is Clinical Associate Professor of Medicine and Director of the Heart Research Followup Program at the University of Rochester School of Medicine and Dentistry, Rochester, New York. He received his M.D. degree from Harvard Medical School and did his internship and residency at the Massachusetts General Hospital, Boston. Dr. Moss’ special areas of interest are clinical cardiology, cardiac arrhythmias and longitudinal postmyocardial infarction studies.
WHEN PRESIDENT EISENHOWER returned to work and resumed full presidential responsibilities after his acute myocardial infarction (AMI) in 1957, a new chapter in coronary disease was written. Thereafter, increasing emphasis was placed on longterm prognosis, and a number of clinical reports were published that assessed posthospital outcome in survivors of AMI. The rationale behind these prognostic stratification studies is that management can be improved by awareness of risk factors and identification of subsets of patients with homogeneous risk. By identifying factors associated with unfavorable outcome, a better understanding of the clinical disease process should ensue, resulting in more appropriate therapy. Risk stratification by functional factors such as ischemia, ventricular arrhythmias, left ventricular function and coronary patency should provide valuable information for devising rational intervention trials to reduce postinfarction morbidity and mortality. The current knowledge of the factors influencing prognosis after myocardial infarction will be reviewed, and groups at low and high risk for postinfarction complications will be described. It is hoped that this prognostic information will be useful to the clinician in the therapeutic management of postcoronary patients. POSTINFARCTION
PROGRAMS
Several prospective programs investigating the posthospital phase of myocardial infarction have made significant contributions to the field, and a summary of the larger studies with appropriate references is presented in Table 1.‘-15 Numerous other studies have been reported, but generally with populations of 6
fewer than 300 patients. These latter studies will be referred to and referenced in the course of this monograph where appropriate. DEMOGRAPHIC COMORBIDITY
AND HISTORICAL FACTORS
AGE The risk of major complications after myocardial infarction is significantly influenced by the age of the patient. The risk relationship with age is not linear, but increases exponentially beginning at 55. Since age is not amenable to intervention, some investigators consider it a risk marker rather than a risk factor. Hagstrom et aLI6 followed, for an extended period of time, 489 patients who survived an AMI. The sudden death rate for this population increased for each decade from 30 to 79 years. However, sudden death did not increase as rapidly in this postinfarction group as the rates of the population at large in the same county. Although the risk of sudden death was far greater for each decade in men who recovered from an infarction than in the general population, this differential diminished with increasing age. Thus, Hagstrom’s data indicate that a greater relative risk of sudden death exists in younger than in older patients with prior myocardial infarction when compared with patients of the same ages without coronary disease. In the Health Insurance Plan of New York City, the 4l/z-year postcoronary mortality was 14.7% for men under 55 years and 20.4% for those over this age.17 Subsequent reports from this group revealed that the 3-year cumulative death rates from any cause were 10.4% for men under 55, 16.7% for men 55-64 and 23.7% for those 65 or older.6 Corresponding 3-year rates for sudden cardiac death in this postinfarction population were 4.5%, 7.2% and 10.4%, respectively. In a number of postinfarction prognostication studies in which patient age was unrestricted, multivariate techniques used increasing age as a weighted factor. In the Peel prognostic index using 6 variables, age 65 or over carried more weight than a prior history of angina, mild hypotension, congestive basilar rales or ST- and T-wave abnormalities, and was weighted equally with a history of exertional dyspnea or Q-waves on the initial ECG.18 Norris et al.ls found that increasing age above 70 years at the time of infarction was associated with significantly reduced 3- and 6-year survival. Moss et al.** using a stepwise discriminant analysis technique for predicting survival after myo-
Follow-up interval
is given in months unless otherwise specified.
12-60
20 years
24
Prognostic significance of VPB; risk stratification by survivorship analyses
Clinical course; VPBs and sudden cardiac death Risk classification by logistic regression analysis Natural history study with life table analyses
6-48 (Average,
24)
Prognostic importance of ECG findings
THE POSTHOSPITAL (p MI)
36
1. -PROSPECTIVE PROGRAMS INVESTIGATING PHASE OF MYOCARDIAL INFARCTION
Coronary Drug Men 565 years; 2,035 Project-Control Group1-3 >3 mo. p MI; NYHA I or II (1965 - 1972) Health Insurance Men ~74 years; 1,739 Plan-N.Y.C.4-r 50% >3 mo. p MI (1972 - 1976) Giiteborg PostMen 567 years; 292 infarction Studya, 9 before discharge; (1968 - 1972) first infarction Framingham Heart Men and women 319 Disease Epidemiology 580 years; Studylo onset of MI (1950 - 1970) Rochester Heart Research Men and women 978 Follow-up Program~~~15 565 years; (1973 - 1978) before discharge
TABLE
cardial infarction in an unrestricted age population, found that increased age was one of the most important factors in identifying patients with increased mortality risk. In contrast, Bigger et a1.2o did not find age a good predictor of early posthospital death after infarction. It appears that Bigger’s population had more extensive myocardial damage than the patients reported by MOSS,” and the increased occurrence of severe left ventricular dysfunction in Bigger’s study overwhelmed the age factor. In a number of postinfarction studies in which patients over age 65 or 70 were excluded, the age factor had a negligible influence on outcome. SEX
The relatively low incidence of coronary heart disease among women in comparison with men is well known. In most of the postinfarction studies reported in the literature, men outnumbered the women by a ratio of roughly 411. After coronary disease becomes clinically manifest in women, is its course similar to that in men? This question is difficult to answer because comparisons of survival between men and women patients with myocardial infarction are rare and limited by the infrequent inclusion of women in such studies. Juergens et a1.21 carried out a retrospective study from the Mayo Clinic records of the 5-year postinfarction survival rates of 127 men and 41 women. At entry, the women were on the average 7 years older than the men, but Juergens could not explain the poorer outcome in the women entirely by this age differential. Honey and Truelove, dealing with patients admitted over a E-year period to the Radcliffe Infirmary, Oxford, found no influence of sex on prognosis either in the first 8 weeks after infarction or during the remainder of the first year. In the Framingham study, 6-year follow-up data in 34 women and 158 men with myocardial infarction revealed no difference in overall survival.23 In a detailed report by the Health Insurance Plan group, the 5-year survival among 108 women and 564 men alive 1 month after infarction was similar.5 Thus, although female sex represents a low risk factor for the development of coronary disease, after a clinical infarction has occurred these women no longer enjoy protection from secondary complications. SOCIAL
CLASS
In cardiac as well as noncardiac conditions, patients in the lower socioeconomic strata of society appear to do less well with chronic disease than individuals in higher social class levels.24 Recently, Weinblatt et al.7 from the Health Insurance Plan study, substantiated a significant relationship between low educa9
tional level and sudden cardiac death during the posthospital phase of myocardial infarction. During a 3-year follow-up period after myocardial infarction, men with 8 years of schooling or less who had complex ventricular premature beats in a l-hour monitoring period had more than 3 times the risk of sudden coronary death found among better educated men with the same arrhythmia. This relationship was independent of traditional risk factors and the usual clinical characteristics affecting prognosis. In the Rochester program,25 postinfarction patients from the lower socioeconomic group (Hollingshead class 4 and 5) had a significantly increased occurrence of sudden cardiac death in the period beginning 6 months or more after hospital discharge when compared with (1) their early (less than 6 months) posthospital interval and (2) the late (more than 6 months) posthospita1 period in upper social class patients (Hollingshead class 1, 2, and 3). The explanation for these findings is unclear but this author believes a multifactorial risk interaction is operative. Patients with lower socioeconomic background may have difficulty adjusting to the consequences of chronic illness with greater unemployment and medical disability, less comprehension and insight into their medical condition and possibly a greater difficulty in altering risk factors (such as hypertension and obesity) than their upper class brethren. The Health Insurance Plan data suggest that the availability of medical care cannot be incriminated as a factor to explain the outcome differential between the lower and upper social classes. PRIOR ANGINA
A clinical history of angina pectoris prior to the index myocardial infarction has negative prognostic implications for longterm survival. In the Health Insurance Plan, the age-adjusted postinfarction death rates at 1,3 and 5 years were 14%, 22% and 33%, respectively, for patients with prior angina pectoris, and only 5%, 14% and 20% for those without this condition.” In the Rochester Heart Research Follow-up Program, a history of angina pectoris prior to myocardial infarction was significantly more frequent in patients who subsequently died than in survivors during an average 3-year follow-up.14 Similarly, Norris et alz6 found that prior angina pectoris resulted in a significant increase in the 6-year postinfarction mortality. In the Goteborg postinfarction study: angina was associated with an increased 2-year mortality but the significance level was borderline (P < 0.10). In all of the aforementioned studies the angina1 symptom was categorized as either present or absent, and such characteristics as decubitus angina, unstable angina and crescendo angina were not included in the analyses. The more ominous forms of angina, such as those indicating extensive coronary 10
disease, are more likely to be associated with increased mortality and reduced survival in the postinfarction period than the more stable forms of angina. PRIOR MYOCARDIAL INFARCTION
It is reasonable to assume that patients with a myocardial infarction prior to their index coronary event will have a worse long-term prognosis than patients suffering their first coronary attack. Since a correlation exists between the extent of cardiac damage and prognosis,2’ patients with one or more prior infarctions would probably have less myocardial reserve and reduced posthospital survivability. Research data from a variety of studies support these assumptions. In both the Peel’* and Norrislg indices, a previous cardiac infarct was associated with significantly increased posthospital mortality. In the Coronary Drug Project, patients with more than 1 prior myocardial infarction had a 3-year mortality approximately twice that of patients with only a first infarction.28 In the Giiteborg postinfarction study,” the l- and 2-year mortality figures for first infarctions were 8% and 12%, respectively, and 22% and 34% for reinfarctions (P < 0.001). In Weinberg’s follow-up of 154 survivors of AMI, the 6-year mortality was 31% in patients without and 56% in patients with a prior infarction.2s Similar results were observed in our Rochester program14 and in the recent postinfarction follow-up study by Luria.30 The type and location of the prior myocardial infarction may also be important predictors of outcome. Although there are very few good data on this point, certain conclusions can be drawn from a variety of related studies. Baum et a1.31 pointed out in 1974 that patients resuscitated from prehospital ventricular fibrillation did better if an acute transmural myocardial infarction evolved than if it did not. Subsequently, Cannom et a1.32 found that patients with nontransmural myocardial infarction have a particularly guarded prognosis. These studies suggest that patients with a prior nontransmural or subendocardial myocardial infarction have residual myocardial ischemia, which may contribute to electrical instability. There is every reason to believe that similar findings will be observed in reinfarction patients in whom the prior event was a nontransmural infarction. PRIOR CARDIAC FUNCTIONAL STATE
At the time of the index myocardial infarction, the patient’s prior functional state can usually be ascertained by a careful medical history. The 4-level New York Heart Association (NYHA) functional classification scheme is particularly useful in this regard. In our Rochester postinfarction study, posthospi11
tal mortality progressively increased with advancing grades of the prehospital NYHA functional state. The 3-year death rates for prehospital NYHA grades I, II, III and IV were 10.5%, 19.4%, 22.2% and 24.7%, respectively. Patients with a history of cardiac symptoms atkss than ordinary activity (III) or at rest (IV) are at particularly high risk. This functional classification by historical questioning provides important qualitative information about global cardiac reserve, and it provides some insight into the status of the heart on which the new infarct is engrafted. OTHER PREEXISTING FACTORS Hypertension is a primary risk factor in the development of coronary heart disease. In their &year postinfarction follow-up study, Pell and D’Alonzo33 observed pronounced excess mortality (P < 0.01) in patients with a history of hypertension prior to the initial infarction. In the New York Health Insurance Plan study, the 3-year postinfarction mortality for patients with initially elevated (> 160/95 mm Hg), borderline and normal blood pressure was 28%, 13% and 9%, respectively.17 In the Rochester Heart Research Follow-up Program, history of hypertension was a significant risk factor for early and late posthospital mortality.13, l4 From these studies and others, hypertension can be considered both a primary and secondary risk factor, a dual role with a multiplier effect, which substantiates its very important contribution to coronary morbidity and mortality. Hypercholesterolemia and diabetes mellitus are metabolic conditions that predispose the patient to premature atherosclerotic disease, including coronary heart disease. The presence of these comorbidity conditions before an index myocardial infarction is associated with only a minimally increased mortality risk during the posthospital period. However, Vedin observed in the Gijteborg study that hypercholesterolemia was an important risk factor in the identification of coronary patients who developed a nonfatal reinfarction within 2 years after the initial infarction.34 Only a limited number of studies have evaluated the relationship between the patient’s smoking history and the subsequent postinfarction clinical course. In the Coronary Drug Project, a history of cigarette smoking was associated with significantly increased 3-year postinfarction mortality.3 In the Health Insurance Plan study, a history of cigarette smoking was associated with an increased probability of death in the 4l/2 years after infarction, but only in those patients who continued to smoke after the index event.17 Current analysis of the Rochester data reveals that patients who smoked cigarettes prior to the index infarction had threefold greater posthospital mortality than nonsmokers. However, this mortality effect was maintained regardless of the 12
patient’s smoking status after the infarction. Discontinuance of smoking did not improve survivability when compared to those who resumed the smoking habit during an average 2-year follow-up. This discrepancy in the smoking findings of the 2 studies may relate to methodologic and population differences, e.g., the Health Insurance Plan enrolled patients of unrestricted age 3- 12 months after an index cardiac event (myocardial infarction and angina), whereas the Rochester study enrolled patients 65 years of age or younger prior to hospital discharge. CLINICAL CHARACTERISTICS CARE UNIT PHASE
DURING
THE CORONARY
The severity of the AM1 is a primary determinant of both the in-hospital and posthospital courses. The magnitude of damage to the myocardium and the extent and severity of obstructive coronary artery disease are reflected in the hemodynamic, ‘ischemit and electrical derangements observed during the acute hospital phase. These functional disorders are intimately related to prognosis after myocardial infarction. LEFT VENTRICULAR DYSFUNCTION
Numerous studies have shown that clinical evaluation of the patient’s hemodynamic status in the Coronary Care Unit (CCU) provides valuable information about posthospital prognosis. Humphries recently summarized information from a dozen or more studies and provided semiquantitative l-year posthospital death rates according to the clinical class at the time of hospital admission.35 Patients without clinical or laboratory signs of left ventricular dysfunction had a mortality of less than 5%. Mild-tomoderate cardiac dysfunction as manifest by auscultatory pulmonary rales and roentgenographic evidence of pulmonary congestion, was associated with a mortality of lo-30%. Significant heart failure with pulmonary edema resulted in 50% mortality. The worst prognosis (more than 50% mortality) occurred in patients who survived cardiogenic shock. More precise evaluation of left ventricular function in the CCU can now be obtained noninvasively by radionuclide ejection fraction determination. Preliminary data suggest that ejection fractions above 50% are associated with a favorable long-term prognosis, those in the 35- 50% range represent an intermediate risk and patients with ejection fractions less than 35% are at high risk of major complications. Invasive hemodynamic monitoring of cardiac output and pulmonary capillary wedge pressure with Swan-Ganz thermodilution catheters have been carried out in both complicated and uncomplicated infarction patients.36 Progressive reduction in 13
cardiac output and elevation of wedge pressure are directly associated with increased short- and long-term mortality. There are a number of easily measured clinical parameters that reflect left ventricular dysfunction and are also useful indicators of posthospital prognosis. Norris et a1.26 found that qualitative cardiomegaly detected on an admission chest x-ray film was associated with significantly increased mortality at 3 and 6 years after the infarction. Vedin et a1.s used a relative heart volume index37 for the quantitation of heart size and observed significantly increased 2-year mortality in patients with cardiomegaly (men - heart size greater than 450 ml per sq. m; women- heart size greater than 400 ml per sq. ml. Helmers38 reported that tachypnea in the CCU with respiratory rates of 28 per minute or above were associated with a twofold increase in 3year mortality. INFARCT SIZE
Extensive myocardial damage at the time of infarction is a permanent liability and a long-term threat to life. Early observations suggested that infarct size or intensity of &hernia could be evaluated in anterior wall infarctions by the magnitude of ST segment elevations in precardial ECG maps.3s Subsequent studies have demonstrated the inaccuracy of this technique.40 A more useful approach is the quantitation of creatine phosphokinase release from the infarct by measurement of total enzyme activity1 or of the activity of its cardiac-specific MB fraction42 in serial venous blood specimens collected for 2 or 3 days after the onset of infarction. Preliminary results suggest that the posthospita1 risk in hospital survivors is directly related to the enzymatically determined infarct size.43 Two other techniques, positive radionuclide imaging“4 and measurement of myoglobin release,45 have also been used to evaluate infarct size but this information has not yet been related to posthospital prognosis. INFARCT LOCATION
The 12-lead ECG is useful for locating the site of the myocardial infarction, especially when there is enzymatic confirmation of myocardial necrosis. Infarcts have been categorized as transmural or nontransmural (subendocardial) depending on the presence or absence of pathologic Q-waves in the absence of major intraventricular conduction abnormalities. Furthermore, the transmural infarcts can be divided into anterior and posterior locations. For many years it was thought that patients with nontransmural myocardial infarctions have a lower incidence of complications and in-hospital mortality than those with transmural 14
infarctions. The concept has been challenged by recent reports indicating that the short-term prognosis and the frequency and complexity of cardiac arrhythmias were similar in patients with nontransmural. and transmural infarction.46 Furthermore, the findings from Seattle in those patients resuscitated from out-ofhospital ventricular fibrillation clearly revealed lower posthospital mortality in individuals with transmural infarction than in those without new ECG Q-waves.31 This finding prompted a reassessment of left ventricular performance and prognosis in patients with different types of infarction. In 1975 Rigo et a1.47 reported the posthospital clinical course of 41 patients with nontransmural and 81 patients with transmural myocardial infarction. In a 20-month follow-up, 18 - 19% mortality was observed in both groups. In a longer follow-up of nontransmural and transmural infarction patients, Cannom et a1.32 observed similar death rates during the first 2 years after hospital discharge. However, 4 years after the index infarction the nontransmural group had 45% mortality compared with 25% for the transmural patients (P < 0.05). The authors concluded that patients with nontransmural infarction have a particularly guarded prognosis, especially in the later posthospital period. With regard to the site of the infarct, the conventional view is that anterior infarcts are associated with increased short- and long-term mortality when compared to posterior and other locations. Numerous population studies, including our own Rochester Heart Research Follow-up Program,15 have substantiated reduced posthospital survivability in anterior as opposed to nonanterior infarctions. On the basis of infarct location alone, the 3year survival rate for anterior infarctions is 85% and for other locations it is 92%. The reason for this discrepancy in survival is somewhat controversial. That is, does the anterior infarct location create more electrical and mechanical dysfunction than comparably sized infarctions at other sites, or is the increased mortality a function of larger infarct size in the anterior location? Anterior myocardial infarction invariably occurs as a result of stenosis or occlusion of the left anterior descending coronary artery. This vessel is the major artery supplying left ventricular muscle, for it perfuses the entire left ventricular anterior wall, a significant portion of the lateral wall and most of the interventricular septum. Thus, an occlusion of this vessel would compromise blood flow to a greater area of the left ventricle than do similar occlusions of the right or circumflex coronary arteries. Accordingly, one might expect more left ventricular dysfunction after anterior than after posterior or inferior infarctions as a result of a greater extent of left ventricular myocardial necrosis in the former. This is exactly what a number of investigators have concluded from their studies. Miller et a1.48 studied cardiac pump function by biplane left ventricular angiography in a 15
