- Email: [email protected]
Impact of treatment strategy on predischarge exercise test in the Thrombolysis in Myocardial Infarction (TIMI) II trial
The
CORONARY
ARTERY DISEASE
I American ( 1 Journal ~ of’ iCardiology
JANUARY 15, 1993, VOL. 71, NO. 2
Impact of Treatment Strategy on Predischarge Exercise Test in the Thrombolysis in Myocardial Infarction (TIMI) II Trial Bernard R. Chaitman, MD, Robert P. McMahon, PhD, Michael Terrin, MD, Liwa T. Younis, MD, PhD, Leslee J. Shaw, MA, Donald A. Weiner, MD, Margaret M. Frederick, PhD, Genell L. Knatterud, PhD, George Sopko, MD, and Eugene Braunwald, MD, for the TIMI Investigators* ergommy was used ischemiiin postinfarction patients who received thronubdytic therapy and were randomized to m invasive VW ws consewative stmtegy in the Tlwombolysis in Myocddial InWction (TM) II trial. The frequency of ischemii mspomesinbothstrategieqmdthe lyearpm@mstii importance ofthedii exercise test outwere examined. At 14 day~thepematageofpatiatswithany adverse outcome (including death, presence of exemise-induced ST-segmed depmssm, or inability to perfom the exercise test) was 33.7% of1,68lrmdomlyassi@mdtothe imvasivestrat-
(relativeriskcompamdwiththo&withoutSTsegmentdepmdonorchestpain0.6; SS%con6 dence interval O.lto 2.9). Among pathts mb domlyassi@mdtotheinvasivestrategy,exe~ cissinducedSTaegmentdepressionorchestpain wasassociatedwithalyearmortaliiof2.5%(4 oflSl)(mktive riskcompamd withthoeewitb
egyumpamdwith3A6%of1,6!3srandomly asmigmdtothe conservative stmtegy (p = 0.57). Ihelyearmortaliiwasgreaterinpatiiwho didnotperfommthepredischargeexercisete8t (7.7K)than in those who dii (l.S%) (p
l-yearmortaliiforthasewith
Prediw
supine
bicycle
toassesspedsbmtmyocmlial
thefonmerwereolder,anda@eaterproportiom werewomen,hedamorefrequenthista#yof myocdiil infarction, and more extemsive eoro nalyarterydisease(p~.01foreachcompat+ son). The l-year mortality in patients with exer ciiseinduced STeegmemt depression or chest pain wasomlyl.4%(3of222)amongthoserandomly conservative strategy where a!egnsdtothe coeonay B amd revascuMzatiom wem recemmemdedifthetestfWsultwasabnonmel
From the Maryland Medical Research Institute, Baltimore, Maryland. Dr. Chaitman’s current address is: St. Louis University Medical Center, 3635 Vista Avenue at Grand Boulevard, P.O. Box 15250, St. Louis, Missouri 63 110-0250. This study was supported by research contracts and grants from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received May 7, 1992; revised manuscript received August 28, 1992, and accepted August 3 1. Address for reprints: TIM1 Coordinating Center, Maryland Medical Research Institute, Inc., 600 Wyndhurst Avenue, Baltimore, Maryland 21210. *Investigators England Journal
and participating centers are published (1989:320;618427).
of Medicine
in the New
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he Thrombolysis in Myocardial Infarction (TIMI) II trial assessed the role of cardiac catheterization 18 to 48 hours after study entry, with percutaneous transluminal coronary angioplasty (FTCA) if appropriate, in patients with acute myocardial infarction treated with recombinant tissue-type plasminogen activator. The principal goal of TIMI II was to determine if this invasive treatment strategy would alter mortality and reinfarction as compared with a conservative strategy. There were no significant differences in the occurrence of death or reinfarction between treatment strategies at 6 weeks or 1 year after enrollment.1-3 F’redischarge submaximal exercise testing is frequently performed after an acute myocardial infarction to determine prognosis, functional capacity and propensity to develop cardiac arrhythmias, and to provide a baseline for exercise prescription in the convalescent phase.“18 Evaluation of postinfarction exercise testing as a procedure for risk stratitication should consider the impact of the referral for coronary angiography in patients with an abnormal test, and subsequent coronary
T
TIMI II EXERCISE RESULTS
131
revascularization. l9 In some patients, the revascularization procedure may influence the natural history of the disease and alter the prognosis associated with abnormalities observed during exercise testing. A second consideration is the use of thrombolytic therapy, a treatment known to decrease mortality, now received by 20 to 40% of patients who present to the hospital with suspected infarction.20~21 There is little information regarding the prognostic role of predischarge exercise testing in patients with myocardial infarction treated with a thrombolytic agent. In this report, we present the frequency of electrocardiographic evidence of exercise-induced ischemia at hospital discharge, document the use of the exercise test to select patients enrolled in the conservative strategy for cardiac catheterization, and compare the prognosis of patients with and without selected exercise test abnormalities in the invasive and conservative strategies. The predischarge exercise test included the use of radionuclide ventriculography, the results of which were reported previously.22
infarction-related artery when the coronary anatomy was suitable 18 to 48 hours after treatment, and 1,658 were randomly assigned to a conservative strategy in which they were evaluated for revascularization if they had spontaneous ischemia after infarction during the hospital phase, or important exercise-induced myocardial ischemia during an exercise test performed before hospital discharge. Of 3,339 patients in the trial, 2,502 (75%) performed exercise testing within 2 weeks of the index event (Figure 1). Exercise electrocardiograms were considered noninterpretable for the development of ischemia in 147 patients, because of electrocardiographic lindings of left ventricular hypertrophy, bundle branch block or excess motion artifact during exercise. This analysis is based on the remaining 2,355 patients with exercise electrocardiograms analyzed at the TIMI Electrocardiographic Core Laboratory (1,168 patients randomly assigned to the invasive strategy and 1,187 to the conservative strategy). Baseline characteristics of the patients who did perform versus those who did not perform the exercise test in the invasive and conservative strategies are listed in Table I. Of 960 patients in whom medication usage at the time of exercise testing was recorded, 66% received B-blocker drugs, 48% calcium antagonist, 26% long-acting nitrates and 5% digoxin within 7 days of testing. Exercise protocol: Exercise was performed in the supine position using a calibrated electronic bicycle ergometer. Heart rate, systemic blood pressure measured by sphygmomanometry, and a 1Zlead electrocardiogram were recorded at baseline, the end of each exercise stage, peak exercise and each minute for 5 minutes into the recovery phase. The initial work load of the 2-stage exercise test was set at 200 kpm and increased to 400 kpm after 3 minutes or to a peak heart rate of 120 beats/min for patients during the limited, predischarge
METHODS Study patients: The details of the TlMI II trial and inclusion/exclusion criteria have been described. *-3 Patients were eligible for enrollment if they had chest discomfort suggestive of acute myocardial ischernia lasting 230 minutes, and ST-segment elevation Lo.1 mV in electrically contiguous leads, were aged <76 and had no contraindications to receiving a thrombolytic drug. Patients were enrolled within 4 hours of the onset of symptoms that precipitated hospital admission. The TIMI II protocol was approved by the human research committee at each participating medical center, and written informed consent was obtained from all patients. In all, 3,339 patients were enrolled; 1,681 were randomly assigned to an invasive strategy of PTCA to the
1 TREATMENT INVASIVE
STRATEGY CONSERVATIVE
1681 NW DEATH $14 DAYS FROM ENTRY STUDY
1658 NW)
76 (4.6)
64 (3.9) t+
FtGlJREl.performanceofexerei!setea
*
1603(95.4)
14 DAY SURVIVORS
ET NOT PERFORMED BY 14 DAYS
1594(96.1)
362 I21.5)
*
333 (20.1)
(ET), ad availability vQta.lherewm :,BBl and 1,658 patii mwlonGxed to invasive swvative stmegbq ~=ele&oawogmm. d
ET PERFORMED BY 14 DAYS NONINTERPRETABLE EXERCISE ECG
4
BY
1241 (73.8) 73 (4.3)
74 (4.5) 1
ET INTERPRETABLE
132
t
1261 (76.0)
1168(69.5)
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71
I+ 1187 (71.6)
JANUARY 15,1993
of
exercise in TIM and respectively.
II
TABLE I Patient Study Entry*
Characteristics
According
to Treatment
Strategy
and Whether
Patients
Performed
invasive
Baseline
Characteristics
Mean age (year) Race (white) Sex (men) Not low risk+ Age 2 70 years Prior myocardial infarction Anterior myocardial Infarction Rales z l/3 of lung fields Hypotension and sinus tachycardia Atrial fibrillation or flutter Pulmonary edema Cardiogenic shock History Angina Congestive heart failure Hypertension Diabetes Current smoker Ever smoked Time from onset to study entry 52 hours Cardiovascular events I 14 days Myocardial infarctlon Recurrent painful ischemic events in hospital New congestive heart failure Any of above CABG
Exercise Test (n = 1,241); n (%) 55.6 1,088 (87.7) 1,059 (85.3) 781 (62.9) i ia (9.5) 154 (12.4) 604 (48.7) 35 (2.8) 63 (5.1) 23 (1.8) 7 (0.6) 12 (1) 652 25 453 130 632 961 323
(52.5) (2) (36.5) (10.5) (50.9) (77.4) (26)
p Valuet
59.5 (88.4) (74.6) (71.3) (18.8) (18.8) (53) (5.2) (5)
0.001 0.71 0.001 0.003 0.001 0.002 0.14 0.02 0.94
8 (2.2) 7 (1.9) 6 (1.7)
0.66 0.01 0.27
221 22 165 61 159 270 101
Test I 14 Days After
Conservative
No Exercise Test (n = 362); n (%I
320 270 258 68 68 192 19 la
an Exercise
(61.2) (6.1) (45.6) (16.8) (43.9) (74.6) (27.9)
0.004 0.001 0.002 0.001 0.02 0.26 0.48
46 (3.7) 254 (20.5)
44 (12.2) 133 (36.7)
0.001 0.001
161 (13) 371 (29.9) 38 (3.1)
102 190 126
0.001 0.001 0.001
(28.2) (52.5) (34.8)
Exercise Test (n = 1,261); n (%I
No Exercise Test (n = 333); n (%)
55.8 1,127 (89.4) i ,066 (84.5) 826 (65.5) 101 (8) 155 (12.3) 662 (52.5) 43 (3.4) 64 (5.1)
288 251 236 59 59 175 16 19
25 (2) a (0.6) 10 (0.8) 651 24 461 158 657 1,000 317
*Analysis is restr&d to 14.day survivors. tp value for difference between patients who did and did not exercise by 14 days within each treatment strategy. $Patient 1s not low risk If any of following are present on admiwon: age 2 70 years, prior myocard!al infarctlon, anterior and SHW tachycardia. atrial fibrillation orflutter, pulmonary edema, orcardiogeruc shock. CABG = coronary artery bypass grafting.
