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J Thorac Cardiovasc Surg 1994;107:1454-1459
© 1994 Mosby, Inc.

SURGERY FOR ACQUIRED HEART DISEASE

Surgical revascularization after fibrinolysis in acute myocardial infarctionLong-term follow-up

São José do Rio Preto, Brazil

From the Instituto de Moléstias Cardiovasculares, São José do Rio Preto, Brazil.

Received for publication June 2, 1993. Accepted for publication Nov. 2, 1993. Address for reprints: José Carlos Nicolau, MD, Instituto de Moléstias Cardiovasculares, Rua Castelo D'Agua, 3030, São José do Rio Preto, 15015-210, Brazil.

Abstract

One hundred twenty-eight patients with myocardial infarction who underwent operation for myocardial revascularization and 147 patients who received medical therapy were followed up for up to 6 years: all patients had received treatment with intravenous streptokinase. In the surgical group, 91.5% of the patients had the region related to the infarction revascularized, and in 82.8% of them the mammary artery was used. Statistically significant differences were not detected between the groups according to infarct size, clinical features, and left ventricular ejection fraction. However, there was a higher risk in the surgical group, as compared with that in the medical group, in terms of anatomic characteristics: 99.2% versus 77.1% of the patients showed more than 70% residual obstruction at the "culprit" coronary artery ( p < 0.001, 95% confidence interval 14.1% to 30.1%) and 76.8% versus 40.7% showed multivessel coronary disease ( p < 0.001, 95% confidence interval 23.7% to 48.5%). In-hospital survival was 95.3% in the surgical group and 89.1% in the medical group ( p = 0.096, 95% confidence interval -0.2% to 12.6%). Significantly higher survivals were obtained for the surgical group both during the first (93% ± 2.3% versus 80.3% ± 3.3%, p = 0.005) and the sixth (86.4% ± 3.4% versus 68.4% ± 4.3%, p = 0.003) year of follow-up. Statistically significant differences were also obtained when in-hospital deaths were excluded. A Cox regression model with 13 variables showed that only age ( p = 0.0422) and medical treatment ( p = 0.0194) correlated independently with mortality. It is concluded that in this nonrandomized study, operation led to a significantly higher survival both on a medium- and long-term basis, when compared with that obtained for patients receiving medical therapy. (J THORAC CARDIOVASC SURG 1994;107:1454-9)

Additional postfibrinolytic procedures such as coronary artery bypass grafting and coronary angioplasty are commonly used. The main objective of these two procedures is to maintain coronary blood flow inasmuch as reinfarction is common and more frequent in patients who undergo thrombolytic treatment than in patients maintained in control groups. ¹

On the other hand, several publications have demonstrated that surgical therapy is suitable after fibrinolytic treatment by either the intravenous or the intracoronary routes. ^2-8 None of the studies available regarding the out-of-hospital medical course of such patients has reported an overall comparison between patients who undergo operation and patients who receive medical therapy. ^9-14

The purpose of this study was to determine the medium-term (first year) and long-term (sixth year) effects of operation for myocardial revascularization as a complement to fibrinolytic therapy with intravenous streptokinase in patients with acute myocardial infarction (AMI).

PATIENTS AND METHODS

A prospective and consecutive study was conducted on 332 patients with myocardial infarction (mean age 55.6 ± 10 years) treated between October 1985 and November 1990 with intravenous streptokinase. This population included all patients who received intravenous streptokinase during that time frame; such treatment was suggested for all patients who fulfilled the following inclusion criteria, and none of them refused to receive the drug: (1) "functional" age of up to 70 years, that is, patients older than 70 years could be included if in good clinical condition and actively working; (2) clinical signs and symptoms of AMI, with symptoms beginning at least 20 minutes and no more than 6 hours before streptokinase infusion was begun; and (3) electrocardiogram with ST segment elevation greater than 1.5 mm in at least two contiguous leads. The exclusion criteria included previous use of streptokinase between 4 days and six months, pregnant women, cardiopulmonary resuscitation maneuver, cerebral stroke in the past 6 months, gastrointestinal/urologic bleeding in the past 3 months, important trauma or operation in the past 6 months, systolic (>180 mm Hg) or diastolic (>110 mm Hg) hypertension unresponsive to sublingual nifedipine, and other life-threatening disease (such as cancer, coma, sepsis). All patients fulfilled at least two of the following criteria for AMI: acute pain with ischemic characteristics for at least 20 minutes, ST segment elevation greater than 1.5 mm in at least two contiguous leads after receiving sublingual dinitrate isosorbide, and creatine kinase MB (CK-MB) elevation of at least double its normal value (>20 IU/L).

