect of prior stroke/TIA per se
on the frequency of ICH after fibrinolysis may be influenced by
number of factors. However, in patients with STEMI with prior ischemic
stroke and other ICH risk factors who have substantial risk for
ICH, another reperfusion strategy should be pursued. Additional
contraindications to fibrinolytic therapy include a recent history
of significant closed head or facial trauma (327).
Estimation
of risk of ICH. Several models have been developed for estimating
the risk of ICH after fibrinolysis (246,328-330).
These models incorporate baseline demographic features of the patient
and also illustrate the impact of certain therapeutic decisions
(e.g., selection of streptokinase versus tPA; dose of tPA used)
(Table 13) (29,246,329,330).
Streptokinase without heparin is the regimen associated with the
lowest ICH rates (Figure 17) (29,246,329,330).
6.3.1.6.3.3. Effect on Mortality
Efficacy of intravenous fibrinolytic therapy in STEMI. It has now
been well established that fibrinolytic therapy provides a survival
benefit for patients with STEMI, based on large, well-controlled
clinical trials (157,261,331,332).
The mechanisms of benefit, which may have different time dependencies,
include salvage of myocardium with reduced infarct size, favorable
effect on infarct healing and myocardial remodeling, and reduced
electrical heterogeneity and potential for life-threatening ventricular
arrhythmia (333). An overview from
9 trials of fibrinolytic therapy (versus control) for STEMI has
shown a highly significant 18% relative reduction in 35-day mortality
(9.6% fibrinolysis versus 11.5% control), which corresponds to a
reduction of 18 deaths per 1000 patients treated when data from
all patient groups are pooled (156).
In patients with ST elevation, a relative mortality reduction of
21% occurred. This survival benefit is maintained over the long
term (up to 10 years) (334,335).
Mortality reduction from fibrinolytic therapy is greatest within
the first hour after symptom onset; thereafter, a decline in benefit
of approximately 1.6 lives per 1000 patients treated is seen per
1-hour delay. Additionally, patients with presumed new LBBB, anterior
infarction, and the greatest area of risk, as exemplified by the
number of ECG leads affected and the extent of ST deviation, derived
maximal benefit from fibrinolytic therapy (Figure
16) (156,336).
Elderly patients. Although the elderly constitute a minority
of the general population, they are the fastest-growing segment
of the population and account for the majority of patients presenting
with MI and a disproportionately high component of death from MI
(46,213,338).
In persons older than 75 years, the overall risk of mortality from
MI is high with and without therapy. Although the proportionate
reduction in mortality for patients older than 75 years treated
within 12 hours with ST elevation or LBBB is somewhat less for patients
less than or equal to 75 years, the absolute number of lives saved
per 1000 patients treated is actually greater (i.e., 34 lives saved
per 1000 patients treated versus 28 for those less than 75 years)
(339).
Registry observations from the Cooperative Cardiovascular Project
(CCP) database by Thiemann and colleagues of 2673 patients between
the age of 75 and 86 years suggested that the 1607 patients receiving
fibrinolytics had a lower 30-day survival than those not treated
with this therapy (340). Some caution
in the interpretation of these observational data is appropriate
because 1) a reversal of this effect toward benefit was seen in
women between the ages of 65 and 75 years derived from a larger
sample, and 2) a substantial proportion of the patients possessed
conventional clinical trial fibrinolytic exclusion criteria (i.e.,
11.8% had systolic blood pressure greater than 180 mm Hg, 18% had
a history of recent trauma or a remote history of peptic ulcer or
internal bleeding, and 6.9% had a history of stroke). Twice as many
patients receiving fibrinolysis (i.e., 2.2% versus 0.9%) had CPR
before arrival as opposed to those without fibrinolysis (340).
In contrast to the CCP study by Thiemann et al., another CCP analysis
in the elderly by Berger et al. indicated that both fibrinolytic
therapy and primary angioplasty were associated with a survival
benefit at 1 year compared with patients receiving neither (341).
Data from the Swedish National Register on the use of fibrinolysis
in 6891 patients 75 years and older with first registry-recorded
STEMI also confirm a 13% adjusted relative risk reduction (95% CI
0.80 to 0.94; p equals 0.001; absolute risk reduction 4%) in the
composite of mortality and cerebral bleeding after 1 year (Figure
18) (342).
6.3.1.6.3.4. Effect on LV Function
Early reperfusion of ischemic myocardium within the risk region
of an occluded infarct-related artery interrupts the wave front
of necrosis (18), reduces ultimate
infarct size, preserves regional and global ventricular function,
and improves survival. Clinical evidence for this paradigm was inconclusive
until the GUSTO-I angiographic trial (343-348).
Global LV ejection fraction (LVEF), a load-dependent measurement,
is an imperfect surrogate for infarct size. Compensatory remote-segment
hyperkinesis, the importantprognostic
effect of ventricular dilation, and the potential effects of a patent
infarct artery independent of myocardial salvage confound the relationship
between early reperfusion, global LV function, and survival. Poor
perfusion at the myocardial cellular level due to microvascular
obstruction further confounds the relationship between early reflow
in the epicardial coronary artery, wall-motion improvement, and
survival. In patients with TIMI 3 flow, those with abnormal myocardial
tissue perfusion have worse LV function and survival than those
with normal perfusion. Myocardial blush on angiography, contrast
perfusion on echocardiography, and prompt complete resolution of
ST elevation are measures of tissue perfusion. Poor perfusion at
the myocardial cellular level is associated with increased morbidity
and mortality. However, the mechanism by which poor tissue perfusion
confers an adverse prognosis is not clear. Evidence of poor tissue
perfusion may be the result of extensive transmural infarction with
tissue edema and increased microvascular resistance (349).
Alternatively, poor microvascular flow may result from distal embolization
of atherothrombotic debris and hence be a target for therapeutic
interventions. Flow in the infarct artery before PCI is associated
with smaller infarct size and better outcome. Infarct size can be
measured with SPECT sestamibi imaging (350),
and this has been done in more than a dozen randomized trials.
6.3.1.6.3.5. Complications of
Fibrinolytic Therapy: Neurological and Other
Class I
1. The occurrence of a change in neurological status during
or after reperfusion therapy, particularly within the first 24 hours
after initiation of treatment, is considered to be due to ICH until
proven otherwise. Fibrinolytic, antiplatelet, and anticoagulant
therapies should be discontinued until brain imaging scan shows
no evidence of ICH. (Level of Evidence: A)
2. Neurology and/or neurosurgery or hematology consultations should
be obtained for STEMI patients who have ICH, as dictated by clinical
circumstances. (Level of Evidence: C)
3. In patients with ICH, infusions of cryoprecipitate, fresh frozen
plasma, protamine, and platelets should be given, as dictated by
clinical circumstances. (Level of Evidence: C)
Class IIa
In patients with ICH it is reasonable to:
a. Optimize blood pressure and blood glucose levels (Level of
Evidence: C)
b. Reduce intracranial pressure with an infusion of mannitol, endotracheal
intubation, and hyperventilation (Level of Evidence: C)
c. Consider neurosurgical evacuation of ICH (Level of Evidence:
C)
Hemorrhagic
complications of fibrinolytic therapy primarily include ICH and
other moderate or severe bleeding that may or may not require transfusion.
The slight but definite excess risk of ICH occurs predominantly
within the first day of therapy (156).
Summaries of the incidence of ICH with various pharmacological reperfusion
regimens are shown in Table 14
(26-31,
33, 158,
261, 320,
322, 324,
331, 351-369).
ICH may refer to parenchymal hemorrhage (PH), intraventricular hemorrhage,
subarachnoid hemorrhage, subdural hematoma, and epidural hematoma.
Between 65% and 77% of ICHs occur within 24 hours of initiation
of treatment, up to 77% occur at lobar/subcortical lobar sites,
15% to 33% are multiple PHs, and up to 15% are combined PH and subdural
hematoma. Typical presenting features include an acute change in
level of consciousness, unifocal or multifocal neurological signs,
coma, headache, nausea, vomiting, and seizures, at times with acute
hypertension. In many cases, onset is catastrophic and rapidly fatal.
Management
of suspected ICH. An algorithm for the management of ICH in
the STEMI setting is provided in Figure
19 (370,371).
Any change in neurological function, particularly in the first 24
hours after treatment, should be regarded as strongly indicative
of PH/intraventricular hemorrhage/ subarachnoid hemorrhage/subdural
hematoma/epidural hematoma until proven otherwise. Fibrinolytic,
anticoagulant, antiplatelet, and combined therapies should be discontinued
as soon as symptoms and signs are recognized. An emergency CT scan
should be performed as soon as possible to identify the specific
type of hemorrhagic complication and to measure the volume of hematoma
(372,373).
It is useful to document the severity of the coagulopathy, although
emergency patient management should not await the results of laboratory
testing. Immediate measures to reduce intracranial pressure are
reasonable and include mannitol infusion, elevation of the head
of the bed to 30 degrees, endotracheal intubation, and hyperventilation
to achieve a pCO2 of 25 to 30 mm Hg. Early involvement of neurologists,
neurosurgeons, and hematologists will optimize treatment decisions.
Once
PH, intraventricular hemorrhage, subarachnoid hemorrhage, subdural
hematoma, or epidural hematoma is documented, the patient should
be given 10 U of cryoprecipitate, which will increase the fibrinogen
level by approximately 0.70 grams per liter and the factor VIII
level by approximately 30% in a 70-kg adult. Fresh frozen plasma
can be used as a source of factors V and VIII and as a volume expander.
In patients who are receiving UFH, 1 mg of protamine for every 100
U of UFH given in the preceding 4 hours may be administered. If
the bleeding time is abnormal, infusion of 6 to 8 U of platelets
is indicated. In rare cases, antifibrinolytic agents, such as epsilon-aminocaproic
acid, may be necessary (374). These
replacement/reversal therapies may theoretically be accompanied
by reocclusion of the infarctrelated artery. Control of blood pressure
and blood glucose levels may require a compromise between competing
cardiologic and neurological concerns. The decision to use various
measures to reduce increased intracranial pressure, such as elevation
of the head of the bed to 30 degrees, mannitol, hyperventilation,
and ventriculostomy, may be based on the consensus of the management
team. The use of mannitol and hyperventilation are reserved for
incipient brain herniation syndromes. After the patient is stabilized,
catheter-based angiography may be necessary if a ruptured berry
aneurysm or arteriovenous malformation is suspected.
In GUSTO-I (375), 46 (17.2%) of
268 PH/subdural hematoma patients underwent neurosurgical evacuation
by open craniotomy or burr-hole craniectomy. Patients who underwent
neurosurgical evacuation had significantly higher 30-day survival
rates than patients who did not (65.2% versus 35.1%, p less than
0.001), particularly in patients with PH. Patients with both PH
and subdural hematoma had a very poor prognosis regardless of surgical
treatment. There was a trend for improved functional status in patients
who underwent neurosurgical evacuation compared with those who did
not (nondisabling stroke 20% versus 12%, p equals 0.15). Although
not definitive, these data suggest that physicians actively consider
neurosurgical interventions in selected patients. For patients with
spinal epidural hematoma and significant neurological deficits occurring
after fibrinolysis, early multilevel decompressive laminectomy should
be performed to minimize long-term disability (376).
Survivors of PH/subdural hematoma/epidural hematoma should receive
supportive care measures, including physical therapy, occupational
therapy, speech therapy, swallowing evaluation, aspiration precautions,
deep vein thrombosis (DVT) prophylaxis (pneumatic compression device),
antibiotic therapy, nutritional support, and rehabilitation, where
appropriate.
The risk of 30-day mortality from ICH after coronary fibrinolysis
may be predicted on the basis of prior trial experience. In GUSTO-I
(322), the ICH mortality rate was
59.7%. Glasgow Coma Scale score, age, time from fibrinolysis to
ICH onset, hydrocephalus, herniation, mass effect, intraventricular
hemorrhage, and volume and location of ICH were significant univariable
predictors, with a strong trend (p equals 0.0546) for neurosurgical
evacuation. The multivariable model showed that Glasgow Coma Scale
score, time from thrombolysis to ICH onset, ICH volume, and age
were significant predictors of mortality (377).
A nomogram has been developed to calculate the risk of dying of
ICH (Figure 20) (377).
Prospective studies are needed to confirm the utility of this nomogram.
6.3.1.6.3.6.
Comparison of Fibrinolytic Agents
All of the fibrinolytic agents currently available and under investigation
are plasminogen activators (378).
They work enzymatically, directly or indirectly, to expose the active
enzymatic center of plasmin. Some comparative features of the approved
fibrinolytic agents for intravenous therapy are presented in Table
15 (379-381).
Data from GUSTO-I (25) and GUSTO-III
(26) suggest that accelerated alteplase
and reteplase (administered as a double bolus) with intravenous
heparin are effective therapies for achieving early coronary reperfusion
and may provide an advantage over streptokinase; however, both are
substantially more expensive and confer a slightly greater risk
of ICH. Thus, the cost-benefit ratio is most favorable for alteplase
or reteplase in patients who present early after onset of chest
pain or symptoms and in those with a large area of injury (e.g.,
anterior infarction) and at low risk of ICH. In ASSENT- 2, weight-adjusted
TNK-tPA (tenecteplase) and alteplase were compared in 16 949 patients.
Covariate-adjusted 30-day mortality was virtually identical (i.e.,
6.18% for tenecteplase and 6.15% for alteplase), which met the predefined
criteria for equivalence. The rates of ICH were also similar (i.e.,
0.93% for tenecteplase and 0.94% for alteplase), but in patients
receiving tenecteplase, there were fewer systemic mild-to-moderate
bleeding complications (26.3% versus 28.95%, p equals 0.0003) and
less requirement for blood transfusion (4.25% versus 5.49%, p equals
0.0002) (28).
There is considerable ongoing investigation into the effectiveness
of fibrinolytic therapy with various ancillary therapies (see Section
6.3.1.6.3.8). In 2 studies that evaluated the combination of
hirudin (desirudin) with alteplase and streptokinase, there was
no improvement in mortality rate, and the therapeutic-to-severe
bleeding window appeared to be very narrow (382,383).
See Section 6.3.1.6.8.1.3 for further discussion.
A
number of proposals for selection of fibrinolytic regimens after
GUSTO-I have been suggested (384-387).
Additional considerations include avoiding the reuse of streptokinase,
preferably indefinitely because of a high prevalence of potentially
neutralizing antibody titers. Alternatively, Simoons and Arnold
(386) proposed considering primary
PCI for those at highest risk (approximately 10% of patients), alteplase
for those at moderate to high risk (40%), streptokinase for those
at low to moderate risk (40%), and no lytic therapy for those at
lowest risk (10%). All of these recommendations await prospective
testing, and no data are available to determine the best modes for
routine clinical practice.