59.1 (86.5) (75.4) (70.9) (17.7) (17.7) (52.6) (4.8) (5.7)
10 (3) 6 (1.8) 4 (1.2)
(51.6) (1.9) (36.6) (12.5) (52.1) (79.3) (25.1)
0.001 0.14 0.001 0.06 0.001 0.01 0.99 0.23 0.64 0.26 0.04 0.48
(56.8) (3.6) (39.6) (15.3) (42.6) (74.2) (28.2)
0.10 0.06 0.30 0.18 0.002 0.04 0.25
40 (3.2) 304 (24.1)
33 (9.9) 155 (46.5)
0.001 0.001
155 (12.3) 414 (32.8) 36 (2.9)
90 (27.1) 197 (59.2) 69 (20.7)
0.001 0.001 0.001
myocardial
189 12 132 51 142 247 94
p Valuet
Infarction.
rales 2 113 of lung fields, hypotension
exercise test. The maximal duration of the test was 6 and ST-80 depression 20.15 mV, and ST-segment slope minutes. The limited, predischarge exercise test was dis- >l mV/s. ST-segment elevation in Q-wave infarct leads continued for the development of progressive chest pain, was determined to be present when J point and ST-80 excessive dyspnea, dizziness, complex ventricular ar- elevation was 9.1 mV as compared with at baseline rhythmias, exertional hypotension, severe ischemic ST- and was not considered an ischemic response. segment depression, excessive fatigue, or achievement of At the time of the hospital discharge study, results target heart rate or work load. were interpreted locally by clinical center staff to deterAt the Electrocardiographic Core Laboratory, each mine if evidence of exercise-induced myocardial ische12-lead electrocardiogram obtained before exercise, at mia was present. For conservative strategy patients, the peak exercise and during recovery was reviewed for ST- TIMI II protocol indicated coronary angiography (to be followed by revascultization if necessary) when spontasegment shifts 20.05 mV. When ST-segment deviation was 20.05 mV, the electrocardiographic leads with the neous or exercise-induced rnyocardial ischemia was most marked ST-segment depression and elevation were present. Otherwise, cardiac catheterization was discourdigitized, using a SummaGraphics microgrid II digitizaged. Indicators of myocardial ischemia considered in er interfaced to an IBM computer. Three consecutive the evaluation for coronary angiography included angicomplexes were digitized at rest and peak exercise, and na pectoris, ST-segment depression 22 mm, a 20 mm in the recovery phas&f ST-segment deviation exceeded Hg reduction in systolic blood pressure, a 5-unit reducthat observed at peak exercise or immediately after ex- tion in left ventricular ejection fraction, and complex ercise. Custom software was used to analyze the rest and ventricular arrhythmias. The test outcome was considmaximal ST-segment changes observed during peak ered inconclusive when the aforementioned indicators exercise or in recovery. 23,24The exercise electrocardiowere absent, and if patients were unable to exercise to graphic response was considered abnormal when either a heart rate of 120 beats/minute or could not perform at of the following 2 criteria were observed in any lead as a work load of 400 kpm. End points: The TIMJ JT protocol required that all compared with at baseline: J point and ST-80 depression 20.1 mV, ST-segment slope
RESULTS
133
deaths and nonfatal events that occurred during followup were reported to the Coordinating Center. Information was collected from all surviving patients for cardiac events including reinfarction, congestive heart failure, presence of angina pectoris and whether a revascularization procedure had been performed. As of January 1991, l-year follow-up for vital status was 99% complete for both treatment strategies. Reinfarction was classified centrally without knowledge of treatment assignment and accepted as documented according to previously published criteria.2 Statistical analysis: To account for all patients who entered the study, a composite 14-day adverse outcome was delined by death within 14 days of study entry, survival to 14 days without a hospital discharge exercise test, or a hospital discharge exercise electrocardiogram with ischemic ST depression present. Analysis of exercise test Iindings as predictors of events (death, death or myocardiaI infarction by 1 year after study entry) was restricted to patients alive at 14 days who performed the exercise test and whose exercise electrocardiogram was analyzed at the Electrocardiographic Core Laboratory. The proportions of patients experiencing events were estimated by the Kaplan-Meier method25; comparisons of survival without events were performed by the log-rank test.26 The relative risk reported for each exercise Iinding estimates the ratio of the risk of events for patients with the linding present to that for those without the finding. The Cox proportional hazards mode127 was used to estimate relative risks and confidence intervals. For comparison of baseline variables, &i-square tests were used to compare categoric variables and t tests for continuous variables. To account for the multiple statistical hypotheses tested, p 4.01 was considered to show evidence of a relation, and p
$ d
75
RESULTS At 14 days after entry in the TIMI II trial, the proportion of patients who died, had not performed the exercise test or had exercise-induced ST-segment depression were similar in the invasive and conservative strategies (Figure 2; p = 0.57). The proportion of patients who died, had a new myocardial infarction, had not performed the exercise test or had exercise-induced STsegment depression were similar in the invasive and conservative strategies (36.0 vs 36.7%; p = 0.69). Patients who did not perform a predischarge exercise test were older, included a larger proportion of women, and had previous myocardial infarctions, and more 2and 3-vessel coronary artery disease (Tables I and II) compared with those who did perform an exercise test. Of 333 conservative and 362 invasive strategy surviving patients who did not perform an exercise test by 14 days after study entry, 59.2% with the conservative strategy and 52.5% with the invasive strategy had experienced 21 event, defined as reinfarction, recurrent painful ischemic events or newly occurring congestive heart failure, by 14 days. These events occurred significantly less often in patients who performed exercise tests (Table I). The mortality between 14 days and 1 year after study entry was significantly less in patients able to perform the low-level exercise test than in those that could not (1.4% [17 of 1,241] vs 6.3% [23 of 3641 for the invasive strategy [p
NO STD STD
f ECO s
50
NONINTERPRETABLE
NO ET BY 14 DAYS
# 8
YI s 14 DAYS DIED
25
s 14 DAYS
FIGURE 2. MorQli exerciseem graphicoNtcommatl4 dayBl6ccoMngtesericpled Wmtment
p = 0.57
I.34
CONSERVATIVE (N=lsSe)
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71
JANUARY 15,1993
s&ate@ &ffweme
in
TIMI in
II.
popoltionabletOeX& WimoNt ST depmesh p-0.02fclranydifkmnm inoutcommMl=mye cardd infaetion; &bf&atiom
INVASIVE (N11681)
for
md
a~
(STD);
other in
R#ue
1.
TABLE II Findings of Protocol According to Whether Exercise
Protocol Catheterization
Cardiac Catheterization Test Was Performed
Among Invasive Strategy Patients < 14 Days After Study Entry
Finding
Protocol cardiac catheterization
performed
Yes No 0 1
No. of vessels with % stenosis 2 60%
TIMI grade of Ml-related
coronary arteryt
1 2 3
Collaterals to Ml-related
coronary artery present
(
1,155 (93.1)
313 (86.5)
0.001
677 258 59 36 2
(60.5) (23.1) (5.3) (0.2)
518 (44.8) 0 (0) 495 (42.9) 140 (12.1) 0 123 (10.7) 45 (3.9) 217 (18.8) 767 (66.6) 3 128 (11.4) 991 (88.6) 35
Missing* Yes No Missing*
ized to the invasive and conservative strategies, respectively. Of 1,168 patients randomized to the invasive strategy with an interpretable exercise electrocardiogram (Figure l), 108 had exercise-induced ST-segment depression 22 but ~2 mm, and 19 had 12 mm. Of 1,187 patients randomized to the conservative strategy (Figure l), 146 had ST-segment depression 21 but c2 mm, and 30 had 22 mm. One-yciau m after exerciee teatie No statistically significant differences according to the study
p Value
125 (11.2)
Missing* None Right Left main Left anterior descending Left circumflex Missing* 0
coronary artery
No Exercise Test (n = 362); n (%)
86 (6.9)
2 3
Ml-related
Exercise Test (n = 1,241); n (%)
49 30 132 95 43 13 6
(13.5) (10) (44) (31.7) (14.3)
0.001
(1.9) 131 (41.8)
0.39
2 (0)
128 (40.9) 46 (14.7)
0 38 9 65 201 0 34 266 13
(12.1) (2.9) (20.8) (64.2)
0.60
(11.3) (88.7)
0.96
criteria were found in either treatment strategy for lyear occurrence of death, or of death or myocardial infarction according to the presence of specific exercise test outcomes (ST-segment depression or elevation, chest pain, and peak heart rate and systolic blood pressure). In the conservative strategy, l-year mortality was 0.6 vs 2.4% in patients with versus without exercise-induced ST-segment depression (relative risk 0.2; p = 0.13). When exercise-induced ST-segment depression or pain was examined, the l-year mortality was 1.4 vs 2.3% for
lo 1 --.