group of 43 patients with remote myocardial infarction. Greater reduction in left ventricular function was observed in anterior than in inferior infarction as a result of the more extensive left ventricular segmental contraction abnormality in the former. Further support of this conclusion was provided by Strauss et a1.49 who evaluated the relationship between infarct size, site of infarction and mortality. Although the infarct size as determined by creatine kinase was similar in anterior and posterior infarctions, the higher mortality associated with the former was related to all the damage occurring in the left ventricle, as opposed to its distribution in both ventricles with inferior infarctions. Thus, patients with anterior wall infarctions are at increased mortality risk because they have more left ventricular muscle necrosis and a greater degree of left ventricular dysfunction than patients with comparably sized infarcts at other locations. Once again, a major determinant of outcome is magnitude of the pump dysfunction. CONDUCTION DISTURBANCES
The development of certain types of conduction disturbances during the CCU phase of AM1 is associated with increased acute, subacute and chronic mortality. Waugh et a1.5o identified patients at high, intermediate and low risk of sudden death in the first postinfarction year according to conduction defects observed during the acute phase. The most accurate predictor of lyear outcome was the status of atrioventricular conduction in combination with the status of intraventricular conduction. Patients at highest risk were those who had any of the following ECG findings while in the CCU: (1) adjacent fascicular block (left anterior hemiblock and right bundle-branch block or left bundle-branch block) plus PR-interval prolongation; (2) nonadjacent fascicular block (left posterior hemiblock and right bundlebranch block; alternating bundle-branch block) regardless of PRinterval; or (3) transient Mobitz type II complete heart block. Thirteen of 26 (50%) such patients died within 1 year of hospital discharge, with the majority (10) dying suddenly. An intermediate risk (27% mortality in 1 year) was observed in patients with per&infarction block, left posterior hemiblock or left bundle-branch block of the complete or incomplete type. Isolated right bundle-branch block, left anterior hemiblock or a combination of these two without PR-interval prolongation was associated with 3% l-year mortality-a similar risk to that of patients without conduction disturbances. Scanlon et a1.51 carried out a retrospective review of the clinical cause of peri-infarction right bundle-branch block and left anterior hemiblock in 13 patients. Four (30%) died suddenly during follow-up, but details of the terminal event were not re16
ported. The development of complete heart block after discharge was not an infrequent event. Atkins et a1.52 studied the prognosis of a similar group of patients who had transient complete heart block complicating AMI. They found that 11 of 13 patients who did not have permanent pacemakers died within 8 months of discharge, whereas 8 who did were still alive. In a review that presents the composite data of a number of investigators, Mullins and Atkins53 substantiate the risk of posthospital sudden death in patients who develop left anterior hemiblock and right bundle-branch block with transient complete heart block, even if normal conduction returns. They recommend the use of permanent pacemakers to reduce the risk of sudden death in these patients. ATRIAL
ARRHYTHMIAS
Atria1 arrhythmias (atria1 tachycardia, atria1 flutter or atria1 fibrillation) occurring in the early CCU phase of AM1 are frequently associated with signs of congestive heart failure and greater overall early mortality. Peel et a1.18 included atria1 arrhythmias in the coronary prognostic index for grading the severity of infarction, but Norris et alIs did not. The prognostic significance of early atria1 arrhythmias in subsequent long-term outcome is unclear. Luria et al. 54 found that occurrence in the CCU of atria1 ectopic beats or atria1 arrhythmias as defined above was associated with significantly increased 2-year mortality. In fact, atria1 arrhythmia was 1 of the 5 variables in the discriminant function that identified patients at high risk of early mortality. In a more recent study, the same group verified the important role of atria1 arrhythmias in prognostication and extended the follow-up to 5 years.30 The Goteborg groups also observed significantly increased 2-year mortality in patients with atria1 fibrillation in the acute phase. In contrast, neither the study of Bigger et a1.20 nor our own in Rochester substantiated the prognostic usefulness of CCU atria1 arrhythmias in posthospita1 outcome. In all likelihood, atria1 arrhythmias per se are not a primary determinant of outcome; rather, they probably reflect a more severe underlying cardiac or pulmonary diseaseconditions associated with increased mortality. VENTRICULAR
ARRHYTHMIAS
What are the posthospital implications of simple and complex ventricular premature beats (VPBs), paroxysmal ventricular tachycardia and primary ventricular fibrillation (VF) with successful resuscitation occurring in the CCU? Moss et a1.12 and Vismara et a1.55*56 found a poor correlation between complex VPBs observed in the CCU and posthospital mortality. Paroxys17
ma1 ventricular tachycardia occurring in the acute phase of myocardial infarction in patients who survived their illness was not associated with increased posthospital mortality when compared with patients without this tachyarrhythmia. deSoyza et a1.57 found that 17 of 18 patients who had paroxysmal ventricular tachycardia in the CCU survived long-term (average 19 months) follow-up. The short- and long-term prognosis of VF complicating AM1 is closely related to the circumstances underlying its development. Stannard et a1.5s reported long-term follow-up of 20 patients with successful resuscitation from primary VF. Eighteen of the 20 patients survived a variable follow-up ranging from months to years. Lie et a1.5s found that more than 90% of patients with primary VF in the CCU could be resuscitated, and this group had a favorable 2-year mortality (less than 10%). In contrast, secondary VF, which results from heart failure, is usually associated with extensive myocardial damage60 and a poor outcome is anticipated. Among hospital survivors of the latter group, Lie et a1.5sfound 50% mortality within 2 years. These findings indicate that ventricular arrhythmias recorded in the CCU are unreliable indicators of subsequent prognosis. The only exception is secondary VF and, once again, the determinant of outcome is the disordered ventricular function and not the complicating tachyarrhythmia. DISCHARGE
CHARACTERISTICS
During the past decade numerous postinfarction patients have been studied prior to discharge or in the early posthospital period in order to identify those at increased mortality risk. The earlier studies evaluated the prognostic importance of various ECG findings. With the introduction of Holter ambulatory recordings, research emphasis shifted to the prognostic role of ventricular arrhythmias. The development of the radionuclide technique for noninvasive evaluation of the ejection fraction and ventricular wall motion permits precise evaluation of the important mechanical cardiac factors that relate to outcome. Twodimensional echocardiography may also be useful in this regard. Recent studies have used coronary and left ventricular angiography in the evaluation of high-risk postinfarction patients who might be candidates for coronary artery bypass surgery. Because of the relative safety of the angiographic studies reported to date and the valuable information which cannot be obtained in any other way, coronary angiography will probably be used more frequently for postinfarction patients. Activity and exercise testing using treadmill and bicycle ergometer techniques in postcoronary patients have provided valuable insight into global cardiac performance as well as ischemic and arrhythmic abnormalities. An electrical stress test using a temporary transvenous 18
pacing stimulus to evaluate ventricular electrical instability has also been reported in postinfarction patients. These studies are providing important insight into electrical, mechanical, ischemic and anatomical factors that influence the clinical course of patients after myocardial infarction. A summary of this rapidly expanding body of information follows. TWELVE-LEAD ECG
In the Health Insurance Plan study, baseline ECGs were recorded at variable times during the early posthospital phase of myocardial infarction.17 The ECGs were coded using the Minnesota criteria for specified abnormalities. ECG ST- and T-wave abnormalities were associated with a threefold increase in mortality during a 4l/z-year follow-up. Connolly et a1.61 recorded ECGs 1 year after myocardial infarction and found the following parameters associated with unfavorable outcome: (1) persistence of transmural or subendocardial infarction patterns; (2) left ventricular hypertrophy; (3) 1 or more VPBs; or (4) a heart rate over 100 per minute. In the Coronary Drug Project, the control group became a valuable source of information about the prognostic value of the postinfarction ECG.’ Several ECG findings provided information independent of the clinical status of the patient on the risk of death during a 3-year follow-up. ST-segment depression was the single most powerful predictor of subsequent death. The presence, size, extent and location of residual Q-waves (Minnesota Code criteria) were independently prognostic, as were left system conduction defects, atria1 fibrillation, tall R-waves in lead II, the depth of the invested T-wave in lead V, and the presence of frequent (more than 1 in 10 recorded beats) VPBs. ECG findings without prognostic significance included supraventricular premature beats, prolonged PR interval, complete right bundlebranch block and low QRS amplitude. The Coronary Drug Project was the first group to evaluate the prognostic importance of the ECG left ventricular hypertrophy pattern (ECG-LVH) after myocardial infarction.28 The ECGLVH pattern, defined only by elevated R-wave amplitude in appropriate leads of the resting ECG (Minnesota Code), was ascertained in 2,760 placebo-treated survivors of myocardial infarction. One hundred eighty-six (6.7%) had ECG-LVH amplitude criteria when recorded an average of 36 months after the last myocardial infarction. The 3-year mortality in men with ECG-LVH was almost twice that in men without (22.6% vs 12.1%, P < 0.01) when the influence of all other variables on mortality was ignored. However, when the relationship between baseline ECG-LVH ,and subsequent mortality was adjusted for confounding ECG and clinical variables, the elevated R-wave 19
amplitude itself had no significantly independent prognostic value. The prognostic importance of ECG-LVH was largely explained by coexisting repolarization (ST- and T-wave) abnormalities. However;-the combination of ECG-LVH by amplitude criteria and ST-segment and T-wave-abnormalities was more important prognostically than the findings of ST-segment depression and T-wave negativity alone. Thus, ECG-LVH by R-wave amplitude criteria in the absence of abnormal ST- and T-wave findings was unrelated to prognosis in postinfarction patients. The relationship between VPBs and long-term outcome was also analyzed in considerable detail in a special report by the Coronary Drug Project.2 Among 2,035 placebo-treated patients in the nationwide study, 235 men (11.5%) had one or more VPBs in their resting 1Zlead ECG. During a 3-year follow-up period, deaths were about twice as frequent (P < 0.01) in those with any VPBs (21.7%) as in those with none (11.4%). Excess long-term risk of death, including sudden death, was associated with increased VPB frequency, with pairs and runs of VPBs and possibly with early-cycle VPBs. The excess risk with these VPB characteristics was independent of the risk associated with other ECG and clinical characteristics. Although the sample of daily ectopic activity represented in the 12-lead ECG is extremely limited, the overall frequency of any VPB (11.5%) in such a small sample is quite significant. As the Coronary Drug Project investigators pointed out, any VPB found during this brief monitoring period probably identified cases having a high frequency of ectopic activity throughout the course of the day. The apparent association of complex VPBs with increased mortality suggested that longer monitoring periods might be worthwhile. This fundamental study set the stage for the use of Holter recordings of various durations (1 - 24 hours) in the prognostic evaluation of cardiac arrhythmias after myocardial infarction. A recent Finnish study suggests that P-wave morphology of the discharge ECG in postinfarction patients is of prognostic value.‘j2 Pohjola et al. correlated P-wave morphology in the discharge ECG with survival in 728 patients with AM1 over a 5year period. During these 5 years 219 patients died, 177 of them as a result of ischemic heart disease. Those morphological aspects of the P-wave that were studied were the P-terminal force (size of the negative portion of the P-wave in chest lead V,), the frontal axis of the terminal P-wave, P-wave duration and atria1 fibrillation. Of 69 patients with abnormal P-terminal force (0.03 mm/set or more negative), 37 (53.6%) died within 5 years compared with 114 deaths among the 558 patients (20.4%) with normal P-terminal force. Most patients with an abnormal Pterminal force died within the first 6 months after discharge. Among 15 patients with frontal axis of the terminal P-wave of 30 degrees or more negative, 8 died (53%). In addition, 5 of 10 20
patients (50%) with atria1 fibrillation died. P-wave duration showed no relationship to mortality. These abnormal ECG Pwave findings, which probably reflect left ventricular failure, are useful indicators of increased mortality risk in the posthospita1 phase of myocardial infarction. Repolarization abnormalities with primary or secondary Q-T prolongation (corrected Q-T of more than .44 seconds) have been associated with electrical instability, ventricular irritability and sudden death. Schwartz et al. 63 have investigated the relationship between the Q-T interval recorded postinfarction on a 12lead ECG and subsequent outcome. They studied 55 patients with a recent myocardial infarction and a matched set of healthy controls. ECGs were recorded every 2 months for 7 years. The corrected Q-T interval (mean of all recorded values) was prolonged in 1 control (2%), 5 of 27 surviving infarction patients (18%) and in 16 of 28 infarction patients (57%) who died suddenly. Prolongation of the QT-interval after myocardial infarction was associated with a 2.2 times greater risk of sudden cardiac death than patients with a normal QT-interval. Similar repolarization abnormalities were noted in the Seattle sudden death study among survivors of out-of-hospital ventricular fibrillation.64 HOLTER
MONITORING
The usefulness of Holter monitoring in the evaluation of asymptomatic cardiac rhythm and conduction disturbances was demonstrated by Hinkle and coworkers with their report in 1969 of arrhythmia findings in 301 overtly healthy, middle-aged men.65 This monitoring technique was first applied to a postinfarction population by Moss and coworkers in 1971.s6 One hundred patients who were convalescing from myocardial infarction had a 6-hour Holter ECG recording performed in the few days before contemplated hospital discharge. Seventy-two percent of the patients had 1 or more VPBs, 20% had multifocal VPBs, 18% had ventricular bigeminy or paired VPBs and 4% had one or more transient runs of ventricular tachycardia. Thirty-six percent of the patients had a disturbing degree or type of ventricular irritability that was unsuspected by their attending physicians and was unrelated to cardiac arrhythmias manifest in the CCU. This descriptive study was quickly followed by a number of outcome-oriented, prospective, postinfarction investigations (Table 2). In 1973 Kotler et al. 67 studied the role of ventricular dysrhythmias as determinants of sudden coronary deaths (within 1 hour of onset of symptoms) in 160 male survivors of myocardial infarction. The study population consisted of male participants in one of the enrolling hospitals (Sinai Hospital, 21
K
*Variable X = Data
VPBs (o/o) Any Frequent* Multiform Bigeminy Pairs Ventricular tachycardia Significance re cardiac death
Age (years) Holter recording
No. of patients
Population
TABLE IN
definition. not available in original
Freq/Cmplx VPB: 3 x risk during 3-yr follow-up
2
80 16 18 X 19
(65 12-hr at S-month intervals; aver. 4.5lpatient
> 3 mo. p MI NYHA I, II 160
2. -OCCURRENCE (VPBs)
41
I
73
39-85 lo-hr
64
p MI
9 Cmplx VPB: 3x risk during 2-yr follow-up
2 wks.
SIGNIFICANCE POSTHOSPITAL
article.
AND THE
I
1 26 27
1-hr
52
ages
X Cmplx VPB: 3x risk during 3-yr follow-up
All
p MI
1739
< 9 mo.
p MI
VENTRICULAR INFARCTION
Cmplx 2.5~ 1-yr
35
VPB: risk during follow-up
I
71 X
100 consecutive patients between the AM1 and the Holter recording; (5) a definition of sudden death analagous to “instantaneous”; and (6) mortality endpoints that did not include nonsudden cardiac death. It is interesting that a recent analysis of the deaths in our Rochester study revealed the preponderance of nonsudden death in the first few months after hospital discharge, with a progressively increasing proportion of sudden deaths occurring 3 months or more after infarction. An overall interpretation of the numerous studies evaluating the significance of VPBs on predischarge Holter recordings is that complex VPB patterns have prognostic power in mortality prediction. However, complex VPBs are only one of many factors associated with increased likelihood of cardiac death. Certainly the extensiveness of the coronary disease process, the degree of 27
1.5
SUDDEN CARDIAC DEATH (55)
/
COMPLEX VPB (216l
P value C”SN 001 cvss 003 S”SN 009
SIMPLE VPB (254)
IO
0 MONTHS I5 -
2 2
20 AFTER
30
MYOCARDIAL
40
50
INFARCTION
NON-SUDDEN CARDIAC DEATH (43) P value Cv*N 001 cvss .OOl Sv*N 020
IO-
3
-
z 2 8 zl Q
SIMPLE “PB 1254) 5
_
-
l ” _---
. . . . . . . . . ---
_e--
O$,,,,“,,,“,“,,,,,,‘,,,l 0
20
IO
MONTHS
AFTER
30
MYOCARDIAL
40
50
INFARCTION
Fig l.-Cumulative sudden (top) and nonsudden (bottom) cardiac mortality for patients with complex (C), simple (S)and no (Njventricular premature beats. Comparisons of the mortality curves between specified patient groups were carried out, and the significance levels are provided with P values. See text for explanation. (From Moss, A., et al.: Ventricular ectopic beats and their relation to sudden and nonsudden cardiac death after myocardial infarction. Circulation 60:998,1979. Used by permission.)
myocardial scarring and the functional state of global cardiac performance must be equally important determinants of outcome. Very few data exist on the prognostic significance of VPBs recorded 1 year or more after myocardial infarction. A few de28
scriptive studies have reported a progressive increase in the frequency and complexity of VPBs recorded at serial times in the first postinfarction year. 6s,‘O Armchair analysis would indicate that if VPBs are becoming more frequent during the time when mortality is diminishing, then VPBs would progressively lose prognostic power in identifying mortality events. A preliminary report from the Rochester program supports this hypothesis.71 In a related investigation of the clinical significance of ventricular tachycardia recorded during ambulatory monitoring after myocardial infarction,72 the findings were consistent with the aforementioned interpretation. Sixty-six patients were identified who had one or more episodes of ventricular tachycardia recorded during postinfarction follow-up recordings conducted over a period of 48 months. A case-control analysis was carried out by matching each ventricular tachycardia patient with an appropriate control patient without this arrhythmia. The overall death rates in the two groups were similar (VT = 16%, control = 8%, P = 0.11). Life table analysis of the survival of the ventricular tachycardia and control patients revealed a 48-month survival of 75% and 87%, respectively. Within the former group, those who died had more severe underlying heart disease than the survivors. The occurrence of ventricular tachycardia in the posthospital phase of myocardial infarction, while associated with a somewhat lower survival rate, does not indicate as much danger as is generally assumed. How does one interpret the prognostic significance of Holterrecorded VPBs in patients with coronary heart disease? The data strongly indicate a gradient of risk which varies inversely with the temporal relationship to the acute coronary event. VPBs recorded 2-3 weeks after infarction have prognostic usefulness in identifying subsequent mortality events, but without discrimination between sudden and nonsudden death; VPBs recorded in the chronic phase of coronary disease have minimal predictive value. ACTIVITY
TOLERANCE
TESTING
Activity testing can induce a variety of arrhythmic, mechanical and ischemic abnormalities, which may have predictive value for various cardiac target events. In the past, AM1 was considered a contraindication to activity testing, but recent studies have shown the feasibility and safety of using a low level activity tolerance test in patients in the late hospital phase of myocardial infarction. A summary of the relevant studies is presented in Table 3. Most centers performing a predischarge activity tolerance test 2-3 weeks after infarction used either a heart-rate-limited, e.g., 130 beats per minute, or symptom-limited procedure. It was hoped that early postcoronary activity 29
Findings (%) Angina ST depression VPBsFollow-up 20 Not available 19 3-mo. mortality: anaina-15%: VPjBs-11%; ’ all patients-5%
(120/min)
100 30-85 Treadmill Heart-ratelimited
No. of patients Age Test
ERICSSON~
SIGNIFICANCE PHASE
Consecutive patients 3 wks. p MI
3.-CLINICAL
Population
TABLE
IBSEN”
OF ACTIVITY MYOCARDIAL
11 49 42 None
209 33-83 Bicycle ergometer Symptom-limited
Consecutive patients 3 wks. p MI
OF
3 wks. all tests 7 11 17 26 9 72 18-mo. morbidity and mortality: increased coronary events in patients with ST depression.