One hundred forty-seven patients (44.3%) received medical therapy, 128 (38.5%) were operated on in the same hospital admission, and the remaining 57 (17.2%) underwent transluminal coronary angioplasty also during the same hospitalization. Invasive treatment (operation or angioplasty) was indicated when more than 70% luminal obstruction of one or more of the major coronary arteries and angiographic demonstration of contractility in the same areas were detected, indicating a significant myocardial area "at risk." Coronary cineangiography and left ventricular (LV) ventriculography were suggested to all patients between 48 and 72 hours after streptokinase infusion (mean 61.2 ± 58.7 hours; median 48 hours) and was actually done on 300 of them. Of the remaining 32 patients, 12 died before the test, 17 refused the test, and three underwent catheterization in other instituions. Contrast LV ejection fraction was obtained with computer software especially developed for this purpose at the Heart Institute in São Paulo, Brazil. With this method, the mean normal ejection fraction was 78% ± 7.3% in our institution.

The protocol was the same for all patients: the streptokinase dose used was 750,000 units infused intravenously over a period of 15 minutes, with 200,000 units injected as a bolus. As adjuvant therapy, in addition to vasodilator drugs, sedatives, and oxygen treatment, the patients received dipyridamole (100 mg orally three times a day) and intravenous heparin (5000 units as a bolus before streptokinase infusion, followed by 1000 units/hr infused continuously, with the dose adjusted to maintain the activated partial thromboplastin time at about twice the control time). This therapeutic procedure was maintained until the operation (surgical group) or coronary arteriography (medical group) were done. After that, in the absence of contraindications, treatment with aspirin was started and heparin and dipyridamole were discontinued. This protocol has been described in detail elsewhere. ¹⁵

Means and standard deviations were obtained with the use of the "Statistics" software, part of Systat (Systat Inc., Evanston, Ill.). ¹⁶ Means and standard deviations were compared by Student's t test for unpaired samples. Proportions were compared by the z test for comparing sample proportions. ¹⁷

Long-term survival data were presented according to the actuarial method described by Kaplan and Meier, ¹⁸ Culter and Ederer, ¹⁹ and Anderson and associates. ²⁰ Because 12 patients in the medical group died before coronary angiography was done, which could lead to some bias in the comparison between groups, the curves were generated with and without in-hospital deaths. Statistical comparison of the curves was done by calculating the ² with one degree of freedom, ²¹ and the percentages were reported with their respective standard errors. The whole curves were compared on a medium-term (first year) and long-term (sixth year) basis. A Cox proportional hazards model was developed at the Institute of Mathematics, Statistics and Computer Science, the University of Campinas, Campinas, Brazil, with the SAS software (SAS Institute Inc., Cary, N.C.). The following variables collected during the in-hospital phase were included in the model and correlated with survival for up to 6 years of follow-up: sex, age, infarct location on electrocardiogram, previous AMI, CK-MB peak, time between the onset of the pain and the beginning of streptokinase infusion, reinfarction, LV global ejection fraction, hypotension during or immediately after streptokinase infusion, residual obstruction at the "culprit" coronary artery, multivessel coronary artery disease, medical "definite" treatment, and AMI-related coronary artery patency.

One hundred percent of the patients who left the hospital alive were followed up yearly through personal or telephone interviews with the patients or their survivors, in the case of death (the majority of the patients did not live in our city and often were from other states). The basic questions asked in the interview were about invasive procedures and deaths during the time interval and the cause of death according to the death certificate. No other questions were asked because of concerns about the reliability of the information.

The confidence interval was set at 95% and differences were considered to be significant when p < 0.05.

RESULTS

In-hospital survival was 89.1% for the medical group, 95.3% for the surgical group (p = 0.096, 95% confidence interval -0.2% to 12.6%), and 91.2% for the angioplasty group (p > 0.1 in relation to the medical group).

