Postinfarct risk stratification

Progress in

Cardiovascular VOL XXIX,

MAY/JUNE

NO 6

Postinfarct Arthur

J. Moss. J. Thomas

Bigger, Jr, and Charles L. Odoroff

T

tal is mechanical pump failure. Myocardial dysfunction is primarily related to the extent of myocardial damage.6 Recent animal and patient studies indicate that the evolution of myocardial infarction is a dynamic and time-dependent process. The size of the infarct is dependent on the amount of myocardium supplied by the occluded or stenotic coronary artery, the extent and timing, if any, of spontaneous thrombolysis, the extent and effectiveness of coronary collaterals, and the magnitude of the myocardial oxygen consumption as influenced by wall tension and catecholamine-related factors. In 197 1, quantitative assessment of the extent of myocardial infarction became possible through the analysis of serial changes in the serum creatine phosphokinase (CPK) activitye7 Subsequent methods that measured the myocardial band (MB) fraction of CPK provided more precise quantitation.8 It quickly became evident that infarction size was one of the major determinants of outcome during the acute, subacute, and chronic phases after myocardial infarction.’ Precise infarct sizing by serial CPK-MB enzyme determination requires frequent plasma

From the Departments of Medicine and Preventive, Family and Rehabilitation Medicine. and the Division of Biostatistics. University of Rochester School of Medicine and Dentistry, Rochester, New York; Department of Medicine, Columbia University College of Physicians and Surgeons, New York. Supported in part by Research Grant HL-22982 from the National Institutes of Health and by funds from the Gebbie Foundation (Jamestown, NY) and other private sources. Address reprint requests to Arthur J. Moss, MD. Box 653, University of Rochester, Medical Center. Rochester, NY 14642. o 1987 by Grune & Stratton, Inc. 0033-0620/87/2906-0001%5.00/0

INFARCT SIZE

The major cause of death in patients with acute myocardial infarction who reach the hospiDiseases,

Vol XXIX,

No 6 iMay/Junet,

1987

Risk Stratification

HE 1DENTIFICATION of patients with increased mortality and morbidity risk after myocardial infarction is gaining increasing attention, for it provides a rational foundation for individualizing diagnostic and therapeutic strategies. Such an approach is cost-effective and has considerable usefulness in an era of cost containment. Furthermore, risk stratification should provide valuable insight into risk mechanisms, thereby enhancing our understanding of the disease process and providing a sound basis for large-scale intervention trials. Our research group has been studying postinfarction risk stratification for several years, and we have focused our investigations on the identification of physiologically meaningful factors that influence outcome. Several recent publications from our Multicenter Post-infarction Research Group have highlighted the independent contributions of mechanical and electric factors to mortality in the posthospital phase after infarction.ls5 This article will review the current knowledge in six major physiologic topic areas as they relate to postinfarction risk stratification: (1) infarct size; (2) ventricular function; (3) ventricular arrhythmias; (4) angina pectoris; (5) exercise testing; and (6) coronary angiography. In addition, we will provide an updated review of multivariate analytic techniques that are being widely applied in the identification of the independent contribution of multiple simultaneous variables to mortality or morbidity events, which may occur at varying follow-up times after the initial evaluation.

Progress in Cmliovascuiar

Diseases

1987:

pp 389-412

389

390

sample collections, at least every four hours for three days, to determine the profile of the timeactivity enzyme release. Computation of the infarct size is derived from an algorithm that quantitates the integrated rate of release of CPK-MB into the blood with proportionality constant and body weight corrections.” The estimation of infarct size from serial changes in CPK-MB activity is directly dependent on the fractional rate of disappearance of CPK-MB from the blood. Roberts and co-workers have pointed out that the disappearance rate of CPKMB may vary substantially from patient to patient, and this variance is the major potential source of error in estimating infarct size. Thus, factors such as anesthesia, barbiturates, and disorders of the reticuloendothelial system, which significantly affect CPK-MB disappearance activity, may introduce error in infarct size computation.” The infarct size index determined from the algorithm is expressed in CPK-MBg-Eq/m’ units. Once quantitation of infarct size became available, several studies substantiated a strong and significant relationship between infarct size and early and late mortality after myocardial infarction.‘-‘* A definitive article by Geltman et al involved a prospective study of 173 first infarct patients younger than 66 years of age who survived acute myocardial infarction for at least 24 hours.’ The mean infarct size index of those who died averaged 46.5 t 5.8 (SEM) units, compared with 21.1 * 1.4 units for survivors (P cc 0.001). Overall survival was significantly better after small (infarct size index < 15 units) or moderatesize infarcts (15 to 30 units) than with large infarcts (>30 units). Regardless of the infarct location, patients with small infarcts had a better prognosis than those with larger infarcts. In this initial report, late mortality was comparable after Q wave (transmural) and non-Q wave (subendocardial) infarctions despite meaningful differences in the initial infarct size index. However, the population of patients with subendocardial infarcts was quite small (n = 31), and the authors presumed a large type II error (falsenegative result). Patients with anterior infarcts had higher mortality than those with inferior infarction, but this difference in survival disappeared when infarct location was corrected for extent of infarction using the infarct size index. Multivariate analysis substantiated the impor-

MOSS

ET AL

tance of infarct size index and peak CPK enzyme activity as independent predictors of outcome in patients sustaining their first infarct. In addition, ventricular ectopic depolarizations were more frequent among patients with modest or large infarcts (infarct size > 15 units) than those with small infarcts, regardless of infarct locus. In subsequent studies, Sobel and associates have explored in a larger population the relationship between the size of the necrosis in Q wave and non-Q wave infarctions and the significance of a second enzyme peak several days after the initial CPK-MB enzyme release in these infarct groups. Marmor et al” found in a population of 200 patients with non-Q wave infarctions were associated with significantly less myocardial damage (11 CPK-MB units) than were Q wave infarctions (25 CPK-MB units). Furthermore, 43% of the non-Q wave and 8% of the Q wave infarctions exhibited early recurrence or an extension of the initial infarct, and this was usually manifest by a second rise in CPK-MB activity beginning 248 hours after onset of the primary infarct. The hospital mortality in patients with non-Q wave infarctions who developed early extension/recurrence was 16%, compared to 7% in those without extension/recurrence. Also, in patients with recurrent infarction, the left ventricular ejection fraction decreased significantly from a mean initial value of 56 + 11% to 34 + 10% ten days later. Roberts’* concluded that the recurrence of necrosis was probably in the same vascular territory as the initial infarction, thus representing an extension within the area at risk rather than a new infarct at a different location. Furthermore, extension of the necrosis in patients with non-Q wave infarctions was associated with an increased l-year mortality when compared to patients without extension. Thus, an extension or enlargement of the size of the infarction as determined by a secondary rise in the CPK-MB enzyme activity occurs predominantly in patients with non-Q wave infarctions, is associated with a reduction in the ejection fraction, and is accompanied by increased hospital and posthospital mortality rates. The pattern of CPK-MB enzyme release after myocardial infarction is quite variable, and slow and rapid release patterns have been noted. Rapid release patterns have been observed in animal models and in patients undergoing intra-

POSTINFARCT

RISK

391

STRATIFICATION

coronary thrombolysis,‘3,‘4 and it is presumed that these patterns are a result of a washout effect. This enzyme washout has been used as an indicator of successful recanalization. Ong et alI5 studied the phenomenon of spontaneous coronary artery recanalization in a population of 52 patients with transmural myocardial infarction. Patients were divided into two groups according to whether the time from baseline to peak CPKMB enzyme activity was rapid (8.8 f 2.5 hours) or slow (19.0 k 4.9 hours). Patients with slow release (n = 28) had no significant change in global or regional ejection fraction pattern from the time of admission to discharge. However, global ejection fraction in patients with rapid release (n = 24) improved from 0.38 + 0.09 to 0.48 + 0.08 (P < 0.001) during hospitalization. The regional ejection fraction of Q wave regions showed similar improvement in the rapid enzyme release group. These findings are consistent with the idea that early enzyme release is a marker for spontaneous reperfusion, is associated with a reduction in infarct size, and results in an overall improvement in ventricular function. The early reperfusion may be due to recanalization from spontaneous thrombolysis, release of coronary spasm, or enhanced collateral flow. The similarity of the enzyme release pattern in the early reperfusion patients and in those undergoing intracoronary thrombolysis suggests that spontaneous thrombolysis is the probable mechanism for the early reperfusion. This study provided strong rationale for conducting trials to limit infarct size and thus preserve ventricular function by early administration of fibrinolytic therapy with either intracoronary streptokinase or intravenous (IV) tissue plasminogen activator. Several other techniques are available for the direct measurement of infarct size, but they have either not been adequately validated or have not gained wide clinical acceptance. Myocardial scintigrams with 99mTc stannous pyrophosphate “hot spot” imaging provides useful qualitative data about the extent, persistence, and anatomic location of the infarctionI and it is useful as a complementary technique to enzymatic infarct sizing. Nuclear magnetic resonance” and single photon emission computerized tomography’* have potential use, but their high cost and unproven clinical value prohibit their routine clinical use for evaluating infarct size at this time. Among the new imaging techniques, posi-

