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CLINICIAN UPDATE

Changing Late Prognosis of Acute Myocardial Infarction


Impact on Management of Ventricular Arrhythmias in the Era of
Reperfusion and the Implantable Cardioverter-Defibrillator
Stefan H. Hohnloser, MD; Bernard J. Gersh, MB, ChB, DPhil
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In science, generally to solve one Case Illustration torial and include myocardial salvage,
set of problems may be to create A 54-year-old man was admitted to the reduced infarct size, and improved left
or discover a whole new set, and hospital after he experienced severe ventricular function and remodeling
of no science is this more true chest pain for approximately 8 hours. (Figure 1). Other factors that probably
than in medicine. He had an acute anterior Q-wave in- contribute substantially to the im-
George P. Elliott, farction, and he underwent coronary proved long-term prognosis include
The American Scholar, 1975 angiography with subsequent recanali- the use of aspirin, -blockers, and
zation of a totally occluded left ante- angiotensin-converting enzyme inhibi-

S
udden cardiac death (SCD) rior descending coronary artery. In ad- tors, frequent concomitant coronary re-
causes approximately 3 million dition, the right coronary artery vascularization by bypass surgery or
fatalities in the United States showed a 50% narrowing. At the time percutaneous coronary intervention,
annually.1 With the advent of the im- of discharge, echocardiography dem- and, more recently, aggressive lipid-
plantable cardioverter-defibrillator onstrated a left ventricular ejection lowering therapy.
(ICD), an intervention that reduces the fraction of 33%. Exercise stress testing
risk of arrhythmogenic death is avail- revealed no evidence of ongoing myo- Epidemiological Impact of
able.2 4 The challenge is to identify cardial ischemia. The patient requested Risk Stratification
risk factors for SCD among most pa- advice concerning his risk for subse- To be epidemiologically meaningful,
tients at relatively low risk, specifi- quent arrhythmias and SCD. prognostic tests must have a high pos-
cally including survivors of acute itive predictive accuracy with a rea-
myocardial infarction (MI), in an era Implications of sonable degree of sensitivity to ensure
when the prognosis is substantially Contemporary Therapeutic that the findings are not restricted to a
better than before the widespread use Guidelines on Mortality small minority of patients. The first
of reperfusion therapy. As in the de- After MI step toward this goal requires knowl-
scription of medicine in the epigraph The in-hospital and late survival rates edge of the total number of sudden
above, reperfusion therapy has solved of patients with acute MI have im- deaths within a specific patient popu-
one set of problems, but the improved proved substantially in the past 2 de- lation expressed as a fraction of total
prognosis has generated a whole new cades. In-hospital mortality decreased mortality within this group. Thus, for
set of questions about risk stratifica- from approximately 16% in the late an intervention specific for SCD, one
tion. This review discusses risk strati- 1970s and early 1980s to 8% to 10% in must not only identify survivors of
fication in contemporary cardiology the early 1990s. The reasons for the acute MI who are at high risk for death
for patients after acute MI. decrease in late mortality are multifac- but also predict whether arrhythmic or

From the J.W. Goethe University, Department of Medicine, Division of Cardiology, Frankfurt, Germany (S.H.H.), and the Division of Cardiovascular
Diseases and Internal Medicine, Mayo Clinic, Rochester, Minn (B.J.G.).
Correspondence to Dr Bernard J. Gersh, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
(Circulation. 2003;107:941-946.)
2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000054211.00668.9B

941
942 Circulation February 25, 2003

intermediate probability of an event


occurring; line A, a low probability;
and line C, a high probability. Irre-
spective of whether the test results are
positive or negative, the event rate for
a high probability (for example, SCD
or late ventricular arrhythmias) is high
and the event rate for a low probability
is low. Accordingly, for patients with a
high or low probability of an event, the
test does not provide substantial incre-
mental value beyond the pretest
knowledge of the likelihood of an
event. However, among patients with
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an intermediate probability of an event


