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Outcome of acute ST-segment elevation myocardial infarction in patients with prior coronary artery bypass surgery receiving thrombolytic therapy
Outcome of acute ST-segment elevation myocardial infarction in patients with prior coronary artery bypass surgery receiving thrombolytic therapy Marino Labinaz, MD,a Michael H. Sketch, Jr, MD,b Stephen G. Ellis, MD,c Bruce M. Abramowitz, MD,c Amanda L. Stebbins, MS,b Karen S. Pieper, MS,b David R. Holmes, Jr, MD,d Robert M. Califf, MD,b and Eric J. Topol, MD,c for the GUSTO-I Investigators Ottawa, Ontario, Canada, Durham, NC, Cleveland, Ohio, and Rochester, Minn
Background Patients with prior coronary bypass surgery with acute ST-segment elevation myocardial infarction (MI) pose an increasingly common clinical problem. We assessed the characteristics and outcomes of such patients undergoing thrombolysis for acute MI.
Methods and Results We compared the characteristics and outcomes of patients in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial (GUSTO-I) who had had prior bypass (n = 1784, 4% of the population) with those without prior coronary artery bypass grafting (CABG), all of whom were randomized to receive one of four thrombolytic strategies. Patients with prior bypass were older with significantly more prior MI and angina. Overall, 30-day mortality was significantly higher in patients with prior bypass (10.7% vs 6.7% for no prior bypass, P < .001); these patients also had significantly more pulmonary edema, sustained hypotension, or cardiogenic shock. Patients with prior bypass showed a 12.5% relative reduction (95% confidence interval, 0% to 41.9%) in 30-day mortality with accelerated alteplase over the streptokinase monotherapies. In the 62% of patients with prior CABG who underwent coronary angiography, the infarct-related vessel was a native coronary artery in 61.9% and a bypass graft in 38.1% of cases. The Thrombolysis in Myocardial Infarction (TIMI) 3 flow rate was 30.5% for culprit native coronary arteries and 31.7% for culprit bypass grafts. Patients with prior bypass had more severe infarct-vessel stenoses (99% [90%, 100%] vs 90% [80%, 99%], P < .001). Conclusions The 30-day mortality in patients with prior CABG was significantly higher than that for patients without prior CABG. As in the overall trial, these patients derived an incremental survival benefit from treatment with accelerated alteplase, but mortality remained high (16.7%) at 1 year. These results are at least partially explained by the higher baseline risk of these patients and by the lower rate of patency of the infarct-related artery. (Am Heart J 2001;141:469-77.)
Although numerous randomized trials have shown that thrombolysis improves vessel patency, preserves left ventricular function, and improves survival after acute myocardial infarction (MI), patients with prior coronary artery bypass grafting (CABG) usually have From the aDivision of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada, bDuke Clinical Research Institute, Durham, NC, the cDepartment of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, and the dDivision of Cardiology, Mayo Clinic, Rochester, Minn. Supported by Bayer, New York, NY, CIBA-Corning, Medfield, Mass, ICI Pharmaceuticals, Wilmington, Del, Genentech, South San Francisco, Calif, and Sanofi Pharmaceuticals, Paris, France. M. L. was a research fellow of the Heart and Stroke Foundation of Canada during this study. Submitted February 17, 2000; accepted October 10, 2000. Reprint requests: Marino Labinaz, MD, University of Ottawa Heart Institute, Department of Medicine, Division of Cardiology, Room 150, 40 Ruskin Ave, Ottawa, Ontario K1Y 4W7, Canada. E-mail: [email protected] Copyright © 2001 by Mosby, Inc. 0002-8703/2001/$12.00 + 0 4/1/112779 doi:10.1067/mhj.2001.112779
been excluded from these trials. As a result, relatively little is known about their natural history and preferred treatment of new acute MI. Data on relatively small numbers of patients in nonrandomized series1,2 suggest that the potential benefits and risks of intravenous thrombolysis may differ for this subgroup because of a larger thrombus burden in the infarct vessel, a smaller myocardial area at risk, and more advanced disease in the remaining native vessels. Furthermore, multivariable analyses have identified prior CABG as an independent risk factor for mortality at 30 days and 1 year after MI.3,4 The optimal treatment strategy for these patients is a major public health issue. The number of patients undergoing CABG increases each year; in 1993 alone, more than 750,000 patients underwent the procedure worldwide.5 Many grafts ultimately will degenerate and cause acute occlusion with the sequelae of ischemia, MI, or death. Sequential angiographic studies have shown first-year failure rates of 15% to 20%6 and later
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annual rates of about 4%. Thus by 10 years about 50% of vein grafts may be occluded.7 Finally, the annual incidence of MI after CABG is 3% to 8%.1,8-11 The Global Utilization of Streptokinase and Tissue Plasminogen Activator (alteplase) for Occluded Coronary Arteries (GUSTO-I) trial was designed to test the hypothesis that early, sustained infarct-artery patency is associated with better survival in patients with evolving acute MI.12 The 41,021 study patients included 1784 with prior CABG who were prospectively selected for subgroup analysis. This report focuses on the early and late outcomes of these patients compared with patients in GUSTO-I without prior CABG and assesses the relative efficacy of the four thrombolytic strategies.
Methods Patients The complete protocol of the GUSTO-I trial has been described,12 as have the methods of data collection, management, and quality assurance and the relationship of the study investigators to the sponsors.12,13 Patients were eligible for randomization if they came to a hospital <6 hours after the onset of symptoms, with chest pain lasting ≥ 20 minutes and accompanied by electrocardiographic (ECG) signs of ≥0.1 mV ST-segment elevation in two or more limb leads or ≥0.2 mV elevation in two or more contiguous precordial leads. Patients with prior CABG were eligible for enrollment. Previous stroke, active bleeding, previous treatment with streptokinase or anistreplase, major trauma or surgery within 6 months, previous enrollment in GUSTO-I, and noncompressible arterial punctures were criteria for exclusion. Uncontrolled hypertension (systolic blood pressure ≥180 mm Hg unresponsive to therapy) was considered a relative contraindication to study enrollment. The institutional review board at each institution approved the protocol, and patients gave informed consent for participation.
Randomization and treatment strategies A central coordinating center reviewed the eligibility of all patients and randomly assigned them to one of four treatment strategies: streptokinase with subcutaneous heparin, streptokinase with intravenous heparin, accelerated alteplase with intravenous heparin, or combined alteplase and streptokinase with intravenous heparin. Intravenous heparin was given for ≥48 hours (longer at the investigator’s discretion); subcutaneous heparin was continued for 7 days or until the patient was discharged. Patient enrollment was not stratified according to prior CABG, nor was there any stratification among the treatment groups with respect to prior CABG. Information about prior CABG was obtained from the patient on enrollment, or from a representative if the patient was unable to communicate. Patients received chewable aspirin ≥160 mg as soon as possible after presentation, followed by 160 to 325 mg daily. The activated partial thromboplastin time was monitored at 6, 12, and 24 hours for titration of the intravenous heparin dose. Patients without a contraindication to β-blockade received 10 mg of intravenous atenolol in two divided doses, followed by an oral dose of 50 to 100 mg daily. All other medications were
prescribed at the discretion of the attending physician. Except for the 2431 patients enrolled in the angiographic substudy,14 the use of coronary angiography was at the discretion of the attending physician, as was the use of angioplasty or CABG.
End points The primary end point was death from any cause within 30 days. Other prospectively defined clinical outcomes were the combined end points of death or nonfatal stroke, death or nonfatal hemorrhagic stroke, and death or nonfatal disabling stroke. One-year mortality also was tabulated. Bleeding complications were classified as severe or life threatening if they were intracerebral or resulted in substantial hemodynamic compromise requiring treatment. Moderate bleeding was defined by the need for transfusion. Minor bleeding referred to other bleeding not requiring transfusion or causing hemodynamic compromise. In this report, coronary stenoses and Thrombolysis In Myocardial Infarction (TIMI) flow grades were estimated by the physicians performing angiography.