No Test by 14 Days
----.--
Exercised
to < Stage 2
-
Exercised to Stage 2 p < 0.001
FlQURE3.MortdiQofpetkntsin conMMtive~whownot pWfOtWlexwdS9t8StcompIIcBdWittl thEtOfUlOSOWbWM8(I#etO
CtOll@W~llWbOUl~OflOW levd, ptwahq+, exercise test (p
2
7
12
17
Weeks
22
27
32
from Study
37
42
47
52
Entry
TIMI II EXERCISE
RESULTS
135
TABLE III Finding of Protocol Cardiac Catheterization Among Invasive Strategy Patients Surviving > 14 Days with Exercise Electrocardiogram < 14 Days After Entry Read by Electrocardiography Core Laboratory, According to Presence of Exercise ST-Depression
Protocol
Catheterization
Protocol cardiac catheterization performed No. of vessels with % stenosis
Ml-related
coronary
Total (n = 1,168)
Finding
z 60%
artery
Mean % stenosis of MI coronary artery TIMI flow grade of Ml coronary arteryt
Yes No 0 1 2 3 Missing* None Right Left anterior descending Left circumflex Missing
1,091 77 115 642 243 57 34 2 490 463
0
; Collaterals present
to Ml coronary
Protocol PTCA performed attempted
3 Missing + 0 Missing + 0
artery
or
ST Depression (n = 127) n (%)
No ST Depression (n = 1,041) n (%)
118
973 68 110 582 211 40 30 2 424 437
(93.5) (6.5) (11.7) (61.7) (22.4) (4.2)
(11.3)
9 5 60 32 17 4 0 66 26
(92.9) (7.1) (4.4) (52.6) (28.1) (14.9) (0) (55.9) (22)
(0.2) (43.6) (44.9)
136
26 (22)
110
0 75.0 117 24 99 794 57 121 936 34 719 449
0 77.9 17 (15) 2 (1.8) 16 (14.2) 78 (69) 5 15 (13.2) 99 (86.8) 4 66 (52) 61 (48)
0 74.6 100 (10.9) 22 (2.4) 83 (9) 716 (77.7) 52 106 (11.2) 837 (88.8) 30 653 (62.7) 388 (37.3)
p Value 0.80 0.001
0.001
0.09 0.14
0.54
0.02
*Number of patients who underwent protocol cardiac catheterization for whom data Item is missing. Percentages based on patients with information for this data item. tRefers toTIM grade after PTCAfor patients who received protocol PTCA. MI = myocardial infarctjon; PTCA = percutaneous translummal coronary angioplasty.
patients with versus without these findings (relative risk 0.6; p = 0.39). Among the invasive strategy patients, l-year mortality in those with versus without exercise-induced STsegment depression was 3.2 vs 1.2% (relative risk 2.8; p = 0.06). The l- year mortality was 2.5 vs 1.2% (relative risk 2.1; p = 0.18) for patients with versus without exercise-induced ST-segment depression or chest pain. ST-segment elevatiom Among conservative strategy patients for whom predischarge resting radionuclide ventriculography data were also available, there was a difference in mean resting left ventricular ejection fraction for those without exercise-induced ST-segment changes, and those with ST-segment depression and STsegment elevation (50.8, 53.6 and 42.5%, respectively; p
THE AMERICAN
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71
vation and depression or no change remained statistically significant (p
gy: The impact of coronary angiographic findings and revascularization on exercise-induced ST-segment depression was examined in the 1,168 patients assigned to the invasive strategy. The percentages of patients with 2- and 3-vessel coronary disease were greater in those with than without exercise-induced ST-segment depression (43.0 vs 26.6%; p
ditirge
exercise
test
to
select patients for cardiac c&hete&ation: Hospital discharge exercise test outcomes among conservative strategy patients (excluding those randomized in TIMI II-A whose protocol cardiac catheterization was required)3 who had not undergone cardiac catheterization before the test were classified locally as positive for 160, negative for 725 and inconclusive for 71. Of these
JANUARY
15.1993
patients, 78 (48.8%) with a positive test, 176 (24.3%) with a negative test and 13 (18.3%) with an inconclusive test underwent cardiac catheterization before the 6week follow- up visit. Ventlicular anhythmias Few patients were observed with isolated premature ventricular beats or more complex ventricular ectopy during exercise. The available evidence did not suggest that these findings were associated with increased l-year mortality risk. DISCUSSION For the purpose of this analysis, an adverse outcome at 14 days was defined by the combined end point of death, presence of exercise-induced ST-segment depression, or inability to perform the exercise test. The percentages of patients with any of these outcomes were similar in the invasive and conservative strategies, although the relative proportions of patients with different adverse outcomes varied; slightly less invasive than conservative strategy patients had ST-segment depression with exercise, and slightly more died or did not exercise. This combined end point for comparison of the 2 treatment strategies was chosen to avoid the biases in comparing strategies based only on the select group of patients who survived 14 days and were able to perform the exercise test. The labeling of inability to perform the exercise test by 14 days as a poor outcome is supported by the large proportion of patients who did not exercise and had cardiovascular events by 14 days, and by the increased l-year mortality and morbidity in this group compared with those who were able to perform the exercise test. Prev&nceufexercise~abnor maliiies in TIMI II: In the prethrombolytic
era, approximately 30% of patients convalescing from an acute myocardial infarction and undergoing predischarge exercise tests developed ischemic ST-segment depression, and 20% developed angina. 11-13In TIMI II patients who underwent exercise testing (all of whom had received tbrombolytic therapy), the frequency of exercise-induced ST-segment depression was only 10.9% in the invasive strategy and 14.8% in the conservative one. The frequency of exercise-induced ST-segment depression 20.1 mV among patients in the conservative strategy was 20.4% for nonanterior infarcts and 9.9% for anterior ones. Exercise-induced chest pain occurred in only 4.3 and 5.7% of patients in the invasive and conservative strategies, respectively. There are several reasons why the occurrence of markers of exercise-induced is-chemia may have been less frequent in the TIMI II patients. The TIMI II protocol required that patients assigned to the invasive strategy undergo cardiac catheterization at 18 to 48 hours after entry, with revascularization if feasible. Patients in the conservative strategy with spontaneous ischemia before hospital discharge were to undergo coronary angiography and revascularization when the anatomy was suitable. Coronary revascularization procedures were performed before the predischarge exercise test in 67.2% of patients assigned to the invasive strategy and in 9.3% assigned to the conservative strategy, reducing the potential to induce ischemia during exercise. All patients in TIMI II received early
thrombolytic therapy, which is associated with a greater frequency of early opening of infarct-related vessels than in those who do not receive a thrombolytic drug, and with a reduction in myocardial infarct size. The frequency of 3-vessel coronary artery disease in TIMI II patients assigned to the invasive strategy was 5.3%, which is less than that of historical control subjects who underwent predischarge exercise testing before the widespread use of thrombolytic agents (prevalence of 3-vesse1 coronary artery disease in earlier studies was 22, 31 and 45%, respectively): 1@32 Exercise-induced myocardial ischemic responses are more frequent in patients with 3-vessel than with l- or 2-vessel coronary artery disease. The predischarge exercise test in TIMI II was performed in the supine position for standardized acquisition of gated blood pool studies. Shaw et al9 reported a greater peak oxygen consumption and a slightly greater frequency of exercise-induced myocardial ischemic responses in 30 postinfarct patients who exercised using a predischarge, upright, low-level, treadmill protocol than in those using a similar supine bicycle ergometry protocol. Thus, several factors may account for the decreased frequency of exercise-induced myocardial ischemic variables in the TIM1 II trial compared with in earlier published series. Prognosic One-year mortality among patients who performed the exercise test within 14 days of study entry was low among patients assigned to either the invasive (1.4%) or conservative (2.3%) strategies. The relatively low mortality rates in this study compared with the TIMI II l-year rates reported by Williams et al33 occur because the latter investigators included patients who died before the exercise test was performed, as well as those who were unable to perform the exercise test shown to have a higher mortality in this series, as well as in other reports.34 The relatively low incidence of fatal events limited the statistical power to detect differences in prognosis associated with exercise test outcomes among patients who performed the test. The conservative treatment strategy recommended that patients with spontaneous or important exercise-induced ST-segment depression undergo coronary angiography and revascularization when possible. Spontaneous rather than exercise-induced angina during the initial hospitalization was a more frequent indication for coronary angiography.35 In patients with positive exercise tests, approximately twice as many were likely to undergo coronary revascularization after the exercise test as were those whose tests were considered negative by the Clinical Center. Targeting conservative strategy patients with evidence of important exercise-induced myocardial ischemia for coronary revascularization (PTCA or coronary artery bypass grafting) probably altered the natural history of these high-risk patients, resulting in a very low l-year mortality comparable to that of patients without exercise-induced angina or ST-segment depression. Among patients assigned to the invasive strategy, the presence of exercise-induced ST-segment depression was associated with a trend toward an increased l-year mortality compared with that of those without this iinding (relative risk 2.8; p = 0.06). Approximately half of TIMI II EXERCISE