tron emission tomography appears to be the most promising for evaluating size and reversibility of myocardial infarction. This technique uses labeled compounds, eg, [“Cl palmitate, for the study of myocardial metabolism.” During radioactive decay, the unstable “C atom emits a positively charged positron that collides with an electron and creates a photon. The photons are sensed by detectors positioned in a circular band around the subject such that cross-sectional images of the myocardial uptake of [“Cl palmitate can be obtained. The rate of uptake is markedly reduced in the presence of ischemia, and there is no uptake in the presence of infarction. This technique can be used to evaluate the fraction of myocardium that is irreversibly injured after infarction, that which is still viable with reversible injury, and that which has a normal uptake. There are many clinical factors that indirectly reflect infarct size that have been used individually and as combined indices in risk stratification. Factors such as systolic BP on admission, shock, auscultatory rales, heart rate, respiratory rate, and pulmonary venous congestion or cardiomegaly on x-ray are almost certainly related to the amount of myocardial damage, either acutely or cumulatively from prior infarctions. Prognostic indices derived from these data, such as the Norris and Peel indices,20*2’ can predict short- and long-term outcome, and these findings indicate that extensive myocardial damage at the time of infarction is a permanent liability. ST segment mapping has been used to evaluate infarct size and the intensity of the coexisting ischemia in anterior infarctions.22 The accuracy of this method has been challenged,23 and the cumbersome methodology and analysis involved have eliminated the application of this method in the clinical setting. Invasive hemodynamic monitoring with the Swan-Ganz thermodilution catheter is useful in providing accurate quantitative information about filling pressure and blood flow, and dysfunctional alterations in these parameters are strongly associated with large infarcts and poor prognosis. VENTRICULAR

FUNCTION

Noninvasive Evaluations Three commonly used noninvasive techniques for evaluation of ventricular function after myo-

392

MOSS

cardial infarction include the radionuclide ejection fraction, echocardiography, and QRS scoring. The radionuclide ejection fraction is the most accurate of the procedures for measuring global ventricular function and has had the widest applicability.24 Ejection fractions can be obtained early after an infarction and periodically during convalescence to determine whether ventricular function is improving or deteriorating. In 1975, Schultz et al showed in a population of 81 postinfarction patients a high correlation between a low left ventricular ejection fraction and frequent ventricular ectopic beats in the late-hospital phase of myocardial infarction.” Furthermore, mortality events during a sixmonth follow-up were confined to patients with ejection fractions to.40 and advanced ventricular arrhythmias by the Lown classification. In 1978, our Multicenter Post-infarction Research Group initiated a large-scale study to identify physiologic risk factors associated with mortality and morbidity events during a l- to 3-year follow-up. Radionuclide ejection fractions were obtained on 799 patients during their hospitalization. Univariate analyses showed a progressive increase in l-year cardiac mortality as the ejection fraction declined below 0.40 (Fig l).’ Multivariate Cox survivorship analyses identified an ejection fraction to.40 and rales

s 0 I 0

1

1

IS

30

RADIONUCLIDE N-

21

I

I

1

45

60

75

EJECTION 244

Fig 1. Cardiac mortality radionuclide ejection fraction discharge after myocardial mission of the N Engl J Med.

FRACTION 382

(%)

152

rate in four categories of determined before hospital infarction. (Reprinted by pervol309, pp 331-336,l SS3.’ 1

ET AL

heard in the upper two thirds of the lung fields while the patient was in the coronary care unit as the two most significant independent risk factors. Patients with these two manifestations of left ventricular dysfunction had an eightfold mortality risk compared to patients without these factors. In a companion report of the same study population, Greenberg et al4 concluded that rales in the coronary care unit provide information about acute phase ventricular dysfunction, possibly ischemic-related reduction in ventricular compliance, whereas the radionuclide ejection fraction obtained a week or so later provides information about residual ventricular performance after the infarct has stabilized. The rales and low ejection fraction findings provide different hemodynamic information at different chronological periods during the acute infarctive process. These interpretations are further substantiated by the observations of Warnowicz et al,26 who noted a marked disparity between acute phase ventricular dysfunction (pulmonary edema) and recovery phase ventricular performance (normal ejection fraction) in selected patients with acute myocardial infarction. Additional studies by our research group highlighted the usefulness of radionuclide studies for identifying patients at risk for certain morbidity events after hospital discharge. Dwyer et al’ found that an ejection fraction to.40 was a significant independent predictor of nonfatal cardiac rehospitalization events (angina, heart failure, arrhythmia, and coronary artery surgery) but not reinfarction in the first year arfter the index infarction. The resting radionuclide ejection fraction clearly has prognostic value, and high risk patients with ejection fractions co.40 can be easily identified. A significant percentage of patients with ejection fractions >0.40 still experience mortality and morbidity events, and it is in this subgroup that exercise radionuclide ejection fraction studies may have their greatest value. Corbett et al*’ studied 6 1 postinfarction patients with submaximal exercise ejection fractions before hospital discharge. The mean ejection fraction in this population was 0.55. the patients with major cardiac events during 6-month follow-up had a significant reduction in peak exercise ejection fraction (0.44 rest to 0.37 exercise), compared to minima1 change in patients with minor cardiac events and an increase in patients

POSTINFARCT

RISK

STRATIFICATION

with no cardiac events (0.66 rest to 0.76 exercise). These findings are in contrast to those of Borer et a1,28 who did not find the exercise ejection fraction a prognostically useful test in postinfarction patients. Borer’s population generally had a low resting ejection fraction, and this finding alone carries such adverse prognostic information that minimal additional information is accrued with exercise studies. It is likely that in patients with normal resting ejection fractions, a reduction in the exercise ejection fraction suggests multivessel coronary disease,29 and this may explain the unfavorable outcome in this group of patients. The echocardiogram has also proved useful in evaluating ventricular function and in risk stratification after infarction. The rationale for use of the echocardiogram is that postmortem studies in patients dying within 30 days after acute myocardial infarction have shown that 72% of the hearts have some thinning and dilatation of the infarcted area of the myocardium within 1 week of the acute infarction.30 Furthermore, approximately one third of hearts with transmural infarction had significant expansion of the infarct zone with obvious cardiac dilatation. It is likely that infarct expansion is deleterious to the heart as a result of the increased demands associated with chamber dilatation. Two-dimensional echocardiography can detect acute alterations in cardiac topography, including regional myocardial dilatation and wall thinning. Eaton et a13’ assessed these changes by serial echocardiography in 28 patients during the first 2 weeks after acute transmural myocardial infarction. Regional end-diastolic segment lengths and wall thickness for anterior and posterior left ventricular walls were calculated. Eight patients showed infarct expansion with disproportionate dilatation and transmural thinning in the infarcted zone that was significantly different (P < 0.005) from changes in noninfarcted regions. This regional expansion led to an overall left ventricular dilatation in these eight patients of 25%, compared to 5% in the 20 patients without infarct expansion. The eight patients with regional expansion had similar peak CPK levels and Killip classification scores to those without this finding, yet their 8-week mortality was significantly higher. Eaton et al concluded that regional cardiac dilatation may be an early,

393

lethal consequence of certain types of transmural infarcts and appears to be an important mechanism of acute cardiac dilatation after myocardial infarction. Several echocardiographic studies have been reported in which the extent of left ventricular dysfunction complicating an acute myocardial infarction has been determined from a “wall motion index”.32‘34 The wall motion index is derived from visualized alterations in segmental left and right ventricular free wall movement and thickening. Each of 11 segments is assigned a numerical value based on the normality or abnormality of wall motion in terms of hypokinesis, akinesis, and dyskinesis. Adding all the values for the segments analyzed and dividing by the number of segments gives an average wall motion index. Gibson et a133used this approach in the evaluation of ventricular function in 75 consecutive patients with acute myocardial infarction. Akinesia or dyskinesia was detected in at least one of the 11 segments in all patients. Severe wall motion abnormalities outside the infarct zone were observed in 47% of patients and correlated with greater prevalence of death (P < 0.05), shock (P < O.Ol), progression to a worse Killip class (P < O.OOl), reinfarction (P < 0.01) and angina (P < 0.10). In 66 patients initially assigned to Killip class I or II, the wall motion index was highly predictive of later hemodynamic deterioration. This study corroborated the earlier work of Heger3* by demonstrating the value of early echocardiography for predicting later hemodynamic deterioration. The relationship between coronary anatomy and ventricular wall motion dysfunction after myocardial infarction has also been investigated by two-dimensional echocardiography. Stamm et a13’ identified by echocardiography three locations of ventricular asynergy (lack of systolic thickening) during an acute myocardial infarction (infarct zone, adjacent to infarct zone, and remote region) and compared these segmental wall motion abnormalities with predischarge coronary angiograms in 30 patients. Myocardial infarction in the distribution of a single coronary vessel produces a distinctive, recognizable pattern of asynergy. The stress of infarction was associated with remote compensatory hyperkinesis in 50% of patients with single-vessel disease. In 75% of patients with multivessel coronary