Current use rates for fibrinolytic therapy. Because many patients
have contraindications or other exclusions for fibrinolytic agents,
it has been difficult to ascertain the proportion of patients with
ST elevation who fail to receive fibrinolytic therapy who actually
should have received such therapy (388).
Critical to any such assessment of appropriateness of care, however,
is whether the diagnosis of STEMI was suspected on entry into the
healthcare system or whether a diagnosis made after 12 to 24 hours
in the hospital or at some later point before hospital discharge.
Some increase in use rates probably can be achieved, but contraindications
prohibit a vast increase in the rate of use of fibrinolysis.
6.3.1.6.3.7. Net Clinical Benefit
The decision to use reperfusion therapy is based on an estimate
of the patient’s underlying risk without treatment, the expected
benefit of the treatment, and the risk of the therapy. In general,
the higher the underlying risk, the more benefit that can be gained
and the fewer the number of patients who need to be treated to save
1 life.
Because decisions about reperfusion must be made rapidly in order
for the intervention to be maximally effective, it is not possible
to take the time to confirm the diagnosis of STEMI before administration
of therapy. Data from the Multicenter Chest Pain Study suggest that
approximately 80% of patients with chest pain and ST-segment elevation
who present to the ED are having a STEMI (227).
Several prediction models for short-term (30 days) (240,242,298,389-393)
and long-term (1 to 6 years) (392,393)
mortality after reperfusion therapy for STEMI have been developed.
These models have been derived from clinical trials (240,242,389,394),
administrative data sets (298,390,392),
and registries (391), and some
have been validated in other clinical trials (242)
or registries (391, 394).
Performance for some of these risk-prediction models, as defined
by the area under the receiver operating characteristic curve, c-index,
or standardized mortality ratio, is similar, with c-indices ranging
from 0.74 to 0.80 and correlation coefficients for the standardized
mortality ratios ranging from 0.89 to 0.92 (298).
The TIMI risk score developed in the InTIME-II trial (242)
performs well compared with data from the TIMI-9 trial and NRMI-3
(394). In NRMI-3, prognostic discriminatory
capacity was similar between patients who received fibrinolytics
and primary PCI (c-index equals 0.80). Substantial differences in
predicted mortality rates (greater than 5%) between those patients
who did or did not receive reperfusion therapy were observed if
the TIMI risk score was greater than or equal to 7 (394).
The expected benefit of fibrinolytic therapy can be estimated from
the clinical trials (156,282).
The fibrinolytic trials showed “absolute mortality reductions
of about 30 per 1000 for those presenting within 0-6 h and of about
20 per 1000 for those presenting 7 to 12 h from onset, and a statistically
uncertain benefit of about 10 per 1000 for those presenting at 13
to 18 h (with more randomized evidence needed in this latter group
to assess reliably the net effects of treatment)” (156).
The relative benefit, however, appeared to vary by age, with a smaller
relative reduction in risk for the oldest patients.
The major risk of pharmacological reperfusion therapy is life-threatening
hemorrhage (105). (See Section
6.3.1.6.3.2 for further information.) A study among Medicare
patients identified older age, female sex, black race, prior stroke,
systolic blood pressure greater than or equal to 160 mm Hg, lower
weight (less than or equal to 65 kg for women, less than or equal
to 80 kg for men), excessive anticoagulation (international normalized
ratio [INR] greater than or equal to 4, prothrombin time greater
than or equal to 24 sec), and choice of fibrinolytic therapy (tPA
associated with greater risk than streptokinase) as risk factors
for intracranial bleeding (246).
Patients with none or 1 of these factors had a risk of 0.69% for
intracranial bleeding, whereas those with 5 or more factors had
a risk of 4.1%. Simoons et al., using data primarily from trials,
identified older age, lower body weight (less than 70 kg), systolic
blood pressure greater than or equal to 170 mm Hg or diastolic blood
pressure greater than or equal to 95 mm Hg, and the use of tPA (versus
streptokinase) as risk factors (329).
Using these factors, a risk score was developed that classified
patients with a risk of hemorrhage from 0.26% to 2.2% (for zero
to 4 risk factors). Although this score uses dichotomous cutpoints
for the risk factors, it is likely that the risk is a continuous
function of the factor (e.g., the higher the blood pressure or the
older the patient, the higher the risk) (322).
Also, the studies of risk were based on older regimens of fibrinolytic
therapy and higher dosages of UFH than are used currently. There
is some evidence that newer agents, with increased fibrin specificity
and bolus administration, may not increase the risk of ICH, but
this issue deserves continued evaluation (156).
In addition, the use of ancillary therapies may influence the risk
of bleeding with fibrinolytic therapy.
6.3.1.6.3.8. Combination Therapy
With GP IIb/IIIa Inhibitors
Class IIb
1. Combination pharmacological reperfusion with abciximab and half-dose
reteplase or tenecteplase may be considered for prevention of reinfarction
(Level of Evidence: A) and other complications of STEMI in selected
patients: anterior location of MI, age less than 75 years, and no
risk factors for bleeding. In two clinical trials of combination
reperfusion, the prevention of reinfarction did not translate into
a survival benefit at either 30 days or 1 year (394a)
(Level of Evidence: B).
2. Combination pharmacological reperfusion with abciximab and half-dose
reteplase or tenecteplase may be considered for prevention of reinfarction
and other complications of STEMI in selected patients: anterior
location of MI, age less than 75 years, and no risk factors for
bleeding in whom an early referral for angiography and PCI (i.e.,
facilitated PCI) is planned. (Level of Evidence: C)
Class III
Combination pharmacological reperfusion with abciximab and half-dose
reteplase or tenecteplase should not be given to patients aged greater
than 75 years because of an increased risk of ICH. (Level of
Evidence: B)
Studies evaluating the use of glycoprotein IIb/IIIa inhibitors
as the sole means of reperfusion (i.e., without a fibrinolytic or
in conjunction with PCI) do not suggest that the isolated use of
a GP IIb/IIIa inhibitor restores TIMI 3 flow in a sufficient proportion
of patients to make it a viable pharmacologic strategy (395a).
To improve rates of achieving TIMI 3 flow by pharmacological rapy
is used, the dose
of fibrinolytic agent is reduced by 50%. A large-scale mortality
study, GUSTO-V (30), tested half-dose
reteplase (5 U and 5 U) and full-dose abciximab (abciximab 0.25
mg/kg bolus and 0.125 mcg/kg/min [maximum of 10 mcg/min] for 12
hours) compared with full-dose reteplase (10 U and 10 U) in 16 588
patients in the first 6 hours of STEMI. Thirty-day mortality rates
were similar in the 2 groups (5.9% versus 5.6%). However, nonfatal
reinfarction rates were reduced in the combination therapy group
(2.3% versus 3.5%, p less than 0.0001), as were other complications
of MI, including VF and tachycardia, high-grade AV block, and septal
or freewall rupture. ICH rates were the same (0.6%), but moderate
to severe bleeding was significantly increased from 2.3% to 4.6%
(p less than 0.001). Excess bleeding risks appear to be limited
to those over the age of 75 years, and the greatest mortality benefit
was seen for those with anterior MI. ICH rates for those older than
75 years were 2.1% versus 1.1% (p equals 0.069) for combination
versus full-dose eteplase. In contrast, the rates were similar for
those younger than 75 years (0.5% versus 0.4%). However, there was
an interaction between age and risk of ICH with therapy. Younger
patients (age less than 70 years) appeared to have significantly
lower ICH rates with combination therapy (398).
Despite the reduction in reinfarction by combination therapy, the
1-year mortality rates were the same (8.38%) in both groups (399).
Although early reinfarction was associated with a marked increase
in 1-year mortality, (22.6% versus 8.0% without reinfarction), this
did not result in an overall mortality difference owing to the low
reinfarction rates. For those younger than 75 years with anterior
MI, 30-day mortality was 4.4% for combination therapy versus 5.8%
(p equals 0.029) for full-dose rPA, and 1-year mortality was 7.1%
versus 8.0% (p equals 0.260), respectively.
ASSENT-3 (31) randomized 6095 patients
with STEMI to full-dose tenecteplase with UFH versus full-dose tenecteplase
with enoxaparin or half-dose tenecteplase plus abciximab plus weight-adjusted,
reduced-dose UFH. Similar to the GUSTOV trial, combination of abciximab
(abciximab 0.25 mg/kg bolus and 0.125 mcg/kg/min [maximum of 10
mcg/min] for 12 hours) and half-dose tenecteplase did not reduce
mortality compared with full-dose tenecteplase but did result in
significantly reduced in-hospital infarction and refractory ischemia.
Notably, the major bleeding rate other than ICH, which was the same
in the 2 groups, was increased from 2.2% to 4.3% (p less than 0.0005).
Those over the age of 75 years were at greatest risk for excess
bleeding, with a 3-fold increase in major bleeding complications.
The tenecteplase plus enoxaparin arm showed superiority compared
with UFH (see Section 6.3.1.7.8.2.1). The need for urgent PCI was
reduced in the GP IIb/IIIa antagonist and fibrinolytic combination
therapy arms in both trials. The heparin regimen, when combination
therapy is used, is a weight-adjusted bolus of 40 U/kg (ASSENT-3)
or 60 U/kg (GUSTO-V) followed by a reduced infusion dose of 7 U/kg/h.
The lower bolus dose is preferable for patients who have an increased
risk for bleeding.
Given the observation that patients with TIMI 3 flow before primary
PCI have the best outcomes (346)
and given the role of GP IIb/IIIa antagonists in PCI, some have
hypothesized that administration of combination GP IIb/IIIa antagonists
and half-dose fibrinolytics will facilitate primary PCI, particularly
when it cannot be accomplished very rapidly. This remains to be
tested prospectively in appropriately sized trials. Combination
pharmacological reperfusion regimens may be associated with a slightly
higher frequency of ICH and a slightly lower frequency of cerebral
infarction and stroke of unknown cause than other reperfusion regimens
(Table 14) (26-30,
31, 33,
158, 261,
320, 322,
324,1331,
351-369,
400).
6.3.1.6.4. PERCUTANEOUS CORONARY
INTERVENTION
Percutaneous coronary intervention is a very effective method for
re-establishing coronary perfusion and is suitable for at least
90% of patients. Considerable data (40,282,401)
support the use of PCI for patients with STEMI. Reported rates of
achieving TIMI 3 flow range from 70% to 90%. There is a 15% reocclusion
rate after PTCA and a 5% reocclusion rate after stenting (402).
Although most evaluations of PCI have been in patients who are eligible
to receive fibrinolytic therapy, considerable experience supports
the value of PCI for patients who may not be suitable for fibrinolytic
therapy because of an increased risk of bleeding (403).
6.3.1.6.4.1. Coronary Angiography
Class I
Diagnostic coronary angiography should be performed:
a. In candidates for primary or rescue PCI. (Level of Evidence:
A)
b. In patients with cardiogenic shock who are candidates for revascularization.
(Level of Evidence: A)
c. In candidates for surgical repair of ventricular septal rupture
(VSR) or severe MR. (Level of
Evidence: B)
d. In patients with persistent hemodynamic and/or electrical instability.
(Level of Evidence: C)
Class III
Coronary angiography should not be performed in patients with extensive
comorbidities in whom the risks of revascularization are likely
to outweigh the benefits. (Level of Evidence: C)
Acute cardiac catheterization has been proposed as an anatomic risk
stratification strategy. A subset of patients will have severe 3-vessel
or left main disease or anatomic features unfavorable for PCI and
may be candidates for urgent or emergency CABG. Another subset of
patients will have spontaneously reperfused and will have minimal
evidence of atherosclerotic obstruction. They can be treated medically,
which avoids the risks of fibrinolytic therapy or PCI. Additionally,
identification of high-risk patients may facilitate additional strategies
that will improve outcome, whereas low-risk patients may be eligible
for early hospital discharge. Coronary angiography should not be
performed in patients with extensive comorbidities or who will not
consent to coronary revascularization regardless of the findings.
6.3.1.6.4.2. Primary PCI
See Table 11 for additional consideration
for selecting reperfusion therapy.
Class I
1. General considerations: If immediately available, primary PCI
should be performed in patients with STEMI (including true posterior
MI) or MI with new or presumably new LBBB who can undergo PCI of
the infarct artery within 12 hours of symptom onset, if performed
in a timely fashion (balloon inflation within 90 minutes of presentation)
by persons skilled in the procedure (individuals who perform more
than 75 PCI procedures per year). The procedure should be supported
by experienced personnel in an appropriate laboratory environment
(a laboratory that performs more than 200 PCI procedures per year,
of which at least 36 are primary PCI for STEMI, and has cardiac
surgery capability). (Level of Evidence: A)
2. Specific considerations:
a. Primary PCI should be performed as quickly as possible with a
goal of a medical contact–to-balloon or door-to-balloon interval
of within 90 minutes. (Level of Evidence: B)
b. If the symptom duration is within 3 hours and the expected door-to-balloon
time minus the expected door-to-needle time is:
i) within 1 hour, primary PCI is generally preferred. (Level
of Evidence: B)
ii) greater than 1 hour, fibrinolytic therapy (fibrinspecific agents)
is generally preferred. (Level of Evidence: B)
c. If symptom duration is greater than 3 hours, primary PCI is generally
preferred and should be performed with a medical contact–to-balloon
or door-to-balloon interval as short as possible and a goal of within
90 minutes. (Level of Evidence: B)
d. Primary PCI should be performed for patients less than 75 years
old with ST elevation or LBBB who develop shock within 36 hours
of MI and are suitable for revascularization that can be performed
within 18 hours of shock unless further support is futile because
of the patient’s wishes or contraindications/unsuitability
for further invasive care. (Level of Evidence: A)
e. Primary PCI should be performed in patients with severe CHF and/or
pulmonary edema (Killip class 3) and onset of symptoms within 12
hours. The medical contact–to-balloon or door-to-balloon time
should be as short as possible (i.e., goal within 90 minutes). (Level
of Evidence: B)
Class
IIa
1. Primary PCI is reasonable for selected patients 75 years or older
with ST elevation or LBBB or who develop shock within 36 hours of
MI and are suitable for revascularization that can be performed
within 18 hours of shock. Patients with good prior functional status
who are suitable for revascularization and agree to invasive care
may be selected for such an invasive strategy. (Level of Evidence:
B)
2. It is reasonable to perform primary PCI for patients with onset
of symptoms within the prior 12 to 24 hours and 1 or more of the
following:
a. Severe CHF (Level of Evidence C)
b. Hemodynamic or electrical instability (Level of Evidence:
C)
c. Persistent ischemic symptoms. (Level of Evidence: C)
Class IIb
The benefit of primary PCI for STEMI patients eligible for
fibrinolysis is not well established when performed by an operator
who performs fewer than 75 PCI procedures per year. (Level of
Evidence: C)
Class III
1. PCI should not be performed in a noninfarct artery at the time
of primary PCI in patients without hemodynamic compromise. (Level
of Evidence: C)
2. Primary PCI should not be performed in asymptomatic patients
more than 12 hours after onset of STEMI if they are hemodynamically
and electrically stable. (Level of Evidence: C)
Primary PCI has been compared with fibrinolytic therapy in 22 randomized
clinical trials (173, 177,
306, 306,
404-421).