RESULTS
137
the patients in the invasive strategy with ST-segment depression had undergone FTCA by the time the exercise test was performed, and only 5 had had a second procedure (FTCA or coronary artery bypass grafting) by the 6-week exercise test. After the coronary anatomy was known, and FTCA was performed, if technically feasible (or coronary bypass grafting, if the patient was not a suitable FTCA candidate), predischarge, exerciseinduced ST-segment depression in patients randomly assigned to the invasive strategy was less likely to influence physicians to recommend additional attempts at coronary revascularization than in those randomly assigned to the conservative strategy. Exe&&nduced STelevation: Exerciseinduced ST-segment elevation was associated with a greater mortality within 1 year, which was similar to previous reports.32T36 Although the difference was not statistically significant, the relatively short l-year followup and the small number of deaths observed reduced the power of this comparison. Left ventricular function was worse in patients with than without exercise-induced ST elevation. Several studies of acute and chronic ischemic heart disease have demonstrated the relation between increased long-term mortality and decreased left ventricular function.37*38 REFERENCES 1. TlMI Research Group. Immediate versus delayed catheterization and angioplasty following thmmbolytic therapy for acute myocardial infarction (TIMI IIA results). JAMA 1988;260:284%2858. 2. TIMJ Study Group. Comparison of invasive and conservative strategies after treatment with i”tmve”ous tissue plasmi”oge” activator in acute myocaldial infalction: results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial. N Engl J Med 1989;320:618627. 3. Rogers WJ, Bairn DS, Gore JM, Brown BG, Roberts R, Williams DO, Cbesebm JH, Babb JD, Sheehan FH, Wackers FJT, i&et BL, Robertson TL, Passamani ER, Ross R, Knaaerud GL, Braunwald E. Canparison of immediate invasive, delayed invasive, and conservative strategies after tissue-type plastiogen activator. Results of the Thmmbolysis in Myocardisl Infarction (TIMI) Phase II-A Trial. Circulation 1990:81:1457-1476. 4. Campbell S, A’Hem R, Quigley P, Vincent R, Jewitt D, Chan&rlain D. Identiiication of patients at low risk of dying after acute myoczdial infarction, by sbnpie clinical and submaximal exercise test criteria. Ew Heart J 1988;9:938-947. S. Fioretti P, Bmwer RW, Sin100n.s ML, Ten Katen H, Beelen A, Bsanhnan T, Lubsen J, Hugenholtz PG. Relative value of clinical variables, bicycle ergomeby, rest dionuclide ventriculography and 24 hour ambulatory electmcsrdiographic monitoring at discharge to predict 1 year survival after myocardisl infarction. J Am Co11 Cardiol 1986840-49. 8. Tubau JF, Chaibnan BR, Boumssa MG, Waters DD. Detection of multivessel coronary disease after myoardial infarction using exercise stress testing and multiple ECG lead systems. Circulation 1980;61:4&52. 7. De Feyter PJ, Van J?.enige MJ, Dighton DH, Viiser FC, De Jong J, Roes JP. Pmgnostic value of exercise testing, cornnary sngiography and left venaiculogmphy 6-8 weeks after myocardial infarction. Circulation 1982;66527-536. 8. Weld FM, Chu KL, Bigger JT Jr, Roh&zky LM. Risk stratification with lowlevel exercise testing 2 weeks after acute myocatdial infarction. Circulation 1981;64:30&314. B. Shaw LJ, Younis LT. Stocke KS, Sharma AK, Chainnan BR. Effects of pasturc on metabolic and henmdyntic predischarge exercise response after acute myocsrdisl infdon. Am J Cardiol 1990;66:134-139. 10. Kmne RJ, Giiespie JA, Weld FM, Miller JP, Moss AJ, and the Multicenter Postinfarction Research Group. Low-level exercise testing after myccardial infarction: usefulness in enhancing clinical risk shatification. Circulorion 1985;71:80-89. 11. Waters DD, Themux P, Halphen C, MizgaIa HF. Clinical predictors of angina following myocardial infarction. Am J Med 1979:66:991-996. 12. Williams WL, Nair RC, Higginson LAJ, Baird MG, Alla” K, Beanlands DS. comparison of clinical and treadmill variables for the prediction of outcome after myocsrdial infarction. J Am CON Cardiol 19W4477-486. 13. Theroux P, Waters DD, Halphen C, Debaisieux JC, h&gala HF. Prognostic value of exercise testing soon after my&al infarction. N Engl J Med 1979; 301:341-345.
I.38
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71
14. Peart I, Seth L, Albers C, Odemuyiwa 0, Hall RJC. Post-infarction exercise testing in patients under 5.5 years. Relation between ischemic abnormalities and the extent of coronary artery disease. Br Hear? J 1986;55:67-74. lS. Schwartz KM, Turner JD, Shettield LT, Roitman DI, Kansal S, Papapietm SE, Mantle JA, Rackley CE, Russell RO, Rogers WJ. Limited exercise testing soon after myocardial infarction. Correlation with early cornnary and left ventricular sngiography. Ann Intern Med 1981;94:727-734. 16. DeBusk RF, Kmemer HC, Nash E, Berger WE, Lew H. Stepwise risk stratification soon after acute myocardial infarction. Am J Cardiol 1983;52:1161-1166. 17. Fioretti P, Brewer RW, Sirnoons ML, Bos RJ, Baardn~a” T, Beelen A, Hugenholtz PG. Prediction of mortality during the fmt year after acute myocardial infarction from clinical variables and stress test at hospital discharge. Am J Cardiol 1985;55:1313-1318. I.& Chaitman BR, Waters DD, Corbara F, Boumsss MG. prediction of multivesse1 disease after inferior myocardial infarction. Circulation 1978;57: 1085-1090. 1s. Kulick DL, Rahin~toola SH. Risk stratification in survivors of acute myocardial infdon: routine cardiac catheterization and sngiogmphy is a reasonable approach in most patients. Am Hen?? J 1991;121:641-656. 20. Grines CL, DeMaria AN. Optimal utiIization of thmmbolytic therapy for acute myocardiaJ infarction: concepts and controversies. J Am CON Cardiol 19w; 16~223-231. 21. Gruppo Italians per lo Studio della Seeptochinasi nell’Infart0 Miocardico (GISSI). Effectiveness of intravenous thmn&olytic treahnent in acute myocardisl infarction. Lancer 1986;1:34%360. 22. Zmt BJ, Wackers FJ, Tenin ML, Ross R, Weiss M, Slater J, Madison J, Bourge RC, Passamani E, Knatterud G, Braunwald E. Assessment of global and regional left venaicular performance at rest and during exercise af?er thmmbolytic therapy for myocsrdial infarction: results of the ‘Ihrombolysis in Myocardial Marction (TIM) II Study. Am J Can&l 1992;69:1-9. 28. Caralis IX?, Wiens G, Shaw L, Younis LT. Haueisen ME, Wiens RD. Chaitman BR. A” off-line digital system for reproducible interpretation of the exercise ECG. J Electrocardiol 1990;23z285-291. 24. Camlis DG, Shaw L, Bilgere B, Younis L, Stccke K, Wiens R, Chaitman BR. Application of computerized exercise electmcardiogrsm digitization interpretation in large clinical trials. J Electrocardiol 1992;25:101-110. 25. Kaplan EL, Meier P. Nonparametric observation from incomplete observations. Journal of the American Statisdcal Association 1958;53:457-481. 26. Prentice RL. Linear rank tests with right censored data. Eiometrika 1978;65:167-179. 27. Cox DR. Regression models and life tables (with discussion). Journal of the Royal Statistical Society B 1972:34:187-220. 28. SAS Institute, Inc. SAS User’s Guide, Version 5 Ed Gary, North Carolina: SAS Institute, 1985. 29. Dixon WJ, ed. BMDP Statistical Software Manual. L.os Angeles: BMDP Statistical Software, 1988. 30. Miller RR, DeMaria AN, Vismsra LA, Sale1 AF, Maxwell KS, Amsterdam EA, Mason DT. Chmnic stable inferior myoc&ial infarction: unsuspected harbinger of high-risk proximal left coronary arterial obstruction amenable to surgical revascularization. Am J Cardioi 1977;39:954-960. 31. Gibson RS, Watson DD, Craddock GB, Crampton RS, Kaiser DL, Denny MJ, Belier GA. Prediction of cardiac events after uncmnplicated myccardial infarction: a prospective study comparing p&&charge exercise thalIiun~-201 scintigraphy and coronary angiogmphy. Circulation 1983:68:321-336. 32. Paine TD, Dye LE. R&mm DI, Sheffield LT, Rackley CE, Russell RO, Rogers WJ. Relation of graded exercise test findings after myocardial infarction to extent of coronary artery disease and left veneicular dysfunction. Am J Cardiol 1978;42:716-723. 33. Williams DO, Bmunwald E, Knatterud G, Babb J, Bresnahan J, Greenberg M, Raizner A, Wasserman A, Robertson T, Ross R, and TIMI Investigators. Oneyear results of the Thmmbolysis in Myocardial Infarction Investigation (TIMI) Phase II Trial. Circulation 1992:85:533-542. 34. Fmelicher VF, Perdue S, Pewen W, Risch M. Applications of meta-analysis using an electronic spread sheet to exercise testing in patients sfter myocardial infarction. Am J Med 1987;83:104.5. 3s. Rogers WJ, Babb JD, Bairn DS, Chesebm JH, Gore JM, Roberts R, Wiiams DO, Frederick M, Passsmani ER, Braunwald E. Selective versus mutine predischarge coronary arteriography atier therapy with recombinant tissue-type plasminogen activator, heparin and aspiring for acute myocardial infarction. J Am Co11 Cardiol 1991;17:1007-1016. 36. Bruce RA, Fisher LD, Pettinger M, Weiner DA, Chaitman BR. ST segment elevation with exercise: a marker for poor ventricular function and poor prognosis: Coronary Artery Surgery Study (CASS) confirmation of Seattle Heart Watch results. Circulation 1988:77:897-!%5. 37. Mock MB, Ringsvist I, Fisher LD, Davis KB, Chaibnan BR, Kouchoukos NT, Kaiser GC, Alderman E, Ryan TJ, Russell RO, Mullin S, Fray D, Killip T, and Participants in the Coronary Artery Surgery Study. Survival of medically breated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation 1982;66:562-568. 38. Ringqvist I, Fisher LD, Mock MB, Davis KB, Wedel H, Chaibnan BR, Pasmani E, Russell RO, Alderma” EL, Kouchoukas NT, Kaiser GC, Ryan TJ, Fray D. Prognostic value of angiogmphic indices of coronary artery disease fmm the Coroniuy Artery Surgery Study (CASS). J Clin Invesr 1983;71:18541866.