394

disease, the infarction stress exceeded the perfusion capacity of the additionally stenosed vessels and resulted in remote asynergy; this was rarely seen in patients with single-vessel disease. The authors also found that the extent of asynergy during acute myocardial infarction overestimated the extent of wall motion abnormality present after recovery from the infarct. One third of patients with single-vessel disease and more than two thirds of patients with multivessel disease had improvement in the extent of asynergy during follow-up echocardiography I to 2 weeks later. The authors concluded that remote asynergy identifies a subset of patients with significant residual myocardium at risk, ie, jeopardized myocardium. Remote asynergy is associated with early reinfarction,33 further myocardial events, and a poor prognosis when compared to patients with normal contractility in adjacent and remote areas of the acute infarction. A third noninvasive technique for evaluating postinfarction ventricular function involves the ECG. Several investigators have used QRS mapping in the evaluation of cardiac function,36-38 but the sensitivity and specificity were less than satisfactory. A different QRS scoring system was developed by Sylvester et al39 that was based on dipole activation of the ventricular myocardium. The criteria for the scoring system were derived from the duration and amplitude ratios of the QRS complex applied to each of ten leads of the standard 12-lead scalar ECG. Patients with left ventricular hypertrophy or conduction abnormalities were excluded. The primary observation in each lead was the duration in milliseconds of the initial Q or R wave. When a single lead met several criteria for either the duration or the amplitude ratio, only the criterion with the greatest number of points was considered. Using this approach, Palmeri et a14’ assessed left ventricular function in 55 postinfarct patients without left ventricular hypertrophy or conduction abnormalities. Multigated radionuclide angiography was used to measure left ventricular ejection fraction as well as segmental wall motion abnormalities. The QRS scores correlated inversely with the ejection fraction (r = -0.88 at 3 weeks after infarction) and were proportional to the severity of the wall motion abnormality. The authors derived a linear regres-

MOSS

ET AL

sion equation to estimate the ejection fraction from the QRS score, EF (%) = 60 - (3 x QRS score), but did not test this equation on an independent population. Two subsequently reported studies confirmed the findings of Palmeri et al, although the correlation between QRS score and left ventricular ejection fraction was weaker. Seino et a14’ studied 32 patients and recorded a correlation coefficient (r) = -0.71 between QRS score and radionuclide ejection fraction. Roubin et a14’ investigated a larger population of 181 patients, used angiography to evaluate the ejection fraction, and prospectively used the QRS score to predict the ejection fraction in 30 patients. The correlation coefficient (r) = -0.81 and the regression equation were similar to Palmeri et aL4’ ie, EF (%) = 66 ~ (3.3 x QRS score). Furthermore, the QRS score predicted angiographic left ventricular ejection fraction to within 12% of the actually recorded value in 29 of 30 subsequent patients. Patients with elevated QRS scores (>7 units using the Palmeri criteria4’) had severe wall motion abnormalities, higher peak CPK values, higher prevalence of multivessel coronary disease, more advanced functional class, and higher l-year mortality. Recently, Frank Marcus, MD, of our Multicenter Post-infarction Research Group retrospectively evaluated the QRS scoring system in 29 first infarct patients who met the Palmeri eligibility criteria. In this multicenter population, the correlation between QRS score and ejection fraction was poor (r = +0.18, P > 0.15) and the QRS score was not a predictor of ventricular function. On the basis of the three reported studies and our own somewhat conflicting findings, it appears that the QRS scoring system requires further clinical investigation before it is routinely applied in the functional and prognostic evaluation of individual postinfarction patients. VENTRICULAR

FUNCTION

Hemodynamic Evaluation

Since the introduction of the Swan-Ganz floatation catheter in the early 1970s for hemodynamic monitoring of infarction patients, numerous groups have documented the therapeutic and prognostic value of this circulatory informa-

POSTINFARCT

Table

1.

RISK

STRATIFICATION

Hemodynamic

Subsets

Myocsrdial

395

in Patients

with

carries greater risk than a wedge pressure elevation > 18 mm Hg. When these two hemodynamic abnormalities coexist, the acute risk appears more than additive. The recording of abnormal circulatory parameters during the early phase of the infarction also has serious long-term prognostic implications.

Acute

infarction Mwtality

PCW>lBmmHg

Subset

Cl <2.2L/min/m’

Rate (%I

I II

NO Ye-3

NO NO

III IV

No

Yes

23

Yes

Yes

51

Abbreviations: cardiac

PCW,

pulmonary

capillary

3 9

wedge

pressure:

VENTRICULAR

Cl,

index.

Reprinted

with

Holter Studies

permission.‘5

tion.43-46 The combined use of serial cardiac index, pulmonary capillary wedge pressure, and arterial pressure measurements in the critically ill infarct patient has proved invaluable. Patients with a depressed cardiac index (~2.2 L/min/ m2), an elevated wedge pressure (2 18 mm Hg), or reduced BP (< 100 mm Hg systolic) have a poor prognosis. Forrester et aP reported a hospital mortality of 5% in 95 patients with a cardiac index >2.2 L/min/m* and 45% in 105 patients with a cardiac index below this value. Shell et a147 observed a 10% 30-day mortality in patients with pulmonary capillary wedge pressures ~18 mm Hg, compared with 33% in patients with higher filling pressures. Similar findings were reported by Cohn et a1.48Combinations of abnormal circulatory parameters have been used to identify hemodynamic subsets with various mortality rates. The hemodynamic classification scheme and the associated in-hospital mortality rates developed by Forrester et a14’ are presented in Table 1. The ordinal increase in mortality with progressive hemodynamic embarrassment is clearly evident. A cardiac index ~2.2 L/min/m’ Table

2.

Frequency

and

Characteristics Duration of Recording

of Ventricular

Recently, three large studies have analyzed 24-hour ECG recordings made about ten days after myocardial infarction using sensitive and specific computerized arrhythmia detectors. ‘*2,49.50The frequency of ventricular premature depolarizations (VPD) is not high at this time; more than half the patients have fewer than 1.0 VPD/h. Only 15% to 25% have ten or more VPD/h (Table 2). The S-shaped curve relating mortality rate to risk is shown in Fig 2. The 50% to 60% of patients with average VPD frequency below l/h have a 2-year mortality rate of about 5%. The curve rises steeply between one and ten VPD/h to mortality rates over 20%1.‘,~+~~ As VPD frequency rises another two orders of magnitude, mortality rates do not increase very much. Mortality rates are 2.5 to 4 times as great for patients with ten or more VPD/h in a 24-hour ECG recording as for patients with lower VPD frequencies (Table 2). Also, the shape of the VPD mortality curve suggests that, if studies are done to test the hypothesis that effective treatment of VPD after myocardial infarction will reduce mortality, the VPD frequency criterion for enrolling should be no higher than IO/h. The Arrhythmias

Frequency

Two

Weeks

after

(h)

0

>l/h

Stanford University

Unwerslty of Rochester

10 6

95 500

24 47

76

30 5

43

University Washington

of Ghent University University

150 238 616

41 26

Columbia MPIP

6-8 10 24

23 17 25

24 45 54

24

819

16 14

58 43 50 41

24

533

16

20 15

MILIS Abbreviation: VT, ventricular ‘R-V/QT < 1 .OO. tR-V/QT

Acute

of VPD (%I

No. of Patients

Institution

ARRHYTHMIAS

210/h

Myocardial

Infarction

VPD Characteristics

(%)

Multiform

Pairs

v-r

R-on-T

16 3

17 1

10”

24 15

15 2

64

31 17

12 11

66

26

11

10

2t 18’ 27* 24. 10.

tachycardia.

< 0.85.

Reprinted with With Antiarrhythmic

permission Drugs.”

of Raven in Fozzard

Press, New York, from Bigger et al: “Epidemiology et al (eds): The Heart and Cardiovascular Sysremt

of Ventricular Scienfific

Arrhythmias

foundations,

and Clinical

@ 1 986.5’

Trials

396

MOSS

sharp rise in the curve relating mortality rate to VPD frequency also implies that protocols designed to determine the ability of antiarrhythmic drugs to reduce VPD frequency should use 10 VPD/h as the enrolling criterion. Previous studies have suggested that “complex” VPD features are at least as important as frequency, ie, have as strong an association with death during follow-up. Early studies proposing this concept used short ECG recordings and polyvalent definitions of complex ventricular arrhythmias.5’.s2 We have looked carefully at the relationship between individual complex VPD features and mortality in two separate large samples of postinfarction patients using 24-hour recordings and have concluded that repetitive, ie, pairs or runs of VPD, are very important predictors of subsequent mortality.2*49,53 Using multivariate statistical techniques, two independent studies found that repetitive VPD are associated with death independent of VPD frequency.2*49 Figure 3 shows survivorship over 3 years as a function of repetitive VPD. An increasing degree of repetitiveness of VPD is associated with decreasing survivorship. Unsustained ventricular tachycardia occurring in a predischarge 24-hour ECG recording has a very strong relationship with subsequent mortality (odds ratio = 4.2) but occurs relatively infrequently, ie, in about 12% of the patients at ten days after myocardial infarction