46 36-67 Treadmill Heart-rate-limited at 3 wks. (130/min)
patients and 11 wks.
MARKIEWICZ’~
TESTING (p MI)
Uncomplicated 3 wks. p MI, at 5,7,9, and
TOLERANCE INFARCTION
IN
THEROUX’~
POSTHOSPITAL
20 30 20 1-yr mortality: ST depression-27% VPBs:17% all patients-9.5%
Consecutive patients without CHF.or chest nain 2 wks. pM1 210 28-70 Treadmill Heart-rate-limited (70% age-predicted max. heart rate)
THE
testing would provoke or uncover potential3 dangerous arrhythmias and, thereby, provide a rational case selection for antiarrhythmic therapy. Ericsson et a1.73 conducted a heart-rate-limiied (120 beats per minute) treadmill exercise test on 100 myccardial infarction patients 3 weeks after the acute episode. The average duration of exercise was 5 minutes and the mean maximal heart rate during the test was 118 beats per minute. VPBs Nere recorded in 3 patients at rest immediately before the test snd in 19 during or after the test. Twenty patients developed alyina pectoris and 5 experienced pronounced dyspnea or fatigue. No severe arrhythmias or reinfarctions were induced by the test. All patients were followed for a minimum of 3 months. Of the 5 patients who died during follow-up, 4 had cardiomegaly, 3 had angina pectoris during the treadmill test and only 2 had exercise-induced VPBs. Ibsen et a1.74 carried out a maximal, symptom-limited bicycle ergometer exercise test on 209 patients 3 weeks after AMI. The exercise test was discontinued because of fatigue in 58%, angina or dyspnea in 24% and rhythm disturbances or pronounced ST-T changes in 9%. On the average, the product of heart rate and systolic blood pressure increased more than twofold. Persistent ECG changes, reinfarction or other serious complications were not observed in connection with the exercise test. Follow-up data were not provided. Markiewicz et a1.75 from the Stanford Rehabilitation Program carried out treadmill exercise tests at 3, 5, 7, 9 and 11 weeks after myocardial infarction in 46 good-risk patients under 70 years of age. The 3-week treadmill test was terminated either because of symptoms or if a target heart rate of 130 beats per minute was achieved. lschemic ST-segment depression, usually unaccompanied by angina pectoris, occurred in 54 of 210 tests (26%) among 21 of 46 patients (45%). In those patients who developed ST depression, there was a significantly increased incidence of subsequent coronary events (ventricular fibrillation with resuscitation, coronary bypass surgery, myocardial reinfarction or sudden cardiac death). Exercise-induced VPBs provided little independent prognostic information. No serious complications occurred in 210 tests. A subsequent study from the Stanford group76 provided further evidence that prognosis was more closely related to exercise-induced ischemic abnormalities (ST-segment depression of more than 0.2 mv) than to the development of complex VPBs. Similar findings have been observed in more representative postinfarction populations by Weld et a1.77 and Smith and co-workers.78 In addition, these investigators found that mechanical dysfunction (low maximal work load) was useful in predicting later cardiac events. A comprehensive study evaluating the prognostic usefulness of exercise testing soon after myocardial infarction was recently reported by Theroux et al.79 A treadmill exercise test was per31
formed 1 day befue.hospital discharge in 210 postinfarction patients who had na overt heart failure and had been free of chest pain for at least k days. The exercise test used the NaughtonHaider proto@ with constant treadmill speed and progressively increasing grade. The test was stopped when one of the following endpoints was reached: angina; a workload of 5 metabolic equivalents; 70% of age-predicted maximal heart rate; severe fatigue, dyspnea cr claudication; appearance of more than 10 VPBs per minute or multiform or paired VPB patterns; or STsegment depressiongreater than 5 mm. During a l-year followup, 65% of patients who had chest pain during the test reported angina as compared with 36% who had no chest discomfort during the test (P < O.OL)l). The l-year death rates for patients with and without exercise-induced ST-segment changes were 27% and 2%, respectively (P < 0.001). Sudden death followed the same pattern. These studies clearly support the usefulness of limited activity tolerance testing for predicting cardiac morbidity and mortality in the posthospital phase of myocardial infarction. With careful patient selection and meticulous monitoring of symptoms and physiologic parameters during the testing procedure, activity testing has been safely performed in numerous centers subserving a wide spectrum of patient populations. Ischemic ST-segment changes during exercise and reduced activity performance appear to have more important predictive value than activityinduced arrhythmias. RADIONUCLIDE EJECTION FRACTION
A number of recent studies have reported the use of the radionuclide ejection fraction (EF) technique in the noninvasive determination of left heart function for identifying patients with increased mortality risk after myocardial infarction. Two radionuclide methods are currently available for determining the left ventricular EF. In 1971, Zaret et alEo and Strauss et al.*l introduced an ECG gated cardiac blood pool scanning technique for noninvasive determination of left ventricular volumes, regional wall motion and EF. Briefly, a 15 mCi dose of technetium-labeled red blood cells or albumin is injected intravenously. After equilibration, a blood pool scan is recorded to outline the chambers of the heart. The scintillation camera is gated by an ECG signal to obtain gamma counts in end-systolic and enddiastolic portions of the cardiac cycle. Computer programs are now available for determining the limits of the left ventricular cavity, and the EF is computed. This multiple gated (MUGA) procedure usually requires 30-45 minutes of patient time, and the optimal left ventricular outline is usually achieved by recordings obtained in the left anterior oblique projection. More 32
recently, a faster technique for determining left ventricular EF was introduced using the initial passage of an intravenously injected radionuclide bolus through the heart. Schelbert et a1.82 have popularized this approach. In essence, this first-pass technique analyzes the time-activity curves generated during the passage of the radionuclide through the left ventricle. Changes in the count rate originating from this chamber during any cardiac cycle reflect changes in the volume between systole and diastole. The fraction of end-diastolic blood volume ejected with each systolic contraction can be calculated from these data. The MUGA and first-pass procedures are now extensively used throughout the country, and excellent correlations have been achieved between each of these radionuclide methods and the more involved contrast angiographic technique. In 1975, Schulze and co-worker&j3 reported the relationship between ventricular arrhythmias in the late hospital phase of myocardial and left ventricular function detected by MUGA in 36 patients. Left ventricular EF and percent wall akinesia were calculated from gated cardiac blood pool scans, myocardial infarct size was estimated from peak creatine phosphokinase values, and VPBs were detected by 24-hour Holter recordings and categorized by the &level Lown grading scheme. Thirteen of 14 patients with Lown class II-IV VPBs had EFs of less than 40% compared with only 8 of 22 patients with class O-I VPBs. Patients with class II-IV VPBs had significantly lower mean EFs (30.5% vs 49.6%, P < 0.011, more extensive akinesia (28.1% vs 16.9%, P < 0.05) and higher mean creatine phosphokinase values (1350 units vs 721 units, P < 0.05) than patients with class 0 -1 VPBs. These results indicate a striking association between depressed left ventricular function and complex VPBs in the late hospital phase of myocardial infarction. The authors suggest that VPBs may not be-an independent risk factor for cardiac death in the convalescent phase of myocardial infarction. Schulze and his associates continued these investigations and, in 1977, they reported a l-year follow-up of 81 patients who had 24-hour Holter recordings and gated cardiac blood pool scans approximately 2 weeks after AMI. In 36 patients (44%) the EF was 40% or more; only 3 had complicated ventricular rhythms (Lawn class III-V). In 45 patients (56%) the ejection fraction was less than 40%; 26 had complex VPBs. Eight patients had documented ventricular fibrillation or instantaneous death during a mean ‘I-month (range 2- 16 months) posthospital followup. Eight patients who died suddenly were all in the subgroup having EF of less than 40% and complicated ventricular arrhythmias. The authors conclude that a low ejection suggests a poor prognosis following myocardial infarction, but the concomitant presence of complex VPBs significantly increases the risk of sudden death in the posthospital period. 33
The radionuclide technique used in these studies provides an easily obtainable, noninvasive means of evaluating ventricular performance in the recovery phase of AMI. This information is important be-se routine clinical and radiographic evaluation generally provides an inadequate assessment of overall cardiac function. In addition, the radionuclide technique may provide a means of evaluating the reserve of the infarcted myocardium in response to exercise stress after discharge. Gated and first-pass approaches can now provide quantitative data about regional wall motion abnormalities, and this information should further enhance the accuracy of the assessment of left ventricular functjon by radionuclides. Since the degree of left ventricular dysfunction has been shown to be a major determinant of morbidity and mortality after myocardial infarction, it is likely that the radionuclide technique will be used routinely in the prognostic evaluation of postcoronary patients. CORONARY AND LEFT VENTRICULAR ANGIOGRAPHY
The most precise way of defining coronary anatomy and evaluating left ventricular function is by contrast angiography. Although this procedure is widely used in the evaluation of symptomatic patients with chronic coronary disease, there is general reluctance to use it in the early post infarction phase. Only a limited number of such studies have been reported in the literature, and to date the procedure has been associated with few if any complications. In 1977, Schulze et a1.85 from Johns Hopkins, reported the angiographic and Holter recorder findings in 38 patients studied lo- 24 days after AMI. There were no complications from the catheterization procedure. Patients with complex VPBs (multiform, paired, R on T or ventricular tachycardia), when compared to those with no or uncomplicated VPBs, had a greater number of proximally narrowed major coronary arteries, a higher coronary score using the Friesinger method,E6 greater incidence of previous myocardial infarction, a greater percentage of abnormal left ventricular segments and lower EF. These findings complemented their prior radionuclide investigationss3> 84 and provided strong support for the significant association between complex VPBs and extensive coronary and myocardial disease. These investigators also used contrast angiography to compare the extent and severity of coronary and myocardial disease in patients with recent transmural and non-transmural MI.87 Fortyeight patients were studied prior to hospital discharge, 31 with transmural and 17 with nontransmural infarction. There were two complications: one patient developed a femoral artery thrombosis following a catheterization (effectively treated surgically); a second patient suffered an embolus to the distal left anterior 34
descending artery on injection of the left coronary artery (the patient made a good recovery). There was no difference between the two groups in the prevalence of single, double or triple vessel coronary artery disease, the extent or severity of coronary stenosis, left ventricular EF or the percentage of akinetic-dyskinetic myocardial segments. The similar angiographic findings in transmural and nontransmural infarction patients suggest that the long-term outcome would also be similar. Follow-up studies have not yet been reported with these patients. Russell and co-workers,88 from the University of Alabama, described the angiographic findings in 34 patients who had the catheterization procedure performed an average of 27 days after AMI. No complications due to angiography were encountered. Those with prior infarction (14) had more severe triple-vessel disease, less single-vessel disease and more total coronary artery disease as judged by the Friesinger score; this group also had lower left ventricular EFs, a greater percentage of abnormal contracting segments and lower left ventricular compliance values. The preliminary data from these studies indicate that coronary and left ventricular angiography can be performed safely in the initial weeks of convalescence after myocardial infarction. At the present time I use early (predischarge) postinfarction angiography only for those patients with recurrent angina that is unresponsive to the usual medical measures. In this high-risk group of unstable patients, severe multivessel coronary disease or left main coronary stenosis may be found. Early coronary bypass surgery may be effective in improving survivability in this select group of patients with a poor prognosis. Coronary and left ventricular angiography is being performed with greater impunity during the first 4-6 months after hospital discharge, i.e., during the subacute phase of myocardial infarction. As a general rule, such studies are only indicated in patients with recurrent chest pain or when a ventricular aneurysm is suspected. However, increasing numbers of angiographic studies are being done in relatively asymptomatic patients during the early posthospital period to clarify the patient’s cardiac status.8s This approach may be useful in individuals whose employment requires vigorous physical exertion. A recent study has provided valuable information on this topic. Paine et a1.,9O from the University of Alabama, studied 100 consecutive patients with contrast angiography and graded treadmill exercise testing at a median of 4 months after myocardial infarction. The studies caused no complications. Thirty-one patients had ECG positive exercise tests and 27 of these (87%) had significant 2- or 3-vessel coronary disease. Of the 21 patients with negative exercise tests, 62% had coronary artery disease in no more than 1 vessel, 33% in 2 vessels and only 5% in 3 vessels. Patients termi35
nating the exercise test because of fatigue or dyspnea showed significant and meaningful correlations between duration of exercise and EF (r = 0.65), and duration of exercise and angiographic scarsize (r = 0.62). The authors conclude that a few months after myocardial infarction the graded exercise test can be performed safely and can be utilized to predict the extent of coronary artery disease and the degree of left ventricular dysfunction in selected groups of patients. These data argue against Youtine” angiography in postinfarction patients and point up the diagnostic usefulness of exercise testing in the functional evaluation of convalescent postinfarction patients. MISCELLANEOUS FACTORS
The association between VPBs and increased cardiac mortality in the posthospital phase of myocardial infarction has highlighted the potential importance of cardiac electrical instability in the predisposition to subsequent ventricular tachycardia or fibrillation. Recently, Greene et a1.g1 used a ventricular pacing technique to assess the likelihood that symptomatic or fatal ventricular arrhythmia would develop after myocardial infarction. They studied 48 postcoronary patients with electrode catheters positioned high in the right atrium and at the apex of the right ventricle. The right atrium was paced at 86 beats per minute and a single ventricular stimulus was introduced at every 8th beat. Ventricular stimuli were first introduced at the QRS complex and progressively moved toward the preceding T-wave at lo-20 msec intervals, thereby scanning electrical diastole. Of the 48 infarct patients studied, 19 had repetitive ventricular responses (2 or more induced VPBs) to the single ventricular pacing stimulus. Fifteen of these 19 (79%) patients had ventricular tachycardia or sudden death within the l-year follow-up period. Of the remaining 29 patients without repetitive ventricular responses, only 4 (14%) had these complications (P < 0.001). Comparisons were made between the usefulness of the repetitive ventricular response and advanced grades of VPBs on Holter monitoring. The specificity and predictive value of these two testing procedures were similar. The sensitivity of the repetitive ventricular response was greater than the Halter monitor but the difference was not statistically significant (P = 0.24). It appears that electrophysiologic stress testing with single ventricular stimuli holds promise for identifying high risk patients. As pointed out earlier, mechanical dysfunction of the left ventricle is an important determinant of outcome. The advent of two-dimensional echocardiography has provided a noninvasive approach to the evaluation of regional ventricular wall motion abnormalities in myocardial infarction patients. Eaton et a1.s2 studied 28 patients during the first 2 weeks after infarction by 36
serial two-dimensional echocardiography. Eight patients showed infarct expansion with disproportionate dilatation and transmural thinning in the infarcted zone that was significantly different from changes in noninfarcted regions. These 8 patients had significantly greater 8-week mortality than the nonexpansion group (4/8 vs O/20, P < 0.004) despite comparable creatine kinase values and clinical severity (Killip) scores. These preliminary findings suggest that echocardiographic detection of topographic alterations in the heart after myocardial infarction has functional and possibly prognostic implications. Not all regions of the heart are equally accessible by echocardiography and, thus, the ultimate usefulness of this technique may be limited- possibly to patients with anterior myocardial infarction. THE POSTHOSPITAL
CLINICAL
COURSE
NATURAL HISTORY
The Framingham study has been unique in providing valuable information on the natural history of various types of cardiovascular disease over prolonged periods of time. Kannel and co-workerslo conducted a 20-year cohort study of 5,127 individuals initially free of coronary heart disease, and recently reported a lo-year follow-up on 319 men and women who developed overt or asymptomatic myocardial infarction. One in 5 men who had a first myocardial infarction died within 1 year, a mortality 14 times that of those free of coronary heart disease. In men who survived the first year, a recognized myocardial infarction was associated with a three- to four-fold increased mortality over the next 9 years. Long-term prognosis was distinctly worse in women than men. Patients with overt and asymptomatic myocardial infarction had similar survival rates after 3 years. A second infarction occurred in 13% of the men and 40% of the women within 5 years of the first infarction. These findings of the natural history of essentially untreated patients are extremely important for they provide a standard of comparison for a variety of intervention trials. CHRONOMETRIC INTERVAL
Numerous studies have shown that the early posthospital phase after an index coronary event is a particularly high-risk period. That is, the rate of reinfarction or cardiac death is inversely related to the chronometric interval after the index coronary event. Gazes et a1.g3 reported that the posthospital mortality decreased from 1.8% per month during the first 3 months after infarction to 0.6% per month during the subsequent 9 37
months. The Health Insurance Plan investigators observed a 1.7% per month mortality during the first 6 months after hospital discharge and a O.l-0.2% per month rate for the next 3l/2 years.4 Similq findings were reported by Pell and D’Alonzo33 in their &year follow-up study of 932 male DuPont employees who survived the hospital phase of AMI. In our own Rochester study, of all the cardiac deaths that occurred during a 4-year follow-up period after the index coronary event, one half of the deaths took place in the first 6 months after hospital discharge. These studies indicate that the early posthospital period after myocardial infarction warrants special attention in any secondary prevention program. RECURRENT SYMPTOMS
The development of angina pectoris or symptoms of left ventricular dysfunction (fatigue, exertional dyspnea, congestive heart failure) during the posthospital phase of myocardial infarction has significant prognostic implications. Recurrent postinfarction angina almost always indicates multivessel coronary disease, and the long-term survival status of these patients is guarded. The earlier angina occurs after infarction, the more significant the prognostic implications. For this reason, many cardiologists are proceeding with exercise testing and coronary angiography in postinfarction patients who develop angina, in order to evaluate more precisely the extent and severity of the coronary disease. Coronary artery bypass graft surgery appears beneficial in those with left main coronary stenosis or triplevessel proximal coronary disease with good distal runoff. In patients with symptoms of left ventricular dysfunction, radionuclide assessment of the EF and regional wall motion provides valuable information. In general this group of patients will have the poorest prognosis. However, the radionuclide study can provide quantitative and qualitative data that are often useful in the clinical management of the individual patient. For example, a surgically correctable aneurysm may be detected by this approach. Furthermore, the effectiveness of afterload reduction therapy in the management of patients with the low output syndrome can be quantitatively evaluated by serial radionuclide EF measurements. The available evidence suggests that augmentation of the radionuclide EF by 10% or more, e.g., from 20% to 30%, by appropriate therapeutic intervention should be accompanied by an improved survival rate. CIGARETTE SMOKING
Although cigarette smoking is a well-recognized primary risk factor in the development of AMI, the effects of continued smok38
ing after the index coronary event on the development of secondary complications is controversial. In the Health Insurance Plan study, patients with myocardial infarction or angina pectoris who continued smoking after the index coronary event had a cumulative probability of death, over a 4.5year follow-up, almost twice that of those who stopped smoking or never smoked.17 However, these findings were obtained from the raw data without correction for the effects of confounding variables. Wilhelmsson et al.94 reported from Goteborg, Sweden, on the smoking habits of 528 men who survived their first myocardial infarction. They compared the reinfarction and cardiac death rates during a 2-year follow-up of those who stopped smoking and those who continued smoking after the initial coronary event. Those who stopped had half the rate of nonfatal recurrences (9% vs 18%, P < 0.01) and half the cardiovascular mortality (5% vs lo%, P < 0.05) of those who continued to smoke. Some caution must be exercised in the simple acceptance of these findings, however, since (1) the categorization of “stopped smoking” and “continued smoking” was made at one point in time- 3 months after AMI, (2) no attempt was made to control for confounding variables and (3) the 2-year myocardial reinfarction rate for the entire population (nonsmokers, ex-smokers, stopped smokers and continued smokers) was twice the cardiac death rate (12.3% vs 6.6%)-a difference that suggests an unusual selection of patients. A recent report from the Framingham studyg5 provides additional interesting information. These investigators assessed the possible benefit of quitting smoking after infarction. The 2-year death rates of the stopped (n = 56) and the continued (n = 139) smoking patients were essentially the same (5.4% and 7.2%). However, in the period from 2-6 years, those who quit smoking did better than those who continued. The life-table approach revealed a 6-year mortality of 18.8% among those who quit and 30.4% among those who continued to smoke. No significant difference in recurrent myocardial infarction rates was observed. In contradistinction to the Gijteborg study, the Framingham data suggest that the long-term benefit of quitting smoking after myocardial infarction does not extend to a reduction in recurrent myocardial infarction. As a result of these confusing findings on the effects of smoking after myocardial infarction, the data from the Rochester program were reviewed. In a myocardial infarction population of 573 patients, 12% never smoked, 27% had stopped smoking prior to the index infarction and 61% were active smokers at the time of hospitalization for AMI. At discharge, smoking recidivism was present in 19% of the prior smokers and increased to 49% by the end of the first postinfarction year. Among patients who were smokers at enrollment (n = 353), the 2Y2-year mortality was 39
similar in those who quit and those who returned to smoking (13.5% vs 11.5%, P value not significant). The clinical characteristics of those who quit and those who continued smoking were remarkably similar. The Rochester findings support the Framingham results and indicate no significant benefit from stopping smoking within the first few years after infarction. Longer abstinence may provide some reduction in postinfarction morbidity and mortality, but this interpretation requires further investigation and substantiation.