An additional trial, SHOCK (301),
which compared medical stabilization with immediate revascularization
for cardiogenic shock, was included along with the above 22 trials
in an overview of primary PCI versus fibrinolysis (40).
These investigations demonstrate that PCI-treated patients experience
lower short-term mortality rates (5.0% versus 7.0%, RR 0.70, 95%
CI 0.58 to 0.85, p equals 0.0002), less nonfatal reinfarction (3.0%
versus 7.0%, RR 0.35, 95% CI 0.27 to 0.45, p equals 0.0003), and
less hemorrhagic stroke (0.05% versus 1.0%, RR 0.05, 95% CI 0.006
to 0.35, p equals 0.0001) than those treated by fibrinolysis but
with an increased risk for major bleeding (7.0% versus 5.0%, RR
1.3, CI 1.02 to 1.65, p equals 0.032) (40).
These results were achieved in medical centers with experienced
providers and under circumstances in which PCI could be performed
promptly after patient presentation (Figure
14) (40).
Additional
considerations that affect the magnitude of the difference between
PCI- and fibrinolysis-treated patients include the fact that UFH
was used as the antithrombin with fibrinolytics as opposed to other
antithrombins such as enoxaparin (see Section
6.3.1.6.8.1.1) or bivalirudin (see Section
6.3.1.6.8.1.2) that are associated with a reduction in the rate
of recurrent MI after fibrinolysis; a smaller but statistically
significant advantage for PCI compared with a fibrn-specific fibrinolytic
versus streptokinase; and variation among the PCI arms as to whether
a stent was implanted or GP IIb/IIIa antagonists were administered.
Figure 14 shows the short-term
and long-term outcomes of patients with STEMI treated by fibrinolysis
versus PCI and the number of patients who need to be treated to
prevent 1 event or cause 1 harmful complication when selecting PCI
instead of fibrinolysis as the reperfusion strategy (Figure
14) (40). When primary PCI is
compared with tPA and the SHOCK trial is excluded, the mortality
rate is 5.5% versus 6.7% (OR 0.81%, 95% CI 0.64 to 1.03, p equals
0.081) (421a).
There
is serious and legitimate concern that a routine policy of primary
PCI for patients with STEMI will result in unacceptable delays in
achieving reperfusion in a substantial number of cases and produce
less than optimal outcomes if performed by less-experienced operators.
The mean time delay for PCI instead of fibrinolysis in the randomized
studies was approximately 40 minutes (40).
Strict performance criteria must be mandated for primary PCI programs
so that long door-to-balloon times and performance by low-volume
or poor-outcome operators/laboratories do not occur. Interventional
cardiologists and centers should strive for outcomes to include
1) medical contact–to-balloon or door-to-balloon times less
than 90 minutes, 2) TIMI 2/3 flow rates obtained in more than 90%
of patients, 3) emergency CABG rate less than 2% among all patients
undergoing the procedure, 4) actual performance of PCI in a high
percentage of patients (85%) brought to the laboratory, and 5) risk
adjusted in-hospital mortality rate less than 7% in patients without
cardiogenic shock. This would result in a risk-adjusted mortality
rate with PCI comparable to that reported for fibrinolytic therapy
in fibrinolytic-eligible patients (40)
and would be consistent with previously reported registry experience
(422-425).
Otherwise, the focus of treatment should be the early use of fibrinolytic
therapy (Figure 14) (40).
PCI
appears to have its greatest mortality benefit in high-risk patients.
In patients with cardiogenic shock, an absolute 9% reduction in
30-day mortality with coronary revascularization instead of immediate
medical stabilization was reported in the SHOCK trial (301).
In NRMI-II, patients with CHF had a 33% relative risk reduction
with primary PCI compared with a 9% relative risk reduction with
fibrinolytic therapy (302). Primary
PCI in patients with anterior STEMI reduces mortality compared with
fibrinolytic therapy, but there is no difference in patients with
nonanterior STEMI (426,427).
Time
from symptom onset to reperfusion is an important predictor of patient
outcome. Two studies (294,295)
have reported increasing mortality rates with increasing door-to-balloon
times. Other studies have shown smaller infarct size, better LV
function, and fewer complications when reperfusion occurs before
PCI (345,346,428).
An analysis of the randomized controlled trials that compared fibrinolysis
with a fibrin-specific agent versus primary PCI suggests that the
mortality benefit with PCI exists when treatment is delayed by no
more than 60 minutes (Figure 15)
(305). Mortality increases significantly
with each 15-minute delay in the time between arrival and restoration
of TIMI 3 flow (door-0=to –TIMI 3 flow time), further underscoring
the importance of timely reperfusion in patients who undergo primary
PCI (429). Importantly, after adjustment
for baseline characteristics, time from symptom onset to balloon
inflation is significantly correlated with 1-year mortality in patients
undergoing primary PCI for STEMI (RR equals 1.08 for each 30-minute
delay from symptom onset to balloon inflation, p equals 0.04) (Figure
21) (275). Given that the door-to-needle
time goal is 30 minutes, this Writing Committee joins the Task Force
on the Management of Acute Myocardial Infarction of the European
Society of Cardiology in lowering the recommended medical contact–to
balloon or door-to-balloon time goal from 120 to 90 minutes in an
attempt to maximize the benefits for reperfusion by PCI (297)
(Figure 22) (294).
If the expected door-to-balloon time exceeds the expected door-to-needle
time by more than 60 minutes, fibrinolytic treatment with a fibrin-specific
agent should be considered unless it is contraindicated. This is
particularly important when symptom duration is less than 3 hours
but is less important with longer symptom duration, when less ischemic
myocardium can be salvaged. In both the CAPTIM trial (173),
which showed lower mortality with prehospital fibrinolysis than
with primary PCI, and the PRAGUE-2 trial (177),
which showed lower mortality with primary PCI after interhospital
transfer than with on-site fibrinolysis, PCI was superior to fibrinolysis
when symptom duration was greater than 2 to 3 hours but not when
symptom duration was shorter (see Section 6.3.1.6.2.1).
In the early hours of STEMI, prompt fibrinolytic therapy can decrease
infarct size and the risk of developing cardiogenic shock (176).
6.3.1.6.4.2.1. Complications
of primary PCI.
Potential complications of an invasive strategy for treating STEMI
include problems with the arterial access site; adverse reactions
to volume loading, contrast medium, and antithrombotic medications;
technical complications; and reperfusion events. Reocclusion occurs
in 10% to 15% of patients after PTCA but in fewer than 5% after
stent implantation. Likewise, angiographic restenosis occurs in
30% to 40% of patients after PTCA but in 15% to 20% after stent
implantation. The management of these complications is beyond the
scope of this guideline (430-432).
6.3.1.6.4.2.2. Primary PCI in
fibrinolytic-ineligible patients.
Class I
Primary PCI should be performed in fibrinolyticineligible patients
who present with STEMI within 12 hours of symptom onset. (Level
of Evidence: C)
Class IIa
It is reasonable to perform primary PCI for fibrinolytic-ineligible
patients with onset of symptoms within the prior 12 to 24 hours
and 1 or more of the following:
a.
Severe CHF (Level of Evidence: C)
b. Hemodynamic or electrical instability (Level of Evidence:
C)
c. Persistent ischemic symptoms. (Level of Evidence: C)
Randomized
controlled trials evaluating the outcome of PCI for patients who
present with STEMI but who are ineligible for fibrinolytic therapy
have not been performed. Few data are available to characterize
the value of primary PCI for this subset of patients with STEMI;
however, the recommendations in Section
4.2 are applicable to these patients. Nevertheless, these patients
are at increased risk for mortality (433),
and there is a general consensus that PCI is an appropriate means
for achieving reperfusion in those who cannot receive fibrinolytics
because of increased risk of bleeding (403,434-436).
6.3.1.6.4.2.3.
Primary PCI without on-site cardiac surgery.
Class IIb
Primary PCI might be considered in hospitals without on-site cardiac
surgery, provided that a proven plan for rapid transport to a cardiac
surgery operating room exists in a nearby hospital with appropriate
hemodynamic support capability for transfer. The procedure should
be limited to patients with STEMI or MI with new, or presumably
new, LBBB on ECG, and should be done in a timely fashion (balloon
inflation within 90 minutes of presentation) by persons skilled
in the procedure (at least 75 PCIs per year) and at hospitals performing
a minimum of 36 primary PCI procedures per year. (Level of Evidence:
B)
Class III
Primary PCI should not be performed in hospitals without on-site
cardiac surgery capabilities and without a proven plan for rapid
transport to a cardiac surgery operating room in a nearby hospital
or without appropriate hemodynamic support capability for transfer.
(Level of Evidence: C)
Reports on emergency primary PCI from hospitals without established
open heart surgery or elective PCI programs have demonstrated generally
favorable results (307,437-450).
PCI in the early phase of an acute STEMI can be difficult and requires
even more skill and experience than routine PCI in the stable patient.
The need for an experienced operator and experienced laboratory
technical support with availability of the broad range of catheters,
guidewires, stents, and other devices (e.g., intra-aortic balloon
pump [IABP]) required for optimum results in an acutely ill patient
is of major importance. Careful patient selection and continuous
quality improvement are critical components of a successful program.
If these complex patients are treated by interventionalists with
limited experience at hospitals with low volume, then the gains
of early intervention may be lost because of increased complications.
In such circumstances, transfer to a center that routinely performs
complex PCI will often be a more effective and efficient course
of action. Fibrinolysis is an acceptable form of therapy and is
preferable to primary PCI by an inexperienced team.
Criteria have been suggested for the performance of primary PCI
at hospitals without on-site cardiac surgery (432,445)
(Tables 16 and 17).
Large-scale registries have shown an inverse relationship between
the number of primary PCI procedures performed and in-hospital mortality
(295,303,304).
The data suggest that both door-to-balloon time and in-hospital
mortality are significantly lower in institutions that perform a
minimum of 36 primary PCI procedures per year (295).
Suboptimal results may relate to operator/staff inexperience and
capabilities and to delays in performing PCI for logistical reasons.
From clinical data and expert consensus, the Committee recommends
that primary PCI for acute STEMI performed at hospitals without
established elective PCI programs should be restricted to those
institutions capable of performing a requisite minimum number of
primary PCI procedures (36 per year) with a proven plan for rapid
and effective PCI and rapid access to cardiac surgery in a nearby
hospital. The benefit of primary PCI is not well established for
operators who perform fewer than 75 PCIs per year or in a hospital
that performs fewer than 36 primary PCI procedures per year. In
addition, the benefit of timely reperfusion of the infarct artery
by primary PCI at sites without on-site surgery must be weighed
against the small but finite risk of harm to the patient related
to the time required to transfer the patient to a site with CABG
surgery capabilities (452,453).
6.3.1.6.4.2.4.
Interhospital transfer for primary PCI.
The enthusiasm for primary PCI has led to the concept of emergency
interhospital transfer for catheter-based reperfusion rather than
fibrinolytic therapy in the initial hospital (454-456).
Complication rates are low during transport, but time
to reperfusion is delayed, which results in larger infarct size
and lower LVEF (457). However,
as noted in Section 6.3.1.6.2.1, selection
bias of patients enrolled in randomized trials likely resulted in
an underestimation of the risk of interhospital transfer expected
in routine practice. Five randomized trials enrolled 2466 patients,
with favorable results for PCI versus fibrinolytic therapy (177,306,408,419,421).
Mortality was reduced with PCI (6.8% versus 9.6%, RR 0.69, 95% CI
0.51 to 0.0.92, p equals 0.01), as was the combined end point of
death, nonfatal reinfarction, and stroke (8.5% versus 15.5%, RR
0.51, 95% CI 0.39 to 0.65, p less than 0.0001). Importantly, mean
time to treatment was delayed only 44 minutes in these studies (Figure
23) (177,306).
In contrast, the time from presentation at the door of the first
hospital to balloon inflation in the second hospital, as recorded
in 1346 patients in NRMI-4, was 185 minutes in the United States
in 2002 (Figure 24) (458).
Emergency transport in Europe is centrally organized and more efficient
than in the United States (Table 18)
(177, 306,
408, 419,
421, 459)
(Van de Werf; oral presentation, American College of Cardiology
52nd Annual Scientific Session, Chicago, IL, March 2003). Delays
in door-to-balloon time versus door-to-needle time of more than
60 minutes because of interhospital transfer might negate the potential
mortality benefit of transfer for primary PCI over immediate intravenous
fibrinolysis with a fibrin-specific agent as shown in these trials
(305). To achieve optimal results,
time from the first hospital door to the balloon inflation in the
second hospital should be as short as possible, with a goal of within
90 minutes. Significant reductions in door-to-balloon times might
be achieved by directly transporting patients to PCI centers rather
than transporting them to the nearest hospital, if interhospital
transfer will subsequently be required to obtain primary PCI.
6.3.1.6.4.3. Primary Stenting
Of the 22 randomized trials that compared primary PCI with fibrinolytic
therapy, 12 involved a comparison of primary PCI with stenting and
fibrinolytic therapy (40, 173,
177, 306, 307,
408, 409,
414, 417-421).
These investigations demonstrate that PCI-treated patients experience
lower mortality rates (5.9% versus 7.7%, OR 0.75, 95% CI 0.60 to
0.94, p equals 0.013), less reinfarction (1.6% versus 5.1%, OR 0.31,
95% CI 0.21 to 0.44, p equals 0.0001), and less hemorrhagic stroke
than those treated by fibrinolysis (40).
Compared with PTCA, intracoronary stents achieve a better immediate
angiographic result with a larger arterial lumen, less reocclusion
and restenosis of the infarct-related artery, and fewer subsequent
ischemic events.