Figure 1. Flow chart showing postulated sequence of effects of reperfusion therapy on occurring (line B), the difference in
electrical stability in the setting of subacute myocardial infarction. AMI indicates acute
myocardial infarction; CABG, coronary artery bypass graft; LV, left ventricular; IRA,
outcomes between a positive and neg-
infarct-related artery; PCI, percutaneous coronary intervention; and PTCA, percutaneous ative test result is substantial.
transluminal coronary angioplasty.
Implications of Reperfusion
nonarrhythmic death is more likely. concepts can be extended to various Therapy on the Mechanisms
Patients for whom arrhythmic death is tests for prognosis. Bayesian principles of Ventricular Arrhythmias
more likely may benefit from preven- can facilitate an understanding of the The genesis of sustained ventricular
tive antiarrhythmic interventions (such effect of a lower event rate on the arrhythmias is based on complex inter-
as ICD implantation), whereas such utility of tests for risk stratification, actions among an arrhythmic substrate,
treatment may provide no advantage such as for survivors of acute MI in the triggering factors, the modulating in-
for patients for whom nonarrhythmic contemporary era. This approach indi- fluence of the autonomic nervous sys-
death is more likely. tem, the electrolyte milieu, and other
cates that the post-test probability of
For risk stratification to be clinically undefined variables.
disease or an event can be calculated
useful, the methods must be applicable
from the sensitivity and specificity of
not only to specialized referral centers Substrate
the test and the pretest probability, and
but also to community hospitals in Clearly, reperfusion reduces infarct
that the post-test probability can be
which the majority of patients with size, improves left ventricular function
acute MI receive care. For this reason, plotted graphically (Figure 2).5
and ventricular remodeling, and, in
invasive procedures are unlikely to For death or arrhythmic events after
many patients, reduces recurrent ische-
gain widespread acceptance; conse- an MI, line B in Figure 2 represents an
mia.6,7 Further evidence that the ar-
quently, current research focuses on rhythmic substrate is altered in patients
the development of noninvasive meth- with a patent infarct-related artery or
ods of risk stratification. Because the in those receiving thrombolytic ther-
highest risk of SCD is within the first apy is provided by a series of other
12 months after the index MI and the studies that demonstrate a lower fre-
majority of events occurs within the quency of late potentials in such
first few months, another prerequisite patients.8,9
for risk stratification for arrhythmic
death is that it be initiated in the Triggers
predischarge period. Reperfusion has little effect on the
frequency of potential arrhythmic trig-
Bayesian Approach to the gers, such as ventricular extrasystoles
Impact of the Changing and nonsustained ventricular
Prognosis on Tests for Risk tachycardia (VT). Differences are
Stratification Figure 2. Bayesian principles applied to modest in the frequency of premature
Bayesian principles are commonly predischarge risk stratification for survi- ventricular complexes (PVCs) be-
used to evaluate the incremental value vors of myocardial infarction (see text tween patients studied in the pre-
for details). Modified from Berman et al5
of a new test for the diagnosis of with permission from W.B. Saunders reperfusion era10 and those in the more
coronary artery disease, but these basic Company. contemporary series.6 Similarly, the
Hohnloser and Gersh Prognosis of Acute Myocardial Infarction 943

frequency of nonsustained VT among of a search for new methods of risk has declined after reperfusion therapy,
a series of patients (60% of whom stratification, which remain a pivotal the correlation between impaired
received thrombolytic therapy)11 does component of the assessment of the LVEF and late mortality persists.6
not seem to be substantially different survivor of MI. According to Bayesian Nonetheless, compared with earlier
from that of earlier studies. principles, the goal of risk stratifica- studies, recent series suggest that the
tion is to identify which patients in a curve relating mortality to ejection
Modifying Factors group with a low pretest likelihood of fraction has shifted to the left, imply-
The autonomic nervous system is a an event occurring are, in fact, at ing that for a given degree of left
pivotal modifier of arrhythmic risk ac- intermediate risk and are most likely to ventricular dysfunction, the increase in
cording to both experimental and clin- receive the greatest incremental bene- mortality is somewhat less than previ-
ical data.12 Studies of patients after fit from diagnostic testing (Figure 2). ously reported (Figure 3). Another
infarction have demonstrated that study emphasized the importance of
baroreflex sensitivity as a marker of Clinical and Demographic Data
impaired diastolic function, the predic-
sympathetic-parasympathetic balance The GISSI-2 (Gruppo Italiano per lo
tive power of which was independent
is substantially and unfavorably in- Studio della Sopravvivenza nellInfarto
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Miocardico II) trial of 10 219 hospital of LVEF.18