Numerous therapeutic measures are utilized in patients after myocardial infarction, and their influence on postinfarction prognosis is uncertain. Relatively few carefully performed clinical trials have been done on these patients, and the therapy currently being used is usually based on experience rather than science. A traditionally prescribed agent like digitalis may not be effective for long-term treatment of postinfarction heart failure in patients with sinus rhythm. The idea of using a drug to drive the diseased heart out of failure by increasing contractility has come under closer scrutiny. Katz% has warned that benefit from inotropic agents like digitalis may be obtained only at the expense of life-shortening myocardial damage. Recently, the idea of unloading the left ventricle with vasodilator drugs has gained considerable acceptance as a result of the beneficial effects observed in patients with congestive cardiomyopathy. No formal trials have yet been reported of long-term treatment of postcoronary patients with afterload reducing agents. Several studies have used antiarrhythmic agents (quinidine, procainamide, phenytoin and aprindine), but beneficial results have not been achieved. /?-Blockers may favorably influence prognosis after myocardial infarction, and a few major studies have been reported that substantiate this position. The Gijteborg group carried out a randomized, double-blind alprenolol-placebo intervention trial in more than 200 postinfarction patients.s7 After a 2-year followup, there was a significant reduction in sudden death occurrence in the alprenolol patients when compared to the placebo group. A recent study from DenmarkS confirmed the beneficial effects of alprenolol in postinfarct patients during a l-year treatment period, but only in patients 65 years of age or younger. The English Multicenter Trial recorded a significant reduction in the incidence of sudden death, cardiac death and nonfatal reinfarction with practolol, and these results were particularly prominent in patients with anterior myocardial infarction.ss However, similar results were not observed by these same English investigators using propranolol in the high risk patients with anterior 40
infarction.*00 A major postinfarction propranolol trial is presently underway in the U.S. to determine if the routine administration of propranolol will improve posthospital survival after myocardial infarction. Although the study results will not be available for a few years, propranolol and related p-blocking agents are often prescribed to postinfarction patients on the basis of the alprenolol and practolol studies. These latter agents are considerably different in that they have intrinsic sympathomimetic activity and propranolol does not. In any event, the widespread and somewhat indiscriminate use of propranolol may be influencing outcome after myocardial infarction in a way that cannot be determined at this time. Antiplatelet aggregating agents like acetylsalicylic acid, dipyridamole and sulfinpyrazone have been studied in patients with cerebral vascular and coronary vascular disease. In 1978 the Anturane F&infarction Trial Research Group reported the preliminary results of a randomized, double-blind multicenter clinical trial comparing sulfinpyrazone and placebo in the reduction of cardiac mortality after myocardial infarction.lol The early results suggest that sulfinpyrazone may be effective in diminishing cardiac mortality in this group of patients, but the completed study has not yet been reported. The results of other postinfarction trials with acetylsalicylic acid and dipyridamole are also pending. Once again, these agents are frequently prescribed despite the nondefinitive nature of the studies to date. The contaminating influence these therapies have on prognosis after infarction cannot presently be ascertained. An increasing number of patients, estimated at 3 - 5% of patients 70 years of age or younger, are undergoing coronary artery bypass graft surgery in the first year after myocardial infarction. When performed for recurrent angina in angiographitally documented left main coronary stenosis or proximal multivessel coronary disease, the bypass surgery may favorably influence long-term prognosis after myocardial infarction. However, definitive studies have not been performed to substantiate this currently practiced therapeutic intervention. In brief summary, it is difficult to determine whether any of the commonly prescribed medications or surgical procedures favorably or unfavorably alter the survival of postcoronary patients after myocardial infarction. In any event, the therapies used must be considered when evaluating factors influencing prognosis in this group of patients. MULTIVARIATE
RISK CLASSIFICATION
Univariate factors that effect outcome after myocardial infarction have been reviewed in the preceding sections. However, multiple factors are operative in most clinical situations, and 41
their combined effects and synergistic interactions may profoundly influence the outcome. Numerous mathematical techniques have been used to identify variable interactions as they pertain to riskdassification. The methods used include two-way contingency analyses, prognostic stratification approaches, regression techniques and survivorship (life-table) analyses. TWO-WAY CONTINGENCY ANALYSES
Two-way comparisons are frequently made to determine the independence of a particular factor to outcome when controlling for a second factor, as well as to evaluate the interaction effect of the two factors on outcome. In the Coronary Drug Project, the association of major ECG abnormalities with S-year mortality was examined according to the presence or absence of other ECG and clinical indicators of severity and prognosis.’ For example, infarct Q-waves were associated with higher mortality irrespective of cardiac enlargement. Multiple comparisons revealed a consistent relationship between various ECG items and excess mortality when other risk factors were considered one at a time. In addition, high death rates resulted from the combination of VPBs in patients with a history of heart failure and ventricular conduction defects in patients with radiographic evidence of cardiac enlargement. In a later publication from the Coronary Drug Project, two-way combinations of VPBs with other clinical risk factors demonstrated a lethal interaction of VPBs with smoking, digitalis treatment, cardiac enlargement and heart failure.* In the Kotler study?’ patients with Lown grade II-V VPBs on Holter recording showed a higher incidence of sudden cardiac death independent of 22 relevant demographic, clinical and ECG characteristics taken one at a time. PROGNOSTICSTRATIFICATION
Prognostic stratification is an analytic technique popularized by Feinstein. lo2 Selected univariate factors are used in bivariate and trivariate combinations to obtain the best partition of patients into low- and high-risk groups over a specific time period. Using this approach, the Rochester programI identified a highrisk group, with a 4-month posthospital cardiac death rate of 14%, by the presence of two or more of the following characteristics: (1) history of angina pectoris at rest or with ordinary levels; (2) development of hypotension and/or congestive heart failure in the CCU; and (3) VPB frequency of 20 or more per hour on a 6-hour Holter recording. The low-risk group had a 3% 4-month mortality and was characterized by none or only one of the above factors. Bigger et al.*O used the same method of analysis in a g-month 42
follow-up study of 100 postinfarction patients. The best prognostic stratification was obtained using the values for peak creatine kinase of more than 585 IU, blood urea nitrogen of 20 or more mg/dl at 2 weeks and the presence of left ventricular failure in the CCU. At 6 months, 10 of 19 patients (55%) with these 3 characteristics had died. The 6-month cardiac death rate of the 71 patients who had none, 1 or 2 of these characteristics was only 5%. The prognostic stratification approach has much to commend it. The technique is methodologically easy to understand and apply, the identified variables provide insight into the mechanisms of the observed phenomena, and the identified high and low risk groups permit more logical intervention strategies. Better understanding of risk mechanisms and improved risk stratification should improve posthospital cardiac care by enhancing the selection of therapy for specific risk groups. REGRESSION
TECHNIQUES
Multiple linear regression, multiple logistic regression and discriminant function analysis are complex biostatistical techniques that permit the evaluation of the independent contributions of multiple simultaneous variables to mortality. In addition, these techniques reduce the multivariate interactions to a score from which risk probability can be derived and risk prediction carried out. Five pertinent classification studies using various multivariate regression techniques are summarized in Table 4. For the most part, the predictor variables reflect historical comorbidity factors, severity of the myocardial infarction, evidence of mechanical ventricular dysfunction and the presence of electrical instability. The predictive efficiency (percentage of correct classifications) of these multivariate regression techniques was quite good. In the Coronary Drug Project,3 a linear regression technique was used to select a combination of five factors that were related to 3-year mortality after myocardial infarction. In order of decreasing significance, the five factors were (1) ST depression on ECG; (2) cardiomegaly on chest x-ray films; (3) advanced NYHA functional state; (4) ventricular conduction defects on ECG; and (5) use of diuretics. These factors were appropriately weighted and the population was classified by decile of risk. The mortalities in the lowest and highest deciles of estimated risk were 2.9% and 38.5%, respectively. Risk prediction using this function was applied to an independent group of patients with very good agreement between the observed and predicted outcomes. A more sophisticated linear regression technique, which has been used in many postinfarction prognostication studies, is the multivariate stepwise discriminant function method. Multiple 43
*Predictive
Efficiency
= correct
sample
USING
83
REGRESSION
92
Stepwise discriminant 175 30-79 6 No Syst. BP (100 mm Hg Chronic lung disease Anterior MI Hx CHF
MULTIVARIATE
Stepwise discriminant 143 unrestricted 24 Yes Syst. BP Blood urea nitrogen Atria1 arrhythmia Hx angina or infarction >l VPB/hr
size.
STUDIES
Stepwise discriminant 100 33-82 24 Yes 1) VPBs: Age Bigeminal or paired VPB VPB frequency Early cycle VPB 2) No VPBs: Age Peel score 1) 91 2) 79
CLASSIFICATION
classification/population
86 (o/o)
Predictive efficiency*
RISK
Linear regression 2,789 30-64 36 No ST depression Cardiomegaly Advanced NYHA Ventricular conduction defects Diuretic therapy
4. - POSTINFARCTION
Analysis technique No. of patients Age (years) Follow-up (months) Holter recording Predictor variables (mortality)
TABLE
/
88
Logistic regression 292 57-69 24 No Dyspnea Upper SGOT quartile CHF Cardiomegaly At. fibrillation
ANALYSIS
variables selected by traditional univariate screening are entered into a multiple discriminant analysis function in a stepwise manner. The variables are selected according to preset criteria by the discriminating power of their contribution to outcome. The selected variables are weighted and expressed mathematically in a linear function, which optimizes the association between the predictor variables and outcome. In 1974 we reported the use of this stepwise discriminant analysis technique in a 2-year postinfarction follow-up of 100 patients.” The population was divided into two groups on the basis of the presence or absence of VPBs on a predischarge Holter recording. In those with VPBs, 91% of the 2-year survivors and nonsurvivors were correctly identified by the discriminant combinations of three ventricular arrhythmia parameters and age. In those without VPBs, 75% of survivors and 100% of nonsurvivors were properly classified simply from age and the Peel score of the severity of the AMI. Using this same analytic technique, Luria and co-workers54 found that the components of the discriminant function for 2-year outcome were (1) admission systolic blood pressure; (2) highest blood urea nitrogen level in the CCU; (3) atria1 arrhythmias in the CCU; (4) angina pectoris for more than 3 months or a previous myocardial infarction; and (5) more than one VPB per hour during an 8-hour Holter recording. In a function analrecent report, Henning et a1.1°3 used discriminant ysis to predict mortality between 30 days and 6 months after infarction on the basis of variables recorded soon after admission. The 4 clinical variables that provided the best discrimination between survivors and nonsurvivors included systolic blood pressure of less than 100 mm Hg, chronic obstructive lung disease, anterior location of the infarct and a history of congestive heart failure. Logistic regression techniques have also been applied in postinfarction prognostication studies. This method uses a logarithmic transform and is theoretically more appropriate than multivariate linear regression and discriminant function analysis when some of the predictor variables are discrete and do not have a multivariate normal distribution. Vedin et aleg used this multivariate logistic regression technique to develop a prognostic function in 292 men with first infarctions, followed for 2 years. The 5 most important predictor variables recorded during the hospital phase were: (1) dyspnea at onset of symptoms of infarction; (2) serum glutamic-oxaloacetic transaminase quartile, (3) left heart failure, (4) relative heart size determined by chest roentgenogram and corrected for body size and (5) atria1 fibrillation. Approximately 60% of the 2-year cardiovascular mortality was concentrated in the highest quartile of the logistic risk function, using the above 5 variables. 45
SURVIVORSHIP
ANALYSES
The multivariate regression techniques require complete follow-up of all individuals in the cohort for the duration of the interval beingstudied. Survivorship techniques use the entire experience of a71 patients in a given population and take into account the varying duration of follow-up due to staggered enrollment and censored observations. We recently reported the use of survivorship methods in the identification of subsets of patients with different survival patterns.15 The study population consisted of 940 postinfarction patients followed for a minimum of 12 months to a maximum of 60 months. Univariate analysis demonstrated that prior myocardial infarction, left ventricular dysfunction in the CCU, anterior myocardial infarction and one or more VPBs on a predischarge 6-hour Holter recording were significantly (P < 0.01) more frequent in patients who died of cardiac cause than in survivors. Survivorship analyses revealed a variety of survival patterns depending on the presence, absence and interactive combination of the above factors (Fig 2). A combination of anterior infarction, left ventricular dysfunction and one or more Holter-recorded VPBs identified a high-risk subset, which made up 15% of the population, and this group had 6-month and 3-year survivals of 85% and 70%, respectively. A low-risk subset, which made up 24% of the population, was Fig 2.-Survival as a function of the posthospital time after myocardial infarction for the total population and for low- and high-risk groups. Low-risk group defined by the absence of prior myocardial infarction (PM/), left ventricular dysfunction (LVD) and ventricular premature beats (VP@. High-risk group identified by the presence of anterior myocardial infarction (AM/), LVD and VPB. LO RISK ” = 224
O-0
2 ca0.60 52 B Q
LO RISK = NO PMI. LVD, VPB HI RISK = AMI + LVD + VPB
0.50
6
12
POSTHOSPITAL MYOCARDIAL 46
24
36
48
MONTHS INFARCTION
AFTER
60
identified by the absence of prior myocardial infarction, left ventricular dysfunction and VPBs, and this group had a 3-year survival of 94%. An intermediate risk group, those not included in the low- and high-risk subsets, made up 62% of the population with l- and 3-year survivals of 94% and 89%, respectively. The intermediateand high-risk groups would seem to have the greatest potential for mortality reduction by appropriate postinfarction intervention measures. By similar reasoning, the lowrisk group can be excluded from any general intervention drug therapy since this group will do extremely well regardless of the treatment used. COMMENT
The various studies reviewed in this multivariate risk classification section indicate the critical importance of extensive myocardial damage and the associated impairment of left ventricular function as major determinants of outcome after myocardial infarction. Furthermore, the presence of VPBs appears to enhance the risk created by damage to the ventricular myocardium. THE GOOD-RISK
PATIENT
In almost all postinfarction studies, patients without specific risk factors generally did very well. In 1975, McNeer et a1.1°4 reported their in-hospital and posthospital findings in a group of patients who had an uncomplicated CCU course. That is, they did not have ventricular tachycardia or fibrillation, 2d- or 3ddegree heart block, pulmonary edema, cardiogenic shock, persistent sinus tachycardia, hypotension, atria1 flutter or fibrillation, or extension of the- infarction. These early uncomplicated patients made up 51% of 522 consecutive patients admitted to the CCU with AMI. Furthermore, this group had no mortality or complications in-hospital or during a 6-month follow-up. A subsequent study’05 by the same group substantiated the safety of early hospital discharge (7 days) in this good risk group. As mentioned earlier, our own Rochester study demonstrated the benign posthospital clinical course of patients without hemodynamic or arrhythmic problems during their hospital stay. ACKNOWLEDGMENTS I gratefully acknowledge the research assistance of Mr. John DeCamilla of the Rochester Heart Research Follow-up Program and thank Mrs. Nancy Kellogg for her superb secretarial assistance in the preparation of this article. 47
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102. 103.
52
Ventricular arrhythmias in the late hospital phase of acute myocardial infarction, Circulation 52:1006, 1975. Schulze, R., Strauss, H., and Pitt, B.: Sudden death in the year following myocardial infarction, Am. J. Med. 62:192, 1977. Schulze, R., frumphries, J., Griffith, L., Ducci, H., Achuff, S., Baird, M., Mellits, E., and Pitt, B.: Left ventricular and coronary angiographic anatomy, Circulation 55:839, 1977. Friesinger, G., Page, E., and Ross, R.: Prognostic significance of coronary arteriography, Trans. Assoc. Am. Physicians 83~78, 1970. Schulze, R., Pitt, B., Griffith, L., Ducci, H., Achuff, S., Baird, M., and Humphries, J.: Coronary angiography and left ventriculography in survivors of transmural and nontransmural myocardial infarction, Am. J. Med. 64:108, 1978. Russell, R., Jr., Rogers, W., Mantle, J., Kouchoukos, N., and Rackley, C.: Coronary arteriography within two months of acute myocardial infarction, Cardiovas. Med. 2:679, 1977. Karimian, H., Joffe, C., Marcus, D., Imm, C., and Weinberg, S.: The clinical importance of coronary arteriography after myocardial infarction, Heart Lung 8:87, 1979. Paine, T., Dye, L., Roitman, D., Sheffield, L., Rackley, C., Russell, R., and Rogers, W.: Relation of graded exercise test findings after myocardial infarction to extent of coronary artery disease and left ventricular dysfunction, Am. J. Cardiol. 42:716, 1978. Greene, H., Reid, P., and Schaeffer, A.: The repetitive ventricular response in man, N. Engl. J. Med., 299:729, 1978. Eaton, L., Weiss, J., Bulkley, B., Garrison, J., and Weisfeldt, M.: Regional cardiac dilatation after acute myocardial infarction, N. Engl. J. Med. 300: 57, 1979. Gazes, P., Kitchell, J., Meltzer, L., Rosenblatt, W., and Roth, 0.: Death rate among 795 patients in first year after myocardial infarction, J.A.M.A. 197: 184,1966. Wilhelmsson, C., Elmfeldt, D., Vedin, J., Tibblin, G., and Wilhelmsen, L.: Smoking and myocardial infarction, Lancet 1:415, 1975. Sparrow, D., and Dawber, T.: The influence of cigarette smoking on prognosis after a first myocardial infarction, J. Chronic Dis. 31:425, 1978. Katz, A.: Biochemical “defect” in the hypertrophied and failing heart. Deleterious or compensatory?, Circulation 47:1076, 1973. Wilhelmsson, C., Vedin, J., Wilhelmsen, L., Tibblin, G., and Werko, L.: Reduction of sudden deaths after myocardial infarction by treatment with alprenolol. Preliminary results, Lancet 2:1157, 1974. Andersen, M., Frederiksen, J., Jurgensen, H., Pedersen, F., Bechsgaard, P., Hansen. D.. Nielsen, B., Pedersen-Biergaard, 0.. and Rasmussen, S.: Effect - of alprenolol on mortality among patients with definite or suspected acute myocardial infarction, Lancet, 2:865, 1979. Green, K., Chamberlain, D., Fulton, R., et al.: Improvement in prognosis of myocardial infarction by long-term 6-adrenoreceptor blockade using practolol. A multicentre international study, Br. Med. J. 3:735,1975. Baber, N.: Multicentre oronranolol uost-infarction trial. Brit. Heart J. 41: 365,1979. Anturane Reinfarction Trial Research Group: Sulfinpyrazone in the prevention of cardiac death after myocardial infarction, N. Engl. J. Med. 298:289,1978. Feinstein, A.: Clinical biostatistics. XV. The process of prognostic stratification (Part 11, Clin. Pharmacol. Ther. 13:442. 1972. Henning, H., Gilpin,.E., Covell, J., Swan, E., G’Rourke, R., and Ross, J.: Prognosis after acute myocardial infarction: A multivariate analysis of mortality and survival, Circulation 59:1124, 1979.
