(Circulation. 1995;91:1855-1860.)
© 1995 American Heart Association, Inc.
Articles |
From the Division of Cardiology, Department of Internal Medicine, University of Michigan Medical Center (Ann Arbor).
Correspondence to Dr Bertram Pitt, Division of Cardiology, Department of Internal Medicine, University of Michigan Medical Center, 1500 East Medical Center Dr, Ann Arbor, MI 48109-0366.
Key Words: testing stress exercise infarcts mortality
| Introduction |
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| Coronary Arteriography |
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80% diameter stenosis, it is
almost certainly hemodynamically significant, with the exception of
those with extensive collaterals. The failure of angiographically
estimated percent diameter stenosis to predict hemodynamic
significance, the occurrence of myocardial ischemia on stress testing,
or recurrent ischemic events on follow-up after infarction is likely
related to several factors, including the difficulty in estimating the
true extent of the atherosclerotic lesion by angiography as well as the
variable role of coronary vasomotor tone. Perhaps of greater importance
is the finding by Little et al9 and Nobuyoshi et
al10 that angiographically significant coronary arterial
lesions of >50% diameter stenosis are not necessarily associated with
subsequent myocardial infarction. In the study of Little et
al9 of serial angiograms, it was found that a large
proportion of recurrent myocardial infarctions was related to lesions
of <50% diameter stenosis (minimal lesion) on the baseline
arteriogram. Coronary arterial spasm as demonstrated by a positive
ergonovine response at angiography has also been identified by Fukai et
al11 as a cause of myocardial infarction in patients with
<50% diameter stenosis. Mechanisms other than classic ergonovine
coronary arterial spasm are likely to account for plaque rupture,
subsequent thrombosis, and infarction in the majority of patients with
"minimal lesions" and subsequent infarction. Coronary angiography
with the presumption that percutaneous transluminal coronary
angioplasty (PTCA) or coronary artery bypass graft surgery (CABG) of
angiographically significant coronary lesions will prevent recurrent
myocardial infarction may not be correct in that subsequent infarction
may be related, as reviewed above, to rupture of an atherosclerotic
plaque in a "minimal lesion," which would not be corrected by
current criteria for PTCA or CABG. In fact, the CASS study could not
show a significant reduction in myocardial infarction after
CABG.12 In a study of patients with one-vessel coronary
artery disease and myocardial infarction, Ogawa et al13
reported 19 episodes of recurrent myocardial infarction over a
follow-up period of 110 months. Only 1 of the 19 recurrent infarcts
could be attributed to the one-vessel lesion on the original
arteriogram. Routine coronary arteriography has not proved to be an
effective strategy to detect recurrent ischemic events, even in
relatively young patients. Cross et al14 have shown that
asymptomatic patients less than 60 years of age with a negative
exercise stress test after infarction have an excellent prognosis
despite the presence of multivessel disease on coronary arteriography.
Based on a study of postinfarction patients less than 40 years old,
Negus et al15 also concluded that routine coronary
arteriography was not indicated in asymptomatic patients after
infarction. Based on a multivariate analysis of 588 patients
discharged after myocardial infarction, Diaz et al16 could
not show that TIMI flow of the infarct-related vessel or the number of
diseased vessels was a predictor of 6-month mortality. Examination of
the infarct-related artery as to whether it is patent or occluded, with
the assumption that a patent artery serves viable myocardial tissue and
an occluded artery serves infarcted tissue, may also be erroneous.