2.49.S4

The Relationship Between Left Ventricular Dysfunction and Ventricular Arrhythmias After Myocardial Infarction

Interest in the relationship between left ventricular dysfunction and ventricular arrhythmias after myocardial infarction stems from a small but provocative study by Schulze et al at Johns Hopkins.2s*5’ Of 8 1 patients who had left ventricular ejection fraction measured by radionuclide ventriculography and ventricular arrhythmias detected by 24-hour ECG recording, eight died. All eight deaths occurred in the subgroup with left ventricular ejection fraction ~40% and “high grade” arrhythmias. Since all deaths occurred in the group with both risk indicators, it is impossible to evaluate the relative importance of left ventricular dysfunction and ventricular arrhythmias in predicting mortality in the Johns Hopkins study. This ambiguity gave rise to two

ET AL

L

30 z i 2 20 i 8 lo-

1

0.1

10

VPD FREQUENCY

100 (VPD/Hour)

Fig 2. S-shaped curve relating mortality tricular premature depolarization frequency Holter recording in postinfarct patients.

rate on

to ven24-hour

conflicting views on the relationship among two variables and mortality: (1) Ventricular arrhythmias are strongly associated with left ventricular dysfunction and are not independently associated with mortality, and (2) The presence of ventricular arrhythmias is a risk indicator for subsequent mortality independent of their association with left ventricular dysfunction. If the second hypothesis were true, then there would be a rationale for treating certain postinfarction ventricular arrhythmias and for performing studies to determine the effect of antiarrhythmic drugs on mortality in patients with potentially malignant ventricular arrhythmias. Recently, two multicenter studies have evalu-

s

70

60’

1

2

3

YEARS Fig 3. Survival over 3 years in postinfarct patients as a function of repetkive VPD on 24-hour Halter recordings. Note: 0, no VPD; 1. single VPD: 2. paired VPD: 3. runs of 23 VPD in a row. Numbers in parentheses indicate the frequency of occurrence of the various patterns.

POSTINFARCT

RISK

397

STRATIFICATION

ated the relationships among left ventricular dysfunction, ventricular arrhythmias, and mortality after myocardial infarction.2,50*56 The Multicenter Post Infarction Program (MPIP) was a nine-hospital natural history study of patients under age 70 who had a proven myocardial infarction. The Multicenter Investigation of the Limitation of Infarct Size (MILIS) study was a five-hospital intervention study of the effect of hyaluronidase, propranolol, or both in patients under age 76 who had acute myocardial infarction. Both studies did a 24-hour ECG recording and a radionuclide ventriculogram about ten days after infarction. Both studies used comparable high quality computer programs to analyze the 24-hour ECG recordings57-59 and standardized procedures for analyzing the radionuclide left ventricular function studies. In both MILIS and MPIP, repetitive VPD were strongly related to mortality after adjusting for left ventricular dysfunction with left ventricular ejection fraction 40.40 (Table 3). Since the risk of dying in the 2 years after myocardial infarction is independently increased by left ventricular dysfunction and ventricular arrhythmias, and multivariate hazard ratios of these two risk indicators can be multiplied to give the overall risk of dying in follow-up. In MPIP, the risk of dying in patients with low left ventricular ejection fraction, high VPD frequency, and repetitive VPD is increased about 12-fold. In MILIS, risk was increased about l6-fold when both repetitive VPD and low left ventricular ejection fraction were present. With recent studies showing definitively that potentially malignant ventricular arrhythmias

Table

3.

Dysfunction,

Ventricular and

Arrhythmias,

Left

After

Myocardial

Mortality

Ventricular Infarction

MPIP No. of patients Av follow-up (mo) VPD

MlLlS

867 22

2 10/h

533 18

20%

15% 26%

Paired VPD Ventricular tachycardia

28% 11%

LVEF < 40% LVEF < 40%. VPD Mortality rates

33% 9%

34% 8%

19% 19% 25%

24% 29% 40% 5%

2 10/h

LVEF < 40% VPD > 10/h LVEF < 40%.

VPD

> 10/h

LVEF

VPD

< 10/h

Abbreviation:

> 40%.

LVEF.

left ventricular

11%

8% ejection

fraction.

are independent indicators of mortality, the next important question is: will reducing potentially malignant ventricular arrhythmias significantly reduce mortality? Several definitive studies of class II (P-blocker) antiarrhythmic drugs have shown a decrease in arrhythmias and in mortality when treatment is used for ~2 years after infarction.6@62 The reduction in mortality rate by P-blocker treatment is greater in patients who have arrhythmias or left ventricular dysfunction during the acute phase of myocardial infarction.63 Also, the reduction in mortality rate during P-blocker treatment is greater in those patients who have substantial reduction in the spontaneous ventricular arrhythmia as a response to treatment.64 Although a number of preliminary or pilot studies have been done to determine whether class I antiarrhythmic drugs are effective in reducing mortality, no definitive trial has been attempted. The results of small pilot studies of class I antiarrhythmic drug treatment after myocardial infarction are not promising.65 However, these trials are severely flawed: patients were not selected for presence of arrhythmias, doses and drugs are not adjusted, antiarrhythmic and proarrhythmic effects were not evaluated. It is not clear that a drug or sequence of drugs can control effectively ventricular arrhythmias after myocardial infarction without producing tolerable adverse effects. It is not clear that a public health approach comparable to the current recommendation for fl-adrenergic blockade is feasible for class I antiarrhythmic drugs. The National Heart Lung and Blood Institute (NHLBI) initiated the Cardiac Arrhythmia Pilot Study to determine whether frequent or repetitive ventricular arrhythmias after myocardial infarction can be effectively controlled with a dosing strategy that permits dose ranging and drug changing.66 Preliminary results suggest that antiarrhythmic therapy is effective in suppressing ventricular ectopy, and a definite NHLBIsponsored trial has been initiated. Exercise Ventricular Arrhythmia Myocardial Infarction

After

In 1977, Granath et al reported a study of the prevalence and prognostic significance of exercise induced ventricular arrhythmias after myocardial infarction in 183 men and 22 women with

398

a mean age of 59 k 9 years6’ The treadmill test 3 weeks after acute myocardial infarction started with a load of 16 or 33 W and was advanced every four to six minutes by 16 W. Exercise was discontinued for (1) angina pectoris or dyspnea; (2) frequent VPD; and (3) heart rate >140/min; 75% of the patients stopped exercise at 150 W of effort. During exercise 3 weeks after myocardial infarction, ventricular arrhythmias occurred in 34 patients (17%). During an average follow-up of over 2 years, 47% (16/34) patients with exercise induced ventricular arrhythmias died, compared to 24% (41/ 171) of those without ventricular arrhythmias. This difference is statistically significant (P < 0.05). The odds of dying were 2.8 times as great for those who had exercise induced ventricular arrhythmias as for those who did not. At 9 weeks after myocardial infarction an exercise test was repeated in 174 of the patients, and 40 of them (23%) had ventricular arrhythmias. During follow-up, 40% (16/40) of the patients with ventricular arrhythmias died, compared to 19% (25/ 134) of the patients without ventricular arrhythmias. This difference is statistically significant. The odds of dying in patients with exercise ventricular arrhythmias in the 9-week exercise test was 2.9 times as great as in those who did not have a ventricular arrhythmias. Weld et al evaluated exercise induced ventricular arrhythmias in 236 patients who performed a low-level exercise test just before hospital discharge.68 This study of exercise testing before discharge enrolled consecutive patients who were under age 70 years. Patients with complicated myocardial infarction were exercised if they were able to walk 100 ft in the hospital hallway. Patients with unstable angina pectoris, systolic BP t90 mm Hg, or unsteady gait were not exercised. The nine-minute exercise protocol was performed one or two days before anticipated hospital discharge. The final three-minute stage was identical to stage I of the standard Bruce exercise protocol, approximately 4 MET. To evaluate ventricular arrhythmias, the ECG was recorded continuously for nine minutes prior to exercise, during exercise, and for ten minutes after exercise was completed. VPD frequency was calculated by dividing the number of VPD by the duration of the recording interval. The study group consisted of 190 men and 46 women, mean age 57 -+ 9 years. The average interval

MOSS

ET AL

between infarction and exercise testing was 16 i4 days. Of the 236 participants, 102 (43%) had one or more VPD during the exercise session and 56 patients (24%) had ten or more VPD/h. Fifty patients (22%) had complex VPD (ie, multiform VPD, R-on-T VPD, paired VPD, or ventricular tachycardia). There was no significant association between exercise test VPD and left ventricular failure in the coronary care unit (CCU), left ventricular failure at the time of exercise, cardiomegaly or pulmonary congestion in the discharge chest x-ray, or exercise duration tnine minutes. VPD were associated significantly with digoxin treatment at the time of the exercise test. Exercise VPD showed a strong association with cardiovascular death within a year of the infarct. Multiple logistic regression analysis indicated that exercise ventricular arrhythmias were significantly and independently associated with mortality after adjusting for age, previous myocardial infarction, cardiomegaly on chest x-ray, pulmonary vascular congestion on chest x-ray, exercise ST depression, and exercise duration. Thus, ventricular arrhythmias are relatively common after myocardial infarction, have a weak association with left ventricular dysfunction, and contribute independently to the prediction of l-year cardiovascular mortality when adjusting for several important clinical variables and other exercise variables that indicate left ventricular dysfunction and myocardial ischemia. Krone et a169 and the MPIP research group used the same predischarge treadmill exercise test protocol as described by Weld et a168to study patients after myocardial infarction. The presence of VPD or paired VPD before, during, or after the exercise test was associated significantly with increased cardiac mortality in the first year. In a stepwise logistic regression model, paired VPD contributed significantly to the prediction of mortality after adjusting for other clinical and exercise variables, eg, pulmonary congestion on chest x-ray, heart rate 290 min, systolic BP < 1 10 mm Hg. Thus, in this study also, exercise related VPD were significantly related to mortality as univariates after adjusting for a variety of clinical and other exercise variables. This study confirms the significant independent value of exercise induced ventricular arrhythmias in predicting cardiac mortality in the year after myocardial infarction.

