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Predictors of non-fatal ischemic events after myocardial infarction
International Elsevier
Journal of Cardiology,
20 (1988) 73-86
73
IJC 00700
Predictors of non-fatal ischemic events after myocardial infarction Gin& Sanz, Amadeo Betriu, Angel Castaiier, Eulalia Roig, Magdalena Heras, Jordi Magri%, Carlos Pare and Francisco Navarro-L6pez Cardiac Unit, Hospital Clinic, University of Barcelona, Spain (Received
23 September
1987; accepted
22 December
1987)
Sanz G, Betriu A, Castaiier A, Roig E, Heras M, MagriZa J, Pare C, Navarro-Lopez F. Predictors of non-fatal ischemic events after myocardial infarction. Int J Cardiol 1988:20:73-86. We characterize predictors of reinfarction and angina in 403 consecutive men aged 60 years or less who underwent heart catheterization within one month (18 + 6 days) after a qualifying myocardial infarction. Angiography showed obstructive lesions (a 50% diameter reduction) in 380 patients. One-, two- and three-vessel disease was found in 143 (36%), 139 (35%) and 98 (29%) patients, respectively. After 57 months of follow-up there were 60 deaths (12%), 41 patients (10%) sustained a new infarction and 210 (52%) had angina. Cox regression analysis selected the number of diseased vessels as the only independent predictor of reinfarction; independent predictors of angina were the number of diseased vessels and a history of angina prior to the qualifying infarction. Risk stratification showed the probability of reinfarction at 6 years to be significantly lower (P < 0.001) in patients with one-vessel disease (12%) than in those with two- (30%) and three-vessel disease (37%). Similarly the probability of angina was also lower (P < 0.001) in patients with one-vessel disease (51%) as compared to those with two- (72%) and three(74%) vessel involvement. Thus multi-vessel disease is the main predictor of new non-fatal ischemic events after myocardial infarction. Key words: Myocardial infarction; Angina; Post-infarction
angina; Reinfarction
Correspondence to: Dr. Gin&s Sanz, Unidad Coronaria, Hospital Clinic, Barcelona, Spain. Supported in part by grant number 616/81 from the FISS (INSALUD).
0167-5273/88/$03.50
0 1988 Elsevier Science Publishers
B.V. (Biomedical
Villarroel
Division)
170, 08036
74
Introduction Factors determining survival after acute myocardial infarction have been studied extensively in recent years [l-8]. Although less attention has been paid to non-fatal ischemic events [2,5,6,8,10], reinfarction represents a high risk irreversible condition and its prevention, as that of sudden death, should be a major therapeutic goal. In this regard, use of beta-blockers after myocardial infarction has been proved to be effective in preventing both sudden death and reinfarction [ll-131. Widespread use of these drugs, however, has been questioned in terms of cost/effectiveness [14]. Similarly, the role of prophylactic surgery and that of percutaneous transluminal coronary angioplasty after myocardial infarction remains unsettled [15,16]. Thus, identification of predictors of reinfarction, together with those of death, appears mandatory to design management policies in infarction survivors. Although persistent or recurrent chest pain after myocardial infarction has been associated to a bad prognosis, factors determining the development of angina after hospital discharge are for the most unknown [17-191. The present study was undertaken: (1) to assess prospectively the prevalence of new non-fatal ischemic events after myocardial infarction; (2) to investigate factors determining the appearance of these events; and, (3) to use survivorship modeling to characterize subsets of patients in different risk categories. Material and Methods Patients From December 1975 to February 1981, 462 men aged 60 years or younger were admitted to our Coronary Care Unit because of a definite myocardial infarction. Acute myocardial infarction was diagnosed when at least two of the following three criteria were present: ischemic chest pain lasting longer than 20 minutes, increase above twice the upper limit of normal of two of the three serum cardiac enzymes (total creatine kinase, aspartate aminotransferase or lactate dehydrogenase) and evolving Q wave abnormalities with acute ST-T wave changes on the electrocardiogram. There were 438 survivors, 35 of whom were excluded from the study because of associated life-threatening conditions (2 patients had cancer, 3 severe car pulmonale, 2 cerebrovascular accidents), dye allergy (1 patient) or refusal of cardiac catheterization (27 patients). No patient was excluded from the study on the basis of a poor cardiac condition. The study protocol was approved by the Institutional Ethics Committee. Clinical evaluation On admission all patients underwent a careful investigation of their risk factors. Each patient was questioned concerning his history of coronary artery disease and use of cigarettes. Diabetes mellitus was considered to be present if the patient was being treated for this condition or if the fasting blood sugar level exceeded 120 mg
per 100 ml (6.7 mm01 per liter). Similarly, hypertension was diagnosed if the patient was already receiving antihypertensive drugs or if the blood pressure was above 165/95 mm Hg. Serum cholesterol and triglyceride levels were measured after a 1Zhour fast in all patients; if either were elevated, hyperlipidemia was diagnosed. Obesity was defined as a weight 15% or more above that considered ideal for a given height. Catheterization
and angiographic procedures
Within four weeks of infarction (18 f 6 days, mean + SD), combined right and left heart catheterization by the percutaneous femoral approach was carried out. Informed consent was obtained from all patients. Single-plane left ventriculography was performed with the patient in the 30” right anterior oblique position. Left ventricular volumes and ejection fraction were determined by the area-length method modified for single-plane calculation [20]. Regional wall motion was assessed according to the method described by Gelberg et al. [21]. All angiograms were assessed by two independent observers. Coronary artery lesions were defined as obstructive if the arterial narrowing exceeded 50% of the luminal diameter. Each patient was classified as having one-, two- or three-vessel disease. Obstructions of diagonal or marginal branches were considered lesions of the left anterior descending or circumflex arteries, respectively. Exercise test
Six months after infarction cycle ergometry was performed in the erect position on an electrically braked Elema Schbnander EM 370 ergometer. A progressive multistage protocol was employed; exercise continued until generalized fatigue, chest pain, shortness of breath, an appreciable fall in blood pressure, or serious arrhythmias occurred. A standard 12-lead electrocardiogram was recorded before the test. During exercise a CM 5 lead was continuously monitored, and recordings were obtained every three minutes and at the end point. A test was judged positive if angina or major ST-segment changes or both occurred. The latter were defined as 1 mm horizontal or downsloping depression lasting at least 0.08 seconds. Exercise performance was expressed as the maximal rate-pressure product (mm Hg mm’ x 102), and workload (watts) achieved by each patient. Follow-up
Patients were seen monthly during the first three months and every three months thereafter. Clinical status, results of physical examination, and a resting electrocardiogram were recorded at each visit. The mean period of follow-up was 57.1 months (range 40-100). Follow-up was completed in 393 of the 403 patients who had angiograms. The other 10 patients were lost to follow-up. Deaths occurring during the follow-up were classified according to the Hinkle classification [22].