JANUARY 15, 1993
CORONARY
ARTERY DISEASE
I American ( 1 Journal ~ of’ iCardiology
JANUARY 15, 1993, VOL. 71, NO. 2
Impact of Treatment Strategy on Predischarge Exercise Test in the Thrombolysis in Myocardial Infarction (TIMI) II Trial Bernard R. Chaitman, MD, Robert P. McMahon, PhD, Michael Terrin, MD, Liwa T. Younis, MD, PhD, Leslee J. Shaw, MA, Donald A. Weiner, MD, Margaret M. Frederick, PhD, Genell L. Knatterud, PhD, George Sopko, MD, and Eugene Braunwald, MD, for the TIMI Investigators* ergommy was used ischemiiin postinfarction patients who received thronubdytic therapy and were randomized to m invasive VW ws consewative stmtegy in the Tlwombolysis in Myocddial InWction (TM) II trial. The frequency of ischemii mspomesinbothstrategieqmdthe lyearpm@mstii importance ofthedii exercise test outwere examined. At 14 day~thepematageofpatiatswithany adverse outcome (including death, presence of exemise-induced ST-segmed depmssm, or inability to perfom the exercise test) was 33.7% of1,68lrmdomlyassi@mdtothe imvasivestrat-
(relativeriskcompamdwiththo&withoutSTsegmentdepmdonorchestpain0.6; SS%con6 dence interval O.lto 2.9). Among pathts mb domlyassi@mdtotheinvasivestrategy,exe~ cissinducedSTaegmentdepressionorchestpain wasassociatedwithalyearmortaliiof2.5%(4 oflSl)(mktive riskcompamd withthoeewitb
egyumpamdwith3A6%of1,6!3srandomly asmigmdtothe conservative stmtegy (p = 0.57). Ihelyearmortaliiwasgreaterinpatiiwho didnotperfommthepredischargeexercisete8t (7.7K)than in those who dii (l.S%) (p
l-yearmortaliiforthasewith
Prediw
supine
bicycle
toassesspedsbmtmyocmlial
thefonmerwereolder,anda@eaterproportiom werewomen,hedamorefrequenthista#yof myocdiil infarction, and more extemsive eoro nalyarterydisease(p~.01foreachcompat+ son). The l-year mortality in patients with exer ciiseinduced STeegmemt depression or chest pain wasomlyl.4%(3of222)amongthoserandomly conservative strategy where a!egnsdtothe coeonay B amd revascuMzatiom wem recemmemdedifthetestfWsultwasabnonmel
From the Maryland Medical Research Institute, Baltimore, Maryland. Dr. Chaitman’s current address is: St. Louis University Medical Center, 3635 Vista Avenue at Grand Boulevard, P.O. Box 15250, St. Louis, Missouri 63 110-0250. This study was supported by research contracts and grants from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received May 7, 1992; revised manuscript received August 28, 1992, and accepted August 3 1. Address for reprints: TIM1 Coordinating Center, Maryland Medical Research Institute, Inc., 600 Wyndhurst Avenue, Baltimore, Maryland 21210. *Investigators England Journal
and participating centers are published (1989:320;618427).
of Medicine
in the New
outS7-segmeMbpre&omarchestpainP.i; 99% confidence interval 0.5 to 94). Thug in pOStillMCtpZitidStreaedWithtlwombdytiC
~andacomsendvestrategy,themendaWMofpeHomGngcardicathetenurkon
.
.
i3lldcorOnay~VaSCU-whenth8plWdi~
chmge
exercise
test is abnonmelresultsinalow
aq@aorST~~,whichiscemtparaMetothatforpatiiwhodonothave these findim (Am J Cardii
exercirccinduced
lSS3;71:13l-138)
he Thrombolysis in Myocardial Infarction (TIMI) II trial assessed the role of cardiac catheterization 18 to 48 hours after study entry, with percutaneous transluminal coronary angioplasty (FTCA) if appropriate, in patients with acute myocardial infarction treated with recombinant tissue-type plasminogen activator. The principal goal of TIMI II was to determine if this invasive treatment strategy would alter mortality and reinfarction as compared with a conservative strategy. There were no significant differences in the occurrence of death or reinfarction between treatment strategies at 6 weeks or 1 year after enrollment.1-3 F’redischarge submaximal exercise testing is frequently performed after an acute myocardial infarction to determine prognosis, functional capacity and propensity to develop cardiac arrhythmias, and to provide a baseline for exercise prescription in the convalescent phase.“18 Evaluation of postinfarction exercise testing as a procedure for risk stratitication should consider the impact of the referral for coronary angiography in patients with an abnormal test, and subsequent coronary
T
TIMI II EXERCISE RESULTS
131
revascularization. l9 In some patients, the revascularization procedure may influence the natural history of the disease and alter the prognosis associated with abnormalities observed during exercise testing. A second consideration is the use of thrombolytic therapy, a treatment known to decrease mortality, now received by 20 to 40% of patients who present to the hospital with suspected infarction.20~21 There is little information regarding the prognostic role of predischarge exercise testing in patients with myocardial infarction treated with a thrombolytic agent. In this report, we present the frequency of electrocardiographic evidence of exercise-induced ischemia at hospital discharge, document the use of the exercise test to select patients enrolled in the conservative strategy for cardiac catheterization, and compare the prognosis of patients with and without selected exercise test abnormalities in the invasive and conservative strategies. The predischarge exercise test included the use of radionuclide ventriculography, the results of which were reported previously.22
infarction-related artery when the coronary anatomy was suitable 18 to 48 hours after treatment, and 1,658 were randomly assigned to a conservative strategy in which they were evaluated for revascularization if they had spontaneous ischemia after infarction during the hospital phase, or important exercise-induced myocardial ischemia during an exercise test performed before hospital discharge. Of 3,339 patients in the trial, 2,502 (75%) performed exercise testing within 2 weeks of the index event (Figure 1). Exercise electrocardiograms were considered noninterpretable for the development of ischemia in 147 patients, because of electrocardiographic lindings of left ventricular hypertrophy, bundle branch block or excess motion artifact during exercise. This analysis is based on the remaining 2,355 patients with exercise electrocardiograms analyzed at the TIMI Electrocardiographic Core Laboratory (1,168 patients randomly assigned to the invasive strategy and 1,187 to the conservative strategy). Baseline characteristics of the patients who did perform versus those who did not perform the exercise test in the invasive and conservative strategies are listed in Table I. Of 960 patients in whom medication usage at the time of exercise testing was recorded, 66% received B-blocker drugs, 48% calcium antagonist, 26% long-acting nitrates and 5% digoxin within 7 days of testing. Exercise protocol: Exercise was performed in the supine position using a calibrated electronic bicycle ergometer. Heart rate, systemic blood pressure measured by sphygmomanometry, and a 1Zlead electrocardiogram were recorded at baseline, the end of each exercise stage, peak exercise and each minute for 5 minutes into the recovery phase. The initial work load of the 2-stage exercise test was set at 200 kpm and increased to 400 kpm after 3 minutes or to a peak heart rate of 120 beats/min for patients during the limited, predischarge
METHODS Study patients: The details of the TlMI II trial and inclusion/exclusion criteria have been described. *-3 Patients were eligible for enrollment if they had chest discomfort suggestive of acute myocardial ischernia lasting 230 minutes, and ST-segment elevation Lo.1 mV in electrically contiguous leads, were aged <76 and had no contraindications to receiving a thrombolytic drug. Patients were enrolled within 4 hours of the onset of symptoms that precipitated hospital admission. The TIMI II protocol was approved by the human research committee at each participating medical center, and written informed consent was obtained from all patients. In all, 3,339 patients were enrolled; 1,681 were randomly assigned to an invasive strategy of PTCA to the
1 TREATMENT INVASIVE
STRATEGY CONSERVATIVE
1681 NW DEATH $14 DAYS FROM ENTRY STUDY
1658 NW)
76 (4.6)
64 (3.9) t+
FtGlJREl.performanceofexerei!setea
*
1603(95.4)
14 DAY SURVIVORS
ET NOT PERFORMED BY 14 DAYS
1594(96.1)
362 I21.5)
*
333 (20.1)
(ET), ad availability vQta.lherewm :,BBl and 1,658 patii mwlonGxed to invasive swvative stmegbq ~=ele&oawogmm. d
ET PERFORMED BY 14 DAYS NONINTERPRETABLE EXERCISE ECG
4
BY
1241 (73.8) 73 (4.3)
74 (4.5) 1
ET INTERPRETABLE
132
t
1261 (76.0)
1168(69.5)
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71
I+ 1187 (71.6)
JANUARY 15,1993
of
exercise in TIM and respectively.