Fig. 1 shows the survivals according to the "definite" approach during the in-hospital phase (angioplasty, operation, or medical treatment) for the entire population (332 patients). Statistically significant differences were obtained for the surgical group in comparison with the medical group for all periods analyzed. Despite the fact that the angioplasty group showed a higher survival than the medical group, the differences were not statistically significant, certainly because of the small number of patients who underwent the invasive procedure.

View larger version (26K): [in this window] [in a new window]   Fig. 1. Actuarial survival curves for entire population according to "definite" approach used. Numbers in parentheses correspond to number of patients included in beginning of each time interval. PTCA, Percutaneous transluminal coronary angioplasty.

View larger version (25K): [in this window] [in a new window]   Fig. 2. Actuarial survival curves according to "definite" approach used, excluding in-hospital deaths. Numbers in parentheses correspond to number of patients included in beginning of each time interval. PTCA, Percutaneous transluminal coronary angioplasty.

Table I presents the characteristics of the three groups analyzed. The surgical and medical groups did not differ significantly from each other according to AMI size, clinical manifestations, and LV systolic function. However, there was significantly higher risk in the surgical group in comparison with that in the medical group in terms of coronary artery lesions. Table II shows the type of graft used to revascularize the area related to the infarction, and Table III lists the number of coronary arteries revascularized, with the respective type of graft used.

DISCUSSION

A search in the literature on patients with myocardial infarction who underwent routine thrombolytic therapy and coronary arteriography showed that 21% to 68.4% of these patients underwent operation for myocardial revascularization during the treatment sequence. ^2-6,9-13 The lowest index (21%) was obtained by the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) group, ¹¹ which is known to be highly aggressive in the use of angioplasty. On the other hand, a percentage of 68.4% was reported by Richardson and colleagues ⁵ for a group of only 19 patients, all treated with intracoronary streptokinase. Excluding papers that included fewer than 100 patients, the percentage of patients who underwent operation in the in-hospital phase fell to 53.8% in a sample of 355 patients, ¹² or to 47.7% in the largest study reported, which included 891 patients. ³ In the present study, 128 patients were operated on during the in-hospital phase (38.5%) and 147 (44.3%) received medical therapy.

There are some important comparisons to be made between the present study and data in the literature for patients operated on after being treated with fibrinolytic drugs. First, the mean age of patients in the literature was 52 to 59.7 years, ^3,10-12,14 as compared with 56.3 ± 9 years for the patients reported on here (Table I). Second, the mean time between fibrinolytic treatment and operation was 3 to 16 days, ^2,3,9,11-13 with the mean of 16 days being obtained when patients operated on up to 90 days after AMI were included. ⁹ If this study is excluded, the maximum mean falls to 9.3 days, as reported by the TAMI group, except for emergency operations. ¹¹ The interval recorded in the present study was 7 ± 3.9 days (Table I). Third, the mean number of revascularized arteries ranged from 2.6 to 3.4, ^3,9,2,14 as compared with 2.64 in the present study (Table III). Fourth, there was a 67% to 88% prevalence of multivessel coronary artery disease, ^3,9,10,14 as compared with 76.8% for the present population (Table I). Fifth, there was 88.9% to 100% in-hospital survival, ^2,3,7-14 withthe largest series (425 and 303 patients ^3,10) showing 95.3% and 93%, respectively. The lowest survivals, 89% and 88.9%, were due to very early operation after the use of thrombolytic treatment. ^7,8 In the present group, whenever possible, there was a time interval of at least 48 hours between streptokinase infusion and the operation, and a survival of 95.3% was obtained.

As mentioned earlier, little information is available in the literature about the long-term course of these patients: in a study with follow-up of 2 to 18 months, only one death was reported among 51 patients studied ⁹; a 2.5% mortality rate was reported for 82 patients followed up for 1 year ¹¹; and in a study with a median follow-up of 1092 days, a 7.2% mortality rate was obtained for 303 patients. ¹⁰ In these papers, in-hospital deaths were excluded and the number of patients referred to the entire population of the study. Finally, two publications used actuarial curves and reported survivals of 92.9% for 2 years ¹² and 88% for 8 years. ¹³ In the present study, the rates were 93% ± 2.3% for 1 year and 86.4% ± 3.4% for 6 years (Fig. 1). Excluding in-hospital deaths, the rates became 97.5% ± 1.4% and 90.6% ± 3.1%, respectively (Fig. 2).