76
Although no attempt was made to standardize medical treatment, all patients were kept on a low-cholesterol diet and moderate exercise was recommended. Surgical treatment was reserved for intractable angina or lesions of the left main coronary artery. Diagnosis of post-infarction angina was made on clinical grounds. A myocardial infarction was considered non-fatal if the patient was discharged from hospital. Statistical analysis A total of 79 variables was identified in each patient from the history, physical examination, exercise test and cardiac catheterization data. These variables were examined by univariate statistical methods to determine differences between patients with and without ischemic events. Student’s t-test, Fisher’s exact test, and the &i-square test were applied when appropriate. The statistical analysis was performed using the Statistical Package for Social Sciences [23]. To identify the variables independently predictive of new coronary events, multivariate analysis with Cox’s regression technique was applied in a stepwise manner to variables reaching .significance in the univariate analysis [24]. Finally, patients were classified in different subsets according to the variables selected by Cox’s regression analysis. Kaplan-Meier actuarial curves were constructed and the log-rank test was used to assess the significance of differences among the various groups [25]. Results Clinical findings Twenty-four of the first 462 patients (5.2%) died before cardiac catheterization. Non-survivors had a higher prevalence of severe congestive heart failure (Killip class
TABLE
1
Clinical
features
of 462 consecutive
patients
with acute myocardial
infarction.
Feature
Non-survivors
CCU survivors
Total in group Age (mean f SD) No. with severe congestive heart failure in the CCU No. with previous infarction Location of infarction Anterior Inferior Combined Nontransmural
24 53+7.3
438 5Ok7.1
17 (71) 6 (26) 13 9 1 1
Figures in parentheses are percentages. * Significant difference between CCU survivors + Significant difference between CCU survivors CCU = coronary care unit.
(54.1) (37.5) (4.2) (4.2)
and non-survivors and non-survivors
14 (3.2) * 38 (8.7) + 170 207 37 24
(38.8) (47.3) (8.4) (5.5)
(P < 0.001). (P < 0.01).
TABLE
2
Clinical
features
of the 438 study candidates
Feature
with myocardial Group
infarction.
of candidates
Non-participants Total in group Age (mean f SD) No. with previous infarction Peak creatine kinase (W/liter) (mean * SD) No. with severe congestive heart failure in the CCU Location of infarction Anterior Inferior Combined Non-transmural Figures in parentheses significance.
35 49.1 f 7.0 2 (5.7)
403 50.6 + 7.1 36 (8.9)
813 i 804.3
1077 f 762.7
2 (5.7) 10 21 1 3
are percentages;
Participants
12 (3) 160 186 36 21
(28.6) (60) (2.6) (8.6)
CCU = coronary
care unit.
(39.7) (46.3) (8.9) (5.2)
All differences
without
statistical
III or IV) (71% vs 3.2%, P < 0.001) and higher prevalence of previous myocardial infarction (26% vs 8.7% P < O.Ol), than survivors. No differences in mean age, infarction location or prevalence of risk factors were found between survivors and non-survivors in this series (Table 1). The time elapsed between the onset of symptoms and admission to the coronary unit was also similar in both groups (8.1 + 5.8 vs 7.2 f 6.7 hours). There were no differences between participants (403) and survivors excluded from the study (35) in age, previous myocardial infarction, infarction location, peak CK levels, occurrence of congestive heart failure or prevalence of risk factors (Table 2). Angiographic data Obstructive coronary lesions were present in 380 patients (94%); complete obstruction of at least one coronary artery was present in 202 instances (50%). One-, two- and three-vessel disease were found in 143 (36%), 139 (35%) and 98 (24%) patients, respectively. Nine patients (2%) showed left main coronary disease, which was always associated with multi-vessel involvement. Ejection fraction was within the normal limits (> 50%) in 164 patients (41%); moderate impairment of left ventricular function (ejection fraction between 21 and 49%) was found in 220 patients (55%), and severe left ventricular dysfunction (ejection fraction < 20%) in 13 patients (3%). Ejection fraction could not be calculated in 6 patients. Mortality There were 50 deaths (12.4%), 15 of them occurring within six months of the acute event. Death was cardiac in origin in 45 cases; 23 of these patients died within
78
one hour of the onset of symptoms (Hinkle class I). In 7 patients detailed information regarding circumstances of death were not available and they were classified as Hinkle class III. New non-fatal ischemic events Non-fatal reinfarction occurred in 41 patients (10%) 21 of whom had developed angina after the qualifying infarction. Of 38 patients with transmural reinfarction,
TABLE
3
Univariate
predictors
of non-fatal
Total in group No. of diseased vessels (mean f SD) Non-obstructive 1 vessel 2 vessel 3 vessel No. with previous myocardial infarction No. with history of hypertension No. with hypertension during follow-up
reinfarction. Reinfarction
No reinfarction
41
312 *
2.25 f 0.73 0 6 (14.6) 19 (46.4) 16 (39)
1.7lkO.89 23 (7.4) 127 (40.7) 102 (32.7) 60 (19.2)
< 0.001
17 (5.3)
< 0.01
22 (54)
108 (34.6)
< 0.05
13 (32)
72 (23)
-=C0.05
8 (19.5)
P value
Figures in parentheses are percentages. * Patients dying during follow-up not included.
TABLE
4
Univariate
predictors
of angina.
Total in group No. of diseased vessels (mean f SD) Non-obstructive 1 vessel 2 vessel 3 vessel No. with previous angina Exercise test Positive Negative Non-conclusive Figures
in parentheses
Angina
Without
210
193
1.8 + 0.8 7 (3.3) 65 (31) 80 (38) 58 (27.6) 124 (59)
are percentages.
27 (20) 87 (64) 22 (16)
angina
P value
1.6*0.8 16 (8.3) 78 (40.4) 59 (30.6) 40 (20.7) 77 (40)
i 0.01
19 (13.7) 110 (79.7) 9 (6.5)
< 0.001
-C 0.001
19
.8.7-
% 1-.-L___
.6> .= -_ P $ e a
.___ '--L. :..
'- ?_.
P
_ _ _ L-I--L& _ L___
.5.4.3.2.l0.0
Years
Patientsat risk
12
3
4
5
6
7
1 vessel-140
136
133
119
101
92
53
35
2 vessel-136 3vesseL- 97
1 16 75
105 67
100
75
43
33
14
60
48
36
15
5
Fig. 1. Probability of remaining diseased vessels. The P values
8
11
free of reinfarction in patients stratified according to the number of represent differences (log-rank test) between the group with one-vessel disease and the other two groups.
location corresponded to that of the previous infarction in 9. Although all 41 patients were discharged alive from hospital, 7 died in the ensuing months (mean 19 months, range 3-45). The results of univariate screening indicated that only 4 of the 79 baseline variables: number of diseased vessels, previous infarction, and hypertension (both before and after the initial infarction) were predictive of reinfarction (Table 3). Cox regression analysis showed that the number of diseased vessels (P < 0.001) was the only independent predictor. In keeping with this observation, Kaplan-Meier analysis showed (Fig. 1) the probability of non-fatal reinfarction at 6 years to be significantly lower in patients with one-vessel disease (12%) as compared with those with two- (30%) and three-vessel (37%) involvement. Further stratification according to ejection fraction in each of these subsets failed to demonstrate the influence of left ventricular function on reinfarction rate. When death and reinfarction were analyzed in association the rate of these combined events at 6 years was also significantly lower in patients with one-vessel disease than in those presenting with either two- or three-vessel disease, regardless of the level of ejection fraction (Fig. 2). Angina developed in 210 patients (52%) and in 7 of them it occurred after a second myocardial infarction. Severe angina (grade III-IV Canadian Cardiovascular Society) was observed in only 35 patients (4.2%). Angina was treated with betablocking agents (35 patients), calcium antagonists (42 patients), nitrates (48 cases) or a combination of drugs (51 patients). Aortocoronary bypass surgery was performed in 26 patients (6.4%). Univariate predictors of angina were the number of diseased vessels, previous history of angina and the result of exercise test (Table 4).