II
TABLE I Patient Study Entry*
Characteristics
According
to Treatment
Strategy
and Whether
Patients
Performed
invasive
Baseline
Characteristics
Mean age (year) Race (white) Sex (men) Not low risk+ Age 2 70 years Prior myocardial infarction Anterior myocardial Infarction Rales z l/3 of lung fields Hypotension and sinus tachycardia Atrial fibrillation or flutter Pulmonary edema Cardiogenic shock History Angina Congestive heart failure Hypertension Diabetes Current smoker Ever smoked Time from onset to study entry 52 hours Cardiovascular events I 14 days Myocardial infarctlon Recurrent painful ischemic events in hospital New congestive heart failure Any of above CABG
Exercise Test (n = 1,241); n (%) 55.6 1,088 (87.7) 1,059 (85.3) 781 (62.9) i ia (9.5) 154 (12.4) 604 (48.7) 35 (2.8) 63 (5.1) 23 (1.8) 7 (0.6) 12 (1) 652 25 453 130 632 961 323
(52.5) (2) (36.5) (10.5) (50.9) (77.4) (26)
p Valuet
59.5 (88.4) (74.6) (71.3) (18.8) (18.8) (53) (5.2) (5)
0.001 0.71 0.001 0.003 0.001 0.002 0.14 0.02 0.94
8 (2.2) 7 (1.9) 6 (1.7)
0.66 0.01 0.27
221 22 165 61 159 270 101
Test I 14 Days After
Conservative
No Exercise Test (n = 362); n (%I
320 270 258 68 68 192 19 la
an Exercise
(61.2) (6.1) (45.6) (16.8) (43.9) (74.6) (27.9)
0.004 0.001 0.002 0.001 0.02 0.26 0.48
46 (3.7) 254 (20.5)
44 (12.2) 133 (36.7)
0.001 0.001
161 (13) 371 (29.9) 38 (3.1)
102 190 126
0.001 0.001 0.001
(28.2) (52.5) (34.8)
Exercise Test (n = 1,261); n (%I
No Exercise Test (n = 333); n (%)
55.8 1,127 (89.4) i ,066 (84.5) 826 (65.5) 101 (8) 155 (12.3) 662 (52.5) 43 (3.4) 64 (5.1)
288 251 236 59 59 175 16 19
25 (2) a (0.6) 10 (0.8) 651 24 461 158 657 1,000 317
*Analysis is restr&d to 14.day survivors. tp value for difference between patients who did and did not exercise by 14 days within each treatment strategy. $Patient 1s not low risk If any of following are present on admiwon: age 2 70 years, prior myocard!al infarctlon, anterior and SHW tachycardia. atrial fibrillation orflutter, pulmonary edema, orcardiogeruc shock. CABG = coronary artery bypass grafting.
59.1 (86.5) (75.4) (70.9) (17.7) (17.7) (52.6) (4.8) (5.7)
10 (3) 6 (1.8) 4 (1.2)
(51.6) (1.9) (36.6) (12.5) (52.1) (79.3) (25.1)
0.001 0.14 0.001 0.06 0.001 0.01 0.99 0.23 0.64 0.26 0.04 0.48
(56.8) (3.6) (39.6) (15.3) (42.6) (74.2) (28.2)
0.10 0.06 0.30 0.18 0.002 0.04 0.25
40 (3.2) 304 (24.1)
33 (9.9) 155 (46.5)
0.001 0.001
155 (12.3) 414 (32.8) 36 (2.9)
90 (27.1) 197 (59.2) 69 (20.7)
0.001 0.001 0.001
myocardial
189 12 132 51 142 247 94
p Valuet
Infarction.
rales 2 113 of lung fields, hypotension
exercise test. The maximal duration of the test was 6 and ST-80 depression 20.15 mV, and ST-segment slope minutes. The limited, predischarge exercise test was dis- >l mV/s. ST-segment elevation in Q-wave infarct leads continued for the development of progressive chest pain, was determined to be present when J point and ST-80 excessive dyspnea, dizziness, complex ventricular ar- elevation was 9.1 mV as compared with at baseline rhythmias, exertional hypotension, severe ischemic ST- and was not considered an ischemic response. segment depression, excessive fatigue, or achievement of At the time of the hospital discharge study, results target heart rate or work load. were interpreted locally by clinical center staff to deterAt the Electrocardiographic Core Laboratory, each mine if evidence of exercise-induced myocardial ische12-lead electrocardiogram obtained before exercise, at mia was present. For conservative strategy patients, the peak exercise and during recovery was reviewed for ST- TIMI II protocol indicated coronary angiography (to be followed by revascultization if necessary) when spontasegment shifts 20.05 mV. When ST-segment deviation was 20.05 mV, the electrocardiographic leads with the neous or exercise-induced rnyocardial ischemia was most marked ST-segment depression and elevation were present. Otherwise, cardiac catheterization was discourdigitized, using a SummaGraphics microgrid II digitizaged. Indicators of myocardial ischemia considered in er interfaced to an IBM computer. Three consecutive the evaluation for coronary angiography included angicomplexes were digitized at rest and peak exercise, and na pectoris, ST-segment depression 22 mm, a 20 mm in the recovery phas&f ST-segment deviation exceeded Hg reduction in systolic blood pressure, a 5-unit reducthat observed at peak exercise or immediately after ex- tion in left ventricular ejection fraction, and complex ercise. Custom software was used to analyze the rest and ventricular arrhythmias. The test outcome was considmaximal ST-segment changes observed during peak ered inconclusive when the aforementioned indicators exercise or in recovery. 23,24The exercise electrocardiowere absent, and if patients were unable to exercise to graphic response was considered abnormal when either a heart rate of 120 beats/minute or could not perform at of the following 2 criteria were observed in any lead as a work load of 400 kpm. End points: The TIMJ JT protocol required that all compared with at baseline: J point and ST-80 depression 20.1 mV, ST-segment slope
RESULTS
133
deaths and nonfatal events that occurred during followup were reported to the Coordinating Center. Information was collected from all surviving patients for cardiac events including reinfarction, congestive heart failure, presence of angina pectoris and whether a revascularization procedure had been performed. As of January 1991, l-year follow-up for vital status was 99% complete for both treatment strategies. Reinfarction was classified centrally without knowledge of treatment assignment and accepted as documented according to previously published criteria.2 Statistical analysis: To account for all patients who entered the study, a composite 14-day adverse outcome was delined by death within 14 days of study entry, survival to 14 days without a hospital discharge exercise test, or a hospital discharge exercise electrocardiogram with ischemic ST depression present. Analysis of exercise test Iindings as predictors of events (death, death or myocardiaI infarction by 1 year after study entry) was restricted to patients alive at 14 days who performed the exercise test and whose exercise electrocardiogram was analyzed at the Electrocardiographic Core Laboratory. The proportions of patients experiencing events were estimated by the Kaplan-Meier method25; comparisons of survival without events were performed by the log-rank test.26 The relative risk reported for each exercise Iinding estimates the ratio of the risk of events for patients with the linding present to that for those without the finding. The Cox proportional hazards mode127 was used to estimate relative risks and confidence intervals. For comparison of baseline variables, &i-square tests were used to compare categoric variables and t tests for continuous variables. To account for the multiple statistical hypotheses tested, p 4.01 was considered to show evidence of a relation, and p
$ d
75
RESULTS At 14 days after entry in the TIMI II trial, the proportion of patients who died, had not performed the exercise test or had exercise-induced ST-segment depression were similar in the invasive and conservative strategies (Figure 2; p = 0.57). The proportion of patients who died, had a new myocardial infarction, had not performed the exercise test or had exercise-induced STsegment depression were similar in the invasive and conservative strategies (36.0 vs 36.7%; p = 0.69). Patients who did not perform a predischarge exercise test were older, included a larger proportion of women, and had previous myocardial infarctions, and more 2and 3-vessel coronary artery disease (Tables I and II) compared with those who did perform an exercise test. Of 333 conservative and 362 invasive strategy surviving patients who did not perform an exercise test by 14 days after study entry, 59.2% with the conservative strategy and 52.5% with the invasive strategy had experienced 21 event, defined as reinfarction, recurrent painful ischemic events or newly occurring congestive heart failure, by 14 days. These events occurred significantly less often in patients who performed exercise tests (Table I). The mortality between 14 days and 1 year after study entry was significantly less in patients able to perform the low-level exercise test than in those that could not (1.4% [17 of 1,241] vs 6.3% [23 of 3641 for the invasive strategy [p
NO STD STD
f ECO s
50
NONINTERPRETABLE
NO ET BY 14 DAYS
# 8
YI s 14 DAYS DIED
25
s 14 DAYS
FIGURE 2. MorQli exerciseem graphicoNtcommatl4 dayBl6ccoMngtesericpled Wmtment
p = 0.57
I.34
CONSERVATIVE (N=lsSe)
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71
JANUARY 15,1993
s&ate@ &ffweme
in
TIMI in
II.
popoltionabletOeX& WimoNt ST depmesh p-0.02fclranydifkmnm inoutcommMl=mye cardd infaetion; &bf&atiom
INVASIVE (N11681)
for
md
a~
(STD);
other in
R#ue
1.
