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J Thorac Cardiovasc Surg 2003;125:809-820
© 2003 The American Association for Thoracic Surgery
Surgery for Acquired Cardiovascular Disease |
From the Klinik ruer Herzchirurgie, Landeskliniken Salzburg, Austria,a Thoraxcenter, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands,b Harefield Hospital, Uxbridge, Middlesex, United Kingdom,c Skejby Sygehus, Arhus N, Denmark,d and Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.e
Received for publication July 27, 2001. Revisions requested Sept 10, 2001; revisions received Nov 38, 2001. Accepted for publication Jan 10, 2002. Address for reprints: Professor F. Unger, MD, MDhc, Klinik fuer Herzchirurgie,Landeskliniken, Muellner Hauptstr. 48, A-5020, Salzburg, Austria (E-mail: f.unger{at}lks.at).
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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1 European statistics estimate the annual need for percutaneous coronary interventions at 739 per million inhabitants and coronary artery bypass grafting at 436 per million inhabitants. 2 Approximately 60% of these patients have multivessel disease and potentially could be treated with either bypass surgery or balloon angioplasty. 3 Despite the publication of a number of trials comparing bypass surgery with angioplasty, 4 the most appropriate treatment is still a matter of debate. These trials suggest that the results are similar in terms of survival and myocardial infarctions but that patients who undergo bypass surgery require fewer reinterventions.
The major concerns of surgeons are incompleteness of revascularization and the high rate of repeat interventions with angioplasty. When interpreting the results from these earlier trials, however, it is important to realize that improvements in both surgical and percutaneous techniques have occurred, calling into question the current validity of these earlier conclusions. Thus although surgery may still be seen as the most appropriate technique for multivessel disease when compared with conventional balloon angioplasty, this may not be true when stent placement—the current standard of practice 5,6—is added to the angioplasty procedure.
The specific aim of this study was to evaluate the clinical outcomes of patients with multivessel coronary artery disease treated with stented angioplasty versus conventional bypass surgery in a large, well-controlled, multicenter, multinational study. This report focuses in detail on outcomes of the surgical cohort. There is also an overall comparison of the outcomes in the surgical and stent groups at 2 years and an analyis of the differences in the pattern of response in patients with diabetes.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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7
Selection of patients
Patients with angina or ischemia but no previous bypass surgery or angioplasty were selected after agreement between surgeons and cardiologists, randomly assigned after written informed consent through a central telephone service, and treated with either surgery or stented angioplasty. Sixty percent of patients in the surgical arm and 57% in the stent arm had stable angina (Canadian Cardiovascular Society class 1, 2, 3, or 4). 8 Unstable angina pectoris (Braunwald class IB, IC, IIB, IIC, IIIB, or IIIC) 9 was present in 35% of the surgical group versus 37% of the stent group, and silent ischemia was present in 5% of the surgical group and 6% of the stent group (Table 1). Patients were eligible for coronary revascularization if they had at least two de novo lesions (located in different vessels and in different territories) potentially amenable to bypass surgery or stent implantation. Patients with left main stem stenosis were excluded.
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10 Exclusion criteria included a left ventricular ejection fraction less than 30%, overt congestive heart failure, a history of previous cerebrovascular accident, transmural myocardial infarction within the previous week, severe hepatic or renal disease, diseased saphenous veins, and the need for concomitant major surgery (eg, valve surgery or resection of aortic or left ventricular aneurysm, carotid endarterectomy, abdominal aortic aneurysm surgery). Finally, patients with intolerance or contraindication to aspirin or ticlopidine and those with neutropenia or thrombocytopenia were also excluded.
General management considerations and operator certification
Surgery and cardiac interventions were performed at 67 sites. The institutions involved in the ARTS trial had to perform at least 400 coronary bypass procedures per year in which the thoracic artery was used in 80% of the cases. 11 The standard procedure for coronary bypass entailed extracorporeal circulation and cardiac arrest. The internal thoracic artery had to be used for revascularization of the left anterior descending coronary artery or the diagonal branches during extracorporeal circulation. The use of other arterial conduit material was discouraged. The remaining vessels could be bypassed by use of the greater saphenous vein in whatever configuration the surgeon deemed appropriate. Anesthetic techniques and the type of cardioplegic solution were not standardized.
A minimum of 500 angioplasty cases per center and a minimum of 100 procedures per year per operator were required for sites to qualify as participants in the ARTS trial. Angiographic criteria for inclusion in the trial have been previously been published elsewhere. 7
End points
The objective of this study was to compare bypass surgery with stented angioplasty with the Cordis Palmaz-Schatz Crown or CrossFlex stent (Cordis Corporation, Miami Lakes, Fla) in patients with multivessel coronary disease. The primary end point was defined as the absence of any of the following major adverse cardiac and cerebrovascular events within 12 months after random assignment: death, cerebrovascular event, documented nonfatal myocardial infarction, or repeated revascularization by percutaneous intervention or bypass surgery. 7,12 In the primary comparison of the two treatment strategies, all deaths (cardiac and noncardiac causes) were reported. Cerebrovascular events were classified into three major categories: stroke, transient ischemic attack, and reversible ischemic neurologic deficit.
After random assignment, all myocardial infarctions were counted as events, whether they occurred spontaneously or in association with coronary artery bypass grafting surgery or angioplasty procedures. Myocardial infarctions were confirmed only after the relevant electrocardiograms were analyzed by the electrocardiographic core laboratory and adjudicated by the clinical events committee. Every subsequent revascularization procedure was recorded, including the reasons for the procedure.
Secondary objectives of the study were to compare both strategies at 2 years with respect to the following: anginal status; medication use; the combined end point of death, myocardial infarction and stroke; and the itemized outcomes of death, myocardial infarction, stroke, or revascularization procedure. Events were counted from the time of random assignment, whereas the clinical status was assessed at predetermined times of 1 month, 6 months, 12 months, and 24 months after the procedure.
One patient was unavailable for follow up, 3 were alive but had withdrawn their consent from further participation in the trial, and 2 patients were never treated with either modality.
Statistical analysis
The required sample size (2 x 600 patients) was based on rejection of the null hypothesis that at 1 year the frequency of major adverse cardiac and cerebrovascular events in favor of bypass surgery (event-free survival) would not exceed 7%. The actual sample size achieved a power of 92% with the assumption of a 2-sided type I error level (
) of .05.
Continuous