80
Cox regression analysis previous angina as the Stratification according probability of developing disease and 72% in those
selected the number of diseased vessels and history of only independent predictors of angina during follow-up. to the number of diseased vessels (Fig. 3) showed the angina at 6 years to be 51% in patients with one-vessel with three-vessel involvement.
1 vessel disease
1 o-~r~~~_~~-~~i_ ._ .9-
--=-~=--~~~,_-_i.
Lr=-.--
-t+-____-_-__ i_-_-._.-._
.8.J.6.52 z P d 2 0
.4.3.2.l0.0
Patients at risk ~~260%--67 EF 21-49%.---71 EFI20%-
2
1
2
3
4
5
6
7
Years c 8
67
65
58
48
43
28
18
15
JO
68
62
53
51
36
25
20
2
2
1
0.0 Patients
at risk
EFL50%---55 EF 21-49 %--77 EFF20%-4
1
2
3
4
5
53
47
43
41
18
68 2
63 2
60 2
58 2
39 2
I
6
Years
1
7
8
14
11
4
31
19
J
Fig. 2. Probability of remaining alive and free of reinfarction in patients with one-, two- and three-vessel disease stratified according to ejection fraction (EF). The P values represent differences (log-rank test) between the group with normal EF and the other two groups.
81
3 vessel disease
I
P < 0,001
L.
1
0.0 Patients at nsk EFL50%---23 EF 21-49
%-.A7
EFS20%-7
1
2
3
4
5
6
7
20
19
18
17
14
5
3
52 3
43 3
40 2
37 2
30 -2-
10
2
Years
, a
Fig. 2 (continued).
Sixty-four patients (16%) developed congestive heart failure; digoxin was preA total scribed in 53 patients. In 5 cases the symptoms occurred after reinfarction. of 136 patients (34%) remained asymptomatic; exercise test, performed in 106 of these patients, was positive in only 18.
“--1__~:~-1,_.____._
P < 0,001 .1 :-.__________
.2.l0.0 Patients at risk
2
3
4
5
6
7
a
102
91
46
33
23
13
75
60
78 50
61
2vessel
-139 ---138
36
24
12
10
6
3vessel
--97
45
35
30
18
12
6
4
3
1 vessel
Fig. 3. Probability
Years 1
of remaining
free of angina
in patients
stratified
vessels. P value as in Fig. 1.
according
to the number
of diseased
82 TABLE Prevalence
5 and predictors
Series
Taylor [2] De Feyter [3] Robin [4] Gibson [5] Norris [6] MPRG [7] Williams [S] MILIS [30] Present series
of new coronary
No. of patients
% of eligible
106 I79 229 140 325 886 226 719 403
39 81 89 61 82 61 97 85 92
12 6 4.2
3.6 13 11.6
5.9
4.4
12.4
A@0
data
yes yes Yes
Y-
yes no no no yes
Predictors
EF; 3-vessel disease Killip class III l ; previous MI; VT and VF; no. of diseased vessels Th-201 scintigraphy; ET; angiography EF; prognostic
Incidence
Predictors
10
EF; VPB; pulmonary rates; NYHC class
6
ST depression; previous MI; CK; exercise duration No ET; ST elevation; inadequate BP response; VPB on ET EF; no. of diseased vessels; CHF at ecu
6.8
3.5
10.1
Length of follow-up (months)
28 24 15 42 22 12 12 57
CABS %
18 13.4 10 17.8 24 13 11.7 2 6.4
Incidence
Predictors
64 42
13.8 6.7
6.4
series.
Angina
Reinfarction
Mortality Incidence
events in representative
Th-201 scintigraphy Stenosis score Predischarge angina; nonperformance on ET
24
Scintigraphy; severe (IV-V)
3.4 unstable No ET
No. of diseased vessels
52.1
No. of diseased vessels; previous
EF = ejection fraction; MI = myocardial infarction; VT = ventricular tachycardia; VF = ventricular fibrillation; ET = exercise test; VPB = ventricular premature beats; CHF = congestive heart failure; CCU = coronary care unit; BP = blood pressure; CABS = coronary artery by-pass surgery.
83
Discussion
The high incidence of new non-fatal coronary events after myocardial infarction has already been noted in large epidemiologic studies [26,27]. The Framingham study showed the incidence rate of a second infarction among men to be 13% at 5 years, whereas that of angina was 33% [26]. More recently, intervention trials such as the Coronary Drug Project (281, the Norwegian Study [ll] and the Beta Blocker Heart Attack Trial [13] have confirmed the Framingham data. Attempts to identify factors determining the appearance of non-fatal ischemic events after myocardial infarction (Table 5) are scarce [2,5,9,10]. However, recognition of baseline clinical or angiographic predictors of recurrent infarction or angina is relevant since secondary prevention by means of drugs, angioplasty or surgery may now be offered to high risk patients [15,29]. Characteristics
of the study
The present series is unique in that as much as 92% of potential candidates were entered into the study and only 10 patients were lost to follow-up. In addition, and at variance with other series, overall results reported herein are not likely to be distorted by surgery since revascularization procedures were restricted to patients with refractory angina and to those with left main coronary artery disease. We set an age limit of 60 years in our study to improve the likelihood of 10 years of follow-up and females were excluded because infarction in women of this age group is uncommon in our environment. Thus, the results of this investigation would apply only to men aged 60 years or less. Despite these limitations, our series included the 70% of all patients admitted to the coronary care unit with a definite myocardial infarction. Reinfarction
We identified the number of diseased vessels as the main determinant of reinfarction. Stratification of patients according to this variable showed the probability of a non-fatal second infarction at 6 years to be significantly higher (P < 0.001) in patients with two- (30%) and three-vessel disease (37%) than in those with one-vessel disease (10%). Norris et al. [6] observed that patients with a large amount of jeopardized myocardium, as assessed by a specially designed score, showed a higher risk of recurrent myocardial infarction. However, in view of the marked variability of the values obtained, the authors concluded that the score was of no practical use for prediction. Discrepancies between Norris data and our own study may well be explained on the basis of the larger proportion of patients who underwent myocardial revascularization in their series (24%). In keeping with our findings are those of Taylor et al. [2], who showed three-vessel disease to be an independent predictor of recurrent myocardial infarction. A previous history of hypertension, post-infarction angina and prior myocardial infarction were also identified as independent predictors of reinfarction. Dif-
84
ferences between these series and ours might be related either to patient selection criteria, study design or both. We could not predict reinfarction throughout variables obtained from the exercise test. Since 10 (25%) of the 41 cases of new myocardial infarction occurred within 6 months of the qualifying episode (before the test was performed) timing of the exercise test was probably inadequate to predict reinfarction. Recently, the MILIS Study Group [30] analyzed the prognostic value of an exercise test performed 6 months after infarction. Recurrent non-fatal myocardial infarction was predicted only by inability to perform the exercise test because of cardiac limitation, but not by any characteristics of exercise performance. Similar results were reported by Dwyer et al. [lo] with a low level predischarge exercise test. However, the role played by the extent of coronary artery disease in prognosis could not be assessed in these studies since selective coronary arteriography was not carried out. As far as our study is concerned, failure to identify other independent predictors of reinfarction was probably due to the fact that additional information provided by new variables is of no statistical significance once the number of diseased vessels, the most powerful predictor, has already been selected. Post-infarction
