- Email: [email protected]
Effects of Thrombolytic Regimen, Early Catheterization, and Predischarge Angiographic Variables on Six-Week Left Ventricular Function
Effects of Thrombolytic Regimen, Early Catheterization, and Predischarge Angiographic Variables on Six-Week Left Ventricular Function Samuel R. Ward, MD, Joseph M. Sutton, MD, Karen S. Pieper, MS, Markus Schwaiger, MD, Robert M. Califf, MD, and Eric J. Topol, MD, for the TAMI Investigators The Thrombolysis and Angioplasty in Acute Myocardial Infarction phase 5 (TAMI-5) trial randomized patients to 1 of 3 thrombolytic regimens (alteplase, urokinase, or both), then further randomized them to acute or deferred catheterization. The group of patients randomized to acute catheterization had improved infarct zone but not global left ventricular function on predischarge left ventriculography. To better explore the late effects of these strategies on global and regional left ventricular function, a subset of patients (n Å 296) were prospectively evaluated at 6 weeks by multiple uptake gated acquisition (MUGA) radionuclide ventriculography scan. Of these patients, 219 had interpretable studies with paired predischarge and late left ventriculographic data for comparison. At 6 weeks, choice of thrombolytic regimen had no impact on either global or infarct-zone left ventricular function. Further, catheterization strategy (acute
vs deferred) did not influence global or infarct-zone function at 6 weeks. In patients randomized to acute catheterization, those undergoing rescue angioplasty had worse infarct-zone wall motion at 6 weeks than patients with a patent infarct vessel not requiring rescue angioplasty (p Å 0.002). The early benefit on regional left ventricular function of triage to acute catheterization after thrombolysis for acute myocardial infarction did not persist at 6 weeks, which is most likely attributable to a high incidence of reocclusion. The worse infarctzone regional wall motion in patients undergoing rescue angioplasty in the acute-catheterization group likely reflects failed reperfusion and illustrates the difficulty in identifying and consequences of early thrombolytic failures. Q1997 by Excerpta Medica, Inc. (Am J Cardiol 1997;79:539–544)
he use of thrombolytic therapy in acute myocardial infarction unequivocally reduces mortality, T regardless of the agent chosen, with empiric post-
triculography at 6 weeks. These data provide a unique window into the effects of early or deferred angiography at follow-up, since no other randomized trial has incorporated a late assessment of global and regional cardiac function in the study design. This allows correlations of treatment strategy and predischarge angiographic and left ventricular function variables with late global and regional left ventricular function.
1–4
thrombolytic coronary intervention failing to convey any survival benefit or improvement in global left ventricular function.5,6 Improvement in global and regional (infarct zone) systolic function has not necessarily translated into improved survival in studies of coronary thrombolysis with or without adjunct angioplasty.7 – 9 The Thrombolysis and Angioplasty in Acute Myocardial Infarction phase 5 (TAMI-5) trial evaluated the effects on various clinical end points of alteplase, urokinase, or combination therapy with either acute (õ90 minutes) catheterization for triage to rescue angioplasty or deferred catheterization. The combination therapy was effective in achieving early and sustained infarct artery patency.10 The cohort assigned to acute catheterization with or without angioplasty had early (5 to 10 day) improved infarctzone wall motion (but not global left ventricular function) compared with the deferred-catheterization group.10 Of the 575 patients randomized, a subset of 296 patients underwent rest and exercise multipleuptake gated acquisition (MUGA) radionuclide venFrom the Cleveland Clinic Foundation, Cleveland, Ohio; and Duke University Medical Center, Durham, North Carolina. Manuscript received June 3, 1996; revised manuscript received and accepted September 30, 1996. Address for reprints: Joseph M. Sutton, MD, Department of Cardiology, F-15, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195.
METHODS The study design and inclusion and exclusion criteria for the main TAMI-5 trial have been described.10 Briefly, 575 patients õ76 years old without cardiogenic shock presenting within 6 hours of acute myocardial infarction (defined by symptoms compatible with acute myocardial infarction and STsegment elevation of 1 mm in 2 contiguous leads) were randomly allocated in a 3 1 2 factorial design to intravenous thrombolysis with either alteplase (100 mg infused over 3 hours), urokinase (1.5 million U bolus and 1.5 million U infused over 90 minutes), or both (urokinase 1.5 million U and alteplase 1 mg/kg infused over 1 hour). Patients were then randomized to acute or deferred (day 5 to 10) catheterization. All patients received 325 mg aspirin orally on entry. Heparin was given as a 5,000-U bolus when thrombolysis began; an infusion of 1,000 U/hour was used to maintain an activated partial thromboplastin time (aPTT) 1.5 to 2 times control for ¢48 hours. In patients undergoing acute cathe-
Q1997 by Excerpta Medica, Inc.
0002-9149/97/$17.00 PII S0002-9149(96)00812-0
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FIGURE 1. Design of the Thrombolysis and Angioplasty in Acute Myocardial Infarction phase 5 (TAMI-5) multiple uptake gated acquisition (MUGA) substudy. PTCA Å percutaneous transluminal coronary angioplasty; t-PA Å tissue plasminogen activator; UK Å urokinase.
TABLE I Baseline Clinical and Catheterization Characteristics in Patients With and Without Multiple-Uptake Gated Acquisition (MUGA) Data Patients Without MUGA Data (n Å 356) Age (yr) Men Risk factors Diabetes mellitus Systemic hypertension Elevated cholesterol Current smoking Prior infarction Prior congestive heart failure Anterior infarction by electrocardiogram Peripheral vascular disease Baseline characteristics Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Rales Not low risk Time to treatment (min) Acute catheterization Rescue angioplasty Deferred catheterization Number of diseased vessels 0 or 1 2 3 Infarct-related artery Left anterior descending Left circumflex Right Left main None or unknown
Patients With MUGA Data (n Å 219)
59 (52, 66) 272 (76%)
56 (49, 65) 168 (77%)
68 150 97 177 51 3 159 18
(19%) (42%) (28%) (50%) (14%) (õ1%) (45%) (5%)
29 102 58 121 23 5 103 12
(13%) (47%) (27%) (55%) (11%) (2%) (47%) (5%)
76 130 80 64 216 174 178 31 178
(64, 87) (112, 147) (70, 90) (18%) (61%) (130, 230) (50%) (17%) (50%)
74 128 80 37 144 180 109 22 110
(64, 86) (116, 143) (70, 90) (17%) (66%) (135, 227) (50%) (20%) (50%)
204 (57%) 91 (26%) 61 (17%)
116 (53%) 64 (29%) 39 (18%)
113 47 176 0 20
81 25 111 1 1
(32%) (13%) (49%) (0%) (6%)
(37%) (11%) (51%) (õ1%) (õ1%)
Values are expressed as number (%) of patients or median (25th, 75th percentiles).