Statistical analysis Selected baseline characteristics and clinical outcomes were compared in patients with and without previous CABG, overall and by treatment assignment. Categorical factors are presented as percentages. Continuous measures are reported as medians (25th, 75th percentiles) unless otherwise indicated. The Wilcoxon sign-rank test was used to assess the univariable relationships between continuous baseline factors and outcomes and prior CABG. The relationship between categorical factors and prior CABG was evaluated with a log-likelihood chi-square test. Similarly, a log-likelihood chi-square test was used to determine whether prior CABG was a prognostic indicator of mortality at 30 days, stroke, bleeding, or other postrandomization complications. Two sets of models have been developed from GUSTO-I that predict mortality. Lee et al3 determined the set of baseline clinical factors that together predict 30-day mortality, and Califf et al4 similarly predicted survival from 30 days to 1 year by use of baseline and hospital-course information. The effect of previous CABG in these two prognostic models was assessed as the effect of prior CABG on survival after adjustment for other known prognostic factors. Long-term survival estimates were described with Kaplan-Meier curves.
Results Patient characteristics Of the 41,021 patients enrolled in the trial between December 27, 1990, and February 22, 1993, 1784 had had prior CABG (90 patients had no prior CABG information and were excluded). Compared with the other patients in the study, those with prior CABG were older, more often male, had more cardiac risk factors, and were more likely to have had a prior MI (65.0% vs 14.2%, P < .001) or a history of angina (77.8% vs 35.0%, P < .001) (Table I). The mean time from prior CABG to the index MI was 8.6 ± 4.6 years. There were no significant differences among patients with prior CABG assigned to the various treatment strategies.
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Table I. Baseline clinical characteristics Prior bypass (n = 1784) Age (y) Female sex (%) Diabetes (%) Former smoker (%) Current smoker (%) Hypertension (%) Systolic blood pressure (mm Hg) Prior infarction (%) Prior angina (%) Prior angioplasty (%) Prior cerebrovascular disease (%)
64.4 (57, 70) 16.2 17.8 43.9 29.8 45.7 128 (112, 143) 65.0 77.8 17.5 4.8
No prior bypass (n = 39,147)
Statistical significance P < .001 P < .001 P < .001 P < .001 P < .001 P < .001 P = .24 P < .001 P < .001 P < .001 P < .001
61.4 (52, 70) 25.6 14.5 26.7 43.5 37.7 130 (112, 144) 14.2 35.0 3.4 1.9
Data are presented as median (25th, 75th percentiles) or percentages.
Compared with patients without prior CABG, patients with prior CABG had a slightly lower incidence of anterior MI and a slightly higher incidence of Killip class II heart failure at the time of presentation (Table II). Of note, patients with or without prior CABG had similar times to enrollment. Among patients with prior CABG, clinical features were evenly distributed among the four treatment groups.
Study medications Overall compliance with the study protocol and medications for the entire group of patients in GUSTO-I was excellent and has been described.12 Of note, patients with prior CABG were much more likely to receive digitalis preparations (21% vs 13%, P < .001), calciumchannel blockers (43% vs 30%, P < .001), and lidocaine (19% vs 16%, P = .002). Patients with prior CABG also were more likely to receive intravenous or oral nitrates (91% vs 86%, P < .001) and angiotensin-converting enzyme inhibitors (25% vs 22%, P = .003). β-Blockers were given to patients with and without prior CABG at equally high frequencies. Patients with prior CABG did not differ among thrombolytic strategies with respect to concomitant medications.
Major clinical outcomes The average 30-day mortality rate in patients with prior CABG for all four treatment strategies was 10.7%, significantly higher than the 6.7% mortality rate for the 39,147 patients without prior CABG (P < .001, Table III). As in the study as a whole, the subgroup of patients with prior CABG who received accelerated alteplase had lower 30-day mortality (9.4%, Figure 1) than did patients in the combined streptokinase groups (10.8%, P = .43). Patients treated with accelerated alteplase continued to have a lower mortality at 1 year, as shown in actuarial analysis (Figure 2, P = .72). Patients with prior CABG, who had more previous cerebrovascular disease at baseline, had a higher rate of
Table II. Clinical features on presentation
Infarct location (%)* Anterior Inferior Other Killip class (%)† I II III or IV Time to enrollment (h) Time to treatment (h) Time to hospitalization (h)‡
Prior bypass (n = 1784)
No prior bypass (n = 39,119)
34.2 61.5 4.2
39.3 57.3 3.3
81.6 16.5 2.0 2.0 (1.3,3.0) 2.8 (2.0, 3.9) 1.5 (0.9, 2.3)
85.5 12.4 2.1 2.0 (1.3, 3.0) 2.8 (2.0, 3.9) 1.5 (1.0, 2.5)
Data are presented as percentages or medians (25th, 75th percentiles). *P = .001 anterior versus other locations, patients with versus without prior bypass. †P < .001 Killip class I versus all others, patients with versus without prior bypass. ‡P < .01 patients with versus without prior bypass.
stroke after thrombolysis, primarily because of an increase in nonhemorrhagic strokes (1.2% vs 0.6%, P = .002). The numbers of patients with prior CABG randomly assigned to each treatment strategy (range 419 to 489) who also had any type of stroke (range 6 to 9 patients per treatment arm) were too small to allow comparisons among thrombolytic regimens. Although no differences were seen between patients with and without prior CABG with respect to severe or lifethreatening bleeding, moderate bleeding occurred more often in patients with prior CABG (13.8% vs 11.3%, P = .002).
Other complications Patients with prior bypass were more likely to have pulmonary edema (22.3% vs 16%, P < .001), sustained hypotension (14.9% vs 11.8%, P < .001), or cardiogenic shock (9% vs 5.8%, P < .001) (Table IV). There were slight reductions in the frequency of sustained hypoten-
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Figure 1
Odds ratios and 95% confidence intervals (CI) for 30-day mortality in the prespecified subgroup of patients with prior CABG, comparing accelerated alteplase with data pooled from both streptokinase regimens.
Table III. Major clinical end points for patients with and without prior bypass surgery, overall and by treatment group Overall
Prior bypass, by treatment group
Prior No prior bypass bypass Statistical (n = 1784) (n = 39,147) significance 24-Hour mortality (%) 30-Day mortality (%) Or nonfatal stroke Or hemorrhagic stroke Or disabling stroke 1-Year mortality
3.5 10.7 11.8 10.7 11.3 17.5
2.6 6.7 7.6 7.0 7.2 9.4
P = .041 P < .001 P < .001 P < .001 P < .001 P < .001
SK-SQ (n = 418)
SK-IV (n = 428)
Alteplase (n = 489)
3.8 10.1 11.2 10.0 10.7 18.1
2.7 11.4 12.7 11.4 12.1 16.9
3.3 9.4 10.8 9.6 10.4 16.7
Combo Statistical (n = 428) significance* 4.2 11.9 12.4 11.9 12.2 18.6
P = .97 P = .43 P = .52 P = .52 P = .58 P = .59
Data are presented as percentages. SK, Streptokinase; SQ, subcutaneous heparin; IV, intravenous heparin; Combo, combination streptokinase and alteplase with intravenous heparin. *For accelerated alteplase versus the combined streptokinase regimens.
sion (P = .003) and cardiogenic shock (P = .09) with accelerated alteplase treatment. Patients with prior CABG were slightly more likely to have ventricular fibrillation, sustained ventricular tachycardia, and acute mitral insufficiency. Patients with previous CABG had lower peak creatine kinase levels, consistent with lesser myocardial necrosis, than did patients who had never undergone CABG (mean 1576 IU/L vs 1949 IU/L, P = .001). Patients with prior bypass also were more likely to have recurrent ischemia (25.8% vs 19.7%, P < .001) and reinfarction (5.9% vs 3.9%, P < .001).