Primary stenting has been compared with primary angioplasty in 9
studies (38,37,460-467).
There were no differences in mortality (3.0% versus 2.8%) or reinfarction
(1.8% versus 2.1%) rates. However, major adverse cardiac events
were reduced, driven by the reduction in subsequent targetvessel
revascularization with stenting (Figure
25) (37).
Preliminary reports suggest that compared with conventional bare
metal stents, drug-eluting stents are not associated with increased
risk when used for primary PCI in patients with STEMI (468).
Postprocedure vessel patency, biomarker release, and the incidence
of short-term adverse events were similar in patients receiving
sirolimus (n equals 186) or bare metal (n equals 183) stents. Thirty-day
event rates of death, reinfarction, or revascularization were 7.5%
versus 10.4%, respectively (p equals 0.4) (468).
6.3.1.6.4.4.
Facilitated PCI
Class IIb
Facilitated PCI might be performed as a reperfusion strategy in
higher-risk patients when PCI is not immediately available and bleeding
risk is low. (Level of Evidence: B)
Facilitated PCI refers to a strategy of planned immediate
PCI after an initial pharmacological regimen such as fulldose fibrinolysis,
half-dose fibrinolysis, a GP IIb/IIIa inhibitor, or a combination
of reduced-dose fibrinolytic therapy and a platelet GP IIb/IIIa
inhibitor. Facilitated PCI should be differentiated from primary
PCI without fibrinolysis or GP IIb/IIIa inhibitor therapy, from
primary PCI with a GP IIb/IIIa inhibitor started at the time of
PCI, and from rescue PCI after unsuccessful fibrinolysis. Potential
advantages include earlier time to reperfusion, improved patient
stability, greater procedural success rates, higher TIMI flow rates,
and improved survival rates (36,
346, 428,
469, 470).
However, preliminary studies have not demonstrated any benefit in
reducing infarct size or improving outcomes (471-473).
It is unlikely that this strategy would be beneficial in low-risk
patients. A strategy of facilitated PCI holds promise in higher-risk
patients when PCI is not immediately available. Potential risks
include increased bleeding complications, especially in those 75
years of age or older (see Section 6.3.1.6.3.8),
and potential limitations include added cost. Several randomized
trials of facilitated PCI with a variety of pharmacological regimens
are in progress (473a).
6.3.1.6.4.5. Rescue PCI
Class I
1. Rescue PCI should be performed in patients less than 75 years
old with ST elevation or LBBB who develop shock within 36 hours
of MI and are suitable for revascularization that can be performed
within 18 hours of shock unless further support is futile because
of the patient’s wishes or contraindications/unsuitability
for further invasive care. (Level of Evidence: B)
2. Rescue PCI should be performed in patients with severe CHF and/or
pulmonary edema (Killip class 3) and onset of symptoms within 12
hours. (Level of Evidence: B)
Class IIa
1. Rescue PCI is reasonable for selected patients 75 years or older
with ST elevation or LBBB or who develop shock within 36 hours of
MI and who are suitable for revascularization that can be performed
within 18 hours of shock. Patients with good prior functional status
who are suitable for revascularization and who agree to invasive
care may be selected for such an invasive strategy. (Level of
Evidence: B)
2. It is reasonable to perform rescue PCI for patients with 1 or
more of the following:
a. Hemodynamic or electrical instability (Level of Evidence:
C)
b. Persistent ischemic symptoms. (Level of Evidence: C)
Immediately after failed fibrinolysis. Intravenous fibrinolytic
therapy successfully restores coronary TIMI 2/3 flow at 90 minutes
in 50% to 85% of patients with STEMI (474).
In those in whom fibrinolysis is unsuccessful, antegrade coronary
flow can usually be restored with PCI. Several studies have demonstrated
the marked beneficial effect of infarctrelated artery patency (obtained
via endogenous, pharmacological, or mechanical recanalization) on
survival in patients with STEMI (475,476).
Survivors of STEMI with a patent infarct-related artery demonstrated
at 90 minutes after treatment have an improved long-term outcome
compared with those with an occluded infarct-related artery, even
when LV systolic function is similar (476).
Rescue (also known as salvage) PCI is defined as PCI within 12 hours
after failed fibrinolysis for patients with continuing or recurrent
myocardial ischemia. Rescue PCI has resulted in higher rates of
early infarct artery patency, improved regional infarct-zone wall
motion, and greater freedom from adverse in-hospital events than
with a deferred PCI strategy or medical therapy. The Randomized
Evaluation of Rescue PCI with Combined Utilization End Points (RESCUE)
trial demonstrated a reduction in rates of in-hospital death and
a combined end point of death and CHF that was maintained up to
1 year after study entry for patients presenting with anterior STEMI
who failed fibrinolytic therapy, when PCI was performed within 8
hours after the onset of symptoms (477).
Improvement in TIMI grade flow from less than or equal to 2 to 3
may offer additional clinical benefit. Similar data are not available
for patients with nonanterior STEMI.
A major problem in adopting a strategy of rescue PCI lies in the
limitation of accurate identification of patients for whom fibrinolytic
therapy has not restored antegrade coronary flow. Unless unsuccessful
fibrinolysis is recognized and corrected quickly (within 3 to 6
hours of onset of symptoms), salvage of ischemic myocardium is unlikely.
Unfortunately, clinical markers of reperfusion, such as relief of
ischemictype chest discomfort, partial resolution of ST-segment
elevation, and reperfusion arrhythmias, have limited predictive
value in identifying failure of fibrinolysis (478).
In a prior era in which the practice of PCI was less mature, immediate
catheterization of all patients after fibrinolytic therapy to identify
those with an occluded infarct artery was found to be impractical,
costly, and often associated with bleeding complications (479,
480). This strategy is being re-evaluated
in clinical trials testing facilitated PCI in the contemporary PCI
setting.
Even in the patient with documented failure of fibrinolysis, rescue
PCI has limitations. Because extensive myocardial necrosis occurs
when coronary occlusion has been present for more than 3 hours (18),
PCI may not salvage a substantial amount of myocardium, considering
the time delay associated with presentation of the patient to the
hospital after onset of symptoms, infusion of the fibrinolytic agent,
recognition of failed fibrinolysis, and subsequent initiation of
PCI. Rescue PCI fails to reestablish antegrade coronary flow in
approximately 10% of patients, and reocclusion of the infarct artery
occurs in as many as 20% of the remainder (481),
although use of GP IIb/IIIa inhibitors and stent implantation may
improve these results. Unsuccessful rescue PCI is associated with
a high mortality rate (482,483).
Finally, coronary reperfusion occurs over the subsequent hours after
fibrinolytic therapy in many patients. Although infarct artery patency
is achieved in only 50% to 85% of patients 90 minutes after fibrinolytic
therapy, it rises to 90% by 24 hours (474).
Such late reperfusion may improve survival without the risk of invasive
procedures coupled with fibrinolytic therapy. Confounding the issue,
both fibrinolytic therapy and PCI may successfully restore flow
in the epicardial artery but fail to improve microvascular perfusion.
Hours to days after failed fibrinolysis. Patency of thee
infarctrelated artery is an important predictor of mortality in
survivors of STEMI (475,476).
Compared with those with a patent infarct artery, survivors of STEMI
with a persistently occluded artery after fibrinolysis, PCI, or
no reperfusion therapy have 1) increased LV dilatation (484),
2) a greater incidence of spontaneous and inducible ventricular
arrhythmias (485), and 3) a poorer
prognosis (486). On the basis of
observational and experimental data, it has been hypothesized that
infarct artery patency may favorably influence LV remodeling and
electrical stability, even if accomplished at a time when salvage
of ischemic myocardium is unlikely (i.e., more than 12 hours to
days after coronary artery occlusion). Five small randomized trials,
which enrolled a total of 562 patients, have directly tested the
hypothesis that mechanical opening of persistent total occlusions
late after MI will improve long-term LV remodeling and clinical
outcomes (the late open-artery hypothesis). Most studies enrolled
a combination of patients that included those who had failed fibrinolysis
and those who had not received reperfusion therapy (487-489),
with a range from almost no fibrinolytic therapy (490)
to fibrinolytic therapy in nearly all patients (491).
There was wide variation in the effect of routine PCI compared with
only medical therapy on LV size and function. Most studies showed
no significant differences between the treatment groups (487,488).
One single-center study of 83 patients with occlusions of the left
anterior descending coronary artery (LAD) reported improved LV volumes
and clinical outcomes (composite of CHF, MI, and death) at 6 months
in the PCI group (490). In contrast,
a multicenter study of 66 patients with LAD occlusions reported
significantly worse LV remodeling, with progressive LV dilation
at 1 year and more clinical events in the PCI group than in those
assigned to optimal medical therapy alone (491).
The latter included very high rates of beta-blocker and ACE inhibitor
use. The largest multicenter study, DECOPI, enrolled 212 patients
and reported no difference in the primary end point, the composite
of death, VT, and MI at 6 months (Steg PG; oral presentation, European
Society of Cardiology Congress 2003, Vienna, Austria, September
2003). Stents were used in 80% of patients in the PCI group, and
GP IIb/IIIa antagonists were used in 9%. The study reached fewer
than one third of the target sample size and was severely underpowered,
as were all the other studies, to assess clinical events.
There are no convincing data to support the routine use of adjuvant
PCI days after failed fibrinolysis or for patients who do not receive
reperfusion therapy. Nevertheless, this is being done in some patients
with STEMI as an extension of the invasive strategy for patients
with NSTEMI. The Occluded Artery Trial (OAT) is currently randomizing
patients to test whether routine PCI days to weeks after MI improves
longterm clinical outcomes in asymptomatic high-risk patients with
an occluded infarct related artery (493).
6.3.1.6.4.6. PCI for Cardiogenic
Shock
Class I
Primary PCI is recommended for patients less than 75 years old with
ST elevation or LBBB who develop shock within 36 hours of MI and
are suitable for revascularization that can be performed within
18 hours of shock unless further support is futile because of the
patient’s wishes or contraindications/unsuitability for further
invasive care. (Level of Evidence: A)
Class IIa
Primary PCI is reasonable for selected patients 75 years or older
with ST elevation or LBBB who develop shock within 36 hours of MI
and are suitable for revascularization that can be performed within
18 hours of shock. Patients with good prior functional status who
are suitable for revascularization and agree to invasive care may
be selected for such an invasive strategy. (Level of Evidence:
B)
Observational studies support the value of PCI for patients who
develop cardiogenic shock in the early hours of STEMI. For patients
who do not have mechanical causes of shock, such as acute MR or
septal or free wall rupture, mortality among those having PCI is
lower than for those treated medically. However, undergoing cardiac
catheterization alone, with or without PCI, is associated with a
lower mortality owing to patient selection bias (494).
Two small randomized clinical trials (301,495)
have further clarified the role of emergency revascularization in
STEMI complicated by cardiogenic shock. Both showed a statistically
insignificant but clinically important absolute 9% reduction in
30-day mortality. In the SHOCK trial (301),
the survival curves continued to progressively diverge such that
at 6 months and 1 year, there was a significant mortality reduction
with emergency revascularization (53% versus 66%, p less than 0.03)
(184). The prespecified subgroup
analysis of patients less than 75 years old showed an absolute 15%
reduction in 30-day mortality (p less than 0.02), whereas there
was no apparent benefit for the small cohort (n equals 56) of patients
more than 75 years old. These data strongly support the approach
that patients younger than 75 years with STEMI complicated by cardiogenic
shock should undergo emergency revascularization and support measures.Three
registries (496-498)
have demonstrated a marked survival benefit for elderly patients
who are clinically selected for revascularization (approximately
1 of 5 patients), so age alone should not disqualify a patient for
early revascularization. (See Section
7.6.5.)
Several additional discussions elsewhere in this guideline are important
to consider in these patients. Intra-aortic balloon pump support
or ventricular assist devices can stabilize hemodynamics so that
revascularization procedures can be performed (see Section
7.6.7.6). Post hoc analyses (499-501)
have suggested that GP IIb/IIIa inhibitors reduce mortality, but
the studies are limited by lower than expected mortality rates,
larger than expected mortality reduction, and small sample sizes
(see Section 6.3.1.6.8.2.3). Although PCI
in a noninfarct artery is not recommended in stable patients, it
can be beneficial in hemodynamically compromised patients if the
stenotic artery perfuses a large area of myocardium and the procedure
can be done efficiently. In patients with significant left main
disease or severe 3-vessel disease and without RV infarction or
major comorbidities such as renal insufficiency or severe pulmonary
disease, CABG can be considered as the revascularization strategy
(see Section 6.3.1.6.5) (Figure
26) (502).
6.3.1.6.4.7. Percutaneous Coronary
Intervention After Fibrinolysis
Class I
1. In patients whose anatomy is suitable, PCI should be performed
when there is objective evidence of recurrent MI. (Level of
Evidence: C)
2. In patients whose anatomy is suitable, PCI should be performed
for moderate or severe spontaneous or provocable myocardial ischemia
during recovery from STEMI. (Level of Evidence: B)
3. In patients whose anatomy is suitable, PCI should be performed
for cardiogenic shock or hemodynamic instability. (See Section
6.3.1.6.4.6.) (Level of Evidence: B)
Class IIa
1. It is reasonable to perform routine PCI in patients with LVEF
less than or equal to 0.40, CHF, or serious ventricular arrhythmias.
(Level of Evidence: C)
2. It is reasonable to perform PCI when there is documented clinical
heart failure during the acute episode, even though subsequent evaluation
shows preserved LV function (LVEF greater than 0.40). (Level
of Evidence: C)
Class IIb
Routine PCI might be considered as part of an invasive strategy
after fibrinolytic therapy. (Level of
Evidence: B)
Immediately after successful fibrinolysis. Randomized prospective
trials examined the efficacy and safety of immediate PCI after fibrinolysis
(479,480,503).
These trialsshowed no benefit of routine PCI of the stenotic infarct-related
artery immediately after fibrinolytic therapy. The strategy did
not appear to salvage myocardium, improve LVEF, or prevent reinfarction
or death. Those subjected to this approach appeared to have an increased
incidence of adverse events, including bleeding, recurrent ischemia,
emergency CABG, and death. These studies have not been repeated
in the modern interventional era with improved equipment, improved
antiplatelet and anticoagulant strategies, and coronary stents,
thus leaving the question of routine PCI early after successful
fibrinolysis unresolved in contemporary practice. Studies of facilitated
PCI are presently enrolling patients (36,396,471,504).