104. 105.
McNeer, course of McNeer, M., and infarction,
J., Wallace, A., Wagner, G., Starmer, C., and Rosati, R.: The acute myocardial infarction, Circulation 51:410, 1975. J., Wagner, G., Ginsburg, P., Wallace, A., McCants, C., Conley, Rosati, R.: Hospital discharge one week after acute myocardial N. Engl. J. MI&. 298:229,1978.
SELF-ASSESSMENT
1. d 2. 3. 4. 5. 6. 7. 8.
a b a b b b a
ANSWERS
9. b
10. a 11. b
12. a, c, d 13. d 14. a 15. b
53
WHEN PRESIDENT EISENHOWER returned to work and resumed full presidential responsibilities after his acute myocardial infarction (AMI) in 1957, a new chapter in coronary disease was written. Thereafter, increasing emphasis was placed on longterm prognosis, and a number of clinical reports were published that assessed posthospital outcome in survivors of AMI. The rationale behind these prognostic stratification studies is that management can be improved by awareness of risk factors and identification of subsets of patients with homogeneous risk. By identifying factors associated with unfavorable outcome, a better understanding of the clinical disease process should ensue, resulting in more appropriate therapy. Risk stratification by functional factors such as ischemia, ventricular arrhythmias, left ventricular function and coronary patency should provide valuable information for devising rational intervention trials to reduce postinfarction morbidity and mortality. The current knowledge of the factors influencing prognosis after myocardial infarction will be reviewed, and groups at low and high risk for postinfarction complications will be described. It is hoped that this prognostic information will be useful to the clinician in the therapeutic management of postcoronary patients. POSTINFARCTION
PROGRAMS
Several prospective programs investigating the posthospital phase of myocardial infarction have made significant contributions to the field, and a summary of the larger studies with appropriate references is presented in Table 1.‘-15 Numerous other studies have been reported, but generally with populations of 6
fewer than 300 patients. These latter studies will be referred to and referenced in the course of this monograph where appropriate. DEMOGRAPHIC COMORBIDITY
AND HISTORICAL FACTORS
AGE The risk of major complications after myocardial infarction is significantly influenced by the age of the patient. The risk relationship with age is not linear, but increases exponentially beginning at 55. Since age is not amenable to intervention, some investigators consider it a risk marker rather than a risk factor. Hagstrom et aLI6 followed, for an extended period of time, 489 patients who survived an AMI. The sudden death rate for this population increased for each decade from 30 to 79 years. However, sudden death did not increase as rapidly in this postinfarction group as the rates of the population at large in the same county. Although the risk of sudden death was far greater for each decade in men who recovered from an infarction than in the general population, this differential diminished with increasing age. Thus, Hagstrom’s data indicate that a greater relative risk of sudden death exists in younger than in older patients with prior myocardial infarction when compared with patients of the same ages without coronary disease. In the Health Insurance Plan of New York City, the 4l/z-year postcoronary mortality was 14.7% for men under 55 years and 20.4% for those over this age.17 Subsequent reports from this group revealed that the 3-year cumulative death rates from any cause were 10.4% for men under 55, 16.7% for men 55-64 and 23.7% for those 65 or older.6 Corresponding 3-year rates for sudden cardiac death in this postinfarction population were 4.5%, 7.2% and 10.4%, respectively. In a number of postinfarction prognostication studies in which patient age was unrestricted, multivariate techniques used increasing age as a weighted factor. In the Peel prognostic index using 6 variables, age 65 or over carried more weight than a prior history of angina, mild hypotension, congestive basilar rales or ST- and T-wave abnormalities, and was weighted equally with a history of exertional dyspnea or Q-waves on the initial ECG.18 Norris et al.ls found that increasing age above 70 years at the time of infarction was associated with significantly reduced 3- and 6-year survival. Moss et al.** using a stepwise discriminant analysis technique for predicting survival after myo-
Follow-up interval
is given in months unless otherwise specified.
12-60
20 years
24
Prognostic significance of VPB; risk stratification by survivorship analyses
Clinical course; VPBs and sudden cardiac death Risk classification by logistic regression analysis Natural history study with life table analyses
6-48 (Average,
24)
Prognostic importance of ECG findings
THE POSTHOSPITAL (p MI)
36
1. -PROSPECTIVE PROGRAMS INVESTIGATING PHASE OF MYOCARDIAL INFARCTION
Coronary Drug Men 565 years; 2,035 Project-Control Group1-3 >3 mo. p MI; NYHA I or II (1965 - 1972) Health Insurance Men ~74 years; 1,739 Plan-N.Y.C.4-r 50% >3 mo. p MI (1972 - 1976) Giiteborg PostMen 567 years; 292 infarction Studya, 9 before discharge; (1968 - 1972) first infarction Framingham Heart Men and women 319 Disease Epidemiology 580 years; Studylo onset of MI (1950 - 1970) Rochester Heart Research Men and women 978 Follow-up Program~~~15 565 years; (1973 - 1978) before discharge
TABLE
cardial infarction in an unrestricted age population, found that increased age was one of the most important factors in identifying patients with increased mortality risk. In contrast, Bigger et a1.2o did not find age a good predictor of early posthospital death after infarction. It appears that Bigger’s population had more extensive myocardial damage than the patients reported by MOSS,” and the increased occurrence of severe left ventricular dysfunction in Bigger’s study overwhelmed the age factor. In a number of postinfarction studies in which patients over age 65 or 70 were excluded, the age factor had a negligible influence on outcome. SEX
The relatively low incidence of coronary heart disease among women in comparison with men is well known. In most of the postinfarction studies reported in the literature, men outnumbered the women by a ratio of roughly 411. After coronary disease becomes clinically manifest in women, is its course similar to that in men? This question is difficult to answer because comparisons of survival between men and women patients with myocardial infarction are rare and limited by the infrequent inclusion of women in such studies. Juergens et a1.21 carried out a retrospective study from the Mayo Clinic records of the 5-year postinfarction survival rates of 127 men and 41 women. At entry, the women were on the average 7 years older than the men, but Juergens could not explain the poorer outcome in the women entirely by this age differential. Honey and Truelove, dealing with patients admitted over a E-year period to the Radcliffe Infirmary, Oxford, found no influence of sex on prognosis either in the first 8 weeks after infarction or during the remainder of the first year. In the Framingham study, 6-year follow-up data in 34 women and 158 men with myocardial infarction revealed no difference in overall survival.23 In a detailed report by the Health Insurance Plan group, the 5-year survival among 108 women and 564 men alive 1 month after infarction was similar.5 Thus, although female sex represents a low risk factor for the development of coronary disease, after a clinical infarction has occurred these women no longer enjoy protection from secondary complications. SOCIAL
CLASS
In cardiac as well as noncardiac conditions, patients in the lower socioeconomic strata of society appear to do less well with chronic disease than individuals in higher social class levels.24 Recently, Weinblatt et al.7 from the Health Insurance Plan study, substantiated a significant relationship between low educa9
tional level and sudden cardiac death during the posthospital phase of myocardial infarction. During a 3-year follow-up period after myocardial infarction, men with 8 years of schooling or less who had complex ventricular premature beats in a l-hour monitoring period had more than 3 times the risk of sudden coronary death found among better educated men with the same arrhythmia. This relationship was independent of traditional risk factors and the usual clinical characteristics affecting prognosis. In the Rochester program,25 postinfarction patients from the lower socioeconomic group (Hollingshead class 4 and 5) had a significantly increased occurrence of sudden cardiac death in the period beginning 6 months or more after hospital discharge when compared with (1) their early (less than 6 months) posthospital interval and (2) the late (more than 6 months) posthospita1 period in upper social class patients (Hollingshead class 1, 2, and 3). The explanation for these findings is unclear but this author believes a multifactorial risk interaction is operative. Patients with lower socioeconomic background may have difficulty adjusting to the consequences of chronic illness with greater unemployment and medical disability, less comprehension and insight into their medical condition and possibly a greater difficulty in altering risk factors (such as hypertension and obesity) than their upper class brethren. The Health Insurance Plan data suggest that the availability of medical care cannot be incriminated as a factor to explain the outcome differential between the lower and upper social classes. PRIOR ANGINA
A clinical history of angina pectoris prior to the index myocardial infarction has negative prognostic implications for longterm survival. In the Health Insurance Plan, the age-adjusted postinfarction death rates at 1,3 and 5 years were 14%, 22% and 33%, respectively, for patients with prior angina pectoris, and only 5%, 14% and 20% for those without this condition.” In the Rochester Heart Research Follow-up Program, a history of angina pectoris prior to myocardial infarction was significantly more frequent in patients who subsequently died than in survivors during an average 3-year follow-up.14 Similarly, Norris et alz6 found that prior angina pectoris resulted in a significant increase in the 6-year postinfarction mortality. In the Goteborg postinfarction study: angina was associated with an increased 2-year mortality but the significance level was borderline (P < 0.10). In all of the aforementioned studies the angina1 symptom was categorized as either present or absent, and such characteristics as decubitus angina, unstable angina and crescendo angina were not included in the analyses. The more ominous forms of angina, such as those indicating extensive coronary 10
disease, are more likely to be associated with increased mortality and reduced survival in the postinfarction period than the more stable forms of angina. PRIOR MYOCARDIAL INFARCTION
It is reasonable to assume that patients with a myocardial infarction prior to their index coronary event will have a worse long-term prognosis than patients suffering their first coronary attack. Since a correlation exists between the extent of cardiac damage and prognosis,2’ patients with one or more prior infarctions would probably have less myocardial reserve and reduced posthospital survivability. Research data from a variety of studies support these assumptions. In both the Peel’* and Norrislg indices, a previous cardiac infarct was associated with significantly increased posthospital mortality. In the Coronary Drug Project, patients with more than 1 prior myocardial infarction had a 3-year mortality approximately twice that of patients with only a first infarction.28 In the Giiteborg postinfarction study,” the l- and 2-year mortality figures for first infarctions were 8% and 12%, respectively, and 22% and 34% for reinfarctions (P < 0.001). In Weinberg’s follow-up of 154 survivors of AMI, the 6-year mortality was 31% in patients without and 56% in patients with a prior infarction.2s Similar results were observed in our Rochester program14 and in the recent postinfarction follow-up study by Luria.30 The type and location of the prior myocardial infarction may also be important predictors of outcome. Although there are very few good data on this point, certain conclusions can be drawn from a variety of related studies. Baum et a1.31 pointed out in 1974 that patients resuscitated from prehospital ventricular fibrillation did better if an acute transmural myocardial infarction evolved than if it did not. Subsequently, Cannom et a1.32 found that patients with nontransmural myocardial infarction have a particularly guarded prognosis. These studies suggest that patients with a prior nontransmural or subendocardial myocardial infarction have residual myocardial ischemia, which may contribute to electrical instability. There is every reason to believe that similar findings will be observed in reinfarction patients in whom the prior event was a nontransmural infarction. PRIOR CARDIAC FUNCTIONAL STATE
At the time of the index myocardial infarction, the patient’s prior functional state can usually be ascertained by a careful medical history. The 4-level New York Heart Association (NYHA) functional classification scheme is particularly useful in this regard. In our Rochester postinfarction study, posthospi11
tal mortality progressively increased with advancing grades of the prehospital NYHA functional state. The 3-year death rates for prehospital NYHA grades I, II, III and IV were 10.5%, 19.4%, 22.2% and 24.7%, respectively. Patients with a history of cardiac symptoms atkss than ordinary activity (III) or at rest (IV) are at particularly high risk. This functional classification by historical questioning provides important qualitative information about global cardiac reserve, and it provides some insight into the status of the heart on which the new infarct is engrafted. OTHER PREEXISTING FACTORS Hypertension is a primary risk factor in the development of coronary heart disease. In their &year postinfarction follow-up study, Pell and D’Alonzo33 observed pronounced excess mortality (P < 0.01) in patients with a history of hypertension prior to the initial infarction. In the New York Health Insurance Plan study, the 3-year postinfarction mortality for patients with initially elevated (> 160/95 mm Hg), borderline and normal blood pressure was 28%, 13% and 9%, respectively.17 In the Rochester Heart Research Follow-up Program, history of hypertension was a significant risk factor for early and late posthospital mortality.13, l4 From these studies and others, hypertension can be considered both a primary and secondary risk factor, a dual role with a multiplier effect, which substantiates its very important contribution to coronary morbidity and mortality. Hypercholesterolemia and diabetes mellitus are metabolic conditions that predispose the patient to premature atherosclerotic disease, including coronary heart disease. The presence of these comorbidity conditions before an index myocardial infarction is associated with only a minimally increased mortality risk during the posthospital period. However, Vedin observed in the Gijteborg study that hypercholesterolemia was an important risk factor in the identification of coronary patients who developed a nonfatal reinfarction within 2 years after the initial infarction.34 Only a limited number of studies have evaluated the relationship between the patient’s smoking history and the subsequent postinfarction clinical course. In the Coronary Drug Project, a history of cigarette smoking was associated with significantly increased 3-year postinfarction mortality.3 In the Health Insurance Plan study, a history of cigarette smoking was associated with an increased probability of death in the 4l/2 years after infarction, but only in those patients who continued to smoke after the index event.17 Current analysis of the Rochester data reveals that patients who smoked cigarettes prior to the index infarction had threefold greater posthospital mortality than nonsmokers. However, this mortality effect was maintained regardless of the 12
patient’s smoking status after the infarction. Discontinuance of smoking did not improve survivability when compared to those who resumed the smoking habit during an average 2-year follow-up. This discrepancy in the smoking findings of the 2 studies may relate to methodologic and population differences, e.g., the Health Insurance Plan enrolled patients of unrestricted age 3- 12 months after an index cardiac event (myocardial infarction and angina), whereas the Rochester study enrolled patients 65 years of age or younger prior to hospital discharge. CLINICAL CHARACTERISTICS CARE UNIT PHASE
DURING
THE CORONARY
The severity of the AM1 is a primary determinant of both the in-hospital and posthospital courses. The magnitude of damage to the myocardium and the extent and severity of obstructive coronary artery disease are reflected in the hemodynamic, ‘ischemit and electrical derangements observed during the acute hospital phase. These functional disorders are intimately related to prognosis after myocardial infarction. LEFT VENTRICULAR DYSFUNCTION
Numerous studies have shown that clinical evaluation of the patient’s hemodynamic status in the Coronary Care Unit (CCU) provides valuable information about posthospital prognosis. Humphries recently summarized information from a dozen or more studies and provided semiquantitative l-year posthospital death rates according to the clinical class at the time of hospital admission.35 Patients without clinical or laboratory signs of left ventricular dysfunction had a mortality of less than 5%. Mild-tomoderate cardiac dysfunction as manifest by auscultatory pulmonary rales and roentgenographic evidence of pulmonary congestion, was associated with a mortality of lo-30%. Significant heart failure with pulmonary edema resulted in 50% mortality. The worst prognosis (more than 50% mortality) occurred in patients who survived cardiogenic shock. More precise evaluation of left ventricular function in the CCU can now be obtained noninvasively by radionuclide ejection fraction determination. Preliminary data suggest that ejection fractions above 50% are associated with a favorable long-term prognosis, those in the 35- 50% range represent an intermediate risk and patients with ejection fractions less than 35% are at high risk of major complications. Invasive hemodynamic monitoring of cardiac output and pulmonary capillary wedge pressure with Swan-Ganz thermodilution catheters have been carried out in both complicated and uncomplicated infarction patients.36 Progressive reduction in 13
cardiac output and elevation of wedge pressure are directly associated with increased short- and long-term mortality. There are a number of easily measured clinical parameters that reflect left ventricular dysfunction and are also useful indicators of posthospital prognosis. Norris et a1.26 found that qualitative cardiomegaly detected on an admission chest x-ray film was associated with significantly increased mortality at 3 and 6 years after the infarction. Vedin et a1.s used a relative heart volume index37 for the quantitation of heart size and observed significantly increased 2-year mortality in patients with cardiomegaly (men - heart size greater than 450 ml per sq. m; women- heart size greater than 400 ml per sq. ml. Helmers38 reported that tachypnea in the CCU with respiratory rates of 28 per minute or above were associated with a twofold increase in 3year mortality. INFARCT SIZE
Extensive myocardial damage at the time of infarction is a permanent liability and a long-term threat to life. Early observations suggested that infarct size or intensity of &hernia could be evaluated in anterior wall infarctions by the magnitude of ST segment elevations in precardial ECG maps.3s Subsequent studies have demonstrated the inaccuracy of this technique.40 A more useful approach is the quantitation of creatine phosphokinase release from the infarct by measurement of total enzyme activity1 or of the activity of its cardiac-specific MB fraction42 in serial venous blood specimens collected for 2 or 3 days after the onset of infarction. Preliminary results suggest that the posthospita1 risk in hospital survivors is directly related to the enzymatically determined infarct size.43 Two other techniques, positive radionuclide imaging“4 and measurement of myoglobin release,45 have also been used to evaluate infarct size but this information has not yet been related to posthospital prognosis. INFARCT LOCATION
The 12-lead ECG is useful for locating the site of the myocardial infarction, especially when there is enzymatic confirmation of myocardial necrosis. Infarcts have been categorized as transmural or nontransmural (subendocardial) depending on the presence or absence of pathologic Q-waves in the absence of major intraventricular conduction abnormalities. Furthermore, the transmural infarcts can be divided into anterior and posterior locations. For many years it was thought that patients with nontransmural myocardial infarctions have a lower incidence of complications and in-hospital mortality than those with transmural 14
infarctions. The concept has been challenged by recent reports indicating that the short-term prognosis and the frequency and complexity of cardiac arrhythmias were similar in patients with nontransmural. and transmural infarction.46 Furthermore, the findings from Seattle in those patients resuscitated from out-ofhospital ventricular fibrillation clearly revealed lower posthospital mortality in individuals with transmural infarction than in those without new ECG Q-waves.31 This finding prompted a reassessment of left ventricular performance and prognosis in patients with different types of infarction. In 1975 Rigo et a1.47 reported the posthospital clinical course of 41 patients with nontransmural and 81 patients with transmural myocardial infarction. In a 20-month follow-up, 18 - 19% mortality was observed in both groups. In a longer follow-up of nontransmural and transmural infarction patients, Cannom et a1.32 observed similar death rates during the first 2 years after hospital discharge. However, 4 years after the index infarction the nontransmural group had 45% mortality compared with 25% for the transmural patients (P < 0.05). The authors concluded that patients with nontransmural infarction have a particularly guarded prognosis, especially in the later posthospital period. With regard to the site of the infarct, the conventional view is that anterior infarcts are associated with increased short- and long-term mortality when compared to posterior and other locations. Numerous population studies, including our own Rochester Heart Research Follow-up Program,15 have substantiated reduced posthospital survivability in anterior as opposed to nonanterior infarctions. On the basis of infarct location alone, the 3year survival rate for anterior infarctions is 85% and for other locations it is 92%. The reason for this discrepancy in survival is somewhat controversial. That is, does the anterior infarct location create more electrical and mechanical dysfunction than comparably sized infarctions at other sites, or is the increased mortality a function of larger infarct size in the anterior location? Anterior myocardial infarction invariably occurs as a result of stenosis or occlusion of the left anterior descending coronary artery. This vessel is the major artery supplying left ventricular muscle, for it perfuses the entire left ventricular anterior wall, a significant portion of the lateral wall and most of the interventricular septum. Thus, an occlusion of this vessel would compromise blood flow to a greater area of the left ventricle than do similar occlusions of the right or circumflex coronary arteries. Accordingly, one might expect more left ventricular dysfunction after anterior than after posterior or inferior infarctions as a result of a greater extent of left ventricular myocardial necrosis in the former. This is exactly what a number of investigators have concluded from their studies. Miller et a1.48 studied cardiac pump function by biplane left ventricular angiography in a 15