Mahmarian et al17 found that 42% of patent
infarct-related arteries with coronary artery stenosis severity of
>80% diameter stenosis had no redistribution of 201Tl,
suggesting infarction, whereas 60% of occluded infarct-related
arteries had complete (13%) or partial (47%) redistribution,
suggesting viable myocardium. Thus, routine coronary arteriography
cannot be justified on the basis of our current knowledge to reliably
predict subsequent risk of noninfarct- or infarct-related arteries to
cause recurrent ischemic events. | Noninvasive Stress Testing |
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Another reason for the relatively low risk of patients in the study by
Moss et al1 is that they excluded patients who could not
exercise because of peripheral vascular disease, pulmonary disease, or
angina pectoris on minimal exertion. Patients who cannot undergo
exercise stress testing have been shown to be at high risk for
recurrent ischemic events.23 If we are to be successful in
predicting recurrent ischemic events, we will need to apply strategies
early after infarction that include those high-risk patients who were
not included in studies such as those by Moss et al1 and
Stevenson et al.2 This can be accomplished in part through
pharmacological stress testing with 201Tl or
echocardiography. Bolognese et al24 have shown that
dipyridamole echocardiography after infarction is a better predictor of
recurrent ischemic events than exercise ECG. Dipyridamole or adenosine
201Tl myocardial imaging may also be of value after
infarction.25 The extent of a 201Tl defect
may, however, be more important in regard to the prediction of
recurrent ischemic events and death than the presence or absence of
201Tl redistribution.17 Mahmarian et
al17 found that 90% of patients with an ischemic event
after infarction had
25% perfusion defect on single-photon emission
computed tomography 201Tl. The positive predictive accuracy
for an ischemic event was 30% when the perfusion defect size was
>30%. In those patients who can exercise, the duration of exercise
and other parameters reflecting exercise performance appear to be
better predictors of recurrent infarction and mortality than the
presence or absence of ST-segment depression.26 The
duration of exercise or workload achieved during exercise likely
reflects the extent of myocardial damage and/or exercise-induced
vasoconstriction. It has been previously shown, before the use of
thrombolytics, that the left ventricular ejection fraction (LVEF) after
infarction was an excellent predictor of ventricular arrhythmias and
survival.27 Studies in patients who have undergone
thrombolysis show that survival is improved for a given LVEF compared
with those who have not undergone thrombolysis.28 There
remains, however, an excellent correlation between the extent of
myocardial damage and subsequent mortality, although at a lower LVEF.
Patients with extensive myocardial damage are at risk for recurrent
ventricular arrhythmias, sudden cardiac death, and progressive heart
failure. Exercise and pharmacological stress testing are at best likely
to be only partially successful in detecting patients with recurrent
myocardial infarction and death since, as pointed out, many recurrent
infarcts occur due to rupture of "minimal" coronary artery
lesions that may not be hemodynamically significant. Hemodynamically
significant lesions, although likely to result in a positive stress
test, may not necessarily result in myocardial infarction or sudden
coronary death. The study by McHenry et al29 on Indiana
State Police illustrates the difficulty with exercise ECG stress
testing and pharmacological stress testing in predicting survival and
recurrent ischemic events. In that study, asymptomatic patients with a
positive exercise ECG stress test were followed for more than 10 years.
At the end of the follow-up period, those with a positive exercise ECG
stress test had a high incidence of subsequent ischemic events.
However, the patients usually presented with symptomatic angina
pectoris before their ischemic event. The larger number of patients
with an initially negative exercise ECG stress test had the highest
number of new myocardial infarctions and incidence of sudden coronary
death.
| Clinical Findings |
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| Conclusions |
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Asymptomatic individuals should undergo clinical risk stratification
after infarction. Patients with a history of prior infarction and those
with evidence of a first anterior Q-wave infarction or extensive
inferior infarction should have a resting determination of LVEF to
detect those with an LVEF of
40% who might be suitable for therapy
with an angiotensin-converting enzyme inhibitor.34
Low-risk individualssuch as those with a first Q-wave infarction,
with an LVEF of >40%, or with three or fewer of the clinical risk
factors described by Kornowski et al30 and more than 50%
of patients with a first infarctionwho are able to exercise should
undergo maximal exercise ECG testing before hospital discharge. A
maximal exercise ECG test has been found safe before hospital discharge
in low-risk patients after infarction, and maximal work capacity has
been shown to be the best exercise variable for identifying patients at
low risk for cardiac death.35 Although it could be argued
that low-risk individuals who can perform an exercise test have a low
risk of recurrent ischemic events and need not undergo formal exercise
testing, it is often reassuring for the patient and his or her family
to realize that the patient can perform moderate exercise after
discharge without risk. Although there may be some sacrifice of
sensitivity, the stress test should be performed with the patient
receiving appropriate medical therapy such as a
ß-adrenergicblocking agent.
Low-risk individuals with a negative exercise ECG test, ie, without
evidence of exercise-induced ST- segment depression or angina
pectoris, should be followed and receive appropriate medical therapy
and risk factor reduction. Those with a positive test with ST-segment
depression of <2 mm and relatively good exercise performance (
7
METs) without exercise-induced angina pectoris should also be followed
medically. The finding of ST-segment depression in this low-risk
clinical subset is likely to have a poor positive predictive accuracy,
as pointed out by Moss et al1 and Stevenson et
al.2 Patients with
2-mm exercise-induced ST-segment
depression, a relatively poor exercise performance, or exercise-induced
angina pectoris should undergo exercise 201Tl or
echocardiography. Only those with an extensive 201Tl defect
(>20% defect score)17 or large wall motion abnormality
on stress echocardiography need to be considered for coronary
angiography and possible PTCA or CABG. Fioretti et al36
and Nielsen et al35 were not able to show that
exercise-induced ischemia as demonstrated by angina pectoris,
ST-segment change, or both was associated with increased mortality in
relatively low-risk patients after myocardial infarction. Only patients
with subsequent postdischarge spontaneous or exercise-induced angina
pectoris despite optimal medical therapy and risk factor reduction
should be considered for elective coronary angiography after discharge.