Hours to days after successful fibrinolysis. It was initially
suggested that elective PCI of the stenotic infarct-related artery
hours to days after fibrinolysis might allow sufficient time for
development of a more stable hemostatic milieu at the site of previous
thrombotic occlusion. In this setting, PCI would be safer and more
effective in reducing the incidence of reocclusion and improving
survival. Two large randomized, prospective trials from an earlier
PCI era tested this hypothesis, with both concluding that 1) there
are fewer complications if PCI is delayed for several days after
fibrinolytic therapy and 2) routine PCI in the absence of spontaneous
or provocable ischemia does not improve LV function or survival
(268,505-507).
Thus, in unselected patients receiving fibrinolytic therapy, PCI
of the stenotic infarctrelated artery in the absence of evidence
of recurrent ischemia within 48 hours did not appear to be beneficial.
Great improvements in equipment, operator experience, and adjunctive
pharmacotherapy have increased PCI success rates and decreased complications.
More recently, the invasive strategy for patients with NSTEMI has
been given a Class I recommendation by the ACC/AHA 2002 Guideline
Update for the Management of Patients With Unstable Angina/NSTEMI
(4). Patients with STEMI are increasingly
being treated similarly as an extension of this approach. Although
6 published reports (472,508-512)
and 1 preliminary report (Lablanche JM; oral presentation, American
Heart Association 2002 Annual Scientific Sessions, November 2002,
Chicago, IL) support this strategy, randomized studies similar to
those in NSTEMI need to be performed.
One study supports the policy of performing catheterization and
subsequent revascularization for patients who do have spontaneous
or inducible angina after STEMI. The DANAMI trial (515)
randomly assigned 1008 survivors of a first acute MI treated with
fibrinolytic therapy within 12 hours of onset of symptoms to catheterization
and subsequent revascularization or standard medical therapy if
they showed evidence of spontaneous or inducible angina. Those who
underwent revascularization had less unstable angina and fewer nonfatal
MIs during a 2.5-year period of follow-up compared with those patients
randomly assigned to medical treatment only (18% and 5.6% versus
30% and 10.5%, respectively).
Days to weeks after successful fibrinolysis. Continued
thrombus lysis and remodeling of the infarct artery stenosis occur
over the days to weeks after successful fibrinolysis, which makes
the underlying residual coronary stenosis more stable and less prone
to rethrombosis and reocclusion. Thus, delaying PCI for days to
weeks after fibrinolysis might improve survival, even though earlier
routine PCI does not. To date, there have not been adequately sized
trials to evaluate this treatment strategy. Two older, small, randomized
trials (516,517)
demonstrated similar LV function, rates of reinfarction, and mortality
in patients randomized to PCI or conservative therapy.
6.3.1.6.5. Acute Surgical Reperfusion.
Class I
Emergency or urgent CABG in patients with STEMI should be undertaken
in the following circumstances:
a. Failed PCI with persistent pain or hemodynamic instability in
patients with coronary anatomy suitable for surgery. (Level
of Evidence: B)
b. Persistent or recurrent ischemia refractory to medical therapy
in patients who have coronary anatomy suitable for surgery, have
a significant area of myocardium at risk, and are not candidates
for PCI or fibrinolytic therapy. (Level of Evidence: B)
c. At the time of surgical repair of postinfarction VSR or mitral
valve insufficiency. (Level of Evidence: B)
d. Cardiogenic shock in patients less than 75 years old with ST
elevation or LBBB or posterior MI who develop shock within 36 hours
of STEMI, have severe multivessel or left main disease, and are
suitable for revascularization that can be performed within 18 hours
of shock, unless further support is futile because of the patient’s
wishes or contraindications/unsuitability for further invasive care
(Level of Evidence: A)
e. Life-threatening ventricular arrhythmias in the presence of greater
than or equal to 50% left main stenosis and/or triple-vessel disease.
(Level of Evidence: B)
Class IIa
1. Emergency CABG can be useful as the primary reperfusion strategy
in patients who have suitable anatomy and who are not candidates
for fibrinolysis or PCI and who
are in the early hours (6 to 12 hours) of an evolving STEMI, especially
if severe multivessel or left main disease is present. (Level
of Evidence: B)
2. Emergency CABG can be effective in selected patients 75 years
or older with ST elevation, LBBB, or posterior MI who develop shock
within 36 hours of STEMI, have severe triple-vessel or left main
disease, and are suitable for revascularization that can be performed
within 18 hours of shock. Patients with good prior functional status
who are suitable for revascularization and agree to invasive care
may be selected for such an invasive strategy. (Level of Evidence:
B)
Class III
1. Emergency CABG should not be performed in patients with persistent
angina and a small area of risk who are hemodynamically stable.
(Level of Evidence: C)
2. Emergency CABG should not be performed in patients with successful
epicardial reperfusion but unsuccessful microvascular reperfusion.
(Level of Evidence: C)
These
recommendations are supplementary to those published recently in
a more complete set of general guidelines and indications for CABG
(518) and are restricted to patients
with STEMI and associated complications. The basis for recommending
surgery in emergency circumstances is the documented benefit of
CABG for severe multivessel disease or left main coronary artery
stenosis, particularly with reduced LV function (518-521),
with the recognition that risk of emergency CABG is greater than
that for elective operation.
The widespread use of fibrinolysis and primary PCI has largely superseded
CABG for acute reperfusion of patients with STEMI. However, CABG
still plays an integral role in the early reperfusion strategy for
some patients. In the PAMI (Primary Angioplasty in Myocardial Infarction)-2
trial (522), of 1100 patients with
MI and without cardiogenic shock, 5% underwent CABG as the primary
reperfusion strategy with STEMI. Mortality was 6.4% if surgery was
undertaken on an urgent or emergency basis versus 2.0% if elective.
Major risk factors for death included poor LV function and advanced
age. In the setting of cardiogenic shock complicating STEMI, emergency
CABG has been used where other interventions have failed or have
not been indicated. In the SHOCK registry (523),
of 136 patients undergoing emergency CABG for cardiogenic shock
due to LV failure, mortality was 27.9% compared to 45.5% in 268
patients undergoing PTCA. For patients undergoing CABG within 18
hours of the onset of shock, mortality was 39.6%. In a review of
25 papers reporting the outcome of CABG in 391 patients with cardiogenic
shock, mortality was 35% (524).
In GUSTO-I, mortality in a similar group of patients was 29% (98
of 340) after CABG and 29% (165 of 567) (422,525,526)
after PTCA. On the basis of these studies, emergency CABG should
only be considered for patients with STEMI with severe coronary
artery disease. In the SHOCK trial, emergency CABG was performed
at a median of 14 hours after the onset of STEMI in 40% of those
who underwent early revascularization; most of the patients undergoing
CABG had significant left main or 3-vessel coronary artery disease.
The 30-day mortality rate was similar to those with less severe
coronary artery disease who underwent PTCA (42% versus 45%).
6.3.1.6.6. Patients With STEMI
Not Receiving Reperfusion
Many
patients with suspected STEMI do not receive reperfusion therapy.
For some of these patients, the lack of treatment represents a missed
opportunity. For others, patient preference led to a decision that
the clinical benefit was not worth the risk of the therapy. Other
patients may have contraindications to treatment owing to comorbid
disease. Few studies have examined the care and outcomes of patients
with suspected STEMI who do not receive reperfusion therapy. Many
of the studies (e.g., beta-blocker trials) that established therapies
for MI patients preceded the reperfusion era, and so their efficacy
in patients with STEMI who did not receive reperfusion is clear.
The acute use of aspirin was shown to be effective in patients who
did and did not receive fibrinolytic therapy. Guideline-based recommendations
for nonreperfusion treatments should not vary whether or not patients
received reperfusion therapy. The major difference is that patients
not receiving reperfusion therapy are considered to have a higher
risk for future adverse events (261).
(See Section 6.3.1.6.8.1.2 for discussion
of the TETAMI trial.)
6.3.1.6.7. Assessment Of Reperfusion
Class IIa
It is reasonable to monitor the pattern of ST elevation, cardiac
rhythm, and clinical symptoms over the 60 to 180 minutes after initiation
of fibrinolytic therapy. Noninvasive findings suggestive of reperfusion
include relief of symptoms, maintenance or restoration of hemodynamic
and or electrical stability, and a reduction of at least 50% of
the initial ST-segment elevation injury pattern on a follow-up ECG
60 to 90 minutes after initiation of therapy. (Level of Evidence:
B)
A high priority exists for the development of simple, accurate,
readily available noninvasive techniques to assess the success of
pharmacological reperfusion early, i.e., 60 to 90 minutes after
administration of therapy. Prior studies evaluating clinical and
ECG outcome measures of reperfusion used angiographic TIMI 2 or
3 flow as the “gold standard”; angiographic assessment
of epicardial flow is now considered inadequate to completely assess
myocardial perfusion. Indeed, it is now clear that microvascular
perfusion may be impaired despite achievement of TIMI 3 flow and
less than 50% coronary narrowing; moreover, abnormal microperfusion
has negative prognostic implications (395,527,528).
Myocardial contrast echocardiography, myocardial angiographic perfusion
with assessment of angiographic
blush in the myocardium, and ECG assessment of ST resolution are
recognized as useful techniques for assessing myocardial perfusion.
The relatively simple and readily available evaluation of the ECG
ST-segment resolution that exceeds 50% at 60 to 90 minutes after
reperfusion is a good indicator of enhanced myocardial perfusion
(527). This finding is also associated
with enhanced recovery of LV function, reduced infarct size, and
improved prognosis (277,349,395,529-531).
In the TIMI-14 study of 888 patients, those with TIMI 3 perfusion
and greater than 70% ST-segment resolution had substantial enhancement
of survival compared with those without ST-segment resolution and
angiographically patent infarct arteries (531).
Santoro and colleagues (532) evaluated
158 consecutive patients with STEMI referred for direct angioplasty
within 6 hours of symptom onset. In their observational study of
patients with TIMI grade 3 flow and less than 30% residual stenosis,
42 patients had less than 50% reduction in maximal ST elevation
in a single lead versus 75 patients with at least 50% reduction
in ST elevation. Those with ST-segment resolution had enhanced infarct-zone
functional recovery and improved ejection fraction. The reduction
of ST-segment elevation was the only independent predictor of functional
recovery.
Persistence of unrelenting ischemic chest pain, absence of resolution
of the qualifying ST-segment elevation, and hemodynamic or electrical
instability are generally indicators of failed pharmacological reperfusion
and the need to consider rescue PCI. Aggressive medical support
may be necessary in the interim. (See Section
6.3.1.6.4.5.)
6.3.1.6.8. Ancillary Therapy
Ancillary
therapy plays a key role in the overall management of patients with
STEMI and can be usefully categorized as conjunctive, in which case
it facilitates and maintains coronary reperfusion, or adjunctive,
which aims to limit the consequences of myocardial ischemia, enhance
myocardial healing, and reduce the likelihood of recurrent events.
6.3.1.6.8.1. Antithrombins as
Ancillary Therapy to Reperfusion Therapy
After rupture of a vulnerable or high-risk plaque, its contents
are exposed to the passing bloodstream. Vulnerable plaques are laden
with both lipid and collagen and are rich in tissue factor, thereby
resulting in activation of the coagulation cascade, which ultimately
results in the deposition f fibrin strands. In addition, platelets
are activated and aggregate. Thrombin that is generated as a consequence
of activation of the coagulation cascade is a pivotal molecule not
only for the formation of fibrin strands but also for activation
of platelets. Therefore, there is considerable rationale for ancillary
therapy to inhibit the coagulation cascade in patients with STEMI,
including both those who do and do not receive reperfusion therapy.
The general term used to include agents that alter the function
of 1 or more proteins in the coagulation cascade is antithrombins
(533). However, such a broad term
does not do justice to the biochemical complexities of agents that
may
inhibit the coagulation cascade at multiple positions (e.g., UFH
and LMWH) or in a single position (e.g., direct antithrombins).
In addition to establishing and maintaining patency of the infarct-related
artery, the rationale for prescribing antithrombins in selected
patients with STEMI includes prevention of DVT, pulmonary embolism,
LV mural thrombus formation, and cerebral embolization.
6.3.1.6.8.1.1. Unfractionated
heparin as ancillary therapy to reperfusion therapy.
Class I
1. Patients undergoing percutaneous or
surgical revascularization should receive UFH. (Level of Evidence:
C)
2. Unfractionated heparin should be given intravenously to patients
undergoing reperfusion therapy with alteplase, reteplase, or tenecteplase
with dosing as follows: bolus of 60 U/kg (maximum 4000 U) followed
by an infusion of 12 U/kg/hr (maximum 1000 U) initially adjusted
to maintain activated partial thromboplastin time (aPTT) at 1.5
to 2.0 times control (approximately 50 to 70 seconds). (Level
of Evidence: C)
3. Unfractionated heparin should be given intravenously to patients
treated with nonselective fibrinolytic agents (streptokinase, anistreplase,
urokinase) who are at high risk for systemic emboli (large or anterior
MI, atrial fibrillation (AF), previous embolus, or known LV thrombus).
(Level of Evidence: B)
4. Platelet counts should be monitored daily in patients taking
UFH. (Level of Evidence: C)
Class IIb
It may be reasonable to administer UFH intravenously to patients
undergoing reperfusion therapy with streptokinase. (Level of
Evidence: B)
Despite the use of UFH (533) in
STEMI for over 40 years, there is continued controversy regarding
its role. In patients who are treated with fibrinolytic therapy,
recommendations for UFH therapy depend on the fibrinolytic agent
chosen. The nonspecific fibrinolytic agents (streptokinase, anistreplase,
and urokinase) that produce a systemic coagulopathy, including depletion
of factors V and VIII and massive production of fibrin(ogen) degradation
products, are themselves anticoagulants. From this perspective,
the need for conjunctive systemic anticoagulation with these agents
conceptually is less compelling. However, the procoagulant potential
of streptokinase, which induces extensive plasmin-mediated thrombin
activity, has been noted as the rationale for antithrombotics (534).
The rationale for UFH is clear for the more fibrin-specific agents,
such as alteplase, reteplase, and tenecteplase. They induce less
effect on the systemic coagulation system, and in many patients,
very little breakdown of fibrinogen or depletion of coagulation
factors is evident (535,536).
Furthermore, the same procoagulant increase in thrombin activity
is seen (534).