terization, rescue angioplasty was performed in 22 patients for either failed thrombolysis (defined as Thrombolysis in Myocardial Infarction [TIMI] grade 0 to 1 flow) or for clinical evidence of ongoing ischemia. Outcomes were assessed by evaluating global 540
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and regional systolic function and infarct artery patency at the day 5 to 10 catheterization and by global and regional systolic function at 6 weeks by MUGA. Patient population: Of the 575 patients randomized in the TAMI-5 trial, 296 underwent both contrast left ventriculography at day 5 to 10 predischarge and rest and exercise MUGA at 6 weeks. The cohort of 219 (74%) patients with interpretable MUGA images is the subject of this analysis. The overall study design is shown in Figure 1. Predischarge coronary angiography and left ventriculography: Global
and infarct-zone systolic ventricular function were assessed by catheterization on day 5 to 10 (predischarge). Global left ventricular ejection fraction was evaluated by the area–length method. Regional left ventricular function in the infarct zone was determined by the centerline chord method of Sheehan et al.11 Values are expressed as SD per chord (SD/chord). Visual luminal narrowing and TIMI flow grade were determined for the infarct-related artery. All angiograms were reviewed by a core angiographic laboratory observer blinded to treatment assignment.
Multiple-uptake gated acquisition scans: Scans were performed 6 weeks after random-
ization and were analyzed by a core laboratory with the interpreter blinded to treatment. Wall segments for analysis were assigned based on infarct lesion MARCH 1, 1997
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TABLE II Baseline Clinical and Catheterization Characteristics in Patients with Interpretable Multiple-Uptake Gated Acquisition (MUGA) Data Aggressive Catheterization
Age (yr) Men Risk factors Diabetes mellitus Systemic hypertension Elevated cholesterol Current smoking Prior infarction Prior congestive heart failure Anterior infarction by electrocardiogram Peripheral vascular disease Baseline characteristics Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Rales Not low risk Time to treatment (min) Number of diseased vessels 0 or 1 2 3 Infarct-related artery Left anterior descending Left circumflex Right Left main None or unknown
Alteplase (n Å 36)
Urokinase (n Å 32)
55 (48, 65) 27 (75%)
55 (50, 63) 28 (88%)
3 22 5 17 3 1 20
3 11 8 21 5 1 15
(8%) (61%) (14%) (47%) (8%) (3%) (56%)
1 (3%) 78 (68, 87) 128 (114, 142) 80 (70, 90) 7 (19%) 27 (75%) 154 (126, 199)
Combination (n Å 41)
(9%) (34%) (25%) (66%) (16%) (3%) (47%)
2 (6%) 75 (66, 84) 124 (117, 134)
Altephase (n Å 35)
Urokinase (n Å 38)
56 (48, 64) 29 (71%)
56 (49, 66) 28 (80%)
62 (50, 68) 26 (68%)
59 (52, 65) 30 (81%)
3 19 12 28 4 0 23
7 18 9 21 2 1 12
6 17 16 17 6 1 18
7 15 8 17 3 1 15
(7%) (46%) (29%) (68%) (10%) (0%) (56%)
3 (7%) 74 (64, 86) 125 (116, 140)
79 (72, 87) 4 (13%) 22 (69%) 188 (149, 257)
Deferred Catheterization
80 (70, 90) 3 (7%) 25 (61%) 197 (145, 222)
(20%) (51%) (26%) (60%) (6%) (3%) (34%)
2 (6%) 72 (61, 81) 130 (113, 148) 80 (74, 90) 5 (14%) 22 (63%) 170 (119, 230)
(16%) (45%) (42%) (45%) (16%) (3%) (47%)
2 (5%) 74 (64, 82) 127 (116, 156) 83 (65, 92) 10 (26%) 26 (68%) 188 (142, 252)
Combination (n Å 37)
(19%) (41%) (22%) (46%) (8%) (3%) (41%)
2 (5%) 73 (66, 88) 129 (118, 160) 80 (68, 97) 8 (22%) 22 (59%) 185 (160, 210)
13 (36%) 14 (39%) 9 (25%)
18 (56%) 8 (25%) 6 (19%)
21 (51%) 12 (29%) 8 (20%)
23 (66%) 8 (23%) 4 (11%)
21 (55%) 13 (34%) 4 (11%)
20 (54%) 9 (24%) 8 (22%)
17 3 16 0 0
12 7 12 1 0
19 4 18 0 0
7 2 25 0 1
14 6 18 0 0
12 3 22 0 0
(47%) (8%) (44%) (0%) (0%)
(38%) (22%) (38%) (3%) (0%)
(46%) (10%) (44%) (0%) (0%)
(20%) (6%) (71%) (0%) (3%)
(37%) (16%) (47%) (0%) (0%)
(32%) (8%) (59%) (0%) (0%)
Values are expressed as number (%) of patients or median (25th, 75th percentiles).
location identified by initial catheterization. Wall motion was evaluated semiquantitatively on a scale of 1 to 4 for each infarct zone (1: normal, 2: mild hypokinesis, 3: moderate to severe hypokinesis, and 4: akinesis/dyskinesis). Global left ventricular ejection fraction was determined both at rest and during peak exercise. Statistical analysis: Continuous measurements are expressed as median and interquartile ranges. Categorical variables are expressed as percentages. The effects of thrombolytic therapy, catheterization strategy, and rescue angioplasty on 5- to 10-day patency were compared with chi-square tests. Predischarge and 6-week ejection fractions (at rest and during exercise) were compared with analysis of variance (ANOVA) techniques. Thrombolytic therapy and catheterization were simultaneously evaluated as predictors of these ejection fraction measurements. The day 5 to 10 infarct-zone wall motion score had a skewed distribution. To meet the underlying assumptions of the ANOVA technique, the score was first transformed to its natural log. The treatment and catheterization strategy effects on loge (infarctzone wall motion) were then compared. No acceptable transformation was found for the 6-week MUGA score. The data were converted into
a scale that had values from 1 to 4: 1 Å score õ2; 2 Å score õ3; 3 Å score õ4; 4 Å score ¢4. Ordinal logistic regression was then used to evaluate the univariable relation of rescue angioplasty, day 5 to 10 patency, day 5 to 10 infarct-zone wall motion, thrombolytic treatment, and catheterization strategy with 6-week MUGA score. This technique was also used to test the effect of rescue angioplasty after having adjusted for the day 5 to 10 wall motion score.