group of 43 patients with remote myocardial infarction. Greater reduction in left ventricular function was observed in anterior than in inferior infarction as a result of the more extensive left ventricular segmental contraction abnormality in the former. Further support of this conclusion was provided by Strauss et a1.49 who evaluated the relationship between infarct size, site of infarction and mortality. Although the infarct size as determined by creatine kinase was similar in anterior and posterior infarctions, the higher mortality associated with the former was related to all the damage occurring in the left ventricle, as opposed to its distribution in both ventricles with inferior infarctions. Thus, patients with anterior wall infarctions are at increased mortality risk because they have more left ventricular muscle necrosis and a greater degree of left ventricular dysfunction than patients with comparably sized infarcts at other locations. Once again, a major determinant of outcome is magnitude of the pump dysfunction. CONDUCTION DISTURBANCES
The development of certain types of conduction disturbances during the CCU phase of AM1 is associated with increased acute, subacute and chronic mortality. Waugh et a1.5o identified patients at high, intermediate and low risk of sudden death in the first postinfarction year according to conduction defects observed during the acute phase. The most accurate predictor of lyear outcome was the status of atrioventricular conduction in combination with the status of intraventricular conduction. Patients at highest risk were those who had any of the following ECG findings while in the CCU: (1) adjacent fascicular block (left anterior hemiblock and right bundle-branch block or left bundle-branch block) plus PR-interval prolongation; (2) nonadjacent fascicular block (left posterior hemiblock and right bundlebranch block; alternating bundle-branch block) regardless of PRinterval; or (3) transient Mobitz type II complete heart block. Thirteen of 26 (50%) such patients died within 1 year of hospital discharge, with the majority (10) dying suddenly. An intermediate risk (27% mortality in 1 year) was observed in patients with per&infarction block, left posterior hemiblock or left bundle-branch block of the complete or incomplete type. Isolated right bundle-branch block, left anterior hemiblock or a combination of these two without PR-interval prolongation was associated with 3% l-year mortality-a similar risk to that of patients without conduction disturbances. Scanlon et a1.51 carried out a retrospective review of the clinical cause of peri-infarction right bundle-branch block and left anterior hemiblock in 13 patients. Four (30%) died suddenly during follow-up, but details of the terminal event were not re16
ported. The development of complete heart block after discharge was not an infrequent event. Atkins et a1.52 studied the prognosis of a similar group of patients who had transient complete heart block complicating AMI. They found that 11 of 13 patients who did not have permanent pacemakers died within 8 months of discharge, whereas 8 who did were still alive. In a review that presents the composite data of a number of investigators, Mullins and Atkins53 substantiate the risk of posthospital sudden death in patients who develop left anterior hemiblock and right bundle-branch block with transient complete heart block, even if normal conduction returns. They recommend the use of permanent pacemakers to reduce the risk of sudden death in these patients. ATRIAL
ARRHYTHMIAS
Atria1 arrhythmias (atria1 tachycardia, atria1 flutter or atria1 fibrillation) occurring in the early CCU phase of AM1 are frequently associated with signs of congestive heart failure and greater overall early mortality. Peel et a1.18 included atria1 arrhythmias in the coronary prognostic index for grading the severity of infarction, but Norris et alIs did not. The prognostic significance of early atria1 arrhythmias in subsequent long-term outcome is unclear. Luria et al. 54 found that occurrence in the CCU of atria1 ectopic beats or atria1 arrhythmias as defined above was associated with significantly increased 2-year mortality. In fact, atria1 arrhythmia was 1 of the 5 variables in the discriminant function that identified patients at high risk of early mortality. In a more recent study, the same group verified the important role of atria1 arrhythmias in prognostication and extended the follow-up to 5 years.30 The Goteborg groups also observed significantly increased 2-year mortality in patients with atria1 fibrillation in the acute phase. In contrast, neither the study of Bigger et a1.20 nor our own in Rochester substantiated the prognostic usefulness of CCU atria1 arrhythmias in posthospita1 outcome. In all likelihood, atria1 arrhythmias per se are not a primary determinant of outcome; rather, they probably reflect a more severe underlying cardiac or pulmonary diseaseconditions associated with increased mortality. VENTRICULAR
ARRHYTHMIAS
What are the posthospital implications of simple and complex ventricular premature beats (VPBs), paroxysmal ventricular tachycardia and primary ventricular fibrillation (VF) with successful resuscitation occurring in the CCU? Moss et a1.12 and Vismara et a1.55*56 found a poor correlation between complex VPBs observed in the CCU and posthospital mortality. Paroxys17
ma1 ventricular tachycardia occurring in the acute phase of myocardial infarction in patients who survived their illness was not associated with increased posthospital mortality when compared with patients without this tachyarrhythmia. deSoyza et a1.57 found that 17 of 18 patients who had paroxysmal ventricular tachycardia in the CCU survived long-term (average 19 months) follow-up. The short- and long-term prognosis of VF complicating AM1 is closely related to the circumstances underlying its development. Stannard et a1.5s reported long-term follow-up of 20 patients with successful resuscitation from primary VF. Eighteen of the 20 patients survived a variable follow-up ranging from months to years. Lie et a1.5s found that more than 90% of patients with primary VF in the CCU could be resuscitated, and this group had a favorable 2-year mortality (less than 10%). In contrast, secondary VF, which results from heart failure, is usually associated with extensive myocardial damage60 and a poor outcome is anticipated. Among hospital survivors of the latter group, Lie et a1.5sfound 50% mortality within 2 years. These findings indicate that ventricular arrhythmias recorded in the CCU are unreliable indicators of subsequent prognosis. The only exception is secondary VF and, once again, the determinant of outcome is the disordered ventricular function and not the complicating tachyarrhythmia. DISCHARGE
CHARACTERISTICS
During the past decade numerous postinfarction patients have been studied prior to discharge or in the early posthospital period in order to identify those at increased mortality risk. The earlier studies evaluated the prognostic importance of various ECG findings. With the introduction of Holter ambulatory recordings, research emphasis shifted to the prognostic role of ventricular arrhythmias. The development of the radionuclide technique for noninvasive evaluation of the ejection fraction and ventricular wall motion permits precise evaluation of the important mechanical cardiac factors that relate to outcome. Twodimensional echocardiography may also be useful in this regard. Recent studies have used coronary and left ventricular angiography in the evaluation of high-risk postinfarction patients who might be candidates for coronary artery bypass surgery. Because of the relative safety of the angiographic studies reported to date and the valuable information which cannot be obtained in any other way, coronary angiography will probably be used more frequently for postinfarction patients. Activity and exercise testing using treadmill and bicycle ergometer techniques in postcoronary patients have provided valuable insight into global cardiac performance as well as ischemic and arrhythmic abnormalities. An electrical stress test using a temporary transvenous 18
pacing stimulus to evaluate ventricular electrical instability has also been reported in postinfarction patients. These studies are providing important insight into electrical, mechanical, ischemic and anatomical factors that influence the clinical course of patients after myocardial infarction. A summary of this rapidly expanding body of information follows. TWELVE-LEAD ECG
In the Health Insurance Plan study, baseline ECGs were recorded at variable times during the early posthospital phase of myocardial infarction.17 The ECGs were coded using the Minnesota criteria for specified abnormalities. ECG ST- and T-wave abnormalities were associated with a threefold increase in mortality during a 4l/z-year follow-up. Connolly et a1.61 recorded ECGs 1 year after myocardial infarction and found the following parameters associated with unfavorable outcome: (1) persistence of transmural or subendocardial infarction patterns; (2) left ventricular hypertrophy; (3) 1 or more VPBs; or (4) a heart rate over 100 per minute. In the Coronary Drug Project, the control group became a valuable source of information about the prognostic value of the postinfarction ECG.’ Several ECG findings provided information independent of the clinical status of the patient on the risk of death during a 3-year follow-up. ST-segment depression was the single most powerful predictor of subsequent death. The presence, size, extent and location of residual Q-waves (Minnesota Code criteria) were independently prognostic, as were left system conduction defects, atria1 fibrillation, tall R-waves in lead II, the depth of the invested T-wave in lead V, and the presence of frequent (more than 1 in 10 recorded beats) VPBs. ECG findings without prognostic significance included supraventricular premature beats, prolonged PR interval, complete right bundlebranch block and low QRS amplitude. The Coronary Drug Project was the first group to evaluate the prognostic importance of the ECG left ventricular hypertrophy pattern (ECG-LVH) after myocardial infarction.28 The ECGLVH pattern, defined only by elevated R-wave amplitude in appropriate leads of the resting ECG (Minnesota Code), was ascertained in 2,760 placebo-treated survivors of myocardial infarction. One hundred eighty-six (6.7%) had ECG-LVH amplitude criteria when recorded an average of 36 months after the last myocardial infarction. The 3-year mortality in men with ECG-LVH was almost twice that in men without (22.6% vs 12.1%, P < 0.01) when the influence of all other variables on mortality was ignored. However, when the relationship between baseline ECG-LVH ,and subsequent mortality was adjusted for confounding ECG and clinical variables, the elevated R-wave 19
amplitude itself had no significantly independent prognostic value. The prognostic importance of ECG-LVH was largely explained by coexisting repolarization (ST- and T-wave) abnormalities. However;-the combination of ECG-LVH by amplitude criteria and ST-segment and T-wave-abnormalities was more important prognostically than the findings of ST-segment depression and T-wave negativity alone. Thus, ECG-LVH by R-wave amplitude criteria in the absence of abnormal ST- and T-wave findings was unrelated to prognosis in postinfarction patients. The relationship between VPBs and long-term outcome was also analyzed in considerable detail in a special report by the Coronary Drug Project.2 Among 2,035 placebo-treated patients in the nationwide study, 235 men (11.5%) had one or more VPBs in their resting 1Zlead ECG. During a 3-year follow-up period, deaths were about twice as frequent (P < 0.01) in those with any VPBs (21.7%) as in those with none (11.4%). Excess long-term risk of death, including sudden death, was associated with increased VPB frequency, with pairs and runs of VPBs and possibly with early-cycle VPBs. The excess risk with these VPB characteristics was independent of the risk associated with other ECG and clinical characteristics. Although the sample of daily ectopic activity represented in the 12-lead ECG is extremely limited, the overall frequency of any VPB (11.5%) in such a small sample is quite significant. As the Coronary Drug Project investigators pointed out, any VPB found during this brief monitoring period probably identified cases having a high frequency of ectopic activity throughout the course of the day. The apparent association of complex VPBs with increased mortality suggested that longer monitoring periods might be worthwhile. This fundamental study set the stage for the use of Holter recordings of various durations (1 - 24 hours) in the prognostic evaluation of cardiac arrhythmias after myocardial infarction. A recent Finnish study suggests that P-wave morphology of the discharge ECG in postinfarction patients is of prognostic value.‘j2 Pohjola et al. correlated P-wave morphology in the discharge ECG with survival in 728 patients with AM1 over a 5year period. During these 5 years 219 patients died, 177 of them as a result of ischemic heart disease. Those morphological aspects of the P-wave that were studied were the P-terminal force (size of the negative portion of the P-wave in chest lead V,), the frontal axis of the terminal P-wave, P-wave duration and atria1 fibrillation. Of 69 patients with abnormal P-terminal force (0.03 mm/set or more negative), 37 (53.6%) died within 5 years compared with 114 deaths among the 558 patients (20.4%) with normal P-terminal force. Most patients with an abnormal Pterminal force died within the first 6 months after discharge. Among 15 patients with frontal axis of the terminal P-wave of 30 degrees or more negative, 8 died (53%). In addition, 5 of 10 20
patients (50%) with atria1 fibrillation died. P-wave duration showed no relationship to mortality. These abnormal ECG Pwave findings, which probably reflect left ventricular failure, are useful indicators of increased mortality risk in the posthospita1 phase of myocardial infarction. Repolarization abnormalities with primary or secondary Q-T prolongation (corrected Q-T of more than .44 seconds) have been associated with electrical instability, ventricular irritability and sudden death. Schwartz et al. 63 have investigated the relationship between the Q-T interval recorded postinfarction on a 12lead ECG and subsequent outcome. They studied 55 patients with a recent myocardial infarction and a matched set of healthy controls. ECGs were recorded every 2 months for 7 years. The corrected Q-T interval (mean of all recorded values) was prolonged in 1 control (2%), 5 of 27 surviving infarction patients (18%) and in 16 of 28 infarction patients (57%) who died suddenly. Prolongation of the QT-interval after myocardial infarction was associated with a 2.2 times greater risk of sudden cardiac death than patients with a normal QT-interval. Similar repolarization abnormalities were noted in the Seattle sudden death study among survivors of out-of-hospital ventricular fibrillation.64 HOLTER
MONITORING
The usefulness of Holter monitoring in the evaluation of asymptomatic cardiac rhythm and conduction disturbances was demonstrated by Hinkle and coworkers with their report in 1969 of arrhythmia findings in 301 overtly healthy, middle-aged men.65 This monitoring technique was first applied to a postinfarction population by Moss and coworkers in 1971.s6 One hundred patients who were convalescing from myocardial infarction had a 6-hour Holter ECG recording performed in the few days before contemplated hospital discharge. Seventy-two percent of the patients had 1 or more VPBs, 20% had multifocal VPBs, 18% had ventricular bigeminy or paired VPBs and 4% had one or more transient runs of ventricular tachycardia. Thirty-six percent of the patients had a disturbing degree or type of ventricular irritability that was unsuspected by their attending physicians and was unrelated to cardiac arrhythmias manifest in the CCU. This descriptive study was quickly followed by a number of outcome-oriented, prospective, postinfarction investigations (Table 2). In 1973 Kotler et al. 67 studied the role of ventricular dysrhythmias as determinants of sudden coronary deaths (within 1 hour of onset of symptoms) in 160 male survivors of myocardial infarction. The study population consisted of male participants in one of the enrolling hospitals (Sinai Hospital, 21
K
*Variable X = Data
VPBs (o/o) Any Frequent* Multiform Bigeminy Pairs Ventricular tachycardia Significance re cardiac death
Age (years) Holter recording
No. of patients
Population
TABLE IN
definition. not available in original
Freq/Cmplx VPB: 3 x risk during 3-yr follow-up
2
80 16 18 X 19
(65 12-hr at S-month intervals; aver. 4.5lpatient
> 3 mo. p MI NYHA I, II 160
2. -OCCURRENCE (VPBs)
41
I
73
39-85 lo-hr
64
p MI
9 Cmplx VPB: 3x risk during 2-yr follow-up
2 wks.
SIGNIFICANCE POSTHOSPITAL
article.
AND THE
I
1 26 27
1-hr
52
ages
X Cmplx VPB: 3x risk during 3-yr follow-up
All
p MI
1739
< 9 mo.
p MI
VENTRICULAR INFARCTION
Cmplx 2.5~ 1-yr
35
VPB: risk during follow-up
I
71 X
100 consecutive patients between the AM1 and the Holter recording; (5) a definition of sudden death analagous to “instantaneous”; and (6) mortality endpoints that did not include nonsudden cardiac death. It is interesting that a recent analysis of the deaths in our Rochester study revealed the preponderance of nonsudden death in the first few months after hospital discharge, with a progressively increasing proportion of sudden deaths occurring 3 months or more after infarction. An overall interpretation of the numerous studies evaluating the significance of VPBs on predischarge Holter recordings is that complex VPB patterns have prognostic power in mortality prediction. However, complex VPBs are only one of many factors associated with increased likelihood of cardiac death. Certainly the extensiveness of the coronary disease process, the degree of 27
1.5
SUDDEN CARDIAC DEATH (55)
/
COMPLEX VPB (216l
P value C”SN 001 cvss 003 S”SN 009
SIMPLE VPB (254)
IO
0 MONTHS I5 -
2 2
20 AFTER
30
MYOCARDIAL
40
50
INFARCTION
NON-SUDDEN CARDIAC DEATH (43) P value Cv*N 001 cvss .OOl Sv*N 020
IO-
3
-
z 2 8 zl Q
SIMPLE “PB 1254) 5
_
-
l ” _---
. . . . . . . . . ---
_e--
O$,,,,“,,,“,“,,,,,,‘,,,l 0
20
IO
MONTHS
AFTER
30
MYOCARDIAL
40
50
INFARCTION
Fig l.-Cumulative sudden (top) and nonsudden (bottom) cardiac mortality for patients with complex (C), simple (S)and no (Njventricular premature beats. Comparisons of the mortality curves between specified patient groups were carried out, and the significance levels are provided with P values. See text for explanation. (From Moss, A., et al.: Ventricular ectopic beats and their relation to sudden and nonsudden cardiac death after myocardial infarction. Circulation 60:998,1979. Used by permission.)
myocardial scarring and the functional state of global cardiac performance must be equally important determinants of outcome. Very few data exist on the prognostic significance of VPBs recorded 1 year or more after myocardial infarction. A few de28
scriptive studies have reported a progressive increase in the frequency and complexity of VPBs recorded at serial times in the first postinfarction year. 6s,‘O Armchair analysis would indicate that if VPBs are becoming more frequent during the time when mortality is diminishing, then VPBs would progressively lose prognostic power in identifying mortality events. A preliminary report from the Rochester program supports this hypothesis.71 In a related investigation of the clinical significance of ventricular tachycardia recorded during ambulatory monitoring after myocardial infarction,72 the findings were consistent with the aforementioned interpretation. Sixty-six patients were identified who had one or more episodes of ventricular tachycardia recorded during postinfarction follow-up recordings conducted over a period of 48 months. A case-control analysis was carried out by matching each ventricular tachycardia patient with an appropriate control patient without this arrhythmia. The overall death rates in the two groups were similar (VT = 16%, control = 8%, P = 0.11). Life table analysis of the survival of the ventricular tachycardia and control patients revealed a 48-month survival of 75% and 87%, respectively. Within the former group, those who died had more severe underlying heart disease than the survivors. The occurrence of ventricular tachycardia in the posthospital phase of myocardial infarction, while associated with a somewhat lower survival rate, does not indicate as much danger as is generally assumed. How does one interpret the prognostic significance of Holterrecorded VPBs in patients with coronary heart disease? The data strongly indicate a gradient of risk which varies inversely with the temporal relationship to the acute coronary event. VPBs recorded 2-3 weeks after infarction have prognostic usefulness in identifying subsequent mortality events, but without discrimination between sudden and nonsudden death; VPBs recorded in the chronic phase of coronary disease have minimal predictive value. ACTIVITY
TOLERANCE
TESTING
Activity testing can induce a variety of arrhythmic, mechanical and ischemic abnormalities, which may have predictive value for various cardiac target events. In the past, AM1 was considered a contraindication to activity testing, but recent studies have shown the feasibility and safety of using a low level activity tolerance test in patients in the late hospital phase of myocardial infarction. A summary of the relevant studies is presented in Table 3. Most centers performing a predischarge activity tolerance test 2-3 weeks after infarction used either a heart-rate-limited, e.g., 130 beats per minute, or symptom-limited procedure. It was hoped that early postcoronary activity 29
Findings (%) Angina ST depression VPBsFollow-up 20 Not available 19 3-mo. mortality: anaina-15%: VPjBs-11%; ’ all patients-5%
(120/min)
100 30-85 Treadmill Heart-ratelimited
No. of patients Age Test
ERICSSON~
SIGNIFICANCE PHASE
Consecutive patients 3 wks. p MI
3.-CLINICAL
Population
TABLE
IBSEN”
OF ACTIVITY MYOCARDIAL
11 49 42 None
209 33-83 Bicycle ergometer Symptom-limited
Consecutive patients 3 wks. p MI
OF
3 wks. all tests 7 11 17 26 9 72 18-mo. morbidity and mortality: increased coronary events in patients with ST depression.