angina
The number of diseased vessels was also found to be the main determinant of post-infarction angina. De Feyter et al. [3] documented the prevalence of multi-vessel disease to be significantly higher among patients with angina pectoris at the time of investigation (6 to 8 weeks following infarction). Since routine coronary angiography has not commonly been performed after myocardial infarction, other reports failed to identify the significance of this variable to predict angina following infarction [9,31]. In keeping with our data are those of Taylor et al. [2], who showed that post-infarction angina was related to the number of segments supplied by stenosed vessels. Our finding that a previous history of angina is an independent predictor of post-infarction angina agrees with earlier reports indicating that angina commonly persists after myocardial infarction [19,31]. Of interest in this regard is the study by Amsterdam et al. [32], who found the prevalence of post-myocardial infarction angina to be higher in patients with previous history of angina (87%) than in those who did not have angina prior to the qualifying infarction (35%). Clinical implications Prior data from our Institution [33] showed the single best predictor of late survival after myocardial infarction to be left ventricular ejection fraction. In that study, the role played by the number of diseased vessels on life expectancy was confined to the subset of patients whose ejection fraction ranged between 21 and 49%, the probability of survival at 6 years being 95% for patients with one-vessel disease and 78% for those with three-vessel disease (P < 0.001). The present investigation demonstrates the number of diseased vessels, but not ejection fraction,
85
to be the only independent predictor of both reinfarction and post-myocardial infarction angina. Thus, identification of the subset of patients with multi-vessel disease appeared to be mandatory. Whether or not routine coronary angiography should be recommended will depend on how accurately non-invasive tests can detect multi-vessel disease, patient status and cost/effectiveness considerations. Furthermore, data from the present study highlight the need for new trials to define the role of coronary angioplasty, and particularly its timing, after acute myocardial infarction to reduce the incidence of new ischemic events.
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86 19 Watters DD, Bosch X, Bouchard A, et al. Comparison of clinical variables derived from a limited predischarge exercise test as predictors of early and late mortality after myocardial infarction. J Am Co11 Cardiol 1985;5:1-8. 20 Sandler H, Dodge HT. The use of single plane angiograms for the calculation of left ventricular volume in man. Am Heart J 1965;75:325-334. 21 Gelberg HJ, Brundage BY, Glantz S, Parmeley WW. Quantitative left ventricular wall motion analysis: a comparison of area chord and radial methods. Circulation 1979;59:991-1000. 22 Hinkle L, Thaler H. Clinical classification of cardiac deaths. Circulation 1982;65:457-464. 23 Nye NH, Hull CH, Jenkins JG, Steinbrenner K, Bent DH. Statistical package for the social sciences. New York: McGraw-Hill, 1975. 24 Cox D. Regression models and life tables. J Stat Sot (B) 1972;34:187-202. 25 Lee ET. Statistical methods for survival data analysis. Belmont, CA: Lifetime Learning Publications, 1980:76-110. 26 Kannel WB, Sorlie P, McNamara PM. Prognosis after initial myocardial infarction: the Framingham Study. Am J Cardiol 1979;44:53-58. 27 Martin CA, Thomson PL, Armstrong BK, Hobbs MST, Klerk ND. Long-term prognosis after recovery from myocardial infarction: a nine year follow-up of the Perth Coronary Register. Circulation 1983;68:961-969. 28 Coronary Drug Project Research Group. Factor influencing long-term prognosis after recovery from myocardial infarction: three year findings of the Coronary Drug Project. J Chron Dis 1974;27:267-285. 29 May GS, Eberlein KA, Furberg CD, Passaman ER, De Mets DL. Secondary prevention after myocardial infarction: a review of long-term trials. Prog Cardiovasc Dis 1982;24:331-352. 30 Stone PH. Turi ZG, Muller JE, et al. Prognostic significance of the treadmill exercise test performance 6 months after myocardial infarction. J Am Co11 Cardiol 1986;8:1007-1017. 31 Waters DD, Theroux P, Halpen C, Mizgala HF. Clinical predictors of angina following myocardiaf infarction. Am J Med 1979;66:991-996. 32 Amsterdam EA, Lee G, Mathews EA, Mason DT. Relationship of myocardial infarction to presence of angina pectoris in patients with coronary heart disease: lack of abolition of angina by infarction. Clin Cardiol 1978;1:31-34. 33 Sanz G, Castaiier A, Betriu A, et al. Determinants of prognosis in survivors of myocardial infarction. A prospective clinical angiographic study. N Engl J Med 1982;306:1065-1070.
Journal of Cardiology,
20 (1988) 73-86
73
IJC 00700
Predictors of non-fatal ischemic events after myocardial infarction Gin& Sanz, Amadeo Betriu, Angel Castaiier, Eulalia Roig, Magdalena Heras, Jordi Magri%, Carlos Pare and Francisco Navarro-L6pez Cardiac Unit, Hospital Clinic, University of Barcelona, Spain (Received
23 September
1987; accepted
22 December
1987)
Sanz G, Betriu A, Castaiier A, Roig E, Heras M, MagriZa J, Pare C, Navarro-Lopez F. Predictors of non-fatal ischemic events after myocardial infarction. Int J Cardiol 1988:20:73-86. We characterize predictors of reinfarction and angina in 403 consecutive men aged 60 years or less who underwent heart catheterization within one month (18 + 6 days) after a qualifying myocardial infarction. Angiography showed obstructive lesions (a 50% diameter reduction) in 380 patients. One-, two- and three-vessel disease was found in 143 (36%), 139 (35%) and 98 (29%) patients, respectively. After 57 months of follow-up there were 60 deaths (12%), 41 patients (10%) sustained a new infarction and 210 (52%) had angina. Cox regression analysis selected the number of diseased vessels as the only independent predictor of reinfarction; independent predictors of angina were the number of diseased vessels and a history of angina prior to the qualifying infarction. Risk stratification showed the probability of reinfarction at 6 years to be significantly lower (P < 0.001) in patients with one-vessel disease (12%) than in those with two- (30%) and three-vessel disease (37%). Similarly the probability of angina was also lower (P < 0.001) in patients with one-vessel disease (51%) as compared to those with two- (72%) and three(74%) vessel involvement. Thus multi-vessel disease is the main predictor of new non-fatal ischemic events after myocardial infarction. Key words: Myocardial infarction; Angina; Post-infarction
angina; Reinfarction
Correspondence to: Dr. Gin&s Sanz, Unidad Coronaria, Hospital Clinic, Barcelona, Spain. Supported in part by grant number 616/81 from the FISS (INSALUD).