Angiographic assessment Overall, 62% of patients with prior CABG underwent diagnostic angiography during hospitalization (Table IV) versus 55% of non-CABG patients (P < .001). The reported indications for angiography were identical among the treatment groups. There was no difference
in the need for emergency angiography or later revascularization within the first 30 days. The left ventricular ejection fraction for CABG patients was 0.48 (0.35, 0.59) compared with 0.52 (0.44, 0.60) in non-CABG patients (P < .001). In patients with prior CABG, 61.9% of infarct vessels were native coronary vessels and 38.1% reflected graft occlusions. Figure 3 shows the differences in TIMI flow grades in the infarct vessels of the patients in this study (P < .001). In patients with prior CABG, approximately 50% of infarct vessels had only TIMI grade 0 or 1 flow, whereas in patients without prior bypass only 29% of infarct vessels had TIMI grade 0 or 1 flow. Conversely, in patients with prior CABG, only 32% of infarct vessels had TIMI grade 3 flow, whereas in patients without prior bypass nearly 50% of infarct vessels had TIMI grade 3 flow. Patients with prior CABG showed no differences in TIMI flow rates, whether the infarct vessel
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Figure 2
Kaplan-Meier curves of mortality to 1 year for patients with prior CABG randomly assigned to receive accelerated alteplase (short dashed line), streptokinase with subcutaneous heparin (long dashed line), streptokinase with intravenous heparin (light solid line), or combination streptokinase and alteplase with intravenous heparin (heavy solid line), plotted with actuarial analysis.
Table IV. Complications after thrombolytic therapy Overall Prior bypass (n = 1784)
No prior bypass (n = 39,119)
CHF or pulmonary edema (%) 22.3 16.0 Sustained hypotension (%) 14.9 11.8 Cardiogenic shock (%) 9.0 5.8 Ventricular fibrillation (%) 8.1 6.6 Sustained V. Tach (%) 7.3 6.1 Atrioventricular block (%)† 8.3 8.3 Atrial fibrillation/flutter (%) 10.0 9.3 Reinfarction (%) 5.9 3.9 Recurrent ischemia (%) 25.8 19.7 Acute mitral insufficiency (%) 2.3 1.4 Ventricular septal defect (%) 0.5 0.5 Angiography (%) 62.0 55.0 Emergency catheterization (%) 16.0 16.0 Angioplasty (%) 31.0 32.0 Peak CK (IU/L) Mean ± SD 1576 ± 1526 1949 ± 1855 Median (25th, 75th) 1115 (498, 1435 (658, 2203) 2686)
By treatment group Statistical significance
P < .001 P < .001 P < .001 P = .021 P = .044 P = .98 P = .34 P < .001 P < .001 P = .002 P = .88 P < .001 P = .97 P = .804
Statistical SK-SQ SK-IV Alteplase Combo signifi(n = 418) (n = 428) (n = 489) (n = 428) cance* 24.1 17.0 10.3 8.8 7.2 10.0 9.3 5.0 24.5 2.4 0.5 60.0 15.7 28.5
22.2 17.2 10.1 8.7 7.8 8.5 12.8 7.6 28.9 2.7 0.7 60.5 18.1 30.9
22.6 11.1 7.4 6.6 6.4 7.4 9.2 6.2 26.3 2.3 0.4 62.8 16.0 33.3
20.3 14.8 8.5 8.2 8.0 7.3 8.7 4.5 23.4 1.9 0.2 65.0 12.8 32.9
P = .83 P = .003 P = .085 P = .15 P = .43 P = .25 P = .28 P = .90 P = .87 P = .75 P = .98 P = .33 P = .73 P = .29
P < .001
Data are presented as percentages unless otherwise indicated. SK, streptokinase; SQ, subcutaneous heparin; IV, intravenous heparin; Combo, combination streptokinase and alteplase with intravenous heparin; CHF, congestive heart failure; V. Tach, ventricular tachycardia; CK, creatine kinase. *For accelerated alteplase versus the combined streptokinase regimens. †Second- or third-degree.
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Figure 3
TIMI flow grade in the infarct-related artery (IRA) for patients without prior bypass (white bars) and those with prior bypass where the IRA was a native coronary (striped bars) or the old bypass graft (black bars). Nearly 50% of all infarct vessels in patients with prior CABG had TIMI grade 0 or 1 flow, compared with only 29% in patients without prior bypass (P < .001). Conversely, only 32% of patients with prior bypass had TIMI grade 3 flow, compared with nearly 50% of patients without prior bypass.
was a graft or a native coronary artery. The average severity of infarct-vessel stenosis was greater in patients with prior CABG than in patients without prior CABG (99% [90%, 100%] vs 90% [80%, 99%], respectively, P < .001). Also, when the infarct-related vessel was a native artery, the stenosis was greater in patients with prior CABG than in those with no prior CABG. For example, when the infarct vessel was the left anterior descending coronary artery, the mean percent stenosis in patients without prior CABG was 84%, but it was 94% in patients with prior CABG. Among patients with prior CABG, however, the severity of stenosis in the IRA did not differ between native arteries or saphenous vein grafts (99% [90%, 100%] vs 99% [90%, 100%], respectively, P = .97).
Discussion This large series of patients with prior CABG and an acute MI provides important information about both the natural history and preferred medical treatment of these patients. At 30 days, the average mortality rate for patients with prior CABG was 10.7% overall, consider-
ably higher than the overall 7.0% mortality for all 41,021 patients enrolled in GUSTO-I. At the end of the first year, the difference in mortality increased further (17.5% vs 9.4% in patients without prior CABG). As described elsewhere, prior CABG is an independent risk factor for mortality at both 30 days and 1 year after MI.3,4 The current study provides a detailed analysis of the clinical and angiographic baseline characteristics, as well as the outcomes, of this high-risk group of patients.
Optimal treatment of patients with prior CABG Although the differences in survival were not statistically significant for this subgroup analysis, the trial had limited power to detect survival differences in all subgroups, particularly one comprising only 4% of the entire population. This report is the only large prospective, randomized study of thrombolytic therapy reporting the outcomes of patients with prior CABG and an acute MI. Although caution is always indicated with subgroup analysis, the clinical outcomes within this subset of patients are consistent, in magnitude and direction across treatments, with the results of the
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GUSTO-I trial as a whole. As in the main study, the subgroup of patients with prior CABG had the lowest mortality rate at 30 days (9.4%) with accelerated alteplase treatment. The lack of statistical significance of this observation in a subgroup analysis is expected; the critical finding is that the point estimate for the treatment effect for the subgroup is almost identical to the point estimate for the effect observed in the trial as a whole, and well within the confidence limits for this estimate.
Stroke risk Patients with prior CABG also had a slightly higher incidence of prior cerebrovascular disease and a slightly higher rate of stroke after thrombolysis. The increase in stroke was due to an increase in nonhemorrhagic stroke, which could relate to the more advanced underlying cerebrovascular disease or worse left ventricular dysfunction in this population. Nevertheless, although there was a higher risk of stroke with accelerated alteplase in the trial overall, the end points of survival without stroke, survival without disabling stroke, and survival without hemorrhagic stroke all were consistent with a net advantage for this treatment strategy compared with streptokinase. The results of this analysis for the subgroup with previous CABG are within the confidence limits for the estimate of treatment effect in the trial as a whole.
Other complications Patients with prior CABG were more likely to have other major complications of acute MI, including pulmonary edema, sustained hypotension, cardiogenic shock, ventricular fibrillation, sustained ventricular tachycardia, acute mitral insufficiency, recurrent ischemia, and reinfarction. The higher incidence of other risk factors associated with a poor prognosis, such as previous MI and advanced age and the lower rate of patency of the IRA, may have contributed to the development of these complications.