Over
60 000 patients were enrolled in the randomized ISIS-3 (357)
and GISSI-2 (Gruppo Italiano per lo Studio della Streptochinasi
nell’Infarto Miocardico)/International (353,354)
trials comparing subcutaneous UFH with no routine heparin in conjunction
with streptokinase, anistreplase, and alteplase. During the period
in which UFH was given, a small reduction in mortality (4 to 5 lives
per 1000 treated) was observed in ISIS-3; however, by 30 days, the
2 to 3 lives saved per 1000 treated was no longer statistically
significant. A small excess rate of hemorrhagic stroke (1 to 2 per
1000 treated patients) was observed together with a larger excess
in systemic bleeding (3 to 5 per 1000 patients), although total
stroke rate was not significantly increased. A meta-analysis of
these and several smaller studies enrolling a total of 68 000 patients
showed that 5 lives were saved per 1000 patients treated with UFH
in addition to streptokinase (537).
In the GUSTO-I trial (25), more
than 20 000 patients treated with streptokinase were randomly assigned
to routine intravenous versus routine subcutaneous UFH. No significant
differences were observed in death, reinfarction, or non-hemorrhagic
stroke rates, whereas excess rates of systemic bleeding and hemorrhagic
strokes (trend) were observed in the intravenous UFH group. There
was a 36% crossover rate from subcutaneous to intravenous UFH in
this trial.
Several
angiographic studies have evaluated coronary perfusion as a function
of UFH therapy (538-540).
More rapid resolution of ST-segment elevation has been reported
in patients treated with intravenous UFH immediately at the time
of streptokinase infusion than in those treated with intravenous
heparin started at a later time, but the OSIRIS study (Optimization
Study of Infarct Reperfusion Investigated by ST Monitoring) showed
no difference in perfusion at 24 hours (539).
In the GUSTO-I angiographic substudy, patients treated with intravenous
UFH had an 88% patency rate at 5 to 7 days compared with a 72% rate
in patients treated with subcutaneous UFH (p less than 0.05), although
less reinfarction occurred in the subcutaneous UFH group (3.4% versus
4.0%, p less than 0.05) (538).
When these angiographic studies are viewed as a whole, intravenous
UFH appears to have no clinical advantage over subcutaneous administration
when used with a nonspecific fibrinolytic agent, and the evidence
for use of subcutaneous UFH is equivocal (541).
There are few data comparing intravenous UFH to placebo.
The clinical importance of the procoagulant increase in thrombin
activity after streptokinase administration is supported by the
beneficial effect of newer antithrombins used in conjunction with
streptokinase (see Section 6.3.1.6.8.1.3).
The HERO (Hirulog and Early Reperfusion or Occlusion)-2 trial demonstrated
reduced reinfarction with intravenous bivalirudin compared with
intravenous UFH (33). The AMI-SK
study demonstrated in patients treated with streptokinase improved
ST-segment resolution at 180 minutes and higher rates of infarct-related
artery patency at 8 days for enoxaparin compared with placebo. The
composite of death, MI, and recurrent angina was reduced, but severe
bleeding was increased (1.6% versus 0.8%), with no difference in
ICH (0% to 0.4%) (542). Additionally,
a preliminary report of 5- year GUSTO-I follow-up data demonstrated
similar survival rates for streptokinase with UFH versus alteplase-assigned
patients. In the context of these new data and the event reduction
(5 fewer deaths per 1000 patients) demonstrated in the meta-analysis
(537), the recommendation for intravenous
UFH administration with non–fibrin-specific fibrinolytic agents
was changed from Class III to Class IIb.
When alteplase is the fibrinolytic agent, the empirical information
to confirm the pathophysiological reasoning discussed above is primarily
inferential. In a series of angiographic trials (543-545),
intravenous UFH led to higher rates of infarct-related artery perfusion
in conjunction with alteplase. A direct relation between duration
of aPTT and the likelihood of infarct-related artery perfusion was
observed (544,545).
An overview (546) points out, however,
that the effects of intravenous UFH on clinical outcomes from these
studies are not so convincing; a significant increase in the rate
of bleeding and nonsignificant increases in rates of reinfarction
and hemorrhagic and nonhemorrhagic stroke are evident (546).
These negative findings are tempered by a point estimate of an 18%
reduction in mortality with broad confidence limits. Until the uncertainty
is resolved, it appears judicious to use UFH for at least 48 hours
with alteplase and to target the aPTT to 1.5 to 2.0 times control
(approximately 50 to 70 seconds).
When primary PCI is chosen as the route of reperfusion, weight-adjusted
boluses of heparin of 70 to 100 U/kg are recommended. This recommendation
does not come specifically from empirical data in the setting of
STEMI but from general observations in the setting of angioplasty
that an activated clotting time of at least 250 to 350 seconds with
the HemoTec device and 300 to 350 seconds with the Hemochron device
is associated with a lower rate of complications than lower activated
clotting times (432,547,548).
When GP IIb/IIIa antagonists are used (see Section 6.3.1.6.8.2.3),
the UFH bolus should be reduced to 50 to 70 U/kg to achieve a target
activated clotting time of 200 seconds with either the HemoTec or
Hemochron device (432). UFH doses
used during PCI for failed fibrinolysis should be similarly reduced
and further lowered if used with GP IIb/IIIa antagonists as well.
The dose of UFH in the fibrinolytic-treated patient remains somewhat
controversial. Given the infarct-related artery perfusion results
just described, it would be reasonable to recommend an aPTT value
more than 3-fold higher than the median control value. However,
observational data strongly support a lower aPTT, because death,
stroke, reinfarction, and bleeding were found to be lowest in the
aPTT range of 50 to 70 seconds, or approximately 1.5 to 2.0 times
the control value (549). Because
of the evidence that the measured effect of UFH on the aPTT is important
for patient outcome and that the predominant variable mediating
the effect of a given dose of heparin is weight (549),
it is important to administer the initial doses of UFH as a weight-adjusted
bolus (541). For fibrin-specific
(alteplase, reteplase, and tenecteplase) fibrinolytic-treated patients,
a 60 U/kg bolus followed
by a maintenance infusion of 12 U/kg/h (with a maximum of 4000 U
bolus and 1000 U/h initial infusion for patients weighing more than
70 kg) is recommended. The recommended weight adjusted dose of UFH,
when it is administered without fibrinolytics, is a 60 to 70 U/kg
IV bolus and a 12 to 15 U/kg/h infusion (4).
Higher UFH doses are required for DVT and pulmonary embolism (80
U/kg and 18 U/kg/h) (550,551).
Other factors that prolong aPTT include age, sex, and creatinine
level. Elderly women may require lower bolus doses. Diabetics, smokers,
and very heavy patients (weight more than 100 kg) may require higher
UFH doses (550,552).
When used with fibrinolytic therapy, an aPTT goal of 60 to 90 seconds
is associated with an unacceptably high rate of ICH (359,553).
The recommendation of an aPTT of 50 to 70 seconds was based on the
GUSTO trials and supported by an overview of several fibrinolytic
trials (325,380).
ASSENT-3 was the first large-scale trial that used the recommended
reduced-dose weight-adjusted UFH regimen (31).
This regimen resulted in similar ICH rates but less bleeding than
the higher dose used in ASSENT-2, without an increase in ischemic
events. An aPTT measurement and dose adjustment are required beginning
at 3 hours for those who receive UFH with fibrinolytics (28).
The aPTT should be remeasured 6 hours after each dose adjustment
until it is in the target range and daily thereafter. There is wide
variability in aPTT measurement between laboratories, and it is
not known what UFH level, as measured by anti-Xa activity, corresponds
with an aPTT of 50 to 70 seconds. However, for most thromboplastin
reagents, this corresponds to 0.2 to 0.5 U/mL heparin by anti-Xa
activity.
Once
UFH has been started, the appropriate duration of therapy is uncertain.
The only randomized trial to address this issue found that discontinuation
of UFH after 24 hours after fibrinolytic therapy with alteplase
resulted in no measurable increase in ischemic events (554),
although this study did not have adequate power to detect modest
differences. A reasonable approach is to use intravenous UFH for
48 hours and then to use UFH according to the clinical characteristics
of the patient. UFH may be discontinued in low-risk patients, given
subcutaneously in patients at high risk of systemic embolization,
and given intravenously in patients at high risk for coronary reocclusion.
There
is concern that when UFH is discontinued abruptly, the patient undergoes
a high-risk period for recurrent thrombosis (heparin rebound) because
of increased thrombin activity (555,556).
Despite this concern, no specific policy has been tested to attempt
to reduce this clinical rebound effect. Several ongoing studies,
however, are reducing UFH infusions in a gradual fashion (e.g.,
by half within 6 hours, then discontinuing over the subsequent 12
hours).
Platelet
counts should be monitored daily in patients being treated with
UFH. Evidence suggests the incidence of heparin-induced thrombocytopenia
is 3% and that this is associated with a substantial risk of prothrombotic
events (557). If the platelet count
drops below 100 000, a test for heparin-induced thrombocytopenia
should be obtained, and the clinician should be vigilant for thrombotic
complications,because the prognosis in patients with thrombocytopenia
is substantially worse (558).
6.3.1.6.8.1.2. Low-molecular-weight
heparin as ancillary therapy to reperfusion therapy.
Class IIb
Low-molecular-weight heparin might be considered an acceptable alternative
to UFH as ancillary therapy for patients aged less than 75 years
who are receiving fibrinolytic therapy, provided that significant
renal dysfunction (serum creatinine greater than 2.5 mg/dL in men
or 2.0 mg/dL in women) is not present. Enoxaparin (30-mg IV bolus
followed by 1.0 mg/kg SC every 12 hours until hospital discharge)
used in combination with full-dose tenecteplase is the most comprehensively
studied regimen in patients aged less than 75 years of age. (Level
of Evidence: B)
Class III
1. Low-molecular-weight heparin should not be used as an alternative
to UFH as ancillary therapy in patients aged more than 75 years
who are receiving fibrinolytic therapy. (Level of Evidence:
B)
2. Low-molecular-weight heparin should not be used as an alternative
to UFH as ancillary therapy in patients less than 75 years who are
receiving fibrinolytic therapy but have significant renal dysfunction
(serum creatinine greater than 2.5 mg/dL in men or 2.0 mg/dL in
women). (Level of Evidence: B)
There have been no definitive phase III randomized trials
of LMWH in patients with STEMI to provide a firm basis for recommendations.
However, a number of phase II clinical trials provide encouraging
information that suggests that LMWH may be an attractive alternative
to UFH. These clinical trials include those with LMWH as ancillary
therapy to fibrinolysis and those in patients not receiving fibrinolysis
(31,158,542,559-567).
These 2 broad categories of trials with LMWH involve either enoxaparin
or dalteparin, the 2 LMWHs studied most extensively in patients
with STEMI. Clinical evaluation of LMWH as ancillary therapy to
most of the commonly prescribed fibrinolytics has been reported
with the exception of reteplase (Table
19) (31,158,542,559-567).
The available data suggest that the rate of early (60 to 90 minutes)
reperfusion of the infarct artery either assessed angiographically
or by noninvasive means is not enhanced by administration of a LMWH.
However, a generally consistent theme of a lower rate of reocclusion
of the infarct artery, reinfarction, or recurrent ischemic events
emerges in patients receiving LMWH regardless of whether the control
group was given placebo or UFH.
The most comprehensive data available are from the ASSENT-3 trial,
in which patients received tenecteplase and either UFH (bolus 60
U/kg; initial infusion 12 U/kg/h; duration of treatment equals 48
hours) or enoxaparin (bolus 30 mg; subcutaneous injections 1.0 mg/kg
every 12 hours; duration of treatment equals duration of hospital
stay) (31). Eachof the elements
of the composite end point of 30-day mortality, in-hospital reinfarction,
or in-hospital recurrent ischemia were reduced with enoxaparin treatment.
This was associated with a slight, nonsignificant increase in noncerebral
bleeding complications. In patients aged more than 75 years, the
rate of noncerebral major bleeds was 4.1% with UFH and 7.2% with
enoxaparin. Patients with significant renal dysfunction (serum creatinine
greater than 2.5 mg/dL for men and greater than 2 mg/dL for women)
were excluded from ASSENT-3, and therefore enoxaparin cannot be
recommended for use in combination with tenecteplase in patients
with severe renal dysfunction until more data are available. At
1 year, no difference was noted in the composite end point noted
above between the UFH and enoxaparin groups in ASSENT-3 (31).
However, results from the third Assessment of the Safety and Efficacy
of a New Thrombolytic PLUS (ASSENT-3 PLUS) trial underscore the
need for continued evaluation of the safety of LMWH as an adjunct
to fibrinolysis (158). Among 1639
patients with STEMI receiving tenecteplase and either enoxaparin
or UFH in a prehospital setting, higher rates of both major bleeding
(4.0% versus 2.8%; p equals 0.18) and ICH (2.2% versus 1.0%; p equals
0.05) were seen in the enoxaparin group than in the UFH group. There
was a significant interaction between patient age and risk of bleeding
because almost all cases of excess ICH were confined to patients
older than 75 years (158,568).
The Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial
Infarction Treatment-Thrombolysis In Myocardial Infarction - Study
25 (EXTRACT-TIMI-25) trial is evaluating enoxaparin versus UFH in
patients receiving fibrinolytic therapy and will provide information
on the efficacy and safety of reduced doses of enoxaparin in the
elderly.
The combination of tirofiban and enoxaparin was studied in 1224
patients presenting with STEMI in the Treatment of Enoxaparin and
Tirofiban in Acute Myocardial Infarction (TETAMI) trial (566).
Patients ineligible for fibrinolysis were randomized in a 2×2
fashion to receive either enoxaparin (intravenous 30 mg bolus and
subcutaneous injection of 1 mg/kg twice daily) or UFH (intravenous
70 U/kg bolus and 15 U/kg/h infusion) with or without tirofiban
(intravenous 10 mcg/kg bolus and 0.1 mcg/kg/min infusion) for 2
to 8 days. There were no differences noted in the primary efficacy
end point (30-day combined incidence of death, reinfarction, or
recurrent angina) between either enoxaparin and UFH monotherapy
groups (15.4% versus 17.3%) or between enoxaparin and UFH combination
groups (16.1% versus 17.2%). Major bleeding was rare and not statistically
different among all 4 groups.
6.3.1.6.8.1.3. Direct antithrombins
as ancillary therapy to reperfusion therapy.
Class IIa
In patients with known heparin-induced thrombocytopenia, it is reasonable
to consider bivalirudin as a useful alternative to heparin to be
used in conjunction with streptokinase. Dosing according to the
HERO 2 regimen (a bolus of 0.25 mg/kg followed by an intravenous
infusion of 0.5 mg/kg/h for the first 12 hours and 0.25 mg/kg/h
for the subsequent 36 hours) (33)
is recommended, but with a reduction in the infusion rate if the
partial thromboplastin time is above 75 seconds within the first
12 hours. (Level of Evidence: B)
A number of direct thrombin inhibitors are now available for use
in heparin-induced thrombocytopenia and DVT but have not yet been
approved for the treatment of acute coronary syndrome (Table
20) (39,359,368,382,383,553,569-573).