creased in patients with an occluded
survivors who received thrombolytic
infarct-related artery compared with Ambulatory Monitoring
therapy identified the following clinical
survivors of MI who have a patent The Beta-blocker Heart Attack Trial
variables (listed in order of importance)
infarct vessel.13 Similarly, studies us- (BHAT) and other studies confirmed a
that were independently predictive of
ing heart rate variability for assess- strong association between the fre-
6-month mortality: 1) ineligibility for an
ment of cardiac autonomic tone have quency of PVCs and mortality. How-
exercise test (for cardiac or noncardiac
conclusively demonstrated that reper- ever, the futility of using only PVCs as
reasons); 2) early left ventricular failure;
fusion therapy is associated with pres- 3) left ventricular dysfunction in the markers for SCD in a contemporary
ervation of vagal tone.14 recovery phase; 4) age older than 70 patient population is demonstrated by
years; 5) electrical instability; 6) late left 6-month survival data from the
Interactions ventricular failure; 7) prior MI; and 8) GISSI-2 trial.19 An increasing fre-
What is far more striking, however, is quency of PVCs was associated with a
history of hypertension.16 For example,
the reduction in the positive predictive in a study of 103 164 patients with MI statistically significant increase in total
value of known triggering factors such who were 65 years or older, a single-risk mortality: 2% for patients with no
as PVCs and nonsustained VT in con- model (including older age, comorbidity, PVCs, 2.7% for patients with 1 to 10
temporary studies.6,11 Moreover, even heart failure, reduced left ventricular PVCs/h, and 5.5% for patients with 10
markers of an arrhythmic substrate ejection fraction [LVEF], and peripheral PVCs/h (SCD rates were 0.6%, 0.8%,
have lost much of their prognostic vascular disease) effectively stratified and 2.1%, respectively). Similarly, in
significance in patients who have re- patients according to their risk of death 1 the Canadian Assessment of Myocar-
ceived reperfusion therapy.9,15 A lower year after discharge. dial Infarction study, the frequency of
incidence of sustained VT or ventric- PVCs was similar to that described in
ular fibrillation in patients with risk Stress Testing the prethrombolytic era (Multicenter
factors previously demonstrated to Several studies examining the role of Postinfarction Research Group study),
have high predictive value reflects the treadmill exercise testing for survivors as was the relationship to mortality.
altered arrhythmogenic milieu after of MI demonstrated that patients with- What is striking, however, is the re-
successful reperfusion and contempo- out ST-segment depression had a
duction in the proportion of patients
rary adjunctive therapy. lower mortality (2% to 3%) than pa-
with left ventricular dysfunction in the
tients with ST-segment depression (ap-
more recent group.6,10 These data were
Current Approaches to Risk proximately 19%). In contrast, the
statistically significant but not clini-
Stratification in the Overall GISSI-2 trial, which compared 2
cally relevant because the rate of
Population of Survivors of MI thrombolytic regimens, demonstrated
that 6-month mortality was similar be- events was so low.
General tween patients with positive stress test Another example relates to the pres-
The overall reduction in late cardiac results and patients with negative re- ence of nonsustained VT on electro-
mortality and ventricular arrhythmias sults, and the main determinant of cardiographic monitoring. In studies
poses a formidable challenge in the prognosis was whether the patient had conducted before the widespread use
identification of the relatively few in- an exercise test.17 of reperfusion therapy in acute MI,
dividuals who have a major arrhythmic nonsustained VT was a marker for
event. Nonetheless, the increasingly Ventricular Function increased risk of subsequent death
favorable prognosis, both early and Although the proportion of patients from any cause or from arrhythmia. In
late after MI, does not negate the value with impaired left ventricular function the thrombolytic era, the prognostic
944 Circulation February 25, 2003

strated a 23% arrhythmic event rate


among patients with inducible VT or
ventricular fibrillation and an event
rate of only 5% among patients with-
out inducible arrhythmias. In patients
with nonsustained VT, the correspond-
ing rates were 14% and 6%, respec-
tively.28 Nonetheless, the lack of spec-
ificity and a growing disenchantment
with antiarrhythmic drugs led to less
use of this invasive approach to pre-
discharge risk stratification. This per-
ception is further supported by the
Multicenter UnSustained Tachycardia
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Trial (MUSTT), in which patients had