POSTINFARCT

RISK

STRATIFICATION

To evaluate the possible effect of treatment on the relationship between ventricular arrhythmias during or after an exercise test on cardiac mortality, Krone et al analyzed separately the subgroups who took or did not take P-blockers or digitalis.69 A total of 187 patients (28%) were taking digoxin, and 207 patients (31%) were taking a B-blocker at the time of the test. Patients were not taken off of either of these drugs before the test. When patients taking P-blockers were analyzed as a separate group, the relationship of VPD to cardiac mortality was seen only in the patients not taking P-blockers. There was no relationship between VPD at the time of the exercise test and cardiac mortality in those taking @blockers. The opposite relationship was seen in patients who were taking digitalis at the time of the exercise test. Only patients who were taking digitalis had a higher incidence of death when exercise VPD also were present; patients not taking digitalis showed no such relationship. These results suggest significant interactions between exercise ventricular arrhythmias and treatment with either digitalis or P-blocking drugs. However, the results should be interpreted with caution, because patients were not randomly selected for treatment with ,&blockers or digitalis, and thus many other important variables aside from treatment are likely to be different between patients taking drugs and those not taking drugs. Electrophysiologic Studies After Myocardial Infarction Electrophysiologic studies are a standard technique for evaluating patients who have sustained ventricular arrhythmias. These studies are used to characterize the type and severity of ventricular arrhythmias and to evaluate treatment. Programmed ventricular stimulation has excellent sensitivity, specificity, and reproducibility for sustained ventricular tachycardia.” Also, the response of inducible ventricular arrhythmias to drug therapy or surgery has excellent predictive accuracy for death and symptomatic arrhythmias. ‘I-75 Because programmed ventricular stimulation requires cardiac catheterization, its ability to predict symptomatic arrhythmias and death after myocardial infarction has not been studied extensively. Since 1981, at least eight studies of programmed ventricular stimulation have been reported that include patients with

399

complicated and those with uncomplicated myocardial infarction.76-83 However, most of the studies are small, done on biased samples, and difficult to interpret. Three groups have reported studies that included more than 100 patients. 76,77*8’~82 These studies provide our best estimate of the prevalence and significance of inducible ventricular arrhythmias after myocardial infarction. Prevalence of inducible ventricular tachycardia. The prevalence of unsustained ventricular tachycardia or sustained ventricular tachycardia after acute myocardial infarction varies with the selection of patients, time of study after infarction, and stimulation protocol. In 198 1, Haerten et al’* reported 64 patients studied an average of 25 days after myocardial infarction. Four basic ventricular pacing rates (120, 140, 160, and 180/min) and one or two premature stimuli were delivered via bipolar catheter electrodes to the right ventricular apex. This protocol provoked unsustained ventricular tachycardia (ie, four complexes to 30 seconds of consecutive VPD) in 30% of the patients and sustained ventricular tachycardia or ventricular fibrillation in 20%. In 1982, Hamer et al reported studies in 70 patients with complicated myocardial infarction (arrhythmias or left ventricular failure).79 Each patient had a continuous 24-hour ECG recording and an electrophysiologic study while off an antiarrhythmic medications. Two ventricular pacing rates (120 and 150/min) and one premature stimulus were delivered to the right ventricular apex in all 70 patients; high current (20 mA) and two premature stimuli were used in 33 patients; and a second right ventricular site was stimulated in 50 patients. Of the 37 patients who underwent the entire protocol, eight had sustained ventricular tachycardia (22%) and four had unsustained ventricular tachycardia (11%) (ie, more than five consecutive complexes). In 1983, Richards et al reported electrophysiologic studies done off antiarrhythmic drugs in 165 patients six to 28 days after uncomplicated myocardial infarction.*’ Ventricular pacing at a rate of lOO/min with one and two premature stimuli was applied to the right ventricular apex and outflow tract at both low (twice threshold) and high (20 mA) current amplitudes. In 38 patients (23%), sustained ventricular tachycardia (> 10 seconds) or ventricular fibrillation was induced. In a 1985 abstract, the same group from

400

Westmead, Australia, reported that 62 of 306 patients (20%) had sustained inducible ventricular arrhythmias when electrophysiologic studies were performed within a month of myocardial infarction.” In 1985, Breithardt et al76 reported 132 patients studied in average of 22 days after myocardial infarction. Four ventricular pacing rates (120, 140, 160, and 180/min) and one and two premature stimuli were delivered to the right ventricular apex or right ventricular outflow tract. When four or more ventricular echo complexes occurred, stimulation was stopped. In this study, 25% of the patients had unsustained ventricular tachycardia (up to 30 seconds), and 20% had sustained ventricular arrhythmias. In 1985, Roy et al’* reported 150 patients studied 12 f 2 days after myocardial infarction with ventricular pacing at two rates (100 and 150/min), one and two premature stimuli and two sites of stimulation; 1 1% had unsustained ventricular tachycardia, 11% had sustained ventricular tachycardia, and 1% had ventricular fibrillation. Thus, studies to date indicate that about 10% to 25% of patients have inducible, sustained ventricular tachycardia soon after myocardial infarction. Interestingly, inducible ventricular arrhythmias are about as likely after uncomplicated myocardial infarction as after complicated infarction. Time course of inducible ventricular tachycardia. Klein et ala4 studied 70 patients 3 to 4 weeks after myocardial infarction and found that 16% had inducible, sustained ventricular tachycardia or ventricular fibrillation. Subsequent studies done at 6 months in 40 patients and at 12 months in 35 patients showed no significant difference in the proportion that was inducible. Costard et al*’ studied 18 patients six and 24 days after infarction with up to three premature stimuli. They found that two patients (11%) were inducible on day 6 and nine (50%) on day 24. Given the disparate results of these two small studies, conclusions cannot be reached about changes in the prevalence of inducible ventricular tachycardia as a function of time after myocardial infarction. Infarct size and prevalence of inducible ventricular tachycardia early after acute myocarRichards et al*’ found a trend dial infarction. for inducible patients to have a higher prevalence of diagnostic Q wave in ECGs and lower left ventricular ejection fractions. These findings

MOSS

ET AL

suggest that inducible ventricular tachycardia is more likely in patients who have large infarcts. On the contrary, Costard et a18’ found no relationship between inducibility of sustained ventricular arrhythmias and peak CPK, left ventricular ejection fraction, area of wall motion abnormality on left ventriculograms, or left ventricular end diastolic pressure. The lack of correlation of inducible sustained arrhythmias with indices of infarct size in the latter study conflicts with data from patients with chronic coronary heart disease and from animal models. Patients with chronic coronary heart disease and large scars, particularly those with ventricular aneurysms, are more likely to have sustained ventricular tachycardia induced during electrophysiologic studies. Spielman studied 58 patients with previous myocardial infarction who had at least 10 VPD/h and left ventricular ejection fraction t50%.86.87 In this group, 50% had inducible sustained ventricular tachycardia, a much higher rate than those found in studies of unselected patients. These data for humans agree with data for animals that show that about 40% of dogs with subacute myocardial infarction will have inducible sustained ventricular arrhythmias.88,89 In dogs with experimental myocardial infarction, the probability of having sustained ventricular tachycardia as a response to programmed ventricular stimulation is very strongly related to infarct size. Prediction of mortality by programmed venData from the three studtricular stimulation. ies of programmed ventricular stimulation early after myocardial infarction with more than 100 patients are summarized in Table 4. In the 1983 Westmead Hospital report,” patients with L 10 seconds of ventricular tachycardia or ventricular fibrillation had a l-year mortality rate of 26%, contrasted with 6% for patients who did not have one of these arrhythmias induced (P < 0.01). In inducible patients, 80% of the deaths were instantaneous, and ventricular tachyarrhythmias were documented in 63%; none of the uninducible patients died instantaneously. In 1985, the same group reported 2 1% mortality for inducible patients, compared to 4% in uninducible patients.77 Also, the Westmead group found that while inducible ventricular tachycardia had a strong relationship with subsequent mortality, ventricular fibrillation did not, a finding con-

POSTINFARCT

RISK

401

STRATIFICATION

Table

4.