Angiographic characteristics The angiographic findings of patients with prior CABG and an acute MI differed significantly from those of patients without a history of bypass. Whether the infarct vessel was a native coronary artery or a vein graft, patients with prior CABG were more likely to have an occluded artery or to have higher percent diameter stenosis at the time of angiography (Figure 3). Although speculative, these patients likely had a greater total atheromatous burden and more advanced disease overall, as well as a greater clot burden, longer lesions, or other factors associated with a higher resistance to thrombolytic therapy. Of course, for the majority of patients, the attending physician—rather than the study protocol—determined the need for angiography; therefore some degree of selection bias may be present for
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all patients studied with angiography. Nevertheless, these data may have implications for the management of patients with previous CABG and acute MI.
Previous studies The results of this study initially appear to be discordant with the findings of other studies. In both the Veterans’ Administration (VA) Coronary Artery Bypass Surgery Cooperative Study15 and the Coronary Artery Surgery Study (CASS) Registry,16 patients with predominantly multivessel coronary disease were treated with either CABG or medical therapy. In the VA study the risk of death because of subsequent MI was higher in the medically treated patients than in the surgically treated patients, a result that seems to contradict the current study at face value. In addition, the observational study from the CASS Registry showed similar findings; the mortality in patients who had a new MI who had been treated medically was almost twice as high as in those who had been treated surgically. The critical issue in understanding the differences in these studies is the inception point of the cohort studied. In both the VA and CASS studies the medical and surgical patients had an equivalent risk at the inception of the follow-up, but patients treated surgically had the benefit of revascularization. Then, in follow-up, those who had an episode of myocardial necrosis without prior revascularization were at higher risk. In our study the inception point for the study was the time of the new MI, with the mean time from the prior bypass being 8.4 years. Patients with prior CABG are at much higher risk, predominantly because they are older and have more left ventricular dysfunction, more severe coronary disease, and more substantial peripheral and cerebral vascular disease. More recently, the BARI (Bypass Angioplasty Revascularization Investigation) investigators observed a significant reduction in mortality in diabetic patients who had a spontaneous Q-wave MI during follow-up who were initially treated with CABG compared with percutaneous transluminal coronary angioplasty (PTCA).17 Therefore these studies indicate that, in patients who have disease severe enough to merit revascularization, CABG will be protective against death should an MI occur in the future. However, because these patients are at higher risk compared with patients whose disease was not severe enough to require a prior revascularization procedure, the outcome of patients with prior CABG would be anticipated to be worse, as seen in our study.
Limitations There are several limitations to this analysis. First, conclusions from this study should be generalized only to those patients with prior CABG who have clinical symptoms of acute MI and diagnostic ECGs. To be eligible for randomization in GUSTO-I, patients were
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required to have ST-segment elevation. Some patients with prior CABG may have a less-specific ECG presentation1,2 depending on the number of other patent grafts, the amount of obstruction in the native coronary system (and thus the amount of myocardium at risk), the amount of myocardial scarring present, and whether the culprit lesion is due to thrombotic occlusion of a native coronary artery, early thrombotic occlusion of a vein graft, or late occlusion of a graft from atherosclerosis. Retrospective analyses of much smaller series1,2 have suggested that up to 75% of infarct vessels in patients with prior CABG are grafts rather than native arteries. That previous studies have more often identified vein grafts as the infarct vessel, whereas the GUSTO-I trial more often identified native arteries, may be due to the small number of patients enrolled in the retrospective series, the types of patients enrolled, or both. For example, in the GUSTO-I trial the relatively long average time from CABG to the new MI is consistent with the angiographic data, which show very advanced disease in both vein grafts and the remaining native arteries. Thus the angiographic data in this study may not represent all patients with prior CABG and acute MI, particularly those with early thrombotic veingraft occlusion and those with less dramatic ECG presentations, who would not have qualified for entry into this study. Second, most angiograms reported herein were performed at the discretion of the attending cardiologist rather than as part of a formal angiographic substudy. Therefore a selection bias (concerning the angiographic data only) toward patients with more severe disease is likely to have played a role. Finally, despite an improvement in clinical outcome and a modest improvement in survival with accelerated alteplase, the overall efficacy of intravenous thrombolysis for new acute MI in patients with prior CABG remained suboptimal. The relatively high 30-day rates of death (10.7% overall and 9.4% with the most effective regimen), recurrent ischemia, other complications, and infarct-vessel occlusion at the time of angiography confirm this. Whether newer thrombolytic agents, medical adjuncts such as low-molecular-weight heparins or platelet glycoprotein IIb/IIIa inhibitors, or more prolonged anticoagulation will accelerate reperfusion, minimize reocclusion, or both remains to be determined. Similarly, there are insufficient data to determine whether thrombolysis or percutaneous coronary revascularization is superior in these complex patients. Other investigators have suggested that acute mechanical revascularization with direct angioplasty18-20 or with devices that attempt to remove thrombus (such as the transluminal extraction catheter)21 may ultimately prove more effective. In fact, Stone et al20 have reported TIMI 3 flow rates of 70.2% in bypass grafts treated with primary mechanical revascularization
(either PTCA or CABG) for acute MI. The TIMI 3 flow rates in that study were significantly better than the 32% TIMI 3 flow rate with thrombolytics in our study. However, in a large observational study reperfusion therapy with either tissue plasminogen activator or PTCA in patients with prior CABG resulted in similar inhospital mortality and the combined end point of death and nonfatal stroke.22 These conflicting results and our findings of a poor prognosis in these patients clearly indicate that a randomized clinical trial is needed to define the optimal reperfusion therapy for acute MI in patients with prior CABG.
Conclusions In summary, patients with prior CABG treated with thrombolytic therapy for acute MI have a significantly worse outcome compared with patients without prior CABG. Patients who have had bypass surgery and who later have an acute MI have more severe infarct-vessel stenoses and a lower incidence of TIMI grade 3 flow, whether the infarct vessel is a graft or a native vessel. Despite a smaller infarct size as determined by peak serum creatine kinase level, patients with prior bypass have more complications after acute MI. Similar to patients without prior CABG, those with prior CABG appear to derive a beneficial effect of treatment with accelerated alteplase compared with streptokinase. These patients are at high risk of adverse clinical outcomes; therefore patients with prior CABG should be included in future trials of reperfusion strategies for acute MI. We thank Anthony C. DeFranco, MD, for his excellent contributions in the research and writing of this report and Pat French for her outstanding editorial work in preparing the manuscript.
References 1. Kavanaugh KM, Topol EJ. Acute intervention during myocardial infarction in patients with prior coronary bypass surgery. Am J Cardiol 1990;65:924-6. 2. Grines CL, Booth DC, Nissen SE, et al. Mechanism of acute myocardial infarction in patients with prior coronary artery bypass grafting and therapeutic implications. Am J Cardiol 1990;65:1292-6. 3. Lee KL, Woodlief LH, Topol EJ, et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction: results from an international trial of 41,021 patients. Circulation 1996;91: 1659-68. 4. Califf RM, Pieper KS, Lee KL, et al. Prediction of 1-year survival after thrombolysis for acute myocardial infarction in the GUSTO-I trial. Circulation 2000;101:2231-8. 5. Loop FD, Lytle BW, Gill CC, et al. Trends in selection and results of coronary artery reoperations. Ann Thorac Surg 1983;36:380-8. 6. Campeau L, Enjalbert M, Lesperance J, et al. Atherosclerosis and late closure of aortocoronary saphenous vein grafts: sequential angiographic studies at 2 weeks, 1 year, 5 to 7 years, and 10 to 12 years after surgery. Circulation 1983;68:II1-7.