0167-5273/88/$03.50
0 1988 Elsevier Science Publishers
B.V. (Biomedical
Villarroel
Division)
170, 08036
74
Introduction Factors determining survival after acute myocardial infarction have been studied extensively in recent years [l-8]. Although less attention has been paid to non-fatal ischemic events [2,5,6,8,10], reinfarction represents a high risk irreversible condition and its prevention, as that of sudden death, should be a major therapeutic goal. In this regard, use of beta-blockers after myocardial infarction has been proved to be effective in preventing both sudden death and reinfarction [ll-131. Widespread use of these drugs, however, has been questioned in terms of cost/effectiveness [14]. Similarly, the role of prophylactic surgery and that of percutaneous transluminal coronary angioplasty after myocardial infarction remains unsettled [15,16]. Thus, identification of predictors of reinfarction, together with those of death, appears mandatory to design management policies in infarction survivors. Although persistent or recurrent chest pain after myocardial infarction has been associated to a bad prognosis, factors determining the development of angina after hospital discharge are for the most unknown [17-191. The present study was undertaken: (1) to assess prospectively the prevalence of new non-fatal ischemic events after myocardial infarction; (2) to investigate factors determining the appearance of these events; and, (3) to use survivorship modeling to characterize subsets of patients in different risk categories. Material and Methods Patients From December 1975 to February 1981, 462 men aged 60 years or younger were admitted to our Coronary Care Unit because of a definite myocardial infarction. Acute myocardial infarction was diagnosed when at least two of the following three criteria were present: ischemic chest pain lasting longer than 20 minutes, increase above twice the upper limit of normal of two of the three serum cardiac enzymes (total creatine kinase, aspartate aminotransferase or lactate dehydrogenase) and evolving Q wave abnormalities with acute ST-T wave changes on the electrocardiogram. There were 438 survivors, 35 of whom were excluded from the study because of associated life-threatening conditions (2 patients had cancer, 3 severe car pulmonale, 2 cerebrovascular accidents), dye allergy (1 patient) or refusal of cardiac catheterization (27 patients). No patient was excluded from the study on the basis of a poor cardiac condition. The study protocol was approved by the Institutional Ethics Committee. Clinical evaluation On admission all patients underwent a careful investigation of their risk factors. Each patient was questioned concerning his history of coronary artery disease and use of cigarettes. Diabetes mellitus was considered to be present if the patient was being treated for this condition or if the fasting blood sugar level exceeded 120 mg
per 100 ml (6.7 mm01 per liter). Similarly, hypertension was diagnosed if the patient was already receiving antihypertensive drugs or if the blood pressure was above 165/95 mm Hg. Serum cholesterol and triglyceride levels were measured after a 1Zhour fast in all patients; if either were elevated, hyperlipidemia was diagnosed. Obesity was defined as a weight 15% or more above that considered ideal for a given height. Catheterization
and angiographic procedures
Within four weeks of infarction (18 f 6 days, mean + SD), combined right and left heart catheterization by the percutaneous femoral approach was carried out. Informed consent was obtained from all patients. Single-plane left ventriculography was performed with the patient in the 30” right anterior oblique position. Left ventricular volumes and ejection fraction were determined by the area-length method modified for single-plane calculation [20]. Regional wall motion was assessed according to the method described by Gelberg et al. [21]. All angiograms were assessed by two independent observers. Coronary artery lesions were defined as obstructive if the arterial narrowing exceeded 50% of the luminal diameter. Each patient was classified as having one-, two- or three-vessel disease. Obstructions of diagonal or marginal branches were considered lesions of the left anterior descending or circumflex arteries, respectively. Exercise test
Six months after infarction cycle ergometry was performed in the erect position on an electrically braked Elema Schbnander EM 370 ergometer. A progressive multistage protocol was employed; exercise continued until generalized fatigue, chest pain, shortness of breath, an appreciable fall in blood pressure, or serious arrhythmias occurred. A standard 12-lead electrocardiogram was recorded before the test. During exercise a CM 5 lead was continuously monitored, and recordings were obtained every three minutes and at the end point. A test was judged positive if angina or major ST-segment changes or both occurred. The latter were defined as 1 mm horizontal or downsloping depression lasting at least 0.08 seconds. Exercise performance was expressed as the maximal rate-pressure product (mm Hg mm’ x 102), and workload (watts) achieved by each patient. Follow-up
Patients were seen monthly during the first three months and every three months thereafter. Clinical status, results of physical examination, and a resting electrocardiogram were recorded at each visit. The mean period of follow-up was 57.1 months (range 40-100). Follow-up was completed in 393 of the 403 patients who had angiograms. The other 10 patients were lost to follow-up. Deaths occurring during the follow-up were classified according to the Hinkle classification [22].
76
Although no attempt was made to standardize medical treatment, all patients were kept on a low-cholesterol diet and moderate exercise was recommended. Surgical treatment was reserved for intractable angina or lesions of the left main coronary artery. Diagnosis of post-infarction angina was made on clinical grounds. A myocardial infarction was considered non-fatal if the patient was discharged from hospital. Statistical analysis A total of 79 variables was identified in each patient from the history, physical examination, exercise test and cardiac catheterization data. These variables were examined by univariate statistical methods to determine differences between patients with and without ischemic events. Student’s t-test, Fisher’s exact test, and the &i-square test were applied when appropriate. The statistical analysis was performed using the Statistical Package for Social Sciences [23]. To identify the variables independently predictive of new coronary events, multivariate analysis with Cox’s regression technique was applied in a stepwise manner to variables reaching .significance in the univariate analysis [24]. Finally, patients were classified in different subsets according to the variables selected by Cox’s regression analysis. Kaplan-Meier actuarial curves were constructed and the log-rank test was used to assess the significance of differences among the various groups [25]. Results Clinical findings Twenty-four of the first 462 patients (5.2%) died before cardiac catheterization. Non-survivors had a higher prevalence of severe congestive heart failure (Killip class
TABLE
1
Clinical
features
of 462 consecutive
patients
with acute myocardial
infarction.
Feature
Non-survivors
CCU survivors
Total in group Age (mean f SD) No. with severe congestive heart failure in the CCU No. with previous infarction Location of infarction Anterior Inferior Combined Nontransmural
24 53+7.3
438 5Ok7.1
17 (71) 6 (26) 13 9 1 1
Figures in parentheses are percentages. * Significant difference between CCU survivors + Significant difference between CCU survivors CCU = coronary care unit.
(54.1) (37.5) (4.2) (4.2)
and non-survivors and non-survivors
14 (3.2) * 38 (8.7) + 170 207 37 24
(38.8) (47.3) (8.4) (5.5)
(P < 0.001). (P < 0.01).