TABLE II Findings of Protocol According to Whether Exercise
Protocol Catheterization
Cardiac Catheterization Test Was Performed
Among Invasive Strategy Patients < 14 Days After Study Entry
Finding
Protocol cardiac catheterization
performed
Yes No 0 1
No. of vessels with % stenosis 2 60%
TIMI grade of Ml-related
coronary arteryt
1 2 3
Collaterals to Ml-related
coronary artery present
(
1,155 (93.1)
313 (86.5)
0.001
677 258 59 36 2
(60.5) (23.1) (5.3) (0.2)
518 (44.8) 0 (0) 495 (42.9) 140 (12.1) 0 123 (10.7) 45 (3.9) 217 (18.8) 767 (66.6) 3 128 (11.4) 991 (88.6) 35
Missing* Yes No Missing*
ized to the invasive and conservative strategies, respectively. Of 1,168 patients randomized to the invasive strategy with an interpretable exercise electrocardiogram (Figure l), 108 had exercise-induced ST-segment depression 22 but ~2 mm, and 19 had 12 mm. Of 1,187 patients randomized to the conservative strategy (Figure l), 146 had ST-segment depression 21 but c2 mm, and 30 had 22 mm. One-yciau m after exerciee teatie No statistically significant differences according to the study
p Value
125 (11.2)
Missing* None Right Left main Left anterior descending Left circumflex Missing* 0
coronary artery
No Exercise Test (n = 362); n (%)
86 (6.9)
2 3
Ml-related
Exercise Test (n = 1,241); n (%)
49 30 132 95 43 13 6
(13.5) (10) (44) (31.7) (14.3)
0.001
(1.9) 131 (41.8)
0.39
2 (0)
128 (40.9) 46 (14.7)
0 38 9 65 201 0 34 266 13
(12.1) (2.9) (20.8) (64.2)
0.60
(11.3) (88.7)
0.96
criteria were found in either treatment strategy for lyear occurrence of death, or of death or myocardial infarction according to the presence of specific exercise test outcomes (ST-segment depression or elevation, chest pain, and peak heart rate and systolic blood pressure). In the conservative strategy, l-year mortality was 0.6 vs 2.4% in patients with versus without exercise-induced ST-segment depression (relative risk 0.2; p = 0.13). When exercise-induced ST-segment depression or pain was examined, the l-year mortality was 1.4 vs 2.3% for
lo 1 --.
No Test by 14 Days
----.--
Exercised
to < Stage 2
-
Exercised to Stage 2 p < 0.001
FlQURE3.MortdiQofpetkntsin conMMtive~whownot pWfOtWlexwdS9t8StcompIIcBdWittl thEtOfUlOSOWbWM8(I#etO
CtOll@W~llWbOUl~OflOW levd, ptwahq+, exercise test (p
2
7
12
17
Weeks
22
27
32
from Study
37
42
47
52
Entry
TIMI II EXERCISE
RESULTS
135
TABLE III Finding of Protocol Cardiac Catheterization Among Invasive Strategy Patients Surviving > 14 Days with Exercise Electrocardiogram < 14 Days After Entry Read by Electrocardiography Core Laboratory, According to Presence of Exercise ST-Depression
Protocol
Catheterization
Protocol cardiac catheterization performed No. of vessels with % stenosis
Ml-related
coronary
Total (n = 1,168)
Finding
z 60%
artery
Mean % stenosis of MI coronary artery TIMI flow grade of Ml coronary arteryt
Yes No 0 1 2 3 Missing* None Right Left anterior descending Left circumflex Missing
1,091 77 115 642 243 57 34 2 490 463
0
; Collaterals present
to Ml coronary
Protocol PTCA performed attempted
3 Missing + 0 Missing + 0
artery
or
ST Depression (n = 127) n (%)
No ST Depression (n = 1,041) n (%)
118
973 68 110 582 211 40 30 2 424 437
(93.5) (6.5) (11.7) (61.7) (22.4) (4.2)
(11.3)
9 5 60 32 17 4 0 66 26
(92.9) (7.1) (4.4) (52.6) (28.1) (14.9) (0) (55.9) (22)
(0.2) (43.6) (44.9)
136
26 (22)
110
0 75.0 117 24 99 794 57 121 936 34 719 449
0 77.9 17 (15) 2 (1.8) 16 (14.2) 78 (69) 5 15 (13.2) 99 (86.8) 4 66 (52) 61 (48)
0 74.6 100 (10.9) 22 (2.4) 83 (9) 716 (77.7) 52 106 (11.2) 837 (88.8) 30 653 (62.7) 388 (37.3)
p Value 0.80 0.001
0.001
0.09 0.14
0.54
0.02
*Number of patients who underwent protocol cardiac catheterization for whom data Item is missing. Percentages based on patients with information for this data item. tRefers toTIM grade after PTCAfor patients who received protocol PTCA. MI = myocardial infarctjon; PTCA = percutaneous translummal coronary angioplasty.
patients with versus without these findings (relative risk 0.6; p = 0.39). Among the invasive strategy patients, l-year mortality in those with versus without exercise-induced STsegment depression was 3.2 vs 1.2% (relative risk 2.8; p = 0.06). The l- year mortality was 2.5 vs 1.2% (relative risk 2.1; p = 0.18) for patients with versus without exercise-induced ST-segment depression or chest pain. ST-segment elevatiom Among conservative strategy patients for whom predischarge resting radionuclide ventriculography data were also available, there was a difference in mean resting left ventricular ejection fraction for those without exercise-induced ST-segment changes, and those with ST-segment depression and STsegment elevation (50.8, 53.6 and 42.5%, respectively; p
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vation and depression or no change remained statistically significant (p
gy: The impact of coronary angiographic findings and revascularization on exercise-induced ST-segment depression was examined in the 1,168 patients assigned to the invasive strategy. The percentages of patients with 2- and 3-vessel coronary disease were greater in those with than without exercise-induced ST-segment depression (43.0 vs 26.6%; p
ditirge
exercise
test
to
select patients for cardiac c&hete&ation: Hospital discharge exercise test outcomes among conservative strategy patients (excluding those randomized in TIMI II-A whose protocol cardiac catheterization was required)3 who had not undergone cardiac catheterization before the test were classified locally as positive for 160, negative for 725 and inconclusive for 71. Of these
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patients, 78 (48.8%) with a positive test, 176 (24.3%) with a negative test and 13 (18.3%) with an inconclusive test underwent cardiac catheterization before the 6week follow- up visit. Ventlicular anhythmias Few patients were observed with isolated premature ventricular beats or more complex ventricular ectopy during exercise. The available evidence did not suggest that these findings were associated with increased l-year mortality risk. DISCUSSION For the purpose of this analysis, an adverse outcome at 14 days was defined by the combined end point of death, presence of exercise-induced ST-segment depression, or inability to perform the exercise test. The percentages of patients with any of these outcomes were similar in the invasive and conservative strategies, although the relative proportions of patients with different adverse outcomes varied; slightly less invasive than conservative strategy patients had ST-segment depression with exercise, and slightly more died or did not exercise. This combined end point for comparison of the 2 treatment strategies was chosen to avoid the biases in comparing strategies based only on the select group of patients who survived 14 days and were able to perform the exercise test. The labeling of inability to perform the exercise test by 14 days as a poor outcome is supported by the large proportion of patients who did not exercise and had cardiovascular events by 14 days, and by the increased l-year mortality and morbidity in this group compared with those who were able to perform the exercise test. Prev&nceufexercise~abnor maliiies in TIMI II: In the prethrombolytic
era, approximately 30% of patients convalescing from an acute myocardial infarction and undergoing predischarge exercise tests developed ischemic ST-segment depression, and 20% developed angina. 11-13In TIMI II patients who underwent exercise testing (all of whom had received tbrombolytic therapy), the frequency of exercise-induced ST-segment depression was only 10.9% in the invasive strategy and 14.8% in the conservative one. The frequency of exercise-induced ST-segment depression 20.1 mV among patients in the conservative strategy was 20.4% for nonanterior infarcts and 9.9% for anterior ones. Exercise-induced chest pain occurred in only 4.3 and 5.7% of patients in the invasive and conservative strategies, respectively. There are several reasons why the occurrence of markers of exercise-induced is-chemia may have been less frequent in the TIMI II patients. The TIMI II protocol required that patients assigned to the invasive strategy undergo cardiac catheterization at 18 to 48 hours after entry, with revascularization if feasible. Patients in the conservative strategy with spontaneous ischemia before hospital discharge were to undergo coronary angiography and revascularization when the anatomy was suitable. Coronary revascularization procedures were performed before the predischarge exercise test in 67.2% of patients assigned to the invasive strategy and in 9.3% assigned to the conservative strategy, reducing the potential to induce ischemia during exercise. All patients in TIMI II received early