RESULTS Baseline characteristics: Of the 296 patients undergoing both day 5 to 10 catheterization and 6-week MUGA, 77 (26%) had MUGA scans that were uninterpretable. Thus, 219 patients (74%) had paired catheterization and MUGA data for interpretation. Baseline clinical and angiographic characteristics for patients with and without interpretable MUGA data were similar (Table I). Baseline clinical and angiographic characteristics for patients with MUGA data by catheterization strategy and thrombolytic regimen are shown in Table II. In this analysis, patients undergoing acute catheterization were less likely to have diabetes, elevated cholesterol, and rales than the deferred-catheterization group. However, they were more likely to have anterior myocardial infarction (p Å 0.07) and left anterior descending artery
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TABLE III Ejection Fraction at Predischarge Catheterization in Patients with Interpretable Multiple-Uptake Gated Acquisition (MUGA) Data Ejection Fraction (%)
Aggressive catheterization Deferred catheterization Overall
Alteplase
Urokinase
Combination
Catheterization Strategy
60 (53, 63) 57 (50, 63) 58 (51, 63)
54 (48, 62) 57 (46, 66) 55 (46, 65)
58 (49, 63) 56 (45, 64) 57 (48, 63)
57 (50, 63) 56 (49, 64)
Values are expressed as median (25th, 75th percentile) at follow-up angiography or emergency catheterization ¢3 days after randomization.
FIGURE 2. Regional (infarct-zone) wall motion score (SD/chord) at day 5 to 10 catheterization based on catheterization strategy and thrombolytic regimen. Horizontal line in each box represents the median; the borders of the box are 25th and 75th percentiles. The asterisk represents the mean while error bars depict the range of extreme values. t-PA Å tissue plasminogen activator; UK Å urokinase.
involvement (p Å 0.02) than the deferred-catheterization group. Infarct artery patency and/or left ventricular function:
The proportion of patients with TIMI grade 2 to 3 flow did not differ by thrombolytic regimen (alteplase 94%, urokinase 86%, combination 93%, p Å 0.20) or catheterization strategy (acute 92%, deferred 91%, p Å 0.75) at day 5 to 10 (predischarge) catheterization. Global left ventricular function at predischarge is depicted in Table III. Figure 2 illustrates regional (infarct zone) wall motion at the time of catheterization by catheterization strategy and thrombolytic regimen. Ejection fraction at predischarge catheterization was unaffected by thrombolytic regimen (p Å 0.29) and catheterization strategy (p Å 0.75). The infarctzone wall motion score did not differ by thrombolytic strategy (p Å 0.54), but acute catheterization patients had a better infarct-zone wall motion score (p Å 0.07) than deferred-catheterization patients. In the acute catheterization group, patients undergoing rescue angioplasty had infarct-zone wall motion similar to those not receiving rescue angioplasty (wall motion score 02.3 vs 02.0, respectively, p Å 0.129). Global and regional left ventricular function at 6 weeks: Thrombolytic regimen and catheterization 542
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strategy had no impact on either rest (p Å 0.331 and 0.600, respectively) or exercise (p Å 0.645 and 0.256, respectively) global ejection fraction at 6 weeks (Table IV and Figure 3). Catheterization strategy, thrombolytic strategy, and predischarge infarct artery patency were not predictive of MUGA score at 6 weeks. Univariate analysis showed that rescue angioplasty was associated with worse 6-week regional wall motion (p Å 0.002) in patients randomized to acute catheterization (Figure 4). Additionally, 5- to 10day infarct-zone score correlated positively with 6-week wall motion (p Å 0.0001). After adjustment for predischarge infarct-zone wall motion score, rescue angioplasty remained predictive of worse regional wall motion at 6 weeks (p Å 0.007).
DISCUSSION
Predischarge patency and left ventricular function: Triage to acute catheterization re-
sulted in improved regional wall motion at 5 to 10 days (p Å 0.07). If this magnitude of effect had been observed with the sample size of the parent study, this finding approaches the same statistical significance (p Å 0.006) as in the main TAMI-5 study (p Å 0.002). The similarity in global left ventricular function at 7 days among treatment strategies is not surprising given the results of previous studies and the current understanding of postinfarction myocardial function.9,12,13 Infarct-zone wall motion declines acutely and improves over several days, whereas noninvolved segments become acutely hypercontractile with function regressing to more normal levels over a similar period. The net result is no change in overall global left ventricular function over time in the majority of infarctions treated acutely with thrombolysis. Global and regional left ventricular function at 6 weeks: The choice of thrombolytic regimen or cath-
eterization strategy did not affect global ventricular function at 6 weeks. In contrast to predischarge data, infarct-zone wall motion at 6 weeks was not influenced by randomization to acute versus deferred catheterization, which may reflect infarct artery reocclusion.14 Reocclusion is common, and its sequelae MARCH 1, 1997
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TABLE IV Follow-up Ejection Fraction at 6-Week Multiple-Uptake Gated Acquisition (MUGA) Testing in Patients with Interpretable MUGA Data Ejection Fraction (%)
Rest value Aggressive catheterization Deferred catheterization Overall Exercise value Aggressive catheterization Deferred catheterization Overall
Alteplase
Urokinase
Combination
Catheterization Strategy
53 (45, 59) 47 (43, 56) 50 (43, 59)
48 (39, 55) 52 (44, 57) 51 (41, 56)
48 (42, 52) 50 (40, 56) 48 (41, 56)
49 (41, 56) 51 (41, 56)
55 (42, 63) 55 (51, 61) 55 (48, 62)
53 (43, 60) 56 (52, 63) 56 (47, 61)
54 (44, 62) 56 (41, 65) 54 (43, 63)
54 (43, 62) 56 (48, 63)
Values are expressed as median (25th, 75th percentile).