Significance

of Programmed

Ventricular

Stimulation

Breithardt” Yr of study No. of patients Days between

1985 132 infarction

and elec-

22

trophysiologic study Stimulus amplitude (mA) Follow-up Prevalence

(mo) of inducible

<2 VT-S

of spontaneous VT-S during

3% 8% VT-S follow-up

VT-S, sustained

ventricular

25% 2%

Denniss”

1985 150

1985 306

12

10 -r2.

10 +_ 5 11% 5 3% 4%

20

10 + 6 20% 23 21% 4%

2 3% 1%

6 8% 0.4%

tachycardia.

gruent with the finding that ventricular fibrillation induced by triple premature stimuli is a nonspecific response in chronic coronary heart disease patients. The Westmead group”**’ also found that electrophysiologic studies done within a month of myocardial infarction predicted sustained ventricular arrhythmias as well as death. The number of deaths in the studies by Breithardt’(’ and Roy ** is too small to assess the relationship between inducible ventricular tachycardia and total or sudden cardiac death. However, Breithardt did find that predischarge electrophysiologic studies after myocardial infarction accurately predicted future occurrences of sustained ventricular tachycardia. Twentyfive percent of 28 patients with inducible ventricular tachycardia experienced sustained ventricular arrhythmias during follow-up, compared to 2% of 104 patients who were not inducible. Thus, the odds of having spontaneous sustained ventricular tachycardia during follow-up were increased 14-fold in patients who had inducible ventricular tachycardia. In the study of Roy et al,** only two patients had symptomatic ventricular tachycardia during follow-up. About 50% of patients with chronic coronary heart disease, frequent ventricular arrhythmias, and reduced left ventricular ejection fraction have inducible sustained ventricular tachycardia, and the mortality rate is substantially higher in inducible patients.86,87 ANGINA

Infarction

Roy”

9

With inducible VT-S Without inducible VT-S Abbreviation:

Myocardial

8

With inducible VT-S Without inducible VT-S Occurrences Spontaneous

After

<1.5

15k 11 21%

No. of deaths Mortality rate

Early

PECTORIS

The first year, particularly the first 6 months, after acute myocardial infarction is notable for a

high frequency of coronary events. Early postinfarction angina causes serious concern because it suggests an ischemic threat. The MPIP study has several advantages for evaluating the clinical significance of early post infarction angina pectoris. First, as a prospective longitudinal cohort study, MPIP lacked many of the biases that inevitably attend either retrospective clinical studies or studies done in the placebo group of randomized intervention trials. However, MPIP is subject to biases due to treatment. The personal physicians of participating patients used conventional treatment as they saw fit. To the extent that conventional treatment modifies natural history, the results of MPIP may be biased. During the 1979 to 1981 study period, postinfarction P-blocker use was not as prevalent as it is today, and calcium channel blockers and angioplasty were not used at all. In MPIP, early postinfarction angina pectoris was defined as central chest pain occurring between two days after myocardial infarction and discharge from the hospital thought by a cardiologist to represent angina pectoris. ECGs were not systematically collected at the time of chest pain, so we do not have information on ST segment change at the time of angina. In MPIP, 33% of patients with myocardial infarction had angina pectoris before discharge.’ Predischarge angina occurred about twice as often in patients who had angina before their myocardial infarction: 48% of the patients with angina pectoris prior to the index infarct had early postinfarction angina, compared to 25% in

402

patients who did not, a statistically significant difference (P < 0.001). The hospital stay was substantially longer for patients who developed early postinfarction angina.3 Also, patients with predischarge angina were about 21/z times as likely to be rehospitalized within a year: 47% compared to 25% for the group without angina (P < 0.001). Patients with early postinfarction angina pectoris were 2’/2 times as likely to experience a nonfatal reinfarction in the first year of follow-up: 10% compared to 4% in patients without angina. Also, patients with early postinfarction angina composed a large fraction of all recurrent myocardial infarction. Of the 5 1 recurrent infarctions in the first year, 54% had previously experienced early postinfarction angina pectoris.3 Early postinfarction angina pectoris was a better predictor of recurrent infarction in the first year than angina or ST depression in an exercise test and also a better predictor than non-Q wave infarction. Despite the association with recurrent infarction, early postinfarction angina had no association with mortality in the first few years of follow-up. The probability of dying within 3 years after acute myocardial infarction is 17% in patients who develop predischarge angina pectoris and 16% in those who do not. Early postinfarction angina was not associated with the important predictors of death after infarction. Patients with early postinfarction angina were not more likely to have rales in the CCU or low values of left ventricular ejection fraction or to have frequent or repetitive VPD detected in a predischarge 24-hour ECG recording. Neither were there any interactions between these variables and angina pectoris with respect to mortality. The relationship between ventricular arrhythmias and left ventricular dysfunction and mortality is not affected by adjusting for angina pectoris. The lack of an association between early postinfarction angina and mortality was unexpected. This lack of association could be attributable to (1) misdiagnosis of angina pectoris, (2) effects of medical or surgical treatment, or (3) diversity of subgroups. The last possibility seems especially likely. It is possible that certain subgroups of patients with early postinfarction angina are at high risk despite the overall lack of association between postinfarction angina and mortality. The mortality rate during follow-up

MOSS

ET AL

was greater (23%) in patients who had angina pectoris before and after the index infarct. Only about half of the patients with early postinfarction angina have ST depression as ECG evidence of ischemia during an angina1 attack. Theroux et al found that while early postinfarction angina without ST changes had no significance, mortality was higher in patients with angina and ST depression. 9o Shuster and Bulkey further subdivided patients with ST segment changes with early postinfarction angina into two subgroups: (1) ST abnormalities in ECG leads remote from the original infarction (ischemia at a distance) and (2) ST abnormalities in the same ECG leads as the original infarction.” This sample of patients is quite biased; both subgroups had excellent left ventricular function (mean left ventricular ejection fraction = 52% t 17%), and triple-vessel coronary artery disease was common (85%). The ischemia at a distance subgroup usually had an occluded or stenotic vessel supplying the infarct and a second stenotic vessel supplying the distant ischemic zone. Those with ischemia in an area of previous infarction usually had a patent but tightly stenotic coronary artery supplying the region of the infarct, and 44% of this group (12/27) had non-Q wave infarction. The mortality was 72% within 6 months in the group with ischemia at a distance and 33% in the group with ischemia in the area of previous infarction. Most of the mortality events were judged to be ischemic. Our understanding of early postinfarction angina is still quite primitive. In the future, it will be important to define better the clinical subsets of postinfarction angina pectoris and to establish the prevalence, prognosis, and optimum treatment strategies for each one. It is likely that we will find that some groups have a very low risk of dying or developing myocardial infarction and these can be managed conservatively without resorting to angiography. Groups at high risk will be subject to coronary angiography and to clinical trials that include aggressive treatment modalities, eg, percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery. EXERCISE

TESTING

Exercise testing prior to hospital discharge is used frequently to detect risk of reinfarction or death. Usually, the Weld or Naughton protocol

POSTINFARCT

RISK

STRATIFICATION

403

Then, the logistic regression program was permitted to remove variables that did not significantly (P < 0.05) improve the fit of the model.‘04 The final model included the variables that are independently and significantly associated with 1-year mortality. These were exercise duration, exercise VPD frequency, and vascular congestion on chest x-ray.68 Neither angina pectoris nor significant ST depression (~0.1 or 20.2 mV) during a predischarge exercise test was predictive of subsequent death or nonfatal myocardial infarction. Krone et al evaluated the ability of exercise testing early after acute myocardial infarction to predict death and recurrent myocardial infarction in 667 patients who enrolled in the MPIP study.69 Increased mortality in the year after infarction was found in patients who had one or more of the following independent predictors: (1) failure to achieve a systolic BP of ~110 mm Hg; (2) inability to complete the nine-minute exercise test; and (3) the presence of paired VPD or any VPD during or after the test. Combining exercise findings with simple clinical variables identified large, low risk subgroups. For example, in 70% of the patients, systolic BP rose to 2110 mm Hg and no pulmonary congestion was present on chest x-ray. This large subgroup had a 1-year mortality rate of l%, compared with a mortality rate of 13% in the remaining 30% of patients. Statistical models showed that exercise testing contributed independent prognostic infor-

is used; the patient performs graded exercise to a maximum of 4 to 5 METS. Some of the major studies of exercise ST segment response to predischarge exercise are summarized in Table 5. The association between exercise ST changes and subsequent mortality varies strikingly among these studies. 68.69,92-98 The odds ratio for death during 1 to 2 years of follow-up in patients with 20.1 mV ST segment depression during exercise ranged from 0.3 to 19; more marked ST depression (>0.2 mV) carried no more prognostic significance. 68*69*96 Considering all of these studies, the likelihood of dying in a year or two after infarction is increased no more than twofold in patients who have ST depression ~0.1 mV during a predischarge exercise test. Variables other than ST changes, eg, exercise endurance or BP response, are better for identifying multivesse1 disease or likelihood of death or nonfatal reinfarction during follow-up.68~69~98~99-102 Weld et al showed that exercise testing before hospital discharge predicts 1-year mortality better than clinical variables.68 These investigators related the four variables in the Norris Coronary Prognostic Index’03 (age, history of previous myocardial infarction, cardiomegaly on chest x-ray, and pulmonary congestion by chest x-ray) and three continuous exercise variables (exercise duration, frequency of VPD, and degree of ST deviation) to l-year cardiac mortality in a group of 236 patients. First, all variables were forced into a multiple logistic regression analysis model. Table

5.