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7. Campeau L, Lesperance J, Bourassa M. Natural history of saphenous vein aortocoronary bypass grafts. Mod Concepts Cardiovasc Dis 1984;53:59-63. 8. Cameron A, Kemp HG Jr, Shimomura S, et al. Aortocoronary bypass surgery: a 7–year follow-up. Circulation 1979;60:9-13. 9. Campeau L, Lesperance J, Hermann J, et al. Loss of the improvement of angina between 1 and 7 years after aortocoronary bypass surgery: correlations with changes in vein grafts and in coronary arteries. Circulation 1979;60:1-5. 10. Johnson WD, Kayser KL, Pedraza PM. Angina pectoris and coronary bypass surgery: patterns of prevalence and recurrence in 3105 consecutive patients followed up to 11 years. Am Heart J 1984;108:1190-7. 11. Kleiman NS, Berman DA, Gaston WR, et al. Early intravenous thrombolytic therapy for acute myocardial infarction in patients with prior coronary artery bypass grafts. Am J Cardiol 1989;63: 102-4. 12. GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673-82. 13. Topol EJ, Armstrong P, Van de Werf F, et al. Confronting the issues of patient safety and investigator conflict of interest in an international clinical trial of myocardial reperfusion. J Am Coll Cardiol 1992;19:1123-8. 14. 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;329:1615-22. 15. Peduzzi P, Detre K, Murphy ML, et al. Ten-year incidence of myocardial infarction and prognosis after infarction: Department of
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16.
17.
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20.
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Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery. Circulation 1991;83:747-55. Davis KB, Alderman EL, Kosinski AS, et al. Early mortality of acute myocardial infarction in patients with and without prior coronary revascularization surgery: a Coronary Artery Surgery Study Registry Study. Circulation 1992;85:2100-9. Detre KM, Lombardero MS, Brooks MM, et al. The effect of previous coronary-artery bypass surgery on the prognosis of patients with diabetes who have acute myocardial infarction: Bypass Angioplasty Revascularization Investigation Investigators. N Engl J Med 2000;342:989-97. O’Keefe JH Jr, Bailey WL, Rutherford BD, et al. Primary angioplasty for acute myocardial infarction in 1,000 consecutive patients: results in an unselected population and high-risk subgroups. Am J Cardiol 1993;72:107-15G. Kahn JK, Rutherford BD, McConahay DR, et al. Usefulness of angioplasty during acute myocardial infarction in patients with prior coronary artery bypass grafting. Am J Cardiol 1990;65:698-702. Stone GW, Brodie BR, Griffin JJ, et al. Clinical and angiographic outcomes in patients with previous coronary artery bypass graft surgery treated with primary balloon angioplasty for acute myocardial infarction: second Primary Angioplasty in Myocardial Infarction Trial (PAMI-2) Investigators. J Am Coll Cardiol 2000;35:605-11. Kaplan BM, Larkin T, Safian RD, et al. Prospective study of extraction atherectomy in patients with acute myocardial infarction. Am J Cardiol 1996;78:383-8. Peterson LR, Chandra NC, French WJ, et al. Reperfusion therapy in patients with acute myocardial infarction and prior coronary artery bypass graft surgery (National Registry of Myocardial Infarction-2). Am J Cardiol 1999;84:1287–91.
Background Patients with prior coronary bypass surgery with acute ST-segment elevation myocardial infarction (MI) pose an increasingly common clinical problem. We assessed the characteristics and outcomes of such patients undergoing thrombolysis for acute MI.
Methods and Results We compared the characteristics and outcomes of patients in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial (GUSTO-I) who had had prior bypass (n = 1784, 4% of the population) with those without prior coronary artery bypass grafting (CABG), all of whom were randomized to receive one of four thrombolytic strategies. Patients with prior bypass were older with significantly more prior MI and angina. Overall, 30-day mortality was significantly higher in patients with prior bypass (10.7% vs 6.7% for no prior bypass, P < .001); these patients also had significantly more pulmonary edema, sustained hypotension, or cardiogenic shock. Patients with prior bypass showed a 12.5% relative reduction (95% confidence interval, 0% to 41.9%) in 30-day mortality with accelerated alteplase over the streptokinase monotherapies. In the 62% of patients with prior CABG who underwent coronary angiography, the infarct-related vessel was a native coronary artery in 61.9% and a bypass graft in 38.1% of cases. The Thrombolysis in Myocardial Infarction (TIMI) 3 flow rate was 30.5% for culprit native coronary arteries and 31.7% for culprit bypass grafts. Patients with prior bypass had more severe infarct-vessel stenoses (99% [90%, 100%] vs 90% [80%, 99%], P < .001). Conclusions The 30-day mortality in patients with prior CABG was significantly higher than that for patients without prior CABG. As in the overall trial, these patients derived an incremental survival benefit from treatment with accelerated alteplase, but mortality remained high (16.7%) at 1 year. These results are at least partially explained by the higher baseline risk of these patients and by the lower rate of patency of the infarct-related artery. (Am Heart J 2001;141:469-77.)
Although numerous randomized trials have shown that thrombolysis improves vessel patency, preserves left ventricular function, and improves survival after acute myocardial infarction (MI), patients with prior coronary artery bypass grafting (CABG) usually have From the aDivision of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada, bDuke Clinical Research Institute, Durham, NC, the cDepartment of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, and the dDivision of Cardiology, Mayo Clinic, Rochester, Minn. Supported by Bayer, New York, NY, CIBA-Corning, Medfield, Mass, ICI Pharmaceuticals, Wilmington, Del, Genentech, South San Francisco, Calif, and Sanofi Pharmaceuticals, Paris, France. M. L. was a research fellow of the Heart and Stroke Foundation of Canada during this study. Submitted February 17, 2000; accepted October 10, 2000. Reprint requests: Marino Labinaz, MD, University of Ottawa Heart Institute, Department of Medicine, Division of Cardiology, Room 150, 40 Ruskin Ave, Ottawa, Ontario K1Y 4W7, Canada. E-mail: [email protected] Copyright © 2001 by Mosby, Inc. 0002-8703/2001/$12.00 + 0 4/1/112779 doi:10.1067/mhj.2001.112779
been excluded from these trials. As a result, relatively little is known about their natural history and preferred treatment of new acute MI. Data on relatively small numbers of patients in nonrandomized series1,2 suggest that the potential benefits and risks of intravenous thrombolysis may differ for this subgroup because of a larger thrombus burden in the infarct vessel, a smaller myocardial area at risk, and more advanced disease in the remaining native vessels. Furthermore, multivariable analyses have identified prior CABG as an independent risk factor for mortality at 30 days and 1 year after MI.3,4 The optimal treatment strategy for these patients is a major public health issue. The number of patients undergoing CABG increases each year; in 1993 alone, more than 750,000 patients underwent the procedure worldwide.5 Many grafts ultimately will degenerate and cause acute occlusion with the sequelae of ischemia, MI, or death. Sequential angiographic studies have shown first-year failure rates of 15% to 20%6 and later
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annual rates of about 4%. Thus by 10 years about 50% of vein grafts may be occluded.7 Finally, the annual incidence of MI after CABG is 3% to 8%.1,8-11 The Global Utilization of Streptokinase and Tissue Plasminogen Activator (alteplase) for Occluded Coronary Arteries (GUSTO-I) trial was designed to test the hypothesis that early, sustained infarct-artery patency is associated with better survival in patients with evolving acute MI.12 The 41,021 study patients included 1784 with prior CABG who were prospectively selected for subgroup analysis. This report focuses on the early and late outcomes of these patients compared with patients in GUSTO-I without prior CABG and assesses the relative efficacy of the four thrombolytic strategies.
Methods Patients The complete protocol of the GUSTO-I trial has been described,12 as have the methods of data collection, management, and quality assurance and the relationship of the study investigators to the sponsors.12,13 Patients were eligible for randomization if they came to a hospital <6 hours after the onset of symptoms, with chest pain lasting ≥ 20 minutes and accompanied by electrocardiographic (ECG) signs of ≥0.1 mV ST-segment elevation in two or more limb leads or ≥0.2 mV elevation in two or more contiguous precordial leads. Patients with prior CABG were eligible for enrollment. Previous stroke, active bleeding, previous treatment with streptokinase or anistreplase, major trauma or surgery within 6 months, previous enrollment in GUSTO-I, and noncompressible arterial punctures were criteria for exclusion. Uncontrolled hypertension (systolic blood pressure ≥180 mm Hg unresponsive to therapy) was considered a relative contraindication to study enrollment. The institutional review board at each institution approved the protocol, and patients gave informed consent for participation.