One, (bivalirudin) has been approved for use in patients with unstable
angina undergoing PCI. A meta-analysis evaluated 11 trials that
collectively enrolled more than 35 000 patients, comparing direct
thrombin inhibitors with UFH (39).
There was an approximately 25% reduction in the incidence of MI
in patients with STEMI treated with either hirudin or bivalirudin,
but there was less evident efficacy for univalent thrombin inhibitors
(argatroban, efegatran, and inogatran). Major bleeding was reduced
with bivalirudin compared with heparin (4.2% versus 9.0%; OR 0.44
[0.34 to 0.56]). There was an excess of bleeding after the use of
hirudin and no difference with univalent inhibitors; statistical
heterogeneity among these 3 groups of trials existed (39).
Subsequent to the meta-analysis, a large phase 3 study (HERO-2)
of 17 073 patients with STEMI who presented within 6 hours of onset
of chest pain was performed to evaluate the efficacy of bivalirudin
versus UFH administered in conjunction with streptokinase (33).
In the HERO-2 trial, bivalirudin did not reduce mortality compared
with UFH (10.8% versus 10.9%) but was associated with a lower rate
of adjudicated myocardial reinfarction within 96 hours (1.6% versus
2.3%, p equals 0.005). Although it was anticipated there would be
fewer hemorrhagic complications with bivalirudin, severe bleeding
occurred in 0.7% of the bivalirudin group versus 0.5% for heparin
(p equals 0.07), and intracerebral bleeding occurred in 0.6% versus
0.4% (p equals 0.09), respectively, possibly related to higher aPTT
levels in the bivalirudin group. The frequency of moderate and mild
bleeding was also greater with bivalirudin (33,323).
Bivalirudin is currently indicated only for anticoagulation in patients
with unstable angina who are undergoing percutaneous coronary angioplasty
(574). On the basis of the data
in the HERO-2 trial, the Writing Committee believes that bivalirudin
could be considered an acceptable alternative to UFH in those patients
with STEMI who receive fibrinolysis with streptokinase, have heparin-induced
thrombocytopenia, and who, in the opinion of the treating physician,
would benefit from anticoagulation.
6.3.1.6.8.1.4. Other
A phase 2 angiographic trial Pentasaccharide as an Adjunct in ST-Segment
Myocardial Infarction (PENTALYSE) evaluated fondaparinux, a synthetic
pentasaccharide that is a highly selective inhibitor of factor Xa.
Fondaparinux selectively binds antithrombin III, inducing a conformational
change that increases the anti-Xa activity of antithrombin III more
than 300 times, which results in dose-dependent inhibition of factor
Xa (575). A total of 333 patients
with evolving STEMI were treated with aspirin and alteplase and
randomized to UFH given intravenously for 48 to 72 hours or to a
low, medium, or high dose of fondaparinux. The percentage of patients
achieving TIMI grade 3 flow at 90 minutes was 68% in the UFH control
group and ranged between 60% and 69% with fondaparinux. Thus, selective
factor Xa inhibition appears to be an attractive therapeutic concept
in patients presenting with STEMI; however, further study is required
before it can be recommended for routine administration.
6.3.1.6.8.2. Antiplatelets
6.3.1.6.8.2.1. Aspirin
Class I
A daily dose of aspirin (initial dose of 162 to 325 mg orally; maintenance
dose of 75 to 162 mg) should be given indefinitely after STEMI to
all patients without a true aspirin allergy. (Level of Evidence:
A)
As discussed in Section
7.4.4 and Section 6.3.1.4, aspirin should
be given to the patient with suspected STEMI as early as possible
and continued indefinitely, regardless of the strategy for reperfusion
and regardless of whether additional antiplatelet agents are administered.
True aspirin allergy is the only exception to this recommendation.
6.3.1.6.8.2.2. Thienopyridines
Class I
1. In patients who have undergone diagnostic cardiac catheterization
and for whom PCI is planned, clopidogrel should be started and continued
for at least 1 month after bare metal stent implantation, for several
months after drug-eluting stent implantation (3 months for sirolimus,
6 months for paclitaxel), and up to 12 months in patients who are
not at high risk for bleeding. (Level of Evidence: B)
2. In patients taking clopidogrel in whom CABG is planned, the drug
should be withheld for at least 5 days, and preferably for 7 days,
unless the urgency for revascularization outweighs the risks of
excess bleeding. (Level of Evidence: B)
Class IIa
Clopidogrel is probably indicated in patients receiving fibrinolytic
therapy who are unable to take aspirin because of hypersensitivity
or major gastrointestinal intolerance. (Level of Evidence: C)
Ticlopidine and clopidogrel are ADP-receptor antagonists and are
quite similar chemically. Ticlopidine can cause neutropenia and
thrombotic thrombocytopenia. Clopidogrel is preferred because of
fewer side effects, lack of need for laboratory monitoring, and
once-daily dosing. Clopidogrel combined with aspirin is recommended
for patients with STEMI who undergo coronary stent implantation
(576-580).
There are no safety data available regarding the combination of
fibrinolytic agents and clopidogrel, but ongoing trials will provide
this information in the future. However, in patients in whom aspirin
is contraindicated because of aspirin sensitivity, clopidogrel is
probably useful as a substitute for aspirin to reduce the risk of
occlusion (581). There are no safety
data comparing 300 and 600 mg as loading doses for clopidogrel.
We do not recommend routine administration of clopidogrel as pretreatment
in patients who have not yet undergone diagnostic cardiac catheterization
and in whom CABG surgery would be performed within 5 to 7 days if
warranted (431).
6.3.1.6.8.2.3. Glycoprotein
IIb/IIIa inhibitors
Class IIa
It is reasonable to start treatment with abciximab as early
as possible before primary PCI (with or without stenting) in patients
with STEMI. (Level of Evidence: B)
Class IIb
Treatment with tirofiban or eptifibatide may be considered before
primary PCI (with or without stenting) in patients with STEMI. (Level
of Evidence: C)
The use of intravenous GP IIb/IIIa receptor inhibitors in combination
with fibrinolytic agents is discussed in Section
6.3.1.6.3.8. Intravenous GP IIb/IIIa receptor inhibitors have
also been studied as supportive antiplatelet therapy in patients
undergoing PCI. Five randomized trials compared abciximab to placebo
control in a collective total of 3666 patients undergoing primary
PCI for STEMI (34-36,38,582).
A total of 1843 patients received abciximab, a relatively small
data set on which to base recommendations for treatment. In addition,
in the setting of primary PCI, periprocedural recurrent MI is not
easily measured, so the benefit of antiplatelet therapy with GP
IIb/IIIa inhibitors is harder to determine. Finally, only 1 of the
trials, CADILLAC (Controlled Abciximab and Device Investigation
to Lower Late Angioplasty Complications), provided data on the effect
of abciximab on patients who underwent PTCA without stenting and
on patients who had a stent implanted at the time of PCI (38).
The ADMIRAL study (Abciximab Before Direct Angioplasty and Stenting
in Myocardial Infarction Regarding Acute and Long-Term Follow-Up)
(36) enrolled 300 patients with
STEMI undergoing primary stenting; half received placebo and half
received abciximab in the mobile intensive care unit or the ED before
arrival at the catheterization laboratory. Abciximab-treated patients
had higher infarct artery patency (TIMI 2/3 flow) rates (25.9% versus
10.8%) before revascularization and a better LVEF (0.61 versus 0.57)
6 months after revascularization. Abciximab-treated patients had
a lower rate of death, reinfarction, or need for subsequent target-vessel
revascularization at 30 days (6.0% versus 14.6%, p equals 0.01)
and at 6 months (7.4% versus 15.9%, p equals 0.02); the majority
of the benefit of abciximab on the composite primary end point in
ADMIRAL was driven by a reduction in urgent target-vessel revascularization.
The CADILLAC study (38) enrolled
2082 patients (88% with STEMI) undergoing primary PTCA or stenting;
half received placebo, and half were treated with abciximab in the
catheterization laboratory. At 30 days, the incidence of the primary
composite end point of death, reinfarction, revascularization, or
disabling stroke was highest in the group assigned to receive PTCA
alone (8.3%), and the lower rates in the other 3 groups were not
significantly different from one another (4.8% PTCA plus abciximab,
5.7% stenting alone, 4.4% stenting plus abciximab). The Anticoagulation
for Cardioversion using Enoxaparin (ACE) study (582)
randomized 400 patients to stenting alone or stenting plus abciximab
(administered immediately before the procedure). At 30 days, the
incidence of the primary composite end point of death, reinfarction,
target-vessel revascularization, or stroke was reduced in the stent-plus-abciximab
group (4.5%) versus the stent alone group (10.5%; p equals 0.023);
the majority of the benefit of abciximab on the primary end point
in the ACE study was driven by a reduction in the rate of reinfarction.
It is unclear whether the different 30-day results in the studies
described above are related to patient selection and risk, timing
of abciximab administration, or patency rates before revascularization
(583). Assessment of the benefit
of abciximab at 6 months varies depending on the composite end point,
with evidence in favor of its use derived from composite end points
of death/reinfarction or death/reinfarction/ urgent target-vessel
revascularization, whereas evidence of long-term benefit of abciximab
is lost if elective revascularization is added to the end point
(34,36,583).
The Writing Committee believes that it is reasonable to start treatment
with abciximab as early as possible in patients undergoing primary
PCI (with or without stenting), but given the size and limitations
of the available data set, assigned a Class IIa recommendation.
The data on tirofiban and eptifibatide in primary PCI are far more
limited than for abciximab. However, given the common mode of action
of the agents, a modest amount of angiographic data (584),
and general clinical experience to date, tirofiban or eptifibatide
may be useful as antiplatelet therapy to support primary PCI for
STEMI, with or without stenting (Class IIb recommendation).
6.3.1.6.9. Other Pharmacological
Measures.
6.3.1.6.9.1. Inhibition of Renin-Angiotensin-
Aldosterone System
Class I
1. An ACE inhibitor should be administered orally within the first
24 hours of STEMI to patients with anterior infarction, pulmonary
congestion, or LVEF less than 0.40, in the absence of hypotension
(systolic blood pressure less than 100 mm Hg or less than 30 mm
Hg below baseline) or known contraindications to that class of medications.
(Level of Evidence: A)
2. An angiotensin receptor blocker (ARB) should be administered
to STEMI patients who are intolerant of ACE inhibitors and who have
either clinical or radiological signs of heart failure or LVEF less
than 0.40. Valsartan
and candesartan have established efficacy for this recommendation.
(Level of Evidence: C)
Class IIa
An ACE inhibitor administered orally within the first 24 hours of
STEMI can be useful in patients without anterior infarction, pulmonary
congestion, or LVEF less than 0.40 in the absence of hypotension
(systolic blood pressure less than 100 mm Hg or less than 30 mmHg
below baseline) or known contraindications to that class of medications.
The expected treatment benefit in such patients is less (5 lives
saved per 1000 patients treated) than for patients with LV dysfunction.
(Level of Evidence: B)
Class III
An intravenous ACE inhibitor should not be given to patients within
the first 24 hours of STEMI because of the risk of hypotension.
(A possible exception may be patients with refractory hypertension.)
(Level of Evidence: B)
A number of large, randomized clinical trials have assessed the
role of ACE inhibitors early in the course of acute MI. All trials
in which ACE inhibitors were administered orally demonstrated a
benefit in mortality. In the ISIS-4 trial, 58000 patients with suspected
acute MI were randomly assigned within the first 24 hours (median
8 hours) to receive either oral captopril or placebo; a significant
7% relative reduction was observed in 5-week mortality among those
randomly assigned to captopril (absolute difference of 4.9 fewer
deaths per 1000 patients treated for 1 month) (152).
The largest benefit was among those with an anterior infarction.
Among the 143 fewer deaths in the group allocated captopril, 44
occurred in days 0 through 1 and 37 in days 2 through 7 (585),
which demonstrates that early therapy is important. In the GISSI-3
trial, more than 19 000 patients with either STsegment elevation
or depression were randomly assigned to lisinopril or open control
(586). There was a significant
reduction in 6-week mortality (OR 0.88; 95% CI 0.79 to 0.99); 60%
of the lives were saved during the first 5 days of treatment. The
SMILE (Survival of Myocardial Infarction: Long-Term Evaluation)
study involved 1556 patients randomly assigned within 24 hours to
receive either placebo or zofenopril (587). The
patient population was restricted to those with anterior MI who
had not received fibrinolytic therapy. Use of an early ACE inhibitor
in this trial suggested a trend of more lives saved in the first
6 weeks (RRR 25%, p equals 0.19). A Chinese captopril study involving
more than 13 600 patients with suspected acute MI also revealed
an approximate 0.5% absolute mortality benefit among those who were
randomly assigned to the ACE inhibitor compared with the control
population (588). A meta-analysis
of these major trials along with 11 smaller trials that collectively
enrolled more than 100 000 patients revealed a 6.5% overall odds
reduction (p equals 0.006) with an absolute benefit of 4.6 fewer
deaths per 1000 patients treated among those who received the ACE
inhibitor (585). These data conclusively
support a role for ACE inhibitors in the early and convalescent
phases of STEMI.
All trials with oral ACE inhibitors have shown benefit from its
early use, including those in which early entry criteria included
clinical suspicion of acute infarctions. Data from these trials
indicate that ACE inhibitors should generally be started within
the first 24 hours, ideally after fibrinolytic therapy has been
completed and blood pressure has stabilized. ACE inhibitors should
not be used if systolic blood pressure is less than 100 mm Hg or
less than 30 mm Hg below baseline, if clinically relevant renal
failure is present, if there is a history of bilateral stenosis
of the renal arteries, or if there is known allergy to ACE inhibitors.
The meta-analyses of the large ACE inhibitor trials have been useful
in defining those patient subgroups most likely to demonstrate the
greatest benefit from early post-MI ACE inhibitor therapy. According
to a meta-analysis of nearly 100000 randomized patients, the benefits
of early oral ACE inhibitors are greatest among those aged 55 to
74 years, with an anterior infarct, and with a heart rate of 80
bpm or higher (589).