On the other hand, 90.5% and 76.5% in-hospital survivals have been reported for patients who received medical treatment, ^2,3 as compared with 89.1% in the present series.

Recently, Taylor and associates ²² reported a 91% cardiac survival for a 6-year follow-up (excluding in-hospital deaths) for a group of patients who received fibrinolytic treatment, 67% of whom had undergone surgical treatment, 12% angioplasty, and the remaining patients medical therapy. The corresponding survival in the present study, taking into account all cause mortality, was 83.7% ± 2.6%.

To our knowledge, the present comparison between medical and surgical patients who received fibrinolytic treatment and who were followed up over a period of up to 6 years is unique. Mathey and associates ¹⁴ reported 90% survival for a group of patients who received streptokinase, with a patent "culprit" coronary artery and operated on in the first 14 days of evolution, versus 81% for a group with a patent "culprit" coronary artery in which medical therapy was used, and 63% for a third group with occlusion of the AMI-related coronary artery. Follow-up time was up to 4 years and in-hospital deaths were included (3.2% of the patients operated on).

DeWood and colleagues, ²³ studying a group of patients with myocardial infarction with a maximum of 24 hours of evolution and in whom fibrinolytic treatment was not given, compared 200 subjects who were operated on with 187 who received conventional treatment (on a nonrandom basis). After 10 years of follow-up, the investigators reported 73% and 69% survivals for the two groups, respectively. By subdividing patients operated on into early intervention (first 6 hours of evolution) and delayed intervention, they obtained rates of 85% and 66%, respectively. In-hospital mortality was included, corresponding to 11.5%, 10.3%, and 2% for the medical, nonearly surgical, and early surgical groups, respectively, with an overall mortality rate of 5.8% for the invasive group.

As shown in Table I of the present paper, the surgical group was similar to the medical group with respect to clinical features, AMI size, and LV systolic function as evaluated by global ejection fraction. However, surgical patients were at a significantly higher risk with respect to the anatomic characteristics of the coronary arteries as evaluated by the percentage of residual obstruction at the "culprit" coronary artery and by the prevalence of multivessel coronary artery disease. Nevertheless, the survival of the invasive group was much higher than that of the medical group, with less than half of the in-hospital mortality rate (4.7% versus 10.9%), and, in the long-term follow-up, with significantly higher survivals for 1 and 6 years, even when in-hospital deaths were excluded (Figs. 1 and 2).

Certainly one of the main reasons for the excellent long-term results obtained with operation was the intensive use of the internal thoracic (mammary) artery, which, as documented by the Cleveland group, ²⁴ leads to a significantly higher survival, in comparison with the use of isolated saphenous grafts. In the present study, 82.8% (106 of 128) of patients received a mammary artery bypass graft (Table III).

Finally, it should be pointed out that the crossover prevalence detected in this study was only six patients (4%), as opposed to 25% for 5 years of follow-up and close to 50% for 10 years of follow-up as obtained by the three large studies that investigated at random patients who underwent medical versus surgical treatment (Veterans Administration, European, and Coronary Artery Surgical Study). ²⁵ In addition, only two of these six patients had been assigned to medical therapy; one of the remaining four patients refused operation, and there were doubts about the best initial approach for the other three patients. This suggests a good patient selection in the present patient population, especially if one considers that, in contrast to the studies mentioned earlier in patients with chronic coronary artery disease, the patients in the present study were all in the acute phase of a myocardial infarction and therefore at a higher risk.

Conclusion
We conclude that in this nonrandomized study myocardial revascularization indicated mainly on the basis of anatomic criteria led to a significantly higher survival, both on a medium- and long-term basis, than that obtained for patients who received medical therapy.

Acknowledgments

We are indebted to Prof. Drs. José F. Ramires, Edwaldo E. Camargo, and Fernando Luchesi for their suggestions in the preparation of the manuscript and to Prof. Dr. Cicília Yuko Wada for statistical advice.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Roberto Vito Ardito Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nicolau, J. C. Articles by Jacob, J. L. B. Search for Related Content PubMed PubMed Citation Articles by Nicolau, J. C. Articles by Jacob, J. L. B.