46 36-67 Treadmill Heart-rate-limited at 3 wks. (130/min)
patients and 11 wks.
MARKIEWICZ’~
TESTING (p MI)
Uncomplicated 3 wks. p MI, at 5,7,9, and
TOLERANCE INFARCTION
IN
THEROUX’~
POSTHOSPITAL
20 30 20 1-yr mortality: ST depression-27% VPBs:17% all patients-9.5%
Consecutive patients without CHF.or chest nain 2 wks. pM1 210 28-70 Treadmill Heart-rate-limited (70% age-predicted max. heart rate)
THE
testing would provoke or uncover potential3 dangerous arrhythmias and, thereby, provide a rational case selection for antiarrhythmic therapy. Ericsson et a1.73 conducted a heart-rate-limiied (120 beats per minute) treadmill exercise test on 100 myccardial infarction patients 3 weeks after the acute episode. The average duration of exercise was 5 minutes and the mean maximal heart rate during the test was 118 beats per minute. VPBs Nere recorded in 3 patients at rest immediately before the test snd in 19 during or after the test. Twenty patients developed alyina pectoris and 5 experienced pronounced dyspnea or fatigue. No severe arrhythmias or reinfarctions were induced by the test. All patients were followed for a minimum of 3 months. Of the 5 patients who died during follow-up, 4 had cardiomegaly, 3 had angina pectoris during the treadmill test and only 2 had exercise-induced VPBs. Ibsen et a1.74 carried out a maximal, symptom-limited bicycle ergometer exercise test on 209 patients 3 weeks after AMI. The exercise test was discontinued because of fatigue in 58%, angina or dyspnea in 24% and rhythm disturbances or pronounced ST-T changes in 9%. On the average, the product of heart rate and systolic blood pressure increased more than twofold. Persistent ECG changes, reinfarction or other serious complications were not observed in connection with the exercise test. Follow-up data were not provided. Markiewicz et a1.75 from the Stanford Rehabilitation Program carried out treadmill exercise tests at 3, 5, 7, 9 and 11 weeks after myocardial infarction in 46 good-risk patients under 70 years of age. The 3-week treadmill test was terminated either because of symptoms or if a target heart rate of 130 beats per minute was achieved. lschemic ST-segment depression, usually unaccompanied by angina pectoris, occurred in 54 of 210 tests (26%) among 21 of 46 patients (45%). In those patients who developed ST depression, there was a significantly increased incidence of subsequent coronary events (ventricular fibrillation with resuscitation, coronary bypass surgery, myocardial reinfarction or sudden cardiac death). Exercise-induced VPBs provided little independent prognostic information. No serious complications occurred in 210 tests. A subsequent study from the Stanford group76 provided further evidence that prognosis was more closely related to exercise-induced ischemic abnormalities (ST-segment depression of more than 0.2 mv) than to the development of complex VPBs. Similar findings have been observed in more representative postinfarction populations by Weld et a1.77 and Smith and co-workers.78 In addition, these investigators found that mechanical dysfunction (low maximal work load) was useful in predicting later cardiac events. A comprehensive study evaluating the prognostic usefulness of exercise testing soon after myocardial infarction was recently reported by Theroux et al.79 A treadmill exercise test was per31
formed 1 day befue.hospital discharge in 210 postinfarction patients who had na overt heart failure and had been free of chest pain for at least k days. The exercise test used the NaughtonHaider proto@ with constant treadmill speed and progressively increasing grade. The test was stopped when one of the following endpoints was reached: angina; a workload of 5 metabolic equivalents; 70% of age-predicted maximal heart rate; severe fatigue, dyspnea cr claudication; appearance of more than 10 VPBs per minute or multiform or paired VPB patterns; or STsegment depressiongreater than 5 mm. During a l-year followup, 65% of patients who had chest pain during the test reported angina as compared with 36% who had no chest discomfort during the test (P < O.OL)l). The l-year death rates for patients with and without exercise-induced ST-segment changes were 27% and 2%, respectively (P < 0.001). Sudden death followed the same pattern. These studies clearly support the usefulness of limited activity tolerance testing for predicting cardiac morbidity and mortality in the posthospital phase of myocardial infarction. With careful patient selection and meticulous monitoring of symptoms and physiologic parameters during the testing procedure, activity testing has been safely performed in numerous centers subserving a wide spectrum of patient populations. Ischemic ST-segment changes during exercise and reduced activity performance appear to have more important predictive value than activityinduced arrhythmias. RADIONUCLIDE EJECTION FRACTION
A number of recent studies have reported the use of the radionuclide ejection fraction (EF) technique in the noninvasive determination of left heart function for identifying patients with increased mortality risk after myocardial infarction. Two radionuclide methods are currently available for determining the left ventricular EF. In 1971, Zaret et alEo and Strauss et al.*l introduced an ECG gated cardiac blood pool scanning technique for noninvasive determination of left ventricular volumes, regional wall motion and EF. Briefly, a 15 mCi dose of technetium-labeled red blood cells or albumin is injected intravenously. After equilibration, a blood pool scan is recorded to outline the chambers of the heart. The scintillation camera is gated by an ECG signal to obtain gamma counts in end-systolic and enddiastolic portions of the cardiac cycle. Computer programs are now available for determining the limits of the left ventricular cavity, and the EF is computed. This multiple gated (MUGA) procedure usually requires 30-45 minutes of patient time, and the optimal left ventricular outline is usually achieved by recordings obtained in the left anterior oblique projection. More 32
recently, a faster technique for determining left ventricular EF was introduced using the initial passage of an intravenously injected radionuclide bolus through the heart. Schelbert et a1.82 have popularized this approach. In essence, this first-pass technique analyzes the time-activity curves generated during the passage of the radionuclide through the left ventricle. Changes in the count rate originating from this chamber during any cardiac cycle reflect changes in the volume between systole and diastole. The fraction of end-diastolic blood volume ejected with each systolic contraction can be calculated from these data. The MUGA and first-pass procedures are now extensively used throughout the country, and excellent correlations have been achieved between each of these radionuclide methods and the more involved contrast angiographic technique. In 1975, Schulze and co-worker&j3 reported the relationship between ventricular arrhythmias in the late hospital phase of myocardial and left ventricular function detected by MUGA in 36 patients. Left ventricular EF and percent wall akinesia were calculated from gated cardiac blood pool scans, myocardial infarct size was estimated from peak creatine phosphokinase values, and VPBs were detected by 24-hour Holter recordings and categorized by the &level Lown grading scheme. Thirteen of 14 patients with Lown class II-IV VPBs had EFs of less than 40% compared with only 8 of 22 patients with class O-I VPBs. Patients with class II-IV VPBs had significantly lower mean EFs (30.5% vs 49.6%, P < 0.011, more extensive akinesia (28.1% vs 16.9%, P < 0.05) and higher mean creatine phosphokinase values (1350 units vs 721 units, P < 0.05) than patients with class 0 -1 VPBs. These results indicate a striking association between depressed left ventricular function and complex VPBs in the late hospital phase of myocardial infarction. The authors suggest that VPBs may not be-an independent risk factor for cardiac death in the convalescent phase of myocardial infarction. Schulze and his associates continued these investigations and, in 1977, they reported a l-year follow-up of 81 patients who had 24-hour Holter recordings and gated cardiac blood pool scans approximately 2 weeks after AMI. In 36 patients (44%) the EF was 40% or more; only 3 had complicated ventricular rhythms (Lawn class III-V). In 45 patients (56%) the ejection fraction was less than 40%; 26 had complex VPBs. Eight patients had documented ventricular fibrillation or instantaneous death during a mean ‘I-month (range 2- 16 months) posthospital followup. Eight patients who died suddenly were all in the subgroup having EF of less than 40% and complicated ventricular arrhythmias. The authors conclude that a low ejection suggests a poor prognosis following myocardial infarction, but the concomitant presence of complex VPBs significantly increases the risk of sudden death in the posthospital period. 33
The radionuclide technique used in these studies provides an easily obtainable, noninvasive means of evaluating ventricular performance in the recovery phase of AMI. This information is important be-se routine clinical and radiographic evaluation generally provides an inadequate assessment of overall cardiac function. In addition, the radionuclide technique may provide a means of evaluating the reserve of the infarcted myocardium in response to exercise stress after discharge. Gated and first-pass approaches can now provide quantitative data about regional wall motion abnormalities, and this information should further enhance the accuracy of the assessment of left ventricular functjon by radionuclides. Since the degree of left ventricular dysfunction has been shown to be a major determinant of morbidity and mortality after myocardial infarction, it is likely that the radionuclide technique will be used routinely in the prognostic evaluation of postcoronary patients. CORONARY AND LEFT VENTRICULAR ANGIOGRAPHY
The most precise way of defining coronary anatomy and evaluating left ventricular function is by contrast angiography. Although this procedure is widely used in the evaluation of symptomatic patients with chronic coronary disease, there is general reluctance to use it in the early post infarction phase. Only a limited number of such studies have been reported in the literature, and to date the procedure has been associated with few if any complications. In 1977, Schulze et a1.85 from Johns Hopkins, reported the angiographic and Holter recorder findings in 38 patients studied lo- 24 days after AMI. There were no complications from the catheterization procedure. Patients with complex VPBs (multiform, paired, R on T or ventricular tachycardia), when compared to those with no or uncomplicated VPBs, had a greater number of proximally narrowed major coronary arteries, a higher coronary score using the Friesinger method,E6 greater incidence of previous myocardial infarction, a greater percentage of abnormal left ventricular segments and lower EF. These findings complemented their prior radionuclide investigationss3> 84 and provided strong support for the significant association between complex VPBs and extensive coronary and myocardial disease. These investigators also used contrast angiography to compare the extent and severity of coronary and myocardial disease in patients with recent transmural and non-transmural MI.87 Fortyeight patients were studied prior to hospital discharge, 31 with transmural and 17 with nontransmural infarction. There were two complications: one patient developed a femoral artery thrombosis following a catheterization (effectively treated surgically); a second patient suffered an embolus to the distal left anterior 34
descending artery on injection of the left coronary artery (the patient made a good recovery). There was no difference between the two groups in the prevalence of single, double or triple vessel coronary artery disease, the extent or severity of coronary stenosis, left ventricular EF or the percentage of akinetic-dyskinetic myocardial segments. The similar angiographic findings in transmural and nontransmural infarction patients suggest that the long-term outcome would also be similar. Follow-up studies have not yet been reported with these patients. Russell and co-workers,88 from the University of Alabama, described the angiographic findings in 34 patients who had the catheterization procedure performed an average of 27 days after AMI. No complications due to angiography were encountered. Those with prior infarction (14) had more severe triple-vessel disease, less single-vessel disease and more total coronary artery disease as judged by the Friesinger score; this group also had lower left ventricular EFs, a greater percentage of abnormal contracting segments and lower left ventricular compliance values. The preliminary data from these studies indicate that coronary and left ventricular angiography can be performed safely in the initial weeks of convalescence after myocardial infarction. At the present time I use early (predischarge) postinfarction angiography only for those patients with recurrent angina that is unresponsive to the usual medical measures. In this high-risk group of unstable patients, severe multivessel coronary disease or left main coronary stenosis may be found. Early coronary bypass surgery may be effective in improving survivability in this select group of patients with a poor prognosis. Coronary and left ventricular angiography is being performed with greater impunity during the first 4-6 months after hospital discharge, i.e., during the subacute phase of myocardial infarction. As a general rule, such studies are only indicated in patients with recurrent chest pain or when a ventricular aneurysm is suspected. However, increasing numbers of angiographic studies are being done in relatively asymptomatic patients during the early posthospital period to clarify the patient’s cardiac status.8s This approach may be useful in individuals whose employment requires vigorous physical exertion. A recent study has provided valuable information on this topic. Paine et a1.,9O from the University of Alabama, studied 100 consecutive patients with contrast angiography and graded treadmill exercise testing at a median of 4 months after myocardial infarction. The studies caused no complications. Thirty-one patients had ECG positive exercise tests and 27 of these (87%) had significant 2- or 3-vessel coronary disease. Of the 21 patients with negative exercise tests, 62% had coronary artery disease in no more than 1 vessel, 33% in 2 vessels and only 5% in 3 vessels. Patients termi35
nating the exercise test because of fatigue or dyspnea showed significant and meaningful correlations between duration of exercise and EF (r = 0.65), and duration of exercise and angiographic scarsize (r = 0.62). The authors conclude that a few months after myocardial infarction the graded exercise test can be performed safely and can be utilized to predict the extent of coronary artery disease and the degree of left ventricular dysfunction in selected groups of patients. These data argue against Youtine” angiography in postinfarction patients and point up the diagnostic usefulness of exercise testing in the functional evaluation of convalescent postinfarction patients. MISCELLANEOUS FACTORS
The association between VPBs and increased cardiac mortality in the posthospital phase of myocardial infarction has highlighted the potential importance of cardiac electrical instability in the predisposition to subsequent ventricular tachycardia or fibrillation. Recently, Greene et a1.g1 used a ventricular pacing technique to assess the likelihood that symptomatic or fatal ventricular arrhythmia would develop after myocardial infarction. They studied 48 postcoronary patients with electrode catheters positioned high in the right atrium and at the apex of the right ventricle. The right atrium was paced at 86 beats per minute and a single ventricular stimulus was introduced at every 8th beat. Ventricular stimuli were first introduced at the QRS complex and progressively moved toward the preceding T-wave at lo-20 msec intervals, thereby scanning electrical diastole. Of the 48 infarct patients studied, 19 had repetitive ventricular responses (2 or more induced VPBs) to the single ventricular pacing stimulus. Fifteen of these 19 (79%) patients had ventricular tachycardia or sudden death within the l-year follow-up period. Of the remaining 29 patients without repetitive ventricular responses, only 4 (14%) had these complications (P < 0.001). Comparisons were made between the usefulness of the repetitive ventricular response and advanced grades of VPBs on Holter monitoring. The specificity and predictive value of these two testing procedures were similar. The sensitivity of the repetitive ventricular response was greater than the Halter monitor but the difference was not statistically significant (P = 0.24). It appears that electrophysiologic stress testing with single ventricular stimuli holds promise for identifying high risk patients. As pointed out earlier, mechanical dysfunction of the left ventricle is an important determinant of outcome. The advent of two-dimensional echocardiography has provided a noninvasive approach to the evaluation of regional ventricular wall motion abnormalities in myocardial infarction patients. Eaton et a1.s2 studied 28 patients during the first 2 weeks after infarction by 36
serial two-dimensional echocardiography. Eight patients showed infarct expansion with disproportionate dilatation and transmural thinning in the infarcted zone that was significantly different from changes in noninfarcted regions. These 8 patients had significantly greater 8-week mortality than the nonexpansion group (4/8 vs O/20, P < 0.004) despite comparable creatine kinase values and clinical severity (Killip) scores. These preliminary findings suggest that echocardiographic detection of topographic alterations in the heart after myocardial infarction has functional and possibly prognostic implications. Not all regions of the heart are equally accessible by echocardiography and, thus, the ultimate usefulness of this technique may be limited- possibly to patients with anterior myocardial infarction. THE POSTHOSPITAL
CLINICAL
COURSE
NATURAL HISTORY
The Framingham study has been unique in providing valuable information on the natural history of various types of cardiovascular disease over prolonged periods of time. Kannel and co-workerslo conducted a 20-year cohort study of 5,127 individuals initially free of coronary heart disease, and recently reported a lo-year follow-up on 319 men and women who developed overt or asymptomatic myocardial infarction. One in 5 men who had a first myocardial infarction died within 1 year, a mortality 14 times that of those free of coronary heart disease. In men who survived the first year, a recognized myocardial infarction was associated with a three- to four-fold increased mortality over the next 9 years. Long-term prognosis was distinctly worse in women than men. Patients with overt and asymptomatic myocardial infarction had similar survival rates after 3 years. A second infarction occurred in 13% of the men and 40% of the women within 5 years of the first infarction. These findings of the natural history of essentially untreated patients are extremely important for they provide a standard of comparison for a variety of intervention trials. CHRONOMETRIC INTERVAL
Numerous studies have shown that the early posthospital phase after an index coronary event is a particularly high-risk period. That is, the rate of reinfarction or cardiac death is inversely related to the chronometric interval after the index coronary event. Gazes et a1.g3 reported that the posthospital mortality decreased from 1.8% per month during the first 3 months after infarction to 0.6% per month during the subsequent 9 37
months. The Health Insurance Plan investigators observed a 1.7% per month mortality during the first 6 months after hospital discharge and a O.l-0.2% per month rate for the next 3l/2 years.4 Similq findings were reported by Pell and D’Alonzo33 in their &year follow-up study of 932 male DuPont employees who survived the hospital phase of AMI. In our own Rochester study, of all the cardiac deaths that occurred during a 4-year follow-up period after the index coronary event, one half of the deaths took place in the first 6 months after hospital discharge. These studies indicate that the early posthospital period after myocardial infarction warrants special attention in any secondary prevention program. RECURRENT SYMPTOMS
The development of angina pectoris or symptoms of left ventricular dysfunction (fatigue, exertional dyspnea, congestive heart failure) during the posthospital phase of myocardial infarction has significant prognostic implications. Recurrent postinfarction angina almost always indicates multivessel coronary disease, and the long-term survival status of these patients is guarded. The earlier angina occurs after infarction, the more significant the prognostic implications. For this reason, many cardiologists are proceeding with exercise testing and coronary angiography in postinfarction patients who develop angina, in order to evaluate more precisely the extent and severity of the coronary disease. Coronary artery bypass graft surgery appears beneficial in those with left main coronary stenosis or triplevessel proximal coronary disease with good distal runoff. In patients with symptoms of left ventricular dysfunction, radionuclide assessment of the EF and regional wall motion provides valuable information. In general this group of patients will have the poorest prognosis. However, the radionuclide study can provide quantitative and qualitative data that are often useful in the clinical management of the individual patient. For example, a surgically correctable aneurysm may be detected by this approach. Furthermore, the effectiveness of afterload reduction therapy in the management of patients with the low output syndrome can be quantitatively evaluated by serial radionuclide EF measurements. The available evidence suggests that augmentation of the radionuclide EF by 10% or more, e.g., from 20% to 30%, by appropriate therapeutic intervention should be accompanied by an improved survival rate. CIGARETTE SMOKING
Although cigarette smoking is a well-recognized primary risk factor in the development of AMI, the effects of continued smok38
ing after the index coronary event on the development of secondary complications is controversial. In the Health Insurance Plan study, patients with myocardial infarction or angina pectoris who continued smoking after the index coronary event had a cumulative probability of death, over a 4.5year follow-up, almost twice that of those who stopped smoking or never smoked.17 However, these findings were obtained from the raw data without correction for the effects of confounding variables. Wilhelmsson et al.94 reported from Goteborg, Sweden, on the smoking habits of 528 men who survived their first myocardial infarction. They compared the reinfarction and cardiac death rates during a 2-year follow-up of those who stopped smoking and those who continued smoking after the initial coronary event. Those who stopped had half the rate of nonfatal recurrences (9% vs 18%, P < 0.01) and half the cardiovascular mortality (5% vs lo%, P < 0.05) of those who continued to smoke. Some caution must be exercised in the simple acceptance of these findings, however, since (1) the categorization of “stopped smoking” and “continued smoking” was made at one point in time- 3 months after AMI, (2) no attempt was made to control for confounding variables and (3) the 2-year myocardial reinfarction rate for the entire population (nonsmokers, ex-smokers, stopped smokers and continued smokers) was twice the cardiac death rate (12.3% vs 6.6%)-a difference that suggests an unusual selection of patients. A recent report from the Framingham studyg5 provides additional interesting information. These investigators assessed the possible benefit of quitting smoking after infarction. The 2-year death rates of the stopped (n = 56) and the continued (n = 139) smoking patients were essentially the same (5.4% and 7.2%). However, in the period from 2-6 years, those who quit smoking did better than those who continued. The life-table approach revealed a 6-year mortality of 18.8% among those who quit and 30.4% among those who continued to smoke. No significant difference in recurrent myocardial infarction rates was observed. In contradistinction to the Gijteborg study, the Framingham data suggest that the long-term benefit of quitting smoking after myocardial infarction does not extend to a reduction in recurrent myocardial infarction. As a result of these confusing findings on the effects of smoking after myocardial infarction, the data from the Rochester program were reviewed. In a myocardial infarction population of 573 patients, 12% never smoked, 27% had stopped smoking prior to the index infarction and 61% were active smokers at the time of hospitalization for AMI. At discharge, smoking recidivism was present in 19% of the prior smokers and increased to 49% by the end of the first postinfarction year. Among patients who were smokers at enrollment (n = 353), the 2Y2-year mortality was 39
similar in those who quit and those who returned to smoking (13.5% vs 11.5%, P value not significant). The clinical characteristics of those who quit and those who continued smoking were remarkably similar. The Rochester findings support the Framingham results and indicate no significant benefit from stopping smoking within the first few years after infarction. Longer abstinence may provide some reduction in postinfarction morbidity and mortality, but this interpretation requires further investigation and substantiation.