a worse prognosis even if arrhythmias
Figure 3. Comparison of patients in the prethrombolytic era (Multicenter Postinfarction were not inducible in the electrophys-
Research Group [MPRG] study) and patients in the thrombolytic era (Canadian Assess-
ment of Myocardial Infarction [CAMI] study). A, Relationship between 1-year mortality iology laboratory.
postdischarge after myocardial infarction and left ventricular ejection fraction (LVEF). B,
Relationship between 1-year mortality postdischarge after myocardial infarction and fre- Noncardiac Risk Factors
quency of premature ventricular contractions (PVCs). A and B reprinted with permission Risk stratification of survivors of MI is
from the American College of Cardiology Foundation. J Am Coll Cardiol. 1996;27:1119
1127.6 C, Distribution of left ventricular ejection fraction (EF) in the MPRG and CAMI primarily based on the use of tradi-
studies. tional measurements that reflect the
presence of left ventricular dysfunc-
significance of nonsustained VT is (BRS), which are considered to be tion, electrical stability, ischemia, and
more controversial.11,19 indicators of cardiac autonomic con- comorbidity. What should not be over-
trol, are useful prognostic indicators of looked, however, is an assessment of
Signal-Averaged the risk of arrhythmic death. After the whole patient, including the pa-
Electrocardiography extensive evaluation of these 2 risk tients age and psychosocial and socio-
For the prediction of late ventricular stratifiers in several retrospective stud- economic status. Although the nontra-
arrhythmias and SCD, several studies ies,11,24,25 investigators in the Auto- ditional psychosocial risk factors are
attested to the value of signal-averaged nomic Tonus and Reflexes After Myo- difficult to quantify, abundant evi-
electrocardiography 20 and pro- cardial Infarction (ATRAMI) study dence links psychosocial influences
grammed ventricular stimulation.21 performed a definitive prospective such as education, income, isolation,
Subsequent studies, however, drew at- study of HRV and BRS determination stress, and depression with increased
tention to the markedly lower positive for risk stratification after acute mortality, probably mediated by al-
predictive value of both tests in pa- MI.26,27 In the ATRAMI study, pro- tered cardiac autonomic tone, which is
tients with a patent infarct-related ar- spectively defined cutoff values were manifested by either increased sympa-
tery and in those who received used for both BRS and HRV, markers thetic or decreased parasympathetic
thrombolytic therapy.15,22,23 In these of autonomic nervous system activity. nervous system activity.29,30
studies, the tests were not altered, but The trial enrolled 1284 survivors of MI
the patient population undergoing test- (63% receiving thrombolytic therapy),
Recommendations for a
ing changed, resulting in the same tests and risk stratification including deter- Stepwise Approach to Risk
being applied to patients who had a mination of HRV and BRS was per- Stratification for Ventricular
lower risk of recurrent ischemic or formed for all participants at the time Arrhythmias in
arrhythmic events. of hospital discharge. Both markers of Asymptomatic Patients After
autonomic tone were found to yield Reperfusion Therapy
Measures of Cardiac high predictive power for subsequent For survivors of MI complicated by
Autonomic Control cardiovascular mortality. congestive heart failure, recurrent is-
Cardiac autonomic control is impor- chemia, or arrhythmias, there is little
tant in the genesis of life-threatening Invasive Electrophysiological controversy about the role of an ag-
ventricular arrhythmias.12 There is ev- Testing gressive therapeutic strategy, including
idence that markers of impaired auto- An analysis of 11 studies of pro- the implantation of an ICD. There is,
nomic tone such as heart rate variabil- grammed electrical stimulation in however, a lack of consensus about the
ity (HRV) and baroreflex sensitivity 1314 patients after an MI demon- optimal and most cost-effective ap-
Hohnloser and Gersh Prognosis of Acute Myocardial Infarction 945

proach to the predischarge assessment the implantation of an ICD. In the of highest risk for arrhythmic events,
of the asymptomatic patient who had MADIT II study, patients were as- will be investigated by these studies.
reperfusion therapy within 6 hours, or signed randomly to receive either ICD Besides allowing evaluation of the ef-
at the most 12 hours, after the onset of therapy or no ICD therapy solely on fectiveness of the respective treat-
symptoms and who had an uncompli- the basis of the finding of an LVEF ments, results of these trials will help
cated clinical course. Available data less than 31% after MI. After enroll- to establish the future role of methods
integrated into a Bayesian approach ment of 1232 patients, the trial was of risk stratification.
suggest the following stepwise ap- stopped because of a significant reduc-
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Changing Late Prognosis of Acute Myocardial Infarction: Impact on Management of
Ventricular Arrhythmias in the Era of Reperfusion and the Implantable
Cardioverter-Defibrillator
Stefan H. Hohnloser and Bernard J. Gersh
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Circulation. 2003;107:941-946
doi: 10.1161/01.CIR.0000054211.00668.9B
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2003 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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