Randomization and treatment strategies A central coordinating center reviewed the eligibility of all patients and randomly assigned them to one of four treatment strategies: streptokinase with subcutaneous heparin, streptokinase with intravenous heparin, accelerated alteplase with intravenous heparin, or combined alteplase and streptokinase with intravenous heparin. Intravenous heparin was given for ≥48 hours (longer at the investigator’s discretion); subcutaneous heparin was continued for 7 days or until the patient was discharged. Patient enrollment was not stratified according to prior CABG, nor was there any stratification among the treatment groups with respect to prior CABG. Information about prior CABG was obtained from the patient on enrollment, or from a representative if the patient was unable to communicate. Patients received chewable aspirin ≥160 mg as soon as possible after presentation, followed by 160 to 325 mg daily. The activated partial thromboplastin time was monitored at 6, 12, and 24 hours for titration of the intravenous heparin dose. Patients without a contraindication to β-blockade received 10 mg of intravenous atenolol in two divided doses, followed by an oral dose of 50 to 100 mg daily. All other medications were
prescribed at the discretion of the attending physician. Except for the 2431 patients enrolled in the angiographic substudy,14 the use of coronary angiography was at the discretion of the attending physician, as was the use of angioplasty or CABG.
End points The primary end point was death from any cause within 30 days. Other prospectively defined clinical outcomes were the combined end points of death or nonfatal stroke, death or nonfatal hemorrhagic stroke, and death or nonfatal disabling stroke. One-year mortality also was tabulated. Bleeding complications were classified as severe or life threatening if they were intracerebral or resulted in substantial hemodynamic compromise requiring treatment. Moderate bleeding was defined by the need for transfusion. Minor bleeding referred to other bleeding not requiring transfusion or causing hemodynamic compromise. In this report, coronary stenoses and Thrombolysis In Myocardial Infarction (TIMI) flow grades were estimated by the physicians performing angiography.
Statistical analysis Selected baseline characteristics and clinical outcomes were compared in patients with and without previous CABG, overall and by treatment assignment. Categorical factors are presented as percentages. Continuous measures are reported as medians (25th, 75th percentiles) unless otherwise indicated. The Wilcoxon sign-rank test was used to assess the univariable relationships between continuous baseline factors and outcomes and prior CABG. The relationship between categorical factors and prior CABG was evaluated with a log-likelihood chi-square test. Similarly, a log-likelihood chi-square test was used to determine whether prior CABG was a prognostic indicator of mortality at 30 days, stroke, bleeding, or other postrandomization complications. Two sets of models have been developed from GUSTO-I that predict mortality. Lee et al3 determined the set of baseline clinical factors that together predict 30-day mortality, and Califf et al4 similarly predicted survival from 30 days to 1 year by use of baseline and hospital-course information. The effect of previous CABG in these two prognostic models was assessed as the effect of prior CABG on survival after adjustment for other known prognostic factors. Long-term survival estimates were described with Kaplan-Meier curves.
Results Patient characteristics Of the 41,021 patients enrolled in the trial between December 27, 1990, and February 22, 1993, 1784 had had prior CABG (90 patients had no prior CABG information and were excluded). Compared with the other patients in the study, those with prior CABG were older, more often male, had more cardiac risk factors, and were more likely to have had a prior MI (65.0% vs 14.2%, P < .001) or a history of angina (77.8% vs 35.0%, P < .001) (Table I). The mean time from prior CABG to the index MI was 8.6 ± 4.6 years. There were no significant differences among patients with prior CABG assigned to the various treatment strategies.
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Table I. Baseline clinical characteristics Prior bypass (n = 1784) Age (y) Female sex (%) Diabetes (%) Former smoker (%) Current smoker (%) Hypertension (%) Systolic blood pressure (mm Hg) Prior infarction (%) Prior angina (%) Prior angioplasty (%) Prior cerebrovascular disease (%)
64.4 (57, 70) 16.2 17.8 43.9 29.8 45.7 128 (112, 143) 65.0 77.8 17.5 4.8
No prior bypass (n = 39,147)
Statistical significance P < .001 P < .001 P < .001 P < .001 P < .001 P < .001 P = .24 P < .001 P < .001 P < .001 P < .001
61.4 (52, 70) 25.6 14.5 26.7 43.5 37.7 130 (112, 144) 14.2 35.0 3.4 1.9
Data are presented as median (25th, 75th percentiles) or percentages.
Compared with patients without prior CABG, patients with prior CABG had a slightly lower incidence of anterior MI and a slightly higher incidence of Killip class II heart failure at the time of presentation (Table II). Of note, patients with or without prior CABG had similar times to enrollment. Among patients with prior CABG, clinical features were evenly distributed among the four treatment groups.
Study medications Overall compliance with the study protocol and medications for the entire group of patients in GUSTO-I was excellent and has been described.12 Of note, patients with prior CABG were much more likely to receive digitalis preparations (21% vs 13%, P < .001), calciumchannel blockers (43% vs 30%, P < .001), and lidocaine (19% vs 16%, P = .002). Patients with prior CABG also were more likely to receive intravenous or oral nitrates (91% vs 86%, P < .001) and angiotensin-converting enzyme inhibitors (25% vs 22%, P = .003). β-Blockers were given to patients with and without prior CABG at equally high frequencies. Patients with prior CABG did not differ among thrombolytic strategies with respect to concomitant medications.
Major clinical outcomes The average 30-day mortality rate in patients with prior CABG for all four treatment strategies was 10.7%, significantly higher than the 6.7% mortality rate for the 39,147 patients without prior CABG (P < .001, Table III). As in the study as a whole, the subgroup of patients with prior CABG who received accelerated alteplase had lower 30-day mortality (9.4%, Figure 1) than did patients in the combined streptokinase groups (10.8%, P = .43). Patients treated with accelerated alteplase continued to have a lower mortality at 1 year, as shown in actuarial analysis (Figure 2, P = .72). Patients with prior CABG, who had more previous cerebrovascular disease at baseline, had a higher rate of
Table II. Clinical features on presentation
Infarct location (%)* Anterior Inferior Other Killip class (%)† I II III or IV Time to enrollment (h) Time to treatment (h) Time to hospitalization (h)‡
Prior bypass (n = 1784)
No prior bypass (n = 39,119)
34.2 61.5 4.2
39.3 57.3 3.3
81.6 16.5 2.0 2.0 (1.3,3.0) 2.8 (2.0, 3.9) 1.5 (0.9, 2.3)
85.5 12.4 2.1 2.0 (1.3, 3.0) 2.8 (2.0, 3.9) 1.5 (1.0, 2.5)
Data are presented as percentages or medians (25th, 75th percentiles). *P = .001 anterior versus other locations, patients with versus without prior bypass. †P < .001 Killip class I versus all others, patients with versus without prior bypass. ‡P < .01 patients with versus without prior bypass.
stroke after thrombolysis, primarily because of an increase in nonhemorrhagic strokes (1.2% vs 0.6%, P = .002). The numbers of patients with prior CABG randomly assigned to each treatment strategy (range 419 to 489) who also had any type of stroke (range 6 to 9 patients per treatment arm) were too small to allow comparisons among thrombolytic regimens. Although no differences were seen between patients with and without prior CABG with respect to severe or lifethreatening bleeding, moderate bleeding occurred more often in patients with prior CABG (13.8% vs 11.3%, P = .002).
Other complications Patients with prior bypass were more likely to have pulmonary edema (22.3% vs 16%, P < .001), sustained hypotension (14.9% vs 11.8%, P < .001), or cardiogenic shock (9% vs 5.8%, P < .001) (Table IV). There were slight reductions in the frequency of sustained hypoten-
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Figure 1
Odds ratios and 95% confidence intervals (CI) for 30-day mortality in the prespecified subgroup of patients with prior CABG, comparing accelerated alteplase with data pooled from both streptokinase regimens.