of concern. All analyses were based on intention to treat and not actual allocation. After adjustment, the 5to 10-day infarct-zone wall motion difference was nonsignificant at p Å 0.07. The difference in 6-week MUGA assessment of left ventricular function was likewise nonsignificant after correction for differences in allocation. We could not directly compare outcomes in patients undergoing rescue angioplasty versus those with failed thrombolysis, because conservatively treated patients were not studied on entry with regard to coronary patency. Late patency, alFIGURE 3. Regional (infarct-zone) left ventricular function as assessed by multiple upthough not as pertinent to myocartake gated acquisition (MUGA) at 6 weeks based on catheterization strategy and dial salvage as earlier reperfusion, thrombolytic regimen. Involved segments were scored based on the following scale: 1: normal, 2: mild hypokinesis, 3: moderate to severe hypokinesis, 4: akinesis and/or may convey an independent surdyskinesis and depicted negatively to parallel 5 to 10 day data. See Figure 2 for box- vival benefit.17 and-whisker plot description. The different methods of evaluating left ventricular function at presignificant, with no therapeutic strategy to date prov- discharge and 6 weeks are a potential confounding factor, especially with regard to regional function. ing beneficial in preventing its occurrence.14 – 16 Interestingly, in the 109 patients randomized to The centerline chord method used with left ventricacute catheterization, rescue angioplasty appeared to ulography is quantitative, whereas the MUGA have a negative effect on regional wall motion com- method is semiquantitative. The use of cardioactive pared with patients not undergoing rescue angio- medications at the time of MUGA scanning was not plasty in the acute catheterization cohort. Closer in- documented. Further angiographic concerns include spection of the data, however, revealed that this the lack of description of collateral flow and uneffect is likely attributable to failed thrombolysis known infarct artery patency at 6 weeks; more arrather than a deleterious effect of rescue angioplasty. teries could have reoccluded in the acute catheteriOf the 22 patients undergoing rescue angioplasty at zation group. These elements could partly explain acute catheterization, all had TIMI grade 0 to 1 flow, the apparent initial benefit conferred by acute cathin contrast to the 9.6% of patients not receiving res- eterization on regional wall motion, and the loss of cue angioplasty at acute catheterization. Lack of such benefit at 6 weeks. The advantage of early catheterization appears to timely reperfusion is a more likely explanation for worse regional wall motion at 6 weeks in patients result from the early assessment and (when approundergoing rescue angioplasty than the procedure it- priate) establishment of reperfusion. The acute catheterization cohort did not show improved infarctself. Study limitations: The relatively small number of zone wall motion at 6 weeks, however, raising the patients in this study and the large percentage (26%) possibility of and highlighting the problem of late of uninterpretable MUGA scans could have led to a reocclusion. The benefits of rescue angioplasty with respect to b-type error. The greater incidence of anterior infarction in the acute catheterization group is certainly left ventricular ejection fraction and infarct-zone wall CORONARY ARTERY DISEASE/VENTRICULAR FUNCTION AFTER THROMBOLYSIS AND ANGIOGRAPHY
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FIGURE 4. Regional (infarct-zone) left ventricular function as assessed by multiple uptake gated acquisition (MUGA) at 6 weeks in patients randomized to acute catheterization with and without rescue angioplasty. See Figure 2 for box-and-whisker plot description.
motion appear to be intermediate between that of successful thrombolysis and failed reperfusion. Infarctzone wall motion was not akinetic in the rescue angioplasty group, but it was significantly more hypokinetic than in the deferred group, who remained clinically stable with apparent successful thrombolysis. A major clinical liability of thrombolysis remains the timely, early identification of therapeutic failure. The optimal time to allow for successful reperfusion and the precise noninvasive marker of infarct artery recanalization are undefined. When reperfusion is ultimately established by mechanical or pharmacologic approaches, the challenge then becomes maintaining patency over the ensuing weeks and months. No therapeutic strategy has proven effective in preventing late reocclusion. New strategies are needed from current and future investigations to ensure long-term coronary patency. Acknowledgment: We are indebted to Patricia Williams for her expert editorial assistance in the preparation of this manuscript.
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1. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled trial. Lancet 1988;1:545–549. 2. Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Lancet 1988;2:525–530. 3. ISAM Study Group. A prospective trial of intravenous streptokinase in acute myocardial infarction: mortality, morbidity and infarct size at 21 days. N Engl J Med 1986;314:465–471. 4. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397–402. 5. Topol EJ, Califf RM, George BS, Kereiakes DJ, Abbottsmith CW, Candela RJ, Lee KL, Pitt B, Stack RS, O*Neill WW. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1987;317:581 – 588. 6. The TIMI Study Group. Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) phase II trial. N Engl J Med 1989;320:618–627. 7. Califf RM, Harrelson-Woodlief L, Topol EJ. Left ventricular ejection fraction may not be useful as an end point of thrombolytic therapy comparative trials. Circulation 1990;82:1847–1853. 8. Henzlova MJ, Bourge RC, Papapietro SE, Maske LE, Morgan TE, Tauxe EL, Rogers WJ. Long-term effect of thrombolytic therapy on left ventricular ejection fraction after acute myocardial infarction. Am J Cardiol 1991;67:1354– 1359. 9. Sutton JM, Topol EJ. Left ventricular function assessment and acute myocardial infarction. Curr Opin Cardiol 1992;7:1035–1045. 10. Califf RM, Topol EJ, Stack RS, Ellis SG, George BS, Kereiakes DJ, Samaha JK, Worley SJ, Anderson JL, Harrelson-Woodlief L, for the TAMI Study Group. Evaluation of combination thrombolytic therapy and timing of cardiac catheterization in acute myocardial infarction. Circulation 1991;83:1543 – 1556. 11. Sheehan FH, Bolson EL, Dodge HT, Mathey DG, Schofer J, Woo HW. Advantages and applications of the centerline method for characterizing regional ventricular function. Circulation 1986;74:293–305. 12. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993;329:1615–1622. 13. Sheehan FH, Braunwald E, Canner P, Dodge HT, Gore J, Van Nette P, Passamani ER, Williams DO, Zaret B. The effect of intravenous thrombolytic therapy of left ventricular function a report on tissue-type plasminogen activator and streptokinase from the Thrombolysis in Myocardial Infarction (TIMI Phase I) trial. Circulation 1987;75:817–829. 14. White HD, French JK, Hamer AW, Brown MA, Williams BF, Ormiston JA, Cross DB. Frequent reocclusion of patent infarct-related arteries between 4 weeks and 1 year: effects of antiplatelet therapy. J Am Coll Cardiol 1995;25:218–223. 15. Veen G, Meyer A, Verheugt FW, Werter CJ, de Swart H, Lie KI, van der Pol JM, Michels HR, Van Eenige MJ. Culprit lesion morphology and stenosis severity in the prediction of reocclusion after coronary thrombolysis: angiographic results of the APRICOT study. J Am Coll Cardiol 1993;22:1755–1762. 16. Ohman EM, Califf RM, Topol EJ, Candela R, Abbottsmith C, Ellis S, Sigmon KN, Kereiakes D, George B, Stack RS for the TAMI Study Group. Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction. Circulation 1990;82:781–791. 17. Lamas GA, Flaker GC, Mitchell G, Smith SC, Gersh BJ, Wun CC, Moye L, Rouleau JD, Pfeffer MA. Effect of infarct artery patency on prognosis after acute myocardial infarction. The Survival and Ventricular Enlargement Investigators. Circulation 1995;92:1101–1109.