ACE inhibitor therapy after STEMI should start with lowdose oral
administration and increase steadily to achieve a full dose within
24 to 48 hours. For example, in ISIS-4, an initial 6.25-mg dose
of captopril was given and, if tolerated, was followed by 12.5 mg
2 hours later, 25 mg 10 to 12 hours later, and then 50 mg twice
per day. GISSI-3 patients received 5 mg or oral lisinopril at the
time of randomization, 5 mg after 24 hours, 10 mg after 48 hours,
and then 10 mg daily for 6 weeks or open control. Similar graded-dose
schedules should be used with other ACE inhibitors such as ramipril,
zofenopril, enalapril, and quinapril. Regarding the potential for
aspirin to blunt the effect of ACE inhibitors, the Writing Committee
thought that any adverse drug interaction between aspirin and ACE
inhibitors was of a small magnitude and was far outweighed by the
benefit of the combined administration of both drugs to patients
recovering from STEMI (430,590,591).
Lower doses of aspirin are likely to minimize any potential interaction.
Finally, the only trial that did not show a benefit with ACE inhibitors
was the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS)
II, in which patients were randomly assigned within the first day
to receive either intravenous enalaprilat or placebo followed by
increasing oral dosages of either enalapril or placebo (592).
This trial was terminated early by its Safety Committee because
of the high probability that a significant benefit of enalapril
over placebo was unlikely to be demonstrated with continuation of
the trial, as well as concern over an adverse effect among elderly
patients who experienced an early hypotensive reaction. The 95%
confidence limits ranged from showing a 7% benefit to 29% harm.
Thus, intravenous enalaprilat should be avoided.
The use of ARBs has not been explored as thoroughly as ACE inhibitors
in patients with STEMI. However, clinical experience in the management
of patients with heart failure and data from clinical trials in
patients with STEMI (see Sections
7.4.3 and 7.6.4)
suggest that ARBs may be useful in patients with depressed LV function
or clinical heart failure who are intolerant of an ACE inhibitor.
Use of aldosterone antagonists in patients with STEMI is discussed
in Sections 7.4.3
and 7.6.4.
6.3.1.6.9.2. Metabolic Modulation of the
Glucose-Insulin Axis
Metabolic modulation of patients with STEMI was originally proposed
by Sodi-Pallares et al. (593) in
1962. A metaanalysis of 1932 patients in trials conducted between
1965 and 1987 demonstrated a 28% relative mortality reduction, with
an absolute benefit of 49 lives saved per 1000 patients treated
(Table 21) (594-597).
Subsequent trials in the reperfusion era show promising but variable
results. High-dose infusions of glucose-insulin-potassium (GIK)
(25% glucose, 50 IU/L soluble insulin, and 80 mmol/L KCl at a rate
of 1.5 mL/kg/h for 24 hours) or a low-dose infusion (10% glucose,
20 IU/L soluble insulin, and 40 mmol/L KCl at a rate of 1 mL/kg/h
for 24 hours) were compared to usual care. The ECLA (Estudios Cardiológicos
Latinoamérica) pilot suggested a relationship between the
time from symptom onset and impact of GIK infusion; a significant
reduction in mortality rate was observed in patients treated 12
hours or less after symptom onset (595).
The high-dose GIK regimen is being tested in large, ongoing international
trials. The potential beneficial effect of GIK in high-risk patients
with acute ischemic syndromes who have been revascularized is supported
by a study of 322 post–cardiac surgery patients with postoperative
cardiogenic shock (598). Those
assigned to GIK had a 34% (p less than 0.02) reduction in in-hospital
mortality. GIK was not superior to placebo in a study of 940 patients
who underwent primary PCI (597).
There appeared to be an interaction between treatment and Killip
class, with possible mortality reduction at 30 days in Killip class
I patients and excess mortality for those in Killip class II or
higher. No definitive recommendations regarding GIK can be formulated
until ongoing trials are completed.
6.3.1.6.9.2.1. Strict glucose
control during STEMI
Class I
An insulin infusion to normalize blood glucose is recommended for
patients with STEMI and complicated courses. (Level of Evidence:
B)
Class IIa
1. During the acute phase (first 24 to 48 hours) of the management
of STEMI in patients with hyperglycemia, it is reasonable to administer
an insulin infusion to normalize blood glucose even in patients
with an uncomplicated course. (Level of Evidence: B)
2. After the acute phase of STEMI, it is reasonable to individualize
treatment of diabetics, selecting from a combination of insulin,
insulin analogs, and oral hypoglycemic agents that achieve the best
glycemic control and are well tolerated. (Level of Evidence:
C)
The
acute phase of STEMI is associated with a dramatic increase in catecholamine
levels in the blood and ischemic myocardium. The insulin level remains
low while cortisol and glucagon levels increase, which leads to
decreased insulin sensitivity that contributes to impaired glucose
utilization. Free fatty acid levels and the concentration of their
metabolites increase, potentiating ischemic injury through several
mechanisms: direct myocardial toxicity, increased oxygen demand,
and direct inhibition of glucose oxidation. It has been suggested
that agents that support glucose oxidation could reduce postischemic
contractile dysfunction. Insulin promotes glucose oxidation, increases
adenosine triphosphate levels, and may improve the fibrinolytic
profile of patients with STEMI (599,600).
Insulin reduces free fatty acids by reducing lipolysis and enhances
glycolysis. Insulin specifically enhances glucose, lactate, and
pyruvate uptake and switches the reliance of the myocardium from
fat to carbohydrate without a change in oxygen consumption. The
oxygen requirement of the heart is stimulated by free fatty acids
without an improvement in mechanical activity (601).
Intensive insulin management of endogenous elevation of glucose
in diabetics, supplemented by potassium as needed, has potential
metabolic benefits similar to GIK for nondiabetics. The DIGAMI study
randomized 620 diabetic patients to intensive insulin therapy with
an insulin-glucose infusion for 24 hours followed by 3 months of
subcutaneous injections of insulin 4 times daily or usual care (602).
With continuous insulin infusion, blood glucose decreased in the
first 24 hours from 15.4 to 9.6 mmol/L in the infusion group versus
15.7 to 11.7 mmol/L in the control group (p less than 0.0001). There
was a trend toward lower 30-day mortality and significantly lower
1-year mortality (18.6% versus 26.1%, p equals 0.027).
Compelling evidence for tight glucose control in intensive care
unit patients (a large proportion of whom were there after cardiac
surgery) supports the importance of intensive insulin therapy to
achieve a normal blood glucose (80 to 110 mg/dL) in critically ill
patients (603,603a).
Van den Berghe et al. reported that 12-month mortality rates were
reduced from 8.0% to 4.6% (p less than 0.04; n equals 1548) for
critically ill patients assigned to intensive insulin therapy (604).
Goldberg et al. reported successful implementation of a nursing
protocol with an insulin infusion to achieve a target blood glucose
of 100 to 139 mg/dL in an intensive care setting (605).
The studies by Van den Berghe et al. and Goldberg et al. underscore
the importance and feasibility of intensive infusion therapy in
the intensive care setting. The precise target blood glucose range
requires further study.
Management of diabetic patients with STEMI should also involve consideration
of long-term hypoglycemic therapy. A review of the oral hypoglycemic
therapy of type 2 diabetes mellitus indicated that with few exceptions,
the available oral antidiabetic agents are equally effective in
lowering glucose levels. Their mechanisms of action are different.
As a result, they appear to have distinct metabolic effects that
may influence their profile and affect cardiovascular risk (606).
As suggested by Inuzzuchi, in terms of hypoglycemic effect alone,
there is no compelling reason to favor one of the major classes
of oral antidiabetic agents (606).
The overarching principle is that diabetic patients with STEMI should
ultimately receive a regimen that achieves the best glycemic control,
is well tolerated, and is likely to be maintained by the patient
over the long term.
Although it is well appreciated that type I diabetic patients require
insulin, most type 2 diabetics will also eventually need insulin
to achieve the target of a HbA1C level less than 7%, a value that
has been shown to be associated with reduced cardiovascular complications.
It is reasonable that the prescription for care of diabetics with
STEMI be individualized, selected from an armamentarium of insulin,
insulin analogs, and oral hypoglycemic agents alone or in combination
(607). A popular combination is
metformin with insulin because it results in similar metabolic control,
less weight gain, lower insulin doses, and fewer hyperglycemic episodes
than insulin alone or insulin plus sulfonylurea therapy (607).
The use of metformin must be tempered with the knowledge that metformin
is contraindicated in the presence of CHF and renal failure. It
should be withheld for 48 hours after intravenous contrast injection
(608).
6.3.1.6.9.3. Magnesium
Class IIa
1. It is reasonable that documented magnesium deficits be corrected,
especially in patients receiving diuretics before the onset of STEMI.
(Level of Evidence: C)
2. It is reasonable that episodes of torsade de pointestype VT associated
with a prolonged QT interval be treated with 1 to 2 grams of magnesium
administered as an IV bolus over 5 minutes. (Level of Evidence:
C)
Class III
In the absence of documented electrolyte deficits or torsade de
pointes-type VT, routine intravenous magnesium should not be administered
to STEMI patients at any level of risk. (Level of Evidence:
A)
Meta-analyses of 7 randomized trials published between 1984 and
1991 suggested a significant mortality benefit of magnesium (4.4%
absolute risk difference [ARD]; OR 0.44, CI 0.27 to 0.71) (609,610).
The Second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2)
subsequently reported a significant reduction in mortality with
magnesium treatment (2.5% ARD; 24% RRR; p equals 0.03) (611).
The ISIS-4 investigators enrolled 58 050 patients, of whom 29 011
were allocated to magnesium and 29 039 to control (152).
There were 2216 deaths (7.64%) by 35 days in the magnesium group
and 2103 deaths (7.24%) in the control group (OR 1.06; CI 0.99 to
1.13), which suggests no mortality benefit of magnesium administration
and even the possibility of slight harm. Critiques of ISIS-4 raised
the possibility that the null effect of magnesium resulted from
late administration of treatment to patients who were predominantly
at low risk (612,613).
The
MAGIC (Magnesium in Coronaries) trial investigated the benefits
of early administration of intravenous magnesium to high-risk patients
with STEMI (stratum I: age 65 years or older and eligible for reperfusion
therapy; stratum II: patients of any age who were not eligible for
reperfusion therapy) (614). At
30 days, 475 (15.3%) patients in the magnesium group and 472 (15.2%)
in the placebo group had died (OR 1.0, 95% CI 0.9 to 1.2, p equals
0.96). Potential explanations for the null effect of magnesium in
MAGIC include the possibility that publication bias and an inadequate
sample size in several earlier trials could have led to an overestimation
of the benefit of magnesium through a large type I error and that
the combination of mechanisms proposed for the benefits of magnesium
overlapped with and were superseded by aspirin, beta-blockers, and
ACE inhibitors (prescribed infrequently in earlier trials but commonly
in ISIS-4 and MAGIC).
Between 1980 and 2002, a total of 68 684 patients were studied in
a series of 15 randomized trials (Table
22) (614- 628).
On the basis of the totality of available evidence, in current coronary
care practice, there is no indication for the routine administration
of intravenous magnesium to patients with STEMI at any level of
risk. Magnesium can continue to be administered for repletion of
documented electrolyte deficits and life-threatening ventricular
arrhythmias such as torsade de pointes (629).
6.3.1.6.9.4. Calcium Channel Blockers
Class IIa
It is reasonable to give verapamil or diltiazem to patients in whom
beta-blockers are ineffective or contraindicated (e.g., bronchospastic
disease) for relief of ongoing ischemia or control of a rapid ventricular
response with AF or atrial flutter after STEMI in the absence of
CHF, LV dysfunction, or AV block. (Level of Evidence: C)
Class III
1. Diltiazem and verapamil are contraindicated in patients with
STEMI and associated systolic LV dysfunction and CHF. (Level
of Evidence: A)
2. Nifedipine (immediate-release form) is contraindicated in the
treatment of STEMI because of the reflex sympathetic activation,
tachycardia, and hypotension associated with its use. (Level
of Evidence: B)
Nifedipine. In patients with STEMI, immediate-release nifedipine
does not reduce the incidence of reinfarction or mortality when
given early (less than 24 hours) or late. Immediate-release nifedipine
may be particularly detrimental in patients with hypotension or
tachycardia; in these patients, it may induce a reduction in coronary
perfusion pressure, disproportionate dilatation of the coronary
arteries adjacent to the ischemic area (so-called “steal”),
and/or reflex activation of the sympathetic nervous system, with
an increase in myocardial oxygen demands (630-637).
Verapamil.
Although the overall results of trials with verapamil showed no
mortality benefits, subgroup analysis showed that immediate-release
verapamil initiated several days after STEMI in patients who were
not candidates for a beta-blocking agent may have been useful in
reducing the incidence of the composite end point of reinfarction
and death, provided LV function was well preserved with no clinical
evidence of heart failure. Verapamil is detrimental to patients
with heart failure or bradyarrhythmias during the first 24 to 48
hours after STEMI (638-641). One
randomized study of 1700 patients less than 75 years of age using
verapamil within 2 weeks of STEMI showed a significant reduction
in major events (death or reinfarction) over 18 months (3.6% ARD;
17% RRR; p equals 0.03) (642).
Diltiazem.
Data from the Multicenter Diltiazem Postinfarction Trial (MDPIT;
Q-wave and non–Q-wave infarction) (643)
and the Diltiazem Reinfarction Study (DRS; non–Q-wave infarction)
(639, 640,
644, 645)
suggest that patients with non–Q-wave MI or those with Q-wave
infarction, preserved LV function, and no evidence of heart failure
may benefit from immediate-release diltiazem. Diltiazem was begun
in MDPIT 3 to 15 days after STEMI and in DRS 24 to 72 hours afterward.
The results of MDPIT may be confounded by the fact that 53% and
55% of placebo- and diltiazem-treated patients, respectively, received
concomitant beta-blocker therapy (643).
Also, both the MDPIT and DRS projects were conducted in an era when
the use of aspirin was not as prevalent as it is today, which raises
further uncertainty about the relevance of their findings for contemporary
management of STEMI. Of particular clinical importance is the detrimental
mortality effect of diltiazem in patients with LV dysfunction. Diltiazem
was tested in patients with STEMI but without CHF who were undergoing
fibrinolytic therapy in the INTERCEPT trial (Incomplete Infarction
Trial of European Research Collaborators Evaluating Prognosis post-Thrombolysis)
(646). No effect on the cumulative
occurrence of fatal and nonfatal end points was demonstrated during
a 6-month follow-up, but there was a modest decrease in nonfatal
cardiac events, in large part due to reductions in recurrent ischemia.
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