Table III. Major clinical end points for patients with and without prior bypass surgery, overall and by treatment group Overall
Prior bypass, by treatment group
Prior No prior bypass bypass Statistical (n = 1784) (n = 39,147) significance 24-Hour mortality (%) 30-Day mortality (%) Or nonfatal stroke Or hemorrhagic stroke Or disabling stroke 1-Year mortality
3.5 10.7 11.8 10.7 11.3 17.5
2.6 6.7 7.6 7.0 7.2 9.4
P = .041 P < .001 P < .001 P < .001 P < .001 P < .001
SK-SQ (n = 418)
SK-IV (n = 428)
Alteplase (n = 489)
3.8 10.1 11.2 10.0 10.7 18.1
2.7 11.4 12.7 11.4 12.1 16.9
3.3 9.4 10.8 9.6 10.4 16.7
Combo Statistical (n = 428) significance* 4.2 11.9 12.4 11.9 12.2 18.6
P = .97 P = .43 P = .52 P = .52 P = .58 P = .59
Data are presented as percentages. SK, Streptokinase; SQ, subcutaneous heparin; IV, intravenous heparin; Combo, combination streptokinase and alteplase with intravenous heparin. *For accelerated alteplase versus the combined streptokinase regimens.
sion (P = .003) and cardiogenic shock (P = .09) with accelerated alteplase treatment. Patients with prior CABG were slightly more likely to have ventricular fibrillation, sustained ventricular tachycardia, and acute mitral insufficiency. Patients with previous CABG had lower peak creatine kinase levels, consistent with lesser myocardial necrosis, than did patients who had never undergone CABG (mean 1576 IU/L vs 1949 IU/L, P = .001). Patients with prior bypass also were more likely to have recurrent ischemia (25.8% vs 19.7%, P < .001) and reinfarction (5.9% vs 3.9%, P < .001).
Angiographic assessment Overall, 62% of patients with prior CABG underwent diagnostic angiography during hospitalization (Table IV) versus 55% of non-CABG patients (P < .001). The reported indications for angiography were identical among the treatment groups. There was no difference
in the need for emergency angiography or later revascularization within the first 30 days. The left ventricular ejection fraction for CABG patients was 0.48 (0.35, 0.59) compared with 0.52 (0.44, 0.60) in non-CABG patients (P < .001). In patients with prior CABG, 61.9% of infarct vessels were native coronary vessels and 38.1% reflected graft occlusions. Figure 3 shows the differences in TIMI flow grades in the infarct vessels of the patients in this study (P < .001). In patients with prior CABG, approximately 50% of infarct vessels had only TIMI grade 0 or 1 flow, whereas in patients without prior bypass only 29% of infarct vessels had TIMI grade 0 or 1 flow. Conversely, in patients with prior CABG, only 32% of infarct vessels had TIMI grade 3 flow, whereas in patients without prior bypass nearly 50% of infarct vessels had TIMI grade 3 flow. Patients with prior CABG showed no differences in TIMI flow rates, whether the infarct vessel
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Figure 2
Kaplan-Meier curves of mortality to 1 year for patients with prior CABG randomly assigned to receive accelerated alteplase (short dashed line), streptokinase with subcutaneous heparin (long dashed line), streptokinase with intravenous heparin (light solid line), or combination streptokinase and alteplase with intravenous heparin (heavy solid line), plotted with actuarial analysis.
Table IV. Complications after thrombolytic therapy Overall Prior bypass (n = 1784)
No prior bypass (n = 39,119)
CHF or pulmonary edema (%) 22.3 16.0 Sustained hypotension (%) 14.9 11.8 Cardiogenic shock (%) 9.0 5.8 Ventricular fibrillation (%) 8.1 6.6 Sustained V. Tach (%) 7.3 6.1 Atrioventricular block (%)† 8.3 8.3 Atrial fibrillation/flutter (%) 10.0 9.3 Reinfarction (%) 5.9 3.9 Recurrent ischemia (%) 25.8 19.7 Acute mitral insufficiency (%) 2.3 1.4 Ventricular septal defect (%) 0.5 0.5 Angiography (%) 62.0 55.0 Emergency catheterization (%) 16.0 16.0 Angioplasty (%) 31.0 32.0 Peak CK (IU/L) Mean ± SD 1576 ± 1526 1949 ± 1855 Median (25th, 75th) 1115 (498, 1435 (658, 2203) 2686)
By treatment group Statistical significance
P < .001 P < .001 P < .001 P = .021 P = .044 P = .98 P = .34 P < .001 P < .001 P = .002 P = .88 P < .001 P = .97 P = .804
Statistical SK-SQ SK-IV Alteplase Combo signifi(n = 418) (n = 428) (n = 489) (n = 428) cance* 24.1 17.0 10.3 8.8 7.2 10.0 9.3 5.0 24.5 2.4 0.5 60.0 15.7 28.5
22.2 17.2 10.1 8.7 7.8 8.5 12.8 7.6 28.9 2.7 0.7 60.5 18.1 30.9
22.6 11.1 7.4 6.6 6.4 7.4 9.2 6.2 26.3 2.3 0.4 62.8 16.0 33.3
20.3 14.8 8.5 8.2 8.0 7.3 8.7 4.5 23.4 1.9 0.2 65.0 12.8 32.9
P = .83 P = .003 P = .085 P = .15 P = .43 P = .25 P = .28 P = .90 P = .87 P = .75 P = .98 P = .33 P = .73 P = .29
P < .001
Data are presented as percentages unless otherwise indicated. SK, streptokinase; SQ, subcutaneous heparin; IV, intravenous heparin; Combo, combination streptokinase and alteplase with intravenous heparin; CHF, congestive heart failure; V. Tach, ventricular tachycardia; CK, creatine kinase. *For accelerated alteplase versus the combined streptokinase regimens. †Second- or third-degree.
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Figure 3
TIMI flow grade in the infarct-related artery (IRA) for patients without prior bypass (white bars) and those with prior bypass where the IRA was a native coronary (striped bars) or the old bypass graft (black bars). Nearly 50% of all infarct vessels in patients with prior CABG had TIMI grade 0 or 1 flow, compared with only 29% in patients without prior bypass (P < .001). Conversely, only 32% of patients with prior bypass had TIMI grade 3 flow, compared with nearly 50% of patients without prior bypass.
was a graft or a native coronary artery. The average severity of infarct-vessel stenosis was greater in patients with prior CABG than in patients without prior CABG (99% [90%, 100%] vs 90% [80%, 99%], respectively, P < .001). Also, when the infarct-related vessel was a native artery, the stenosis was greater in patients with prior CABG than in those with no prior CABG. For example, when the infarct vessel was the left anterior descending coronary artery, the mean percent stenosis in patients without prior CABG was 84%, but it was 94% in patients with prior CABG. Among patients with prior CABG, however, the severity of stenosis in the IRA did not differ between native arteries or saphenous vein grafts (99% [90%, 100%] vs 99% [90%, 100%], respectively, P = .97).
Discussion This large series of patients with prior CABG and an acute MI provides important information about both the natural history and preferred medical treatment of these patients. At 30 days, the average mortality rate for patients with prior CABG was 10.7% overall, consider-
ably higher than the overall 7.0% mortality for all 41,021 patients enrolled in GUSTO-I. At the end of the first year, the difference in mortality increased further (17.5% vs 9.4% in patients without prior CABG). As described elsewhere, prior CABG is an independent risk factor for mortality at both 30 days and 1 year after MI.3,4 The current study provides a detailed analysis of the clinical and angiographic baseline characteristics, as well as the outcomes, of this high-risk group of patients.
Optimal treatment of patients with prior CABG Although the differences in survival were not statistically significant for this subgroup analysis, the trial had limited power to detect survival differences in all subgroups, particularly one comprising only 4% of the entire population. This report is the only large prospective, randomized study of thrombolytic therapy reporting the outcomes of patients with prior CABG and an acute MI. Although caution is always indicated with subgroup analysis, the clinical outcomes within this subset of patients are consistent, in magnitude and direction across treatments, with the results of the
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GUSTO-I trial as a whole. As in the main study, the subgroup of patients with prior CABG had the lowest mortality rate at 30 days (9.4%) with accelerated alteplase treatment. The lack of statistical significance of this observation in a subgroup analysis is expected; the critical finding is that the point estimate for the treatment effect for the subgroup is almost identical to the point estimate for the effect observed in the trial as a whole, and well within the confidence limits for this estimate.