Prognostic

Significance

Before

et al, 1978’*

Krone Weld

Sam

Yes No Yes

et al, 1 980s3

NO Yes

et al, 1979’”

No Yes No

et al, 197gs5

Srinivasan

*Odds

Yes No

et al, 198 lea

Smith

Theroux

Yes NO

et al, 1 98569

Starling

et al, 198 1 96

Yes No Yes No

et al, 1979”

of cardiac

of Exercise Discharge

Exercise ST Depression 20.1 mV

Investigator Kaku

Hospital

death

and/or

recurrent

acute

myocardial

After

No. of Patients

Induced

ST Depression

Myocerdial

Infarction

Cardiac Deaths

14

0

31 167

3 7

500 52 183

25 7 14

42 88 18

4 6 4

67 20

0 4

42 18 136 64 146

1 6 7 16 2

infarction

occurring

~0.1

Nonfatal Reinfarctions

13

mV

Odds Ratio*

P

0.3

PO.05

0.9

>0.05

45 3

1.9

>0.05

7 6

2.0

1>0.05

6 2

3.6

>0.05

7.3

<0.05

9.0

co.05

19.7

<0.05

8 2 1 -

when

exercise

ST depression

is present

v absent.

404

MOSS

mation predicting mortality and recurrent nonfatal myocardial infarction. ST segment depression >O. 1 mV during or after exercise was not significantly associated with subsequent cardiac death or nonfatal reinfarction. Angina occurred during or soon after exercise in 115 patients (I 7%). and these patients were twice as likely to die of a cardiac cause in the first year as those who developed no angina during exercise. Angina during or after the exercise test provided predictive information independent from that of ST segment changes. Angina and ST segment depression each predicted the occurrence of coronary artery bypass graft surgery, and together they were impressive in their ability to predict surgery; 27% of those with both findings had surgery, compared with 9% with neither. About 7% of the patients in MPIP had coronary artery bypass surgery during the year after myocardial infarction. If surgery influences mortality or the recurrence of nonfatal reinfarction, then surgery will confound the relationship between exercise angina or ST depression and subsequent death or reinfarction. However, surgery was not thought to be a major confounding factor in MPIP, and two previous studies in which no patient underwent coronary bypass surgery showed no relationship between ST depression in early postinfarction exercise tests and mortality.‘05*‘06 Exercise With Radionuclide or Function Studies

Perfusion

The sensitivity of exercise tests to identify ischemic risk after infarction is reduced in patients with anterior myocardial infarction and/or severe left ventricular dysfunction. Recently, radionuclide techniques have been used with exercise tests to search for multivessel disease and jeopardized myocardium after myocardial infarction. Turner et al performed exercise thallium 201 perfusion scans, left ventriculograms, and coronary angiograms in 32 patients before discharge after infarction.“’ Exercise thallium perfusion scans were slightly more sensitive than exercise ST changes in identifying patients with inferior myocardial infarction and LAD stenosis. However, less than half of the patients with anterior myocardial infarction and left circumflex or right coronary artery lesions could be identified by either test. Rigo et al also found that exercise thallium perfusion scans

ET AL

were sensitive and specific in identifying multivessel coronary artery disease in patients with inferior myocardial infarction but not in patients with anterior myocardial infarction.“’ Radionuelide ventriculography has been used to evaluate global left ventricular ejection fraction and regional wall motion abnormalities during exercise after myocardial infarction.271’09,“oCorbett et al studied 60 patients and found that the exercise radionuclide ventriculogram was more sensitive and specific in predicting reinfarction or death than either the exercise ECG or resting left ventricular ejection fraction.*’ Upton et al studied 42 patients with exercise ECG and exercise radionuclide ventriculogram 3 and 8 weeks after infarction.“’ Only 21% of their patients developed 0.1 mV ST segment depression during exercise at 3 or 8 weeks. The radionuclide ventriculogram was more sensitive: 53% developed either a decrease in left ventricular ejection fraction or an increase in wall motion abnormalities during exercise. However, a decrease in global left ventricular ejection fraction during exercise is a nonspecific marker of coronary artery disease.“’ The only study specifically designed to evaluate the sensitivity and specificity of the exercise radionuclide ventriculogram to detect multivessel coronary artery diseaseafter infarction obtained results very similar to those found with exercise ECG and thallium perfusion scans.“’ A five-point decrease in global left ventricular ejection fraction had a sensitivity of 64% and a specificity of 92% for detecting multivessel diseasein inferior myocardial infarction but did not distinguish single-vesselfrom multivessel diseasein anterior myocardial infarction. Hung et al compared symptom-limited treadmill exercise electrocardiography, exercise thallium perfusion scintigraphy, and rest and exercise radionuclide ventriculography in 117 men aged 54 + 9 years tested 3 weeks after myocardial infarction.“* Patients with clinical problems, eg, arrhythmias, heart failure, unstable angina, and conduction defects, were excluded from the study. The resting ejection fraction was 0.49 +0.17, only 2% had previous myocardial infarction, and only 27% had anterior myocardial infarcts. During an average follow-up period of 11.6 months, two deaths, one cardiac arrest, and five nonfatal recurrent myocardial infarctions occurred; these were called “hard medical

POSTINFARCT

RISK

405

STRATIFICATION

events.” In addition, 14 patients were hospitalized for other important coronary events during follow-up: four for unstable angina pectoris, one for congestive heart failure, and nine for coronary artery bypass graft surgery. The findings in the diagnostic studies done 3 weeks after the index infarct were related either to the hard medical events or to the combined events (hard plus other important cardiac events) to compare the predictive accuracy of the tests. The Cox regression model was used to evaluate the independence of the associations between test findings and outcomes. Hung et al suggested that myocardial ischemia is manifested not only by traditional indices such as exercise induced ST segment depression and angina pectoris and by reversible thallium perfusion defects, but also by a low peak treadmill work load and by a decrease in left ventricular ejection fraction during exercise.“’ These workers emphasized that in this group of patients with good functional capacity, the peak treadmill work load was strongly associated with exercise induced ST segment depression and angina pectoris, while a decrease in left ventricular ejection fraction was significantly correlated with thallium defect scores. These authors emphasized the error of restricting positive test results to angina pectoris and ST segment depression, ignoring important information from variables such as peak treadmill work load, heart rate, and BP. In the multivariate analyses, exercise induced reduction in left ventricular ejection fraction and the peak treadmill workload were picked as the only independent predictors of hard medical events; these same two variables plus recurrent ischemic chest pain in the CCU were the predictors of “combined events.” Thallium myocardial perfusion scans discriminated between high and low risk patients, but the prognostic information provided by thallium scans was redundant with that provided by an exercise induced decrease in left ventricular ejection fraction on radionuclide ventriculogram. Not only was the change in left ventricular ejection fraction with exercise a better discriminator than thallium scans, but also it was much less expensive. It should be pointed out that this excellent comparative study is weakened by the small number of end points and will need further confirmation before the conclusions can be accepted. In contrast to the findings of

Hung et al, Miller et al found that high and low risk patients were identified better by resting radionuclide left ventricular ejection fraction than by exercise left ventricular ejection fraction in a group of patients with low left ventricular ejection fraction at rest.“’ Recently there has been interest in investigating the feasibility and safety of thallium scintigraphy after injection of dipyridamole IV. The rationale for this maneuver is that myocardial perfusion scintigraphy may be more sensitive than the standard exercise test and dipyridamole infusion may provide a greater stress than submaximal exercise for revealing ischemia. Leppo et al studied 51 patients with dipyridamolethallium scintigraphy one to two days before hospital discharge after myocardial infarction (ten to 16 days after admission).“* During the dipyridamole test, eight patients developed angina pectoris and seven developed ST segment depression. In addition, 33 patients (65%) had thallium redistribution during serial scans after dipyridamole injection. The stress perfusion scans were related to the 12 coronary events that occurred during a mean of 19 months follow-up: eight deaths and four nonfatal myocardial infarctions. Thallium redistribution was the only variable picked up a multiple logistic regression model as a predictor of coronary events. It should be pointed out that with the small number of outcomes to relate to the dipyridamole-thallium scintigraphy, the conclusions of this study are tentative. Nevertheless, these results are encouraging, and additional studies are warranted to establish the efficacy and safety to this diagnostic approach. The exercise ECG with or without adjunctive radionuclide techniques is reasonably sensitive and specific in identifying multivessel coronary artery disease in patients with inferior myocardial infarction or non-Q wave infarction, but neither exercise alone nor exercise combined with radionuclide techniques is reliable for detecting multivessel disease and jeopardized myocardium in patients with anterior myocardial infarction and/or severe left ventricular IO.113 Also, it should be noted that there have been no large postinfarction studies done with radionuclide exercise or dipyridamole tests. Therefore, we do not know how much, if any, they may improve the diagnostic dysfunction.2’~IO’~I