TABLE
2
Clinical
features
of the 438 study candidates
Feature
with myocardial Group
infarction.
of candidates
Non-participants Total in group Age (mean f SD) No. with previous infarction Peak creatine kinase (W/liter) (mean * SD) No. with severe congestive heart failure in the CCU Location of infarction Anterior Inferior Combined Non-transmural Figures in parentheses significance.
35 49.1 f 7.0 2 (5.7)
403 50.6 + 7.1 36 (8.9)
813 i 804.3
1077 f 762.7
2 (5.7) 10 21 1 3
are percentages;
Participants
12 (3) 160 186 36 21
(28.6) (60) (2.6) (8.6)
CCU = coronary
care unit.
(39.7) (46.3) (8.9) (5.2)
All differences
without
statistical
III or IV) (71% vs 3.2%, P < 0.001) and higher prevalence of previous myocardial infarction (26% vs 8.7% P < O.Ol), than survivors. No differences in mean age, infarction location or prevalence of risk factors were found between survivors and non-survivors in this series (Table 1). The time elapsed between the onset of symptoms and admission to the coronary unit was also similar in both groups (8.1 + 5.8 vs 7.2 f 6.7 hours). There were no differences between participants (403) and survivors excluded from the study (35) in age, previous myocardial infarction, infarction location, peak CK levels, occurrence of congestive heart failure or prevalence of risk factors (Table 2). Angiographic data Obstructive coronary lesions were present in 380 patients (94%); complete obstruction of at least one coronary artery was present in 202 instances (50%). One-, two- and three-vessel disease were found in 143 (36%), 139 (35%) and 98 (24%) patients, respectively. Nine patients (2%) showed left main coronary disease, which was always associated with multi-vessel involvement. Ejection fraction was within the normal limits (> 50%) in 164 patients (41%); moderate impairment of left ventricular function (ejection fraction between 21 and 49%) was found in 220 patients (55%), and severe left ventricular dysfunction (ejection fraction < 20%) in 13 patients (3%). Ejection fraction could not be calculated in 6 patients. Mortality There were 50 deaths (12.4%), 15 of them occurring within six months of the acute event. Death was cardiac in origin in 45 cases; 23 of these patients died within
78
one hour of the onset of symptoms (Hinkle class I). In 7 patients detailed information regarding circumstances of death were not available and they were classified as Hinkle class III. New non-fatal ischemic events Non-fatal reinfarction occurred in 41 patients (10%) 21 of whom had developed angina after the qualifying infarction. Of 38 patients with transmural reinfarction,
TABLE
3
Univariate
predictors
of non-fatal
Total in group No. of diseased vessels (mean f SD) Non-obstructive 1 vessel 2 vessel 3 vessel No. with previous myocardial infarction No. with history of hypertension No. with hypertension during follow-up
reinfarction. Reinfarction
No reinfarction
41
312 *
2.25 f 0.73 0 6 (14.6) 19 (46.4) 16 (39)
1.7lkO.89 23 (7.4) 127 (40.7) 102 (32.7) 60 (19.2)
< 0.001
17 (5.3)
< 0.01
22 (54)
108 (34.6)
< 0.05
13 (32)
72 (23)
-=C0.05
8 (19.5)
P value
Figures in parentheses are percentages. * Patients dying during follow-up not included.
TABLE
4
Univariate
predictors
of angina.
Total in group No. of diseased vessels (mean f SD) Non-obstructive 1 vessel 2 vessel 3 vessel No. with previous angina Exercise test Positive Negative Non-conclusive Figures
in parentheses
Angina
Without
210
193
1.8 + 0.8 7 (3.3) 65 (31) 80 (38) 58 (27.6) 124 (59)
are percentages.
27 (20) 87 (64) 22 (16)
angina
P value
1.6*0.8 16 (8.3) 78 (40.4) 59 (30.6) 40 (20.7) 77 (40)
i 0.01
19 (13.7) 110 (79.7) 9 (6.5)
< 0.001
-C 0.001
19
.8.7-
% 1-.-L___
.6> .= -_ P $ e a
.___ '--L. :..
'- ?_.
P
_ _ _ L-I--L& _ L___
.5.4.3.2.l0.0
Years
Patientsat risk
12
3
4
5
6
7
1 vessel-140
136
133
119
101
92
53
35
2 vessel-136 3vesseL- 97
1 16 75
105 67
100
75
43
33
14
60
48
36
15
5
Fig. 1. Probability of remaining diseased vessels. The P values
8
11
free of reinfarction in patients stratified according to the number of represent differences (log-rank test) between the group with one-vessel disease and the other two groups.
location corresponded to that of the previous infarction in 9. Although all 41 patients were discharged alive from hospital, 7 died in the ensuing months (mean 19 months, range 3-45). The results of univariate screening indicated that only 4 of the 79 baseline variables: number of diseased vessels, previous infarction, and hypertension (both before and after the initial infarction) were predictive of reinfarction (Table 3). Cox regression analysis showed that the number of diseased vessels (P < 0.001) was the only independent predictor. In keeping with this observation, Kaplan-Meier analysis showed (Fig. 1) the probability of non-fatal reinfarction at 6 years to be significantly lower in patients with one-vessel disease (12%) as compared with those with two- (30%) and three-vessel (37%) involvement. Further stratification according to ejection fraction in each of these subsets failed to demonstrate the influence of left ventricular function on reinfarction rate. When death and reinfarction were analyzed in association the rate of these combined events at 6 years was also significantly lower in patients with one-vessel disease than in those presenting with either two- or three-vessel disease, regardless of the level of ejection fraction (Fig. 2). Angina developed in 210 patients (52%) and in 7 of them it occurred after a second myocardial infarction. Severe angina (grade III-IV Canadian Cardiovascular Society) was observed in only 35 patients (4.2%). Angina was treated with betablocking agents (35 patients), calcium antagonists (42 patients), nitrates (48 cases) or a combination of drugs (51 patients). Aortocoronary bypass surgery was performed in 26 patients (6.4%). Univariate predictors of angina were the number of diseased vessels, previous history of angina and the result of exercise test (Table 4).
80
Cox regression analysis previous angina as the Stratification according probability of developing disease and 72% in those
selected the number of diseased vessels and history of only independent predictors of angina during follow-up. to the number of diseased vessels (Fig. 3) showed the angina at 6 years to be 51% in patients with one-vessel with three-vessel involvement.
1 vessel disease
1 o-~r~~~_~~-~~i_ ._ .9-
--=-~=--~~~,_-_i.
Lr=-.--
-t+-____-_-__ i_-_-._.-._
.8.J.6.52 z P d 2 0
.4.3.2.l0.0
Patients at risk ~~260%--67 EF 21-49%.---71 EFI20%-
2
1
2
3
4
5
6
7
Years c 8
67
65
58
48
43
28
18
15
JO
68
62
53
51
36
25
20
2
2
1
0.0 Patients
at risk
EFL50%---55 EF 21-49 %--77 EFF20%-4
1
2
3
4
5
53
47
43
41
18
68 2
63 2
60 2
58 2
39 2
I
6
Years
1
7
8
14
11
4
31
19
J
Fig. 2. Probability of remaining alive and free of reinfarction in patients with one-, two- and three-vessel disease stratified according to ejection fraction (EF). The P values represent differences (log-rank test) between the group with normal EF and the other two groups.