Numerous therapeutic measures are utilized in patients after myocardial infarction, and their influence on postinfarction prognosis is uncertain. Relatively few carefully performed clinical trials have been done on these patients, and the therapy currently being used is usually based on experience rather than science. A traditionally prescribed agent like digitalis may not be effective for long-term treatment of postinfarction heart failure in patients with sinus rhythm. The idea of using a drug to drive the diseased heart out of failure by increasing contractility has come under closer scrutiny. Katz% has warned that benefit from inotropic agents like digitalis may be obtained only at the expense of life-shortening myocardial damage. Recently, the idea of unloading the left ventricle with vasodilator drugs has gained considerable acceptance as a result of the beneficial effects observed in patients with congestive cardiomyopathy. No formal trials have yet been reported of long-term treatment of postcoronary patients with afterload reducing agents. Several studies have used antiarrhythmic agents (quinidine, procainamide, phenytoin and aprindine), but beneficial results have not been achieved. /?-Blockers may favorably influence prognosis after myocardial infarction, and a few major studies have been reported that substantiate this position. The Gijteborg group carried out a randomized, double-blind alprenolol-placebo intervention trial in more than 200 postinfarction patients.s7 After a 2-year followup, there was a significant reduction in sudden death occurrence in the alprenolol patients when compared to the placebo group. A recent study from DenmarkS confirmed the beneficial effects of alprenolol in postinfarct patients during a l-year treatment period, but only in patients 65 years of age or younger. The English Multicenter Trial recorded a significant reduction in the incidence of sudden death, cardiac death and nonfatal reinfarction with practolol, and these results were particularly prominent in patients with anterior myocardial infarction.ss However, similar results were not observed by these same English investigators using propranolol in the high risk patients with anterior 40
infarction.*00 A major postinfarction propranolol trial is presently underway in the U.S. to determine if the routine administration of propranolol will improve posthospital survival after myocardial infarction. Although the study results will not be available for a few years, propranolol and related p-blocking agents are often prescribed to postinfarction patients on the basis of the alprenolol and practolol studies. These latter agents are considerably different in that they have intrinsic sympathomimetic activity and propranolol does not. In any event, the widespread and somewhat indiscriminate use of propranolol may be influencing outcome after myocardial infarction in a way that cannot be determined at this time. Antiplatelet aggregating agents like acetylsalicylic acid, dipyridamole and sulfinpyrazone have been studied in patients with cerebral vascular and coronary vascular disease. In 1978 the Anturane F&infarction Trial Research Group reported the preliminary results of a randomized, double-blind multicenter clinical trial comparing sulfinpyrazone and placebo in the reduction of cardiac mortality after myocardial infarction.lol The early results suggest that sulfinpyrazone may be effective in diminishing cardiac mortality in this group of patients, but the completed study has not yet been reported. The results of other postinfarction trials with acetylsalicylic acid and dipyridamole are also pending. Once again, these agents are frequently prescribed despite the nondefinitive nature of the studies to date. The contaminating influence these therapies have on prognosis after infarction cannot presently be ascertained. An increasing number of patients, estimated at 3 - 5% of patients 70 years of age or younger, are undergoing coronary artery bypass graft surgery in the first year after myocardial infarction. When performed for recurrent angina in angiographitally documented left main coronary stenosis or proximal multivessel coronary disease, the bypass surgery may favorably influence long-term prognosis after myocardial infarction. However, definitive studies have not been performed to substantiate this currently practiced therapeutic intervention. In brief summary, it is difficult to determine whether any of the commonly prescribed medications or surgical procedures favorably or unfavorably alter the survival of postcoronary patients after myocardial infarction. In any event, the therapies used must be considered when evaluating factors influencing prognosis in this group of patients. MULTIVARIATE
RISK CLASSIFICATION
Univariate factors that effect outcome after myocardial infarction have been reviewed in the preceding sections. However, multiple factors are operative in most clinical situations, and 41
their combined effects and synergistic interactions may profoundly influence the outcome. Numerous mathematical techniques have been used to identify variable interactions as they pertain to riskdassification. The methods used include two-way contingency analyses, prognostic stratification approaches, regression techniques and survivorship (life-table) analyses. TWO-WAY CONTINGENCY ANALYSES
Two-way comparisons are frequently made to determine the independence of a particular factor to outcome when controlling for a second factor, as well as to evaluate the interaction effect of the two factors on outcome. In the Coronary Drug Project, the association of major ECG abnormalities with S-year mortality was examined according to the presence or absence of other ECG and clinical indicators of severity and prognosis.’ For example, infarct Q-waves were associated with higher mortality irrespective of cardiac enlargement. Multiple comparisons revealed a consistent relationship between various ECG items and excess mortality when other risk factors were considered one at a time. In addition, high death rates resulted from the combination of VPBs in patients with a history of heart failure and ventricular conduction defects in patients with radiographic evidence of cardiac enlargement. In a later publication from the Coronary Drug Project, two-way combinations of VPBs with other clinical risk factors demonstrated a lethal interaction of VPBs with smoking, digitalis treatment, cardiac enlargement and heart failure.* In the Kotler study?’ patients with Lown grade II-V VPBs on Holter recording showed a higher incidence of sudden cardiac death independent of 22 relevant demographic, clinical and ECG characteristics taken one at a time. PROGNOSTICSTRATIFICATION
Prognostic stratification is an analytic technique popularized by Feinstein. lo2 Selected univariate factors are used in bivariate and trivariate combinations to obtain the best partition of patients into low- and high-risk groups over a specific time period. Using this approach, the Rochester programI identified a highrisk group, with a 4-month posthospital cardiac death rate of 14%, by the presence of two or more of the following characteristics: (1) history of angina pectoris at rest or with ordinary levels; (2) development of hypotension and/or congestive heart failure in the CCU; and (3) VPB frequency of 20 or more per hour on a 6-hour Holter recording. The low-risk group had a 3% 4-month mortality and was characterized by none or only one of the above factors. Bigger et al.*O used the same method of analysis in a g-month 42
follow-up study of 100 postinfarction patients. The best prognostic stratification was obtained using the values for peak creatine kinase of more than 585 IU, blood urea nitrogen of 20 or more mg/dl at 2 weeks and the presence of left ventricular failure in the CCU. At 6 months, 10 of 19 patients (55%) with these 3 characteristics had died. The 6-month cardiac death rate of the 71 patients who had none, 1 or 2 of these characteristics was only 5%. The prognostic stratification approach has much to commend it. The technique is methodologically easy to understand and apply, the identified variables provide insight into the mechanisms of the observed phenomena, and the identified high and low risk groups permit more logical intervention strategies. Better understanding of risk mechanisms and improved risk stratification should improve posthospital cardiac care by enhancing the selection of therapy for specific risk groups. REGRESSION
TECHNIQUES
Multiple linear regression, multiple logistic regression and discriminant function analysis are complex biostatistical techniques that permit the evaluation of the independent contributions of multiple simultaneous variables to mortality. In addition, these techniques reduce the multivariate interactions to a score from which risk probability can be derived and risk prediction carried out. Five pertinent classification studies using various multivariate regression techniques are summarized in Table 4. For the most part, the predictor variables reflect historical comorbidity factors, severity of the myocardial infarction, evidence of mechanical ventricular dysfunction and the presence of electrical instability. The predictive efficiency (percentage of correct classifications) of these multivariate regression techniques was quite good. In the Coronary Drug Project,3 a linear regression technique was used to select a combination of five factors that were related to 3-year mortality after myocardial infarction. In order of decreasing significance, the five factors were (1) ST depression on ECG; (2) cardiomegaly on chest x-ray films; (3) advanced NYHA functional state; (4) ventricular conduction defects on ECG; and (5) use of diuretics. These factors were appropriately weighted and the population was classified by decile of risk. The mortalities in the lowest and highest deciles of estimated risk were 2.9% and 38.5%, respectively. Risk prediction using this function was applied to an independent group of patients with very good agreement between the observed and predicted outcomes. A more sophisticated linear regression technique, which has been used in many postinfarction prognostication studies, is the multivariate stepwise discriminant function method. Multiple 43
*Predictive
Efficiency
= correct
sample
USING
83
REGRESSION
92
Stepwise discriminant 175 30-79 6 No Syst. BP (100 mm Hg Chronic lung disease Anterior MI Hx CHF
MULTIVARIATE
Stepwise discriminant 143 unrestricted 24 Yes Syst. BP Blood urea nitrogen Atria1 arrhythmia Hx angina or infarction >l VPB/hr
size.
STUDIES
Stepwise discriminant 100 33-82 24 Yes 1) VPBs: Age Bigeminal or paired VPB VPB frequency Early cycle VPB 2) No VPBs: Age Peel score 1) 91 2) 79
CLASSIFICATION
classification/population
86 (o/o)
Predictive efficiency*
RISK
Linear regression 2,789 30-64 36 No ST depression Cardiomegaly Advanced NYHA Ventricular conduction defects Diuretic therapy
4. - POSTINFARCTION
Analysis technique No. of patients Age (years) Follow-up (months) Holter recording Predictor variables (mortality)
TABLE
/
88
Logistic regression 292 57-69 24 No Dyspnea Upper SGOT quartile CHF Cardiomegaly At. fibrillation
ANALYSIS
variables selected by traditional univariate screening are entered into a multiple discriminant analysis function in a stepwise manner. The variables are selected according to preset criteria by the discriminating power of their contribution to outcome. The selected variables are weighted and expressed mathematically in a linear function, which optimizes the association between the predictor variables and outcome. In 1974 we reported the use of this stepwise discriminant analysis technique in a 2-year postinfarction follow-up of 100 patients.” The population was divided into two groups on the basis of the presence or absence of VPBs on a predischarge Holter recording. In those with VPBs, 91% of the 2-year survivors and nonsurvivors were correctly identified by the discriminant combinations of three ventricular arrhythmia parameters and age. In those without VPBs, 75% of survivors and 100% of nonsurvivors were properly classified simply from age and the Peel score of the severity of the AMI. Using this same analytic technique, Luria and co-workers54 found that the components of the discriminant function for 2-year outcome were (1) admission systolic blood pressure; (2) highest blood urea nitrogen level in the CCU; (3) atria1 arrhythmias in the CCU; (4) angina pectoris for more than 3 months or a previous myocardial infarction; and (5) more than one VPB per hour during an 8-hour Holter recording. In a function analrecent report, Henning et a1.1°3 used discriminant ysis to predict mortality between 30 days and 6 months after infarction on the basis of variables recorded soon after admission. The 4 clinical variables that provided the best discrimination between survivors and nonsurvivors included systolic blood pressure of less than 100 mm Hg, chronic obstructive lung disease, anterior location of the infarct and a history of congestive heart failure. Logistic regression techniques have also been applied in postinfarction prognostication studies. This method uses a logarithmic transform and is theoretically more appropriate than multivariate linear regression and discriminant function analysis when some of the predictor variables are discrete and do not have a multivariate normal distribution. Vedin et aleg used this multivariate logistic regression technique to develop a prognostic function in 292 men with first infarctions, followed for 2 years. The 5 most important predictor variables recorded during the hospital phase were: (1) dyspnea at onset of symptoms of infarction; (2) serum glutamic-oxaloacetic transaminase quartile, (3) left heart failure, (4) relative heart size determined by chest roentgenogram and corrected for body size and (5) atria1 fibrillation. Approximately 60% of the 2-year cardiovascular mortality was concentrated in the highest quartile of the logistic risk function, using the above 5 variables. 45
SURVIVORSHIP
ANALYSES
The multivariate regression techniques require complete follow-up of all individuals in the cohort for the duration of the interval beingstudied. Survivorship techniques use the entire experience of a71 patients in a given population and take into account the varying duration of follow-up due to staggered enrollment and censored observations. We recently reported the use of survivorship methods in the identification of subsets of patients with different survival patterns.15 The study population consisted of 940 postinfarction patients followed for a minimum of 12 months to a maximum of 60 months. Univariate analysis demonstrated that prior myocardial infarction, left ventricular dysfunction in the CCU, anterior myocardial infarction and one or more VPBs on a predischarge 6-hour Holter recording were significantly (P < 0.01) more frequent in patients who died of cardiac cause than in survivors. Survivorship analyses revealed a variety of survival patterns depending on the presence, absence and interactive combination of the above factors (Fig 2). A combination of anterior infarction, left ventricular dysfunction and one or more Holter-recorded VPBs identified a high-risk subset, which made up 15% of the population, and this group had 6-month and 3-year survivals of 85% and 70%, respectively. A low-risk subset, which made up 24% of the population, was Fig 2.-Survival as a function of the posthospital time after myocardial infarction for the total population and for low- and high-risk groups. Low-risk group defined by the absence of prior myocardial infarction (PM/), left ventricular dysfunction (LVD) and ventricular premature beats (VP@. High-risk group identified by the presence of anterior myocardial infarction (AM/), LVD and VPB. LO RISK ” = 224
O-0
2 ca0.60 52 B Q
LO RISK = NO PMI. LVD, VPB HI RISK = AMI + LVD + VPB
0.50
6
12
POSTHOSPITAL MYOCARDIAL 46
24
36
48
MONTHS INFARCTION
AFTER
60
identified by the absence of prior myocardial infarction, left ventricular dysfunction and VPBs, and this group had a 3-year survival of 94%. An intermediate risk group, those not included in the low- and high-risk subsets, made up 62% of the population with l- and 3-year survivals of 94% and 89%, respectively. The intermediateand high-risk groups would seem to have the greatest potential for mortality reduction by appropriate postinfarction intervention measures. By similar reasoning, the lowrisk group can be excluded from any general intervention drug therapy since this group will do extremely well regardless of the treatment used. COMMENT
The various studies reviewed in this multivariate risk classification section indicate the critical importance of extensive myocardial damage and the associated impairment of left ventricular function as major determinants of outcome after myocardial infarction. Furthermore, the presence of VPBs appears to enhance the risk created by damage to the ventricular myocardium. THE GOOD-RISK
PATIENT
In almost all postinfarction studies, patients without specific risk factors generally did very well. In 1975, McNeer et a1.1°4 reported their in-hospital and posthospital findings in a group of patients who had an uncomplicated CCU course. That is, they did not have ventricular tachycardia or fibrillation, 2d- or 3ddegree heart block, pulmonary edema, cardiogenic shock, persistent sinus tachycardia, hypotension, atria1 flutter or fibrillation, or extension of the- infarction. These early uncomplicated patients made up 51% of 522 consecutive patients admitted to the CCU with AMI. Furthermore, this group had no mortality or complications in-hospital or during a 6-month follow-up. A subsequent study’05 by the same group substantiated the safety of early hospital discharge (7 days) in this good risk group. As mentioned earlier, our own Rochester study demonstrated the benign posthospital clinical course of patients without hemodynamic or arrhythmic problems during their hospital stay. ACKNOWLEDGMENTS I gratefully acknowledge the research assistance of Mr. John DeCamilla of the Rochester Heart Research Follow-up Program and thank Mrs. Nancy Kellogg for her superb secretarial assistance in the preparation of this article. 47
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SELF-ASSESSMENT
1. d 2. 3. 4. 5. 6. 7. 8.
a b a b b b a
ANSWERS
9. b
10. a 11. b
12. a, c, d 13. d 14. a 15. b
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