MOSS

and predictive performance of standard exercise testing. Finally, we do not know what the outcome will be of clinical actions based on these tests. To identify a problem and define it suggests approaches but does not assure their success. CORONARY

ANGIOGRAPHY

Coronary angiography can be performed safely in patients with acute myocardial infarction prior to hospital discharge.“4-“9 Possible indications for early coronary angiography are listed in Table 6. We recommend early coronary angiography for patients with non-Q wave infarction and postinfarction angina with ST changes. The role of coronary angiography to evaluate the presence of multivessel coronary artery diseaseand jeopardized myocardium postinfarction in asymptomatic patients is not established. Noninvasive methods are so sensitive and specific in identifying jeopardized myocardium in patients with inferior myocardial infarction that coronary angiography can be limited to those who have positive predischarge noninvasive tests. Due to the high prevalence (50% to 80%) of ischemic jeopardy in these patients, about half will ultimately have coronary angiography. When angiography shows a lesion in the left anterior descendingcoronary artery in an asymptomatic patient, medical therapy is usually the best treatment option. In patients with anterior myocardial infarction or severe left ventricular dysfunction, noninvasive methods are poor for detecting ischemic jeopardy. Although left ventricular dysfunction is the major determinant of mortality in patients with myocardial infarction, triple-vessel disease independently increasesrisk.“’ Sanz et al found that patients with a left ventricular ejection fraction of 21% to 49% and triple-vessel disease had a significantly higher mortality rate than patients with single- or double-vesseldiseaseand the same range of left ventricular ejection fraction.‘18 Coronary bypass surgery improved survival and reduced symptoms in chronically sympTable

6. Possible Angiography Angina Non-Q Inferior Anterior

Indications for Early Coronary After Myocardial Infarction

with ST depression wave infarct (especially anterior) infarct with positive exercise test infarct and LVEF < 30%

ET AL

tomatic patients with triple-vessel disease and left ventricular dysfunction.‘20-‘22In view of the poor survival of postinfarction patients with left ventricular dysfunction and triple-vessel disease, a randomized trial of surgical v medical therapy is warranted in this group. Sanz recommended surgery as conventional treatment for this subgroup. Coronary bypass surgery might not only alleviate ischemic jeopardy, but it also might improve left ventricular function.123*‘24Angioplasty may serve the same purpose. Because of the poor prognosis and high prevalence of multivesseldiseasein patients with severe left ventricular dysfunction and the marginal performance of noninvasive methods to detect ischemic jeopardy, it is reasonable to obtain coronary angiography in patients with left ventricular ejection fraction ~30% after infarction. About 15% of postinfarction patients will get coronary angiograms on the basis of this recommendation. It remains to be determined whether recognition and treatment of ischemic jeopardy with medical therapy, coronary angioplasty, or coronary artery bypassgraft surgery will improve survival in patients with severe left ventricular dysfunction. MULTIVARIATE

ANALYTIC

TECHNIQUES

The statistical challenge for the analysis of data from postinfarction risk stratification studiesis to describe the relationships between causal factors and the responseof interest in the presence of factors that can bias interpretation of the data. There have been substantial recent developments of statistical procedures to approach such problems, and the logic of interpreting analyses of data that are observational has received increased attention.‘2s.‘26 Evidence to guide diagnostic and therapeutic strategies comes from studies of animal models, observational studies, and clinical trials. We shall focus on the logic of observational studies and the statistical techniques that are appropriate for them, using clinical trials as a standard of comparison. Approximately 90% of the literature cited in this review is from observational studies. This empirical fact indicates the importance of observational studies in clinical medicine. Assessing the relationship between digitalis and mortality in postinfarction patients provides a convenient example. An association between

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407

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digitalis, the presumed causal factor, and mortality, the response variable, has been reported in several recent articles. These observations may or may not indicate a causal association, since other factors may influence this relationship. The principal limitation of observational studies is that the inferred relationship between a causal factor and a response may be subject to systematic error, or bias, because of the presence of measured and unmeasured confounding factors associated with both the causal factor and the response. For example, if patients receiving digitalis had lower ejection fractions, were older, and had higher mortality rates than patients not receiving digitalis, it would be difficult to disentangle the mortality effect of digitalis from that due to low ejection fraction and older age. When it is feasible to do so, the pitfalls inherent in an observational study can be overcome by a clinical trial. Clinical trials eliminate the systematic error due to confounding factors by randomizing the assignment of subjects to the causal factor. In a typical clinical trial, patients would be randomly assigned to one of two treatments; eg, digitalis or placebo. The physical act of randomization converts the systematic bias due to the confounding factor (low ejection fraction) into sampling error. Sampling error is easily handled by conventional statistical techniques. Since randomization effectively eliminates bias, randomized clinical trials are the standard against which scientific studies are judged. The primary reason why clinical trials are not more widely used is that they are often difficult and expensive to carry out. The investigator is often left with the observational approach as the only feasible method for conducting a study. The investigator must balance the freedom from systematic error and the large expense of a clinical trial against the potential for bias and the lower cost of an observational study. Observational studies frequently generate important hypotheses, and they can provide the scientific rationale for conducting definite clinical trials. There is a body of statistical procedures that can reduce to some extent the systematic error from confounding covariates in observational trials, so long as an observed value for the factor is recorded for each individual. Much of the criticism of observational studies turns on the search for unmeasured confounding factors.

There are no techniques, except randomization, that can protect against the systematic error from unmeasured confounding covariates. The best strategy available for correcting for systematic error in observational studies is to use statistical adjustment techniques. The techniques can generally be grouped under the rubric of methods called covariate adjustment. It must be emphasized that these techniques only adjust for imbalances in confounding factors that are measured. A brief word about the specific techniques of analysis is in order because so many new techniques have appeared in the medical literature in recent years. Most of the techniques can be considered variations of simple linear regression, in which the slope of a straight line quantitates the relationship between a response variable such as mortality rate and a causal variable such as infarct size. The specific technique used depends on whether the variables are continuous (eg, CPK-MB in gEq/m’ units) or categoric (eg, yes/no or alive/dead), and whether there is uniform follow-up or a variable time until the response event occurs (censoring; time-dependent survivorship). For each of the cases where (1) both the causal-confounding and response variables are continuous, (2) both are categoric, or (3) one is continuous and the other is categoric, the techniques of analysis are different. Table 7, adapted from Feinberg,“’ provides an outline of the indicated statistical techniques for analysis of continuous or categoric variables of the causal-confounding and response types. For a discussion of observational studies. cliniTable

7.

Application

of Multivariate

Analytic

Techniques

Variables

Causal-Confounding

ReSpOW9

Continuous Categorical

Continuous Continuous

Continuous categorical

and

Continuous

Continuous

Categorical

Categorical

Categorical

Continuous categorical

Adapted

and

with

Categorical

Analytic Multiple Analysis Analysis

Technique regression of variance of covariance

Logistic regression Cox proportional hazard Log-linear models istic regression Logistic regression Cox proportional hazard

permission.‘27

log-

40%

MOSS

cal trials, randomization, and the principles of covariate adjustment, Anderson et alIz and Fleiss’26 are excellent sources. Feinberg12’ provides an introduction to log-linear models, Cox and Oakes,‘28 the proportional hazard survivorship model, and McCullagh and Nelder,‘29 generalized linear models. Ingelfinger et al13’ describe some of the practical aspects of analyzing and interpreting clinical data. CONCLUSION

Risk stratification of postinfarction patients has provided considerable insight into the mortality mechanisms that are operative in this group of patients. The importance of infarct size and the potential for limiting acute infarct extension with thrombolytic therapy are areas of intense interest at this time. Left ventricular dysfunction and complex ventricular arrhythmias contribute independent mortality risks, and therapeutic clinical trials are currently underway to determine if postinfarction survival can be

ET AL

improved by appropriate treatment of patients with mechanical and electrical dysfunction. Myocardial ischemia as manifest by angina pectoris and detected by noninvasive exercise testing is now being recognized as a central mechanism in postinfarction morbidity and mortality events. One can expect more investigative and clinical attention to this topic in the future. The indications and timing for coronary angiography after infarction are still being charted, and further studies are needed to identify which patients would most benefit from this type of study. Finally, our ability to identify meaningful, significant, potent, and independent risk factors in postinfarction patients has been significantly enhanced by our ability to apply appropriate statistical procedures to the large amount of data that has been generated in recent years from this population. By identifying the risks and testing the safety and efficacy of interventional therapies, progress in this field should continue to accelerate.

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