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vs deferred) did not influence global or infarct-zone function at 6 weeks. In patients randomized to acute catheterization, those undergoing rescue angioplasty had worse infarct-zone wall motion at 6 weeks than patients with a patent infarct vessel not requiring rescue angioplasty (p Å 0.002). The early benefit on regional left ventricular function of triage to acute catheterization after thrombolysis for acute myocardial infarction did not persist at 6 weeks, which is most likely attributable to a high incidence of reocclusion. The worse infarctzone regional wall motion in patients undergoing rescue angioplasty in the acute-catheterization group likely reflects failed reperfusion and illustrates the difficulty in identifying and consequences of early thrombolytic failures. Q1997 by Excerpta Medica, Inc. (Am J Cardiol 1997;79:539–544)
he use of thrombolytic therapy in acute myocardial infarction unequivocally reduces mortality, T regardless of the agent chosen, with empiric post-
triculography at 6 weeks. These data provide a unique window into the effects of early or deferred angiography at follow-up, since no other randomized trial has incorporated a late assessment of global and regional cardiac function in the study design. This allows correlations of treatment strategy and predischarge angiographic and left ventricular function variables with late global and regional left ventricular function.
1–4
thrombolytic coronary intervention failing to convey any survival benefit or improvement in global left ventricular function.5,6 Improvement in global and regional (infarct zone) systolic function has not necessarily translated into improved survival in studies of coronary thrombolysis with or without adjunct angioplasty.7 – 9 The Thrombolysis and Angioplasty in Acute Myocardial Infarction phase 5 (TAMI-5) trial evaluated the effects on various clinical end points of alteplase, urokinase, or combination therapy with either acute (õ90 minutes) catheterization for triage to rescue angioplasty or deferred catheterization. The combination therapy was effective in achieving early and sustained infarct artery patency.10 The cohort assigned to acute catheterization with or without angioplasty had early (5 to 10 day) improved infarctzone wall motion (but not global left ventricular function) compared with the deferred-catheterization group.10 Of the 575 patients randomized, a subset of 296 patients underwent rest and exercise multipleuptake gated acquisition (MUGA) radionuclide venFrom the Cleveland Clinic Foundation, Cleveland, Ohio; and Duke University Medical Center, Durham, North Carolina. Manuscript received June 3, 1996; revised manuscript received and accepted September 30, 1996. Address for reprints: Joseph M. Sutton, MD, Department of Cardiology, F-15, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195.
METHODS The study design and inclusion and exclusion criteria for the main TAMI-5 trial have been described.10 Briefly, 575 patients õ76 years old without cardiogenic shock presenting within 6 hours of acute myocardial infarction (defined by symptoms compatible with acute myocardial infarction and STsegment elevation of 1 mm in 2 contiguous leads) were randomly allocated in a 3 1 2 factorial design to intravenous thrombolysis with either alteplase (100 mg infused over 3 hours), urokinase (1.5 million U bolus and 1.5 million U infused over 90 minutes), or both (urokinase 1.5 million U and alteplase 1 mg/kg infused over 1 hour). Patients were then randomized to acute or deferred (day 5 to 10) catheterization. All patients received 325 mg aspirin orally on entry. Heparin was given as a 5,000-U bolus when thrombolysis began; an infusion of 1,000 U/hour was used to maintain an activated partial thromboplastin time (aPTT) 1.5 to 2 times control for ¢48 hours. In patients undergoing acute cathe-
Q1997 by Excerpta Medica, Inc.
0002-9149/97/$17.00 PII S0002-9149(96)00812-0
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FIGURE 1. Design of the Thrombolysis and Angioplasty in Acute Myocardial Infarction phase 5 (TAMI-5) multiple uptake gated acquisition (MUGA) substudy. PTCA Å percutaneous transluminal coronary angioplasty; t-PA Å tissue plasminogen activator; UK Å urokinase.
TABLE I Baseline Clinical and Catheterization Characteristics in Patients With and Without Multiple-Uptake Gated Acquisition (MUGA) Data Patients Without MUGA Data (n Å 356) Age (yr) Men Risk factors Diabetes mellitus Systemic hypertension Elevated cholesterol Current smoking Prior infarction Prior congestive heart failure Anterior infarction by electrocardiogram Peripheral vascular disease Baseline characteristics Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Rales Not low risk Time to treatment (min) Acute catheterization Rescue angioplasty Deferred catheterization Number of diseased vessels 0 or 1 2 3 Infarct-related artery Left anterior descending Left circumflex Right Left main None or unknown
Patients With MUGA Data (n Å 219)
59 (52, 66) 272 (76%)
56 (49, 65) 168 (77%)
68 150 97 177 51 3 159 18
(19%) (42%) (28%) (50%) (14%) (õ1%) (45%) (5%)
29 102 58 121 23 5 103 12
(13%) (47%) (27%) (55%) (11%) (2%) (47%) (5%)
76 130 80 64 216 174 178 31 178
(64, 87) (112, 147) (70, 90) (18%) (61%) (130, 230) (50%) (17%) (50%)
74 128 80 37 144 180 109 22 110
(64, 86) (116, 143) (70, 90) (17%) (66%) (135, 227) (50%) (20%) (50%)
204 (57%) 91 (26%) 61 (17%)
116 (53%) 64 (29%) 39 (18%)
113 47 176 0 20
81 25 111 1 1
(32%) (13%) (49%) (0%) (6%)
(37%) (11%) (51%) (õ1%) (õ1%)
Values are expressed as number (%) of patients or median (25th, 75th percentiles).