thrombolytic therapy, which is associated with a greater frequency of early opening of infarct-related vessels than in those who do not receive a thrombolytic drug, and with a reduction in myocardial infarct size. The frequency of 3-vessel coronary artery disease in TIMI II patients assigned to the invasive strategy was 5.3%, which is less than that of historical control subjects who underwent predischarge exercise testing before the widespread use of thrombolytic agents (prevalence of 3-vesse1 coronary artery disease in earlier studies was 22, 31 and 45%, respectively): 1@32 Exercise-induced myocardial ischemic responses are more frequent in patients with 3-vessel than with l- or 2-vessel coronary artery disease. The predischarge exercise test in TIMI II was performed in the supine position for standardized acquisition of gated blood pool studies. Shaw et al9 reported a greater peak oxygen consumption and a slightly greater frequency of exercise-induced myocardial ischemic responses in 30 postinfarct patients who exercised using a predischarge, upright, low-level, treadmill protocol than in those using a similar supine bicycle ergometry protocol. Thus, several factors may account for the decreased frequency of exercise-induced myocardial ischemic variables in the TIM1 II trial compared with in earlier published series. Prognosic One-year mortality among patients who performed the exercise test within 14 days of study entry was low among patients assigned to either the invasive (1.4%) or conservative (2.3%) strategies. The relatively low mortality rates in this study compared with the TIMI II l-year rates reported by Williams et al33 occur because the latter investigators included patients who died before the exercise test was performed, as well as those who were unable to perform the exercise test shown to have a higher mortality in this series, as well as in other reports.34 The relatively low incidence of fatal events limited the statistical power to detect differences in prognosis associated with exercise test outcomes among patients who performed the test. The conservative treatment strategy recommended that patients with spontaneous or important exercise-induced ST-segment depression undergo coronary angiography and revascularization when possible. Spontaneous rather than exercise-induced angina during the initial hospitalization was a more frequent indication for coronary angiography.35 In patients with positive exercise tests, approximately twice as many were likely to undergo coronary revascularization after the exercise test as were those whose tests were considered negative by the Clinical Center. Targeting conservative strategy patients with evidence of important exercise-induced myocardial ischemia for coronary revascularization (PTCA or coronary artery bypass grafting) probably altered the natural history of these high-risk patients, resulting in a very low l-year mortality comparable to that of patients without exercise-induced angina or ST-segment depression. Among patients assigned to the invasive strategy, the presence of exercise-induced ST-segment depression was associated with a trend toward an increased l-year mortality compared with that of those without this iinding (relative risk 2.8; p = 0.06). Approximately half of TIMI II EXERCISE
RESULTS
137
the patients in the invasive strategy with ST-segment depression had undergone FTCA by the time the exercise test was performed, and only 5 had had a second procedure (FTCA or coronary artery bypass grafting) by the 6-week exercise test. After the coronary anatomy was known, and FTCA was performed, if technically feasible (or coronary bypass grafting, if the patient was not a suitable FTCA candidate), predischarge, exerciseinduced ST-segment depression in patients randomly assigned to the invasive strategy was less likely to influence physicians to recommend additional attempts at coronary revascularization than in those randomly assigned to the conservative strategy. Exe&&nduced STelevation: Exerciseinduced ST-segment elevation was associated with a greater mortality within 1 year, which was similar to previous reports.32T36 Although the difference was not statistically significant, the relatively short l-year followup and the small number of deaths observed reduced the power of this comparison. Left ventricular function was worse in patients with than without exercise-induced ST elevation. Several studies of acute and chronic ischemic heart disease have demonstrated the relation between increased long-term mortality and decreased left ventricular function.37*38 REFERENCES 1. TlMI Research Group. Immediate versus delayed catheterization and angioplasty following thmmbolytic therapy for acute myocardial infarction (TIMI IIA results). JAMA 1988;260:284%2858. 2. TIMJ Study Group. Comparison of invasive and conservative strategies after treatment with i”tmve”ous tissue plasmi”oge” activator in acute myocaldial infalction: results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial. N Engl J Med 1989;320:618627. 3. Rogers WJ, Bairn DS, Gore JM, Brown BG, Roberts R, Williams DO, Cbesebm JH, Babb JD, Sheehan FH, Wackers FJT, i&et BL, Robertson TL, Passamani ER, Ross R, Knaaerud GL, Braunwald E. Canparison of immediate invasive, delayed invasive, and conservative strategies after tissue-type plastiogen activator. Results of the Thmmbolysis in Myocardisl Infarction (TIMI) Phase II-A Trial. Circulation 1990:81:1457-1476. 4. Campbell S, A’Hem R, Quigley P, Vincent R, Jewitt D, Chan&rlain D. Identiiication of patients at low risk of dying after acute myoczdial infarction, by sbnpie clinical and submaximal exercise test criteria. Ew Heart J 1988;9:938-947. S. Fioretti P, Bmwer RW, Sin100n.s ML, Ten Katen H, Beelen A, Bsanhnan T, Lubsen J, Hugenholtz PG. Relative value of clinical variables, bicycle ergomeby, rest dionuclide ventriculography and 24 hour ambulatory electmcsrdiographic monitoring at discharge to predict 1 year survival after myocardisl infarction. J Am Co11 Cardiol 1986840-49. 8. Tubau JF, Chaibnan BR, Boumssa MG, Waters DD. Detection of multivessel coronary disease after myoardial infarction using exercise stress testing and multiple ECG lead systems. Circulation 1980;61:4&52. 7. De Feyter PJ, Van J?.enige MJ, Dighton DH, Viiser FC, De Jong J, Roes JP. Pmgnostic value of exercise testing, cornnary sngiography and left venaiculogmphy 6-8 weeks after myocardial infarction. Circulation 1982;66527-536. 8. Weld FM, Chu KL, Bigger JT Jr, Roh&zky LM. Risk stratification with lowlevel exercise testing 2 weeks after acute myocatdial infarction. Circulation 1981;64:30&314. B. Shaw LJ, Younis LT. Stocke KS, Sharma AK, Chainnan BR. Effects of pasturc on metabolic and henmdyntic predischarge exercise response after acute myocsrdisl infdon. Am J Cardiol 1990;66:134-139. 10. Kmne RJ, Giiespie JA, Weld FM, Miller JP, Moss AJ, and the Multicenter Postinfarction Research Group. Low-level exercise testing after myccardial infarction: usefulness in enhancing clinical risk shatification. Circulorion 1985;71:80-89. 11. Waters DD, Themux P, Halphen C, MizgaIa HF. Clinical predictors of angina following myocardial infarction. Am J Med 1979:66:991-996. 12. Williams WL, Nair RC, Higginson LAJ, Baird MG, Alla” K, Beanlands DS. comparison of clinical and treadmill variables for the prediction of outcome after myocsrdial infarction. J Am CON Cardiol 19W4477-486. 13. Theroux P, Waters DD, Halphen C, Debaisieux JC, h&gala HF. Prognostic value of exercise testing soon after my&al infarction. N Engl J Med 1979; 301:341-345.
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14. Peart I, Seth L, Albers C, Odemuyiwa 0, Hall RJC. Post-infarction exercise testing in patients under 5.5 years. Relation between ischemic abnormalities and the extent of coronary artery disease. Br Hear? J 1986;55:67-74. lS. Schwartz KM, Turner JD, Shettield LT, Roitman DI, Kansal S, Papapietm SE, Mantle JA, Rackley CE, Russell RO, Rogers WJ. Limited exercise testing soon after myocardial infarction. Correlation with early cornnary and left ventricular sngiography. Ann Intern Med 1981;94:727-734. 16. DeBusk RF, Kmemer HC, Nash E, Berger WE, Lew H. Stepwise risk stratification soon after acute myocardial infarction. Am J Cardiol 1983;52:1161-1166. 17. Fioretti P, Brewer RW, Sirnoons ML, Bos RJ, Baardn~a” T, Beelen A, Hugenholtz PG. Prediction of mortality during the fmt year after acute myocardial infarction from clinical variables and stress test at hospital discharge. Am J Cardiol 1985;55:1313-1318. I.& Chaitman BR, Waters DD, Corbara F, Boumsss MG. prediction of multivesse1 disease after inferior myocardial infarction. Circulation 1978;57: 1085-1090. 1s. Kulick DL, Rahin~toola SH. Risk stratification in survivors of acute myocardial infdon: routine cardiac catheterization and sngiogmphy is a reasonable approach in most patients. Am Hen?? J 1991;121:641-656. 20. Grines CL, DeMaria AN. Optimal utiIization of thmmbolytic therapy for acute myocardiaJ infarction: concepts and controversies. J Am CON Cardiol 19w; 16~223-231. 21. Gruppo Italians per lo Studio della Seeptochinasi nell’Infart0 Miocardico (GISSI). Effectiveness of intravenous thmn&olytic treahnent in acute myocardisl infarction. Lancer 1986;1:34%360. 22. Zmt BJ, Wackers FJ, Tenin ML, Ross R, Weiss M, Slater J, Madison J, Bourge RC, Passamani E, Knatterud G, Braunwald E. 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Journal of the Royal Statistical Society B 1972:34:187-220. 28. SAS Institute, Inc. SAS User’s Guide, Version 5 Ed Gary, North Carolina: SAS Institute, 1985. 29. Dixon WJ, ed. BMDP Statistical Software Manual. L.os Angeles: BMDP Statistical Software, 1988. 30. Miller RR, DeMaria AN, Vismsra LA, Sale1 AF, Maxwell KS, Amsterdam EA, Mason DT. Chmnic stable inferior myoc&ial infarction: unsuspected harbinger of high-risk proximal left coronary arterial obstruction amenable to surgical revascularization. Am J Cardioi 1977;39:954-960. 31. Gibson RS, Watson DD, Craddock GB, Crampton RS, Kaiser DL, Denny MJ, Belier GA. Prediction of cardiac events after uncmnplicated myccardial infarction: a prospective study comparing p&&charge exercise thalIiun~-201 scintigraphy and coronary angiogmphy. Circulation 1983:68:321-336. 32. Paine TD, Dye LE. R&mm DI, Sheffield LT, Rackley CE, Russell RO, Rogers WJ. 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Bruce RA, Fisher LD, Pettinger M, Weiner DA, Chaitman BR. ST segment elevation with exercise: a marker for poor ventricular function and poor prognosis: Coronary Artery Surgery Study (CASS) confirmation of Seattle Heart Watch results. Circulation 1988:77:897-!%5. 37. Mock MB, Ringsvist I, Fisher LD, Davis KB, Chaibnan BR, Kouchoukos NT, Kaiser GC, Alderman E, Ryan TJ, Russell RO, Mullin S, Fray D, Killip T, and Participants in the Coronary Artery Surgery Study. Survival of medically breated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation 1982;66:562-568. 38. Ringqvist I, Fisher LD, Mock MB, Davis KB, Wedel H, Chaibnan BR, Pasmani E, Russell RO, Alderma” EL, Kouchoukas NT, Kaiser GC, Ryan TJ, Fray D. Prognostic value of angiogmphic indices of coronary artery disease fmm the Coroniuy Artery Surgery Study (CASS). J Clin Invesr 1983;71:18541866.
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