Stroke risk Patients with prior CABG also had a slightly higher incidence of prior cerebrovascular disease and a slightly higher rate of stroke after thrombolysis. The increase in stroke was due to an increase in nonhemorrhagic stroke, which could relate to the more advanced underlying cerebrovascular disease or worse left ventricular dysfunction in this population. Nevertheless, although there was a higher risk of stroke with accelerated alteplase in the trial overall, the end points of survival without stroke, survival without disabling stroke, and survival without hemorrhagic stroke all were consistent with a net advantage for this treatment strategy compared with streptokinase. The results of this analysis for the subgroup with previous CABG are within the confidence limits for the estimate of treatment effect in the trial as a whole.
Other complications Patients with prior CABG were more likely to have other major complications of acute MI, including pulmonary edema, sustained hypotension, cardiogenic shock, ventricular fibrillation, sustained ventricular tachycardia, acute mitral insufficiency, recurrent ischemia, and reinfarction. The higher incidence of other risk factors associated with a poor prognosis, such as previous MI and advanced age and the lower rate of patency of the IRA, may have contributed to the development of these complications.
Angiographic characteristics The angiographic findings of patients with prior CABG and an acute MI differed significantly from those of patients without a history of bypass. Whether the infarct vessel was a native coronary artery or a vein graft, patients with prior CABG were more likely to have an occluded artery or to have higher percent diameter stenosis at the time of angiography (Figure 3). Although speculative, these patients likely had a greater total atheromatous burden and more advanced disease overall, as well as a greater clot burden, longer lesions, or other factors associated with a higher resistance to thrombolytic therapy. Of course, for the majority of patients, the attending physician—rather than the study protocol—determined the need for angiography; therefore some degree of selection bias may be present for
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all patients studied with angiography. Nevertheless, these data may have implications for the management of patients with previous CABG and acute MI.
Previous studies The results of this study initially appear to be discordant with the findings of other studies. In both the Veterans’ Administration (VA) Coronary Artery Bypass Surgery Cooperative Study15 and the Coronary Artery Surgery Study (CASS) Registry,16 patients with predominantly multivessel coronary disease were treated with either CABG or medical therapy. In the VA study the risk of death because of subsequent MI was higher in the medically treated patients than in the surgically treated patients, a result that seems to contradict the current study at face value. In addition, the observational study from the CASS Registry showed similar findings; the mortality in patients who had a new MI who had been treated medically was almost twice as high as in those who had been treated surgically. The critical issue in understanding the differences in these studies is the inception point of the cohort studied. In both the VA and CASS studies the medical and surgical patients had an equivalent risk at the inception of the follow-up, but patients treated surgically had the benefit of revascularization. Then, in follow-up, those who had an episode of myocardial necrosis without prior revascularization were at higher risk. In our study the inception point for the study was the time of the new MI, with the mean time from the prior bypass being 8.4 years. Patients with prior CABG are at much higher risk, predominantly because they are older and have more left ventricular dysfunction, more severe coronary disease, and more substantial peripheral and cerebral vascular disease. More recently, the BARI (Bypass Angioplasty Revascularization Investigation) investigators observed a significant reduction in mortality in diabetic patients who had a spontaneous Q-wave MI during follow-up who were initially treated with CABG compared with percutaneous transluminal coronary angioplasty (PTCA).17 Therefore these studies indicate that, in patients who have disease severe enough to merit revascularization, CABG will be protective against death should an MI occur in the future. However, because these patients are at higher risk compared with patients whose disease was not severe enough to require a prior revascularization procedure, the outcome of patients with prior CABG would be anticipated to be worse, as seen in our study.
Limitations There are several limitations to this analysis. First, conclusions from this study should be generalized only to those patients with prior CABG who have clinical symptoms of acute MI and diagnostic ECGs. To be eligible for randomization in GUSTO-I, patients were
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required to have ST-segment elevation. Some patients with prior CABG may have a less-specific ECG presentation1,2 depending on the number of other patent grafts, the amount of obstruction in the native coronary system (and thus the amount of myocardium at risk), the amount of myocardial scarring present, and whether the culprit lesion is due to thrombotic occlusion of a native coronary artery, early thrombotic occlusion of a vein graft, or late occlusion of a graft from atherosclerosis. Retrospective analyses of much smaller series1,2 have suggested that up to 75% of infarct vessels in patients with prior CABG are grafts rather than native arteries. That previous studies have more often identified vein grafts as the infarct vessel, whereas the GUSTO-I trial more often identified native arteries, may be due to the small number of patients enrolled in the retrospective series, the types of patients enrolled, or both. For example, in the GUSTO-I trial the relatively long average time from CABG to the new MI is consistent with the angiographic data, which show very advanced disease in both vein grafts and the remaining native arteries. Thus the angiographic data in this study may not represent all patients with prior CABG and acute MI, particularly those with early thrombotic veingraft occlusion and those with less dramatic ECG presentations, who would not have qualified for entry into this study. Second, most angiograms reported herein were performed at the discretion of the attending cardiologist rather than as part of a formal angiographic substudy. Therefore a selection bias (concerning the angiographic data only) toward patients with more severe disease is likely to have played a role. Finally, despite an improvement in clinical outcome and a modest improvement in survival with accelerated alteplase, the overall efficacy of intravenous thrombolysis for new acute MI in patients with prior CABG remained suboptimal. The relatively high 30-day rates of death (10.7% overall and 9.4% with the most effective regimen), recurrent ischemia, other complications, and infarct-vessel occlusion at the time of angiography confirm this. Whether newer thrombolytic agents, medical adjuncts such as low-molecular-weight heparins or platelet glycoprotein IIb/IIIa inhibitors, or more prolonged anticoagulation will accelerate reperfusion, minimize reocclusion, or both remains to be determined. Similarly, there are insufficient data to determine whether thrombolysis or percutaneous coronary revascularization is superior in these complex patients. Other investigators have suggested that acute mechanical revascularization with direct angioplasty18-20 or with devices that attempt to remove thrombus (such as the transluminal extraction catheter)21 may ultimately prove more effective. In fact, Stone et al20 have reported TIMI 3 flow rates of 70.2% in bypass grafts treated with primary mechanical revascularization
(either PTCA or CABG) for acute MI. The TIMI 3 flow rates in that study were significantly better than the 32% TIMI 3 flow rate with thrombolytics in our study. However, in a large observational study reperfusion therapy with either tissue plasminogen activator or PTCA in patients with prior CABG resulted in similar inhospital mortality and the combined end point of death and nonfatal stroke.22 These conflicting results and our findings of a poor prognosis in these patients clearly indicate that a randomized clinical trial is needed to define the optimal reperfusion therapy for acute MI in patients with prior CABG.
Conclusions In summary, patients with prior CABG treated with thrombolytic therapy for acute MI have a significantly worse outcome compared with patients without prior CABG. Patients who have had bypass surgery and who later have an acute MI have more severe infarct-vessel stenoses and a lower incidence of TIMI grade 3 flow, whether the infarct vessel is a graft or a native vessel. Despite a smaller infarct size as determined by peak serum creatine kinase level, patients with prior bypass have more complications after acute MI. Similar to patients without prior CABG, those with prior CABG appear to derive a beneficial effect of treatment with accelerated alteplase compared with streptokinase. These patients are at high risk of adverse clinical outcomes; therefore patients with prior CABG should be included in future trials of reperfusion strategies for acute MI. We thank Anthony C. DeFranco, MD, for his excellent contributions in the research and writing of this report and Pat French for her outstanding editorial work in preparing the manuscript.
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