terization, rescue angioplasty was performed in 22 patients for either failed thrombolysis (defined as Thrombolysis in Myocardial Infarction [TIMI] grade 0 to 1 flow) or for clinical evidence of ongoing ischemia. Outcomes were assessed by evaluating global 540
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and regional systolic function and infarct artery patency at the day 5 to 10 catheterization and by global and regional systolic function at 6 weeks by MUGA. Patient population: Of the 575 patients randomized in the TAMI-5 trial, 296 underwent both contrast left ventriculography at day 5 to 10 predischarge and rest and exercise MUGA at 6 weeks. The cohort of 219 (74%) patients with interpretable MUGA images is the subject of this analysis. The overall study design is shown in Figure 1. Predischarge coronary angiography and left ventriculography: Global
and infarct-zone systolic ventricular function were assessed by catheterization on day 5 to 10 (predischarge). Global left ventricular ejection fraction was evaluated by the area–length method. Regional left ventricular function in the infarct zone was determined by the centerline chord method of Sheehan et al.11 Values are expressed as SD per chord (SD/chord). Visual luminal narrowing and TIMI flow grade were determined for the infarct-related artery. All angiograms were reviewed by a core angiographic laboratory observer blinded to treatment assignment.
Multiple-uptake gated acquisition scans: Scans were performed 6 weeks after random-
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TABLE II Baseline Clinical and Catheterization Characteristics in Patients with Interpretable Multiple-Uptake Gated Acquisition (MUGA) Data Aggressive Catheterization
Age (yr) Men Risk factors Diabetes mellitus Systemic hypertension Elevated cholesterol Current smoking Prior infarction Prior congestive heart failure Anterior infarction by electrocardiogram Peripheral vascular disease Baseline characteristics Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Rales Not low risk Time to treatment (min) Number of diseased vessels 0 or 1 2 3 Infarct-related artery Left anterior descending Left circumflex Right Left main None or unknown
Alteplase (n Å 36)
Urokinase (n Å 32)
55 (48, 65) 27 (75%)
55 (50, 63) 28 (88%)
3 22 5 17 3 1 20
3 11 8 21 5 1 15
(8%) (61%) (14%) (47%) (8%) (3%) (56%)
1 (3%) 78 (68, 87) 128 (114, 142) 80 (70, 90) 7 (19%) 27 (75%) 154 (126, 199)
Combination (n Å 41)
(9%) (34%) (25%) (66%) (16%) (3%) (47%)
2 (6%) 75 (66, 84) 124 (117, 134)
Altephase (n Å 35)
Urokinase (n Å 38)
56 (48, 64) 29 (71%)
56 (49, 66) 28 (80%)
62 (50, 68) 26 (68%)
59 (52, 65) 30 (81%)
3 19 12 28 4 0 23
7 18 9 21 2 1 12
6 17 16 17 6 1 18
7 15 8 17 3 1 15
(7%) (46%) (29%) (68%) (10%) (0%) (56%)
3 (7%) 74 (64, 86) 125 (116, 140)
79 (72, 87) 4 (13%) 22 (69%) 188 (149, 257)
Deferred Catheterization
80 (70, 90) 3 (7%) 25 (61%) 197 (145, 222)
(20%) (51%) (26%) (60%) (6%) (3%) (34%)
2 (6%) 72 (61, 81) 130 (113, 148) 80 (74, 90) 5 (14%) 22 (63%) 170 (119, 230)
(16%) (45%) (42%) (45%) (16%) (3%) (47%)
2 (5%) 74 (64, 82) 127 (116, 156) 83 (65, 92) 10 (26%) 26 (68%) 188 (142, 252)
Combination (n Å 37)
(19%) (41%) (22%) (46%) (8%) (3%) (41%)
2 (5%) 73 (66, 88) 129 (118, 160) 80 (68, 97) 8 (22%) 22 (59%) 185 (160, 210)
13 (36%) 14 (39%) 9 (25%)
18 (56%) 8 (25%) 6 (19%)
21 (51%) 12 (29%) 8 (20%)
23 (66%) 8 (23%) 4 (11%)
21 (55%) 13 (34%) 4 (11%)
20 (54%) 9 (24%) 8 (22%)
17 3 16 0 0
12 7 12 1 0
19 4 18 0 0
7 2 25 0 1
14 6 18 0 0
12 3 22 0 0
(47%) (8%) (44%) (0%) (0%)
(38%) (22%) (38%) (3%) (0%)
(46%) (10%) (44%) (0%) (0%)
(20%) (6%) (71%) (0%) (3%)
(37%) (16%) (47%) (0%) (0%)
(32%) (8%) (59%) (0%) (0%)
Values are expressed as number (%) of patients or median (25th, 75th percentiles).
location identified by initial catheterization. Wall motion was evaluated semiquantitatively on a scale of 1 to 4 for each infarct zone (1: normal, 2: mild hypokinesis, 3: moderate to severe hypokinesis, and 4: akinesis/dyskinesis). Global left ventricular ejection fraction was determined both at rest and during peak exercise. Statistical analysis: Continuous measurements are expressed as median and interquartile ranges. Categorical variables are expressed as percentages. The effects of thrombolytic therapy, catheterization strategy, and rescue angioplasty on 5- to 10-day patency were compared with chi-square tests. Predischarge and 6-week ejection fractions (at rest and during exercise) were compared with analysis of variance (ANOVA) techniques. Thrombolytic therapy and catheterization were simultaneously evaluated as predictors of these ejection fraction measurements. The day 5 to 10 infarct-zone wall motion score had a skewed distribution. To meet the underlying assumptions of the ANOVA technique, the score was first transformed to its natural log. The treatment and catheterization strategy effects on loge (infarctzone wall motion) were then compared. No acceptable transformation was found for the 6-week MUGA score. The data were converted into
a scale that had values from 1 to 4: 1 Å score õ2; 2 Å score õ3; 3 Å score õ4; 4 Å score ¢4. Ordinal logistic regression was then used to evaluate the univariable relation of rescue angioplasty, day 5 to 10 patency, day 5 to 10 infarct-zone wall motion, thrombolytic treatment, and catheterization strategy with 6-week MUGA score. This technique was also used to test the effect of rescue angioplasty after having adjusted for the day 5 to 10 wall motion score.