The decision to perform PTCA or CABG in this group rests on the premise
that PTCA or CABG will prevent recurrent symptomatic angina pectoris
and improve the patient's quality of life, not necessarily reduce the
possibility of reinfarction or the rate of mortality.
Patients in the low-risk clinical subset as defined by Kornowski et al30 who cannot exercise should undergo pharmacological stress testing with 201Tl or echocardiography since they are at increased risk for recurrent ischemic events compared to those who can exercise.23 Only those with extensive stress 201Tl defects17 or wall motion abnormalities on echocardiography need to be referred for angiography and considered for PTCA or CABG.
High-risk patients, ie, those with more than three clinical risk
factors described by Kornowski et al30 or those with the
clinical risk factors identified by Arnold et al,32 and
those with an LVEF of
40% or an abnormal signal-averaged ECG with
late potentials should undergo exercise or pharmacological stress
testing with 201Tl or echocardiography. Only those with a
positive test as demonstrated by an extensive 201Tl defect,
wall motion abnormality, or exercise-induced angina pectoris should be
considered for coronary angiography and, if suitable, PTCA or CABG.
PTCA or CABG in those with angiographically significant lesions should
be performed to prevent recurrent angina pectoris as well as cardiac
death. Although revascularization of angiographically significant
lesions may not prevent recurrent myocardial infarction, it may make
the myocardium more able to withstand the effects of plaque rupture and
thrombosis from a minimal lesion and therefore improve survival. The
most effective strategy for reducing recurrent myocardial infarction,
and therefore mortality, should include strategies to prevent plaque
formation and rupture of minimal lesions regardless of whether
angiographically significant lesions are revascularized. There is
evidence to suggest that this can be achieved, at least in part, by
several strategies, including aspirin, Coumadin, LDL cholesterol
reduction, ß-adrenergic receptorblocking agents, and
angiotensin-converting enzyme inhibitors.37 38
This discussion is not meant to deemphasize the importance of PTCA or
CABG in symptomatic individuals and those at high risk for recurrent
myocardial infarction but rather to emphasize the importance of
"minimal" lesions and new lesion formation in recurrent
myocardial infarction and to point out the limitations of applying
exercise or pharmacological stress testing with 201Tl or
echocardiography, each of which has (although they have a 90%
sensitivity or specificity for detecting angiographically significant
coronary artery lesions and a high negative predictive accuracy)
relatively poor positive predictive accuracy for recurrent myocardial
infarction and death, especially in relatively low-risk subsets after
infarction. Future efforts should be directed at developing both
clinical and laboratory techniques for detecting patients at risk for
recurrent myocardial infarction, such as the noninvasive assessment of
endothelial dysfunction; the evaluation of cytokines, thrombotic, and
fibrinolytic factors; activation of the renin-angiotensin system; and
endothelin release. Genotyping to predict high-risk subsets in regard
to activation of the renin-angiotensin system may also be of
value.39 New understanding of the pathophysiology of
plaque rupture and thrombosis after plaque rupture holds promise for
new diagnostic and therapeutic strategies.40 41
However,
until this new understanding can be applied and validated, we need to
have a clear view of the effectiveness, limitations, and cost
implications of currently available diagnostic strategies to predict
recurrent myocardial infarction and death after infarction. The
suggested strategy outlined in the Figure
, although
imperfect, reflects my approach to the present information. Some
might agree to eliminate all stress testing in low-risk individuals who
can exercise, whereas others may believe that the exercise ECG is an
unnecessary step and that even low-risk patients should undergo
exercise 201Tl or echocardiographic stress testing. It is,
however, likely that the strategy outlined in the Figure
, or
some
modification of it, will be more cost effective and more accurate than
the strategy of performing coronary angiography in all or most patients
after infarction. There is, however, a clear need to prospectively
validate this or other proposed strategies in large-scale trials to
ensure that patients receive the most effective and cost-effective
care.
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Received August 10, 1994; revision received October 5, 1994; accepted October 14, 1994.
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