81
3 vessel disease
I
P < 0,001
L.
1
0.0 Patients at nsk EFL50%---23 EF 21-49
%-.A7
EFS20%-7
1
2
3
4
5
6
7
20
19
18
17
14
5
3
52 3
43 3
40 2
37 2
30 -2-
10
2
Years
, a
Fig. 2 (continued).
Sixty-four patients (16%) developed congestive heart failure; digoxin was preA total scribed in 53 patients. In 5 cases the symptoms occurred after reinfarction. of 136 patients (34%) remained asymptomatic; exercise test, performed in 106 of these patients, was positive in only 18.
“--1__~:~-1,_.____._
P < 0,001 .1 :-.__________
.2.l0.0 Patients at risk
2
3
4
5
6
7
a
102
91
46
33
23
13
75
60
78 50
61
2vessel
-139 ---138
36
24
12
10
6
3vessel
--97
45
35
30
18
12
6
4
3
1 vessel
Fig. 3. Probability
Years 1
of remaining
free of angina
in patients
stratified
vessels. P value as in Fig. 1.
according
to the number
of diseased
82 TABLE Prevalence
5 and predictors
Series
Taylor [2] De Feyter [3] Robin [4] Gibson [5] Norris [6] MPRG [7] Williams [S] MILIS [30] Present series
of new coronary
No. of patients
% of eligible
106 I79 229 140 325 886 226 719 403
39 81 89 61 82 61 97 85 92
12 6 4.2
3.6 13 11.6
5.9
4.4
12.4
A@0
data
yes yes Yes
Y-
yes no no no yes
Predictors
EF; 3-vessel disease Killip class III l ; previous MI; VT and VF; no. of diseased vessels Th-201 scintigraphy; ET; angiography EF; prognostic
Incidence
Predictors
10
EF; VPB; pulmonary rates; NYHC class
6
ST depression; previous MI; CK; exercise duration No ET; ST elevation; inadequate BP response; VPB on ET EF; no. of diseased vessels; CHF at ecu
6.8
3.5
10.1
Length of follow-up (months)
28 24 15 42 22 12 12 57
CABS %
18 13.4 10 17.8 24 13 11.7 2 6.4
Incidence
Predictors
64 42
13.8 6.7
6.4
series.
Angina
Reinfarction
Mortality Incidence
events in representative
Th-201 scintigraphy Stenosis score Predischarge angina; nonperformance on ET
24
Scintigraphy; severe (IV-V)
3.4 unstable No ET
No. of diseased vessels
52.1
No. of diseased vessels; previous
EF = ejection fraction; MI = myocardial infarction; VT = ventricular tachycardia; VF = ventricular fibrillation; ET = exercise test; VPB = ventricular premature beats; CHF = congestive heart failure; CCU = coronary care unit; BP = blood pressure; CABS = coronary artery by-pass surgery.
83
Discussion
The high incidence of new non-fatal coronary events after myocardial infarction has already been noted in large epidemiologic studies [26,27]. The Framingham study showed the incidence rate of a second infarction among men to be 13% at 5 years, whereas that of angina was 33% [26]. More recently, intervention trials such as the Coronary Drug Project (281, the Norwegian Study [ll] and the Beta Blocker Heart Attack Trial [13] have confirmed the Framingham data. Attempts to identify factors determining the appearance of non-fatal ischemic events after myocardial infarction (Table 5) are scarce [2,5,9,10]. However, recognition of baseline clinical or angiographic predictors of recurrent infarction or angina is relevant since secondary prevention by means of drugs, angioplasty or surgery may now be offered to high risk patients [15,29]. Characteristics
of the study
The present series is unique in that as much as 92% of potential candidates were entered into the study and only 10 patients were lost to follow-up. In addition, and at variance with other series, overall results reported herein are not likely to be distorted by surgery since revascularization procedures were restricted to patients with refractory angina and to those with left main coronary artery disease. We set an age limit of 60 years in our study to improve the likelihood of 10 years of follow-up and females were excluded because infarction in women of this age group is uncommon in our environment. Thus, the results of this investigation would apply only to men aged 60 years or less. Despite these limitations, our series included the 70% of all patients admitted to the coronary care unit with a definite myocardial infarction. Reinfarction
We identified the number of diseased vessels as the main determinant of reinfarction. Stratification of patients according to this variable showed the probability of a non-fatal second infarction at 6 years to be significantly higher (P < 0.001) in patients with two- (30%) and three-vessel disease (37%) than in those with one-vessel disease (10%). Norris et al. [6] observed that patients with a large amount of jeopardized myocardium, as assessed by a specially designed score, showed a higher risk of recurrent myocardial infarction. However, in view of the marked variability of the values obtained, the authors concluded that the score was of no practical use for prediction. Discrepancies between Norris data and our own study may well be explained on the basis of the larger proportion of patients who underwent myocardial revascularization in their series (24%). In keeping with our findings are those of Taylor et al. [2], who showed three-vessel disease to be an independent predictor of recurrent myocardial infarction. A previous history of hypertension, post-infarction angina and prior myocardial infarction were also identified as independent predictors of reinfarction. Dif-
84
ferences between these series and ours might be related either to patient selection criteria, study design or both. We could not predict reinfarction throughout variables obtained from the exercise test. Since 10 (25%) of the 41 cases of new myocardial infarction occurred within 6 months of the qualifying episode (before the test was performed) timing of the exercise test was probably inadequate to predict reinfarction. Recently, the MILIS Study Group [30] analyzed the prognostic value of an exercise test performed 6 months after infarction. Recurrent non-fatal myocardial infarction was predicted only by inability to perform the exercise test because of cardiac limitation, but not by any characteristics of exercise performance. Similar results were reported by Dwyer et al. [lo] with a low level predischarge exercise test. However, the role played by the extent of coronary artery disease in prognosis could not be assessed in these studies since selective coronary arteriography was not carried out. As far as our study is concerned, failure to identify other independent predictors of reinfarction was probably due to the fact that additional information provided by new variables is of no statistical significance once the number of diseased vessels, the most powerful predictor, has already been selected. Post-infarction
angina
The number of diseased vessels was also found to be the main determinant of post-infarction angina. De Feyter et al. [3] documented the prevalence of multi-vessel disease to be significantly higher among patients with angina pectoris at the time of investigation (6 to 8 weeks following infarction). Since routine coronary angiography has not commonly been performed after myocardial infarction, other reports failed to identify the significance of this variable to predict angina following infarction [9,31]. In keeping with our data are those of Taylor et al. [2], who showed that post-infarction angina was related to the number of segments supplied by stenosed vessels. Our finding that a previous history of angina is an independent predictor of post-infarction angina agrees with earlier reports indicating that angina commonly persists after myocardial infarction [19,31]. Of interest in this regard is the study by Amsterdam et al. [32], who found the prevalence of post-myocardial infarction angina to be higher in patients with previous history of angina (87%) than in those who did not have angina prior to the qualifying infarction (35%). Clinical implications Prior data from our Institution [33] showed the single best predictor of late survival after myocardial infarction to be left ventricular ejection fraction. In that study, the role played by the number of diseased vessels on life expectancy was confined to the subset of patients whose ejection fraction ranged between 21 and 49%, the probability of survival at 6 years being 95% for patients with one-vessel disease and 78% for those with three-vessel disease (P < 0.001). The present investigation demonstrates the number of diseased vessels, but not ejection fraction,
85
to be the only independent predictor of both reinfarction and post-myocardial infarction angina. Thus, identification of the subset of patients with multi-vessel disease appeared to be mandatory. Whether or not routine coronary angiography should be recommended will depend on how accurately non-invasive tests can detect multi-vessel disease, patient status and cost/effectiveness considerations. Furthermore, data from the present study highlight the need for new trials to define the role of coronary angioplasty, and particularly its timing, after acute myocardial infarction to reduce the incidence of new ischemic events.