RESULTS Baseline characteristics: Of the 296 patients undergoing both day 5 to 10 catheterization and 6-week MUGA, 77 (26%) had MUGA scans that were uninterpretable. Thus, 219 patients (74%) had paired catheterization and MUGA data for interpretation. Baseline clinical and angiographic characteristics for patients with and without interpretable MUGA data were similar (Table I). Baseline clinical and angiographic characteristics for patients with MUGA data by catheterization strategy and thrombolytic regimen are shown in Table II. In this analysis, patients undergoing acute catheterization were less likely to have diabetes, elevated cholesterol, and rales than the deferred-catheterization group. However, they were more likely to have anterior myocardial infarction (p Å 0.07) and left anterior descending artery
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TABLE III Ejection Fraction at Predischarge Catheterization in Patients with Interpretable Multiple-Uptake Gated Acquisition (MUGA) Data Ejection Fraction (%)
Aggressive catheterization Deferred catheterization Overall
Alteplase
Urokinase
Combination
Catheterization Strategy
60 (53, 63) 57 (50, 63) 58 (51, 63)
54 (48, 62) 57 (46, 66) 55 (46, 65)
58 (49, 63) 56 (45, 64) 57 (48, 63)
57 (50, 63) 56 (49, 64)
Values are expressed as median (25th, 75th percentile) at follow-up angiography or emergency catheterization ¢3 days after randomization.
FIGURE 2. Regional (infarct-zone) wall motion score (SD/chord) at day 5 to 10 catheterization based on catheterization strategy and thrombolytic regimen. Horizontal line in each box represents the median; the borders of the box are 25th and 75th percentiles. The asterisk represents the mean while error bars depict the range of extreme values. t-PA Å tissue plasminogen activator; UK Å urokinase.
involvement (p Å 0.02) than the deferred-catheterization group. Infarct artery patency and/or left ventricular function:
The proportion of patients with TIMI grade 2 to 3 flow did not differ by thrombolytic regimen (alteplase 94%, urokinase 86%, combination 93%, p Å 0.20) or catheterization strategy (acute 92%, deferred 91%, p Å 0.75) at day 5 to 10 (predischarge) catheterization. Global left ventricular function at predischarge is depicted in Table III. Figure 2 illustrates regional (infarct zone) wall motion at the time of catheterization by catheterization strategy and thrombolytic regimen. Ejection fraction at predischarge catheterization was unaffected by thrombolytic regimen (p Å 0.29) and catheterization strategy (p Å 0.75). The infarctzone wall motion score did not differ by thrombolytic strategy (p Å 0.54), but acute catheterization patients had a better infarct-zone wall motion score (p Å 0.07) than deferred-catheterization patients. In the acute catheterization group, patients undergoing rescue angioplasty had infarct-zone wall motion similar to those not receiving rescue angioplasty (wall motion score 02.3 vs 02.0, respectively, p Å 0.129). Global and regional left ventricular function at 6 weeks: Thrombolytic regimen and catheterization 542
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strategy had no impact on either rest (p Å 0.331 and 0.600, respectively) or exercise (p Å 0.645 and 0.256, respectively) global ejection fraction at 6 weeks (Table IV and Figure 3). Catheterization strategy, thrombolytic strategy, and predischarge infarct artery patency were not predictive of MUGA score at 6 weeks. Univariate analysis showed that rescue angioplasty was associated with worse 6-week regional wall motion (p Å 0.002) in patients randomized to acute catheterization (Figure 4). Additionally, 5- to 10day infarct-zone score correlated positively with 6-week wall motion (p Å 0.0001). After adjustment for predischarge infarct-zone wall motion score, rescue angioplasty remained predictive of worse regional wall motion at 6 weeks (p Å 0.007).
DISCUSSION
Predischarge patency and left ventricular function: Triage to acute catheterization re-
sulted in improved regional wall motion at 5 to 10 days (p Å 0.07). If this magnitude of effect had been observed with the sample size of the parent study, this finding approaches the same statistical significance (p Å 0.006) as in the main TAMI-5 study (p Å 0.002). The similarity in global left ventricular function at 7 days among treatment strategies is not surprising given the results of previous studies and the current understanding of postinfarction myocardial function.9,12,13 Infarct-zone wall motion declines acutely and improves over several days, whereas noninvolved segments become acutely hypercontractile with function regressing to more normal levels over a similar period. The net result is no change in overall global left ventricular function over time in the majority of infarctions treated acutely with thrombolysis. Global and regional left ventricular function at 6 weeks: The choice of thrombolytic regimen or cath-
eterization strategy did not affect global ventricular function at 6 weeks. In contrast to predischarge data, infarct-zone wall motion at 6 weeks was not influenced by randomization to acute versus deferred catheterization, which may reflect infarct artery reocclusion.14 Reocclusion is common, and its sequelae MARCH 1, 1997
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TABLE IV Follow-up Ejection Fraction at 6-Week Multiple-Uptake Gated Acquisition (MUGA) Testing in Patients with Interpretable MUGA Data Ejection Fraction (%)
Rest value Aggressive catheterization Deferred catheterization Overall Exercise value Aggressive catheterization Deferred catheterization Overall
Alteplase
Urokinase
Combination
Catheterization Strategy
53 (45, 59) 47 (43, 56) 50 (43, 59)
48 (39, 55) 52 (44, 57) 51 (41, 56)
48 (42, 52) 50 (40, 56) 48 (41, 56)
49 (41, 56) 51 (41, 56)
55 (42, 63) 55 (51, 61) 55 (48, 62)
53 (43, 60) 56 (52, 63) 56 (47, 61)
54 (44, 62) 56 (41, 65) 54 (43, 63)
54 (43, 62) 56 (48, 63)
Values are expressed as median (25th, 75th percentile).