References 1 Henning H, Gilpin E, Gowll SW, Swan EA, G’Rourke RA, Ross J Jr. Prognosis after acute myocardial infarction: a multivariate analysis of mortality and survival. Circulation 1979;59:1124-1136. 2 Taylor GJ, Humphries JO, Mellitus ED, et al. Predictors of clinical course, coronary anatomy and left ventricular function after recovery from acute myocardial infarction. Circulation 1980,62:960-970. 3 De Feyter PJ, Van Eenige MJ, Dighton DH, Visser FC. Prognostic value of exercise testing, coronary angiography and left ventriculography 6-8 weeks after myocardial infarction. Circulation 1982;66:527-536. 4 Robin GS, Harris PJ, Bernstein L, Kelly DT. Coronary anatomy and prognosis after myocardial infarction in patients 60 years of age and younger. Circulation 1983;67:743-749. 5 Gibson RS, Watson DD, Carddock GB, et al. Predictors of cardiac events after uncomplicated myocardial infarction: a prospective study comparing predischarge exercise thallium-202 scintigraphy and coronary angiography. Circulation 1983;68:321-336. 6 Norris RM, Bamaby PF, Brandt PNT, et al. Prognosis after recovery from first acute myocardial infarction: determinants of reinfarction and sudden death. Am J Cardiol 1984;53:408-413. 7 Multicenter Postinfarction Research Group. Risk stratification and survival after myocardial infarction. N Engl J Med 1983;309:331-336. 8 Williams WL, Nair RC, Higginson LAS, Bairal MG, Allan K, Beanlands DS. Comparison of clinical and treadmill variables for the prediction of outcome after myocardial infarction. J Am Co11 Cardiol 1984;4:477-486. 9 Thdroux P, Waters DD, Halphen C, Debaisieux JC, Mizgala HF. Prognostic value of exercise testing soon after myocardial infarction. N Engl J Med 1979;301:341-345. 10 Dwyer EM, McMaster P, Greenberg H and the Multicenter Postinfarction Research Group. Non-fatal cardiac events and recurrent infarction in the year after acute myocardial infarction. J Am Co11 Cardiol 1984;4:695-702. 11 The Norwegian Multicenter Study Group. Timolol induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. Lancet 1979;2:865-871. 12 Anderson MP, Bechsgaard P, Frederiksen J, et al. Effect of alprenolol on mortality among patients with definite or suspected acute myocardial infarction. Lancet 1979;2:865-871. 13 Beta-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. J Am Med Assoc 1982;247:1707-1712. 14 Friedewald WT. Beta-adrenergic blockade after myocardial infarction: clinical and public health implications of the reported beta-blocker clinical trials. Circulation 1983;67(suppl I):llO-111. 15 Epstein SE, Palmeri ST, Patterson RE. Evaluation of patients after acute myocardial infarction. N Engl J Med 1982;307:1487-1492. 16 Principal investigators of CASS and their associates. Myocardial infarction and mortality in the Coronary Artery Surgery Study (CASS) randomized trial. N Engl J Med 1984;310:750-758. 17 Shuster EH, Bulkley BH. Early postinfarction angina: ischemia at a distance and ischemia in the infarct zone. N Engl J Med 1981;305:1101-1105. 18 Chaturvedi NC, Walsh MJ, Evans A, Mumo P, Boyle DM, Barber JM. Selection of patients for early discharge after acute myocardial infarction. Br Heart J 1974;36:533-535.
86 19 Watters DD, Bosch X, Bouchard A, et al. Comparison of clinical variables derived from a limited predischarge exercise test as predictors of early and late mortality after myocardial infarction. J Am Co11 Cardiol 1985;5:1-8. 20 Sandler H, Dodge HT. The use of single plane angiograms for the calculation of left ventricular volume in man. Am Heart J 1965;75:325-334. 21 Gelberg HJ, Brundage BY, Glantz S, Parmeley WW. Quantitative left ventricular wall motion analysis: a comparison of area chord and radial methods. Circulation 1979;59:991-1000. 22 Hinkle L, Thaler H. Clinical classification of cardiac deaths. Circulation 1982;65:457-464. 23 Nye NH, Hull CH, Jenkins JG, Steinbrenner K, Bent DH. Statistical package for the social sciences. New York: McGraw-Hill, 1975. 24 Cox D. Regression models and life tables. J Stat Sot (B) 1972;34:187-202. 25 Lee ET. Statistical methods for survival data analysis. Belmont, CA: Lifetime Learning Publications, 1980:76-110. 26 Kannel WB, Sorlie P, McNamara PM. Prognosis after initial myocardial infarction: the Framingham Study. Am J Cardiol 1979;44:53-58. 27 Martin CA, Thomson PL, Armstrong BK, Hobbs MST, Klerk ND. Long-term prognosis after recovery from myocardial infarction: a nine year follow-up of the Perth Coronary Register. Circulation 1983;68:961-969. 28 Coronary Drug Project Research Group. Factor influencing long-term prognosis after recovery from myocardial infarction: three year findings of the Coronary Drug Project. J Chron Dis 1974;27:267-285. 29 May GS, Eberlein KA, Furberg CD, Passaman ER, De Mets DL. Secondary prevention after myocardial infarction: a review of long-term trials. Prog Cardiovasc Dis 1982;24:331-352. 30 Stone PH. Turi ZG, Muller JE, et al. Prognostic significance of the treadmill exercise test performance 6 months after myocardial infarction. J Am Co11 Cardiol 1986;8:1007-1017. 31 Waters DD, Theroux P, Halpen C, Mizgala HF. Clinical predictors of angina following myocardiaf infarction. Am J Med 1979;66:991-996. 32 Amsterdam EA, Lee G, Mathews EA, Mason DT. Relationship of myocardial infarction to presence of angina pectoris in patients with coronary heart disease: lack of abolition of angina by infarction. Clin Cardiol 1978;1:31-34. 33 Sanz G, Castaiier A, Betriu A, et al. Determinants of prognosis in survivors of myocardial infarction. A prospective clinical angiographic study. N Engl J Med 1982;306:1065-1070.