of concern. All analyses were based on intention to treat and not actual allocation. After adjustment, the 5to 10-day infarct-zone wall motion difference was nonsignificant at p Å 0.07. The difference in 6-week MUGA assessment of left ventricular function was likewise nonsignificant after correction for differences in allocation. We could not directly compare outcomes in patients undergoing rescue angioplasty versus those with failed thrombolysis, because conservatively treated patients were not studied on entry with regard to coronary patency. Late patency, alFIGURE 3. Regional (infarct-zone) left ventricular function as assessed by multiple upthough not as pertinent to myocartake gated acquisition (MUGA) at 6 weeks based on catheterization strategy and dial salvage as earlier reperfusion, thrombolytic regimen. Involved segments were scored based on the following scale: 1: normal, 2: mild hypokinesis, 3: moderate to severe hypokinesis, 4: akinesis and/or may convey an independent surdyskinesis and depicted negatively to parallel 5 to 10 day data. See Figure 2 for box- vival benefit.17 and-whisker plot description. The different methods of evaluating left ventricular function at presignificant, with no therapeutic strategy to date prov- discharge and 6 weeks are a potential confounding factor, especially with regard to regional function. ing beneficial in preventing its occurrence.14 – 16 Interestingly, in the 109 patients randomized to The centerline chord method used with left ventricacute catheterization, rescue angioplasty appeared to ulography is quantitative, whereas the MUGA have a negative effect on regional wall motion com- method is semiquantitative. The use of cardioactive pared with patients not undergoing rescue angio- medications at the time of MUGA scanning was not plasty in the acute catheterization cohort. Closer in- documented. Further angiographic concerns include spection of the data, however, revealed that this the lack of description of collateral flow and uneffect is likely attributable to failed thrombolysis known infarct artery patency at 6 weeks; more arrather than a deleterious effect of rescue angioplasty. teries could have reoccluded in the acute catheteriOf the 22 patients undergoing rescue angioplasty at zation group. These elements could partly explain acute catheterization, all had TIMI grade 0 to 1 flow, the apparent initial benefit conferred by acute cathin contrast to the 9.6% of patients not receiving res- eterization on regional wall motion, and the loss of cue angioplasty at acute catheterization. Lack of such benefit at 6 weeks. The advantage of early catheterization appears to timely reperfusion is a more likely explanation for worse regional wall motion at 6 weeks in patients result from the early assessment and (when approundergoing rescue angioplasty than the procedure it- priate) establishment of reperfusion. The acute catheterization cohort did not show improved infarctself. Study limitations: The relatively small number of zone wall motion at 6 weeks, however, raising the patients in this study and the large percentage (26%) possibility of and highlighting the problem of late of uninterpretable MUGA scans could have led to a reocclusion. The benefits of rescue angioplasty with respect to b-type error. The greater incidence of anterior infarction in the acute catheterization group is certainly left ventricular ejection fraction and infarct-zone wall CORONARY ARTERY DISEASE/VENTRICULAR FUNCTION AFTER THROMBOLYSIS AND ANGIOGRAPHY
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FIGURE 4. Regional (infarct-zone) left ventricular function as assessed by multiple uptake gated acquisition (MUGA) at 6 weeks in patients randomized to acute catheterization with and without rescue angioplasty. See Figure 2 for box-and-whisker plot description.
motion appear to be intermediate between that of successful thrombolysis and failed reperfusion. Infarctzone wall motion was not akinetic in the rescue angioplasty group, but it was significantly more hypokinetic than in the deferred group, who remained clinically stable with apparent successful thrombolysis. A major clinical liability of thrombolysis remains the timely, early identification of therapeutic failure. The optimal time to allow for successful reperfusion and the precise noninvasive marker of infarct artery recanalization are undefined. When reperfusion is ultimately established by mechanical or pharmacologic approaches, the challenge then becomes maintaining patency over the ensuing weeks and months. No therapeutic strategy has proven effective in preventing late reocclusion. New strategies are needed from current and future investigations to ensure long-term coronary patency. Acknowledgment: We are indebted to Patricia Williams for her expert editorial assistance in the preparation of this manuscript.
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1. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled trial. Lancet 1988;1:545–549. 2. Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Lancet 1988;2:525–530. 3. ISAM Study Group. A prospective trial of intravenous streptokinase in acute myocardial infarction: mortality, morbidity and infarct size at 21 days. N Engl J Med 1986;314:465–471. 4. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397–402. 5. Topol EJ, Califf RM, George BS, Kereiakes DJ, Abbottsmith CW, Candela RJ, Lee KL, Pitt B, Stack RS, O*Neill WW. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1987;317:581 – 588. 6. The TIMI Study Group. Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) phase II trial. N Engl J Med 1989;320:618–627. 7. Califf RM, Harrelson-Woodlief L, Topol EJ. Left ventricular ejection fraction may not be useful as an end point of thrombolytic therapy comparative trials. Circulation 1990;82:1847–1853. 8. Henzlova MJ, Bourge RC, Papapietro SE, Maske LE, Morgan TE, Tauxe EL, Rogers WJ. Long-term effect of thrombolytic therapy on left ventricular ejection fraction after acute myocardial infarction. Am J Cardiol 1991;67:1354– 1359. 9. Sutton JM, Topol EJ. Left ventricular function assessment and acute myocardial infarction. Curr Opin Cardiol 1992;7:1035–1045. 10. Califf RM, Topol EJ, Stack RS, Ellis SG, George BS, Kereiakes DJ, Samaha JK, Worley SJ, Anderson JL, Harrelson-Woodlief L, for the TAMI Study Group. Evaluation of combination thrombolytic therapy and timing of cardiac catheterization in acute myocardial infarction. Circulation 1991;83:1543 – 1556. 11. Sheehan FH, Bolson EL, Dodge HT, Mathey DG, Schofer J, Woo HW. Advantages and applications of the centerline method for characterizing regional ventricular function. Circulation 1986;74:293–305. 12. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993;329:1615–1622. 13. Sheehan FH, Braunwald E, Canner P, Dodge HT, Gore J, Van Nette P, Passamani ER, Williams DO, Zaret B. The effect of intravenous thrombolytic therapy of left ventricular function a report on tissue-type plasminogen activator and streptokinase from the Thrombolysis in Myocardial Infarction (TIMI Phase I) trial. Circulation 1987;75:817–829. 14. White HD, French JK, Hamer AW, Brown MA, Williams BF, Ormiston JA, Cross DB. Frequent reocclusion of patent infarct-related arteries between 4 weeks and 1 year: effects of antiplatelet therapy. J Am Coll Cardiol 1995;25:218–223. 15. Veen G, Meyer A, Verheugt FW, Werter CJ, de Swart H, Lie KI, van der Pol JM, Michels HR, Van Eenige MJ. Culprit lesion morphology and stenosis severity in the prediction of reocclusion after coronary thrombolysis: angiographic results of the APRICOT study. J Am Coll Cardiol 1993;22:1755–1762. 16. Ohman EM, Califf RM, Topol EJ, Candela R, Abbottsmith C, Ellis S, Sigmon KN, Kereiakes D, George B, Stack RS for the TAMI Study Group. Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction. Circulation 1990;82:781–791. 17. Lamas GA, Flaker GC, Mitchell G, Smith SC, Gersh BJ, Wun CC, Moye L, Rouleau JD, Pfeffer MA. Effect of infarct artery patency on prognosis after acute myocardial infarction. The Survival and Ventricular Enlargement Investigators. Circulation 1995;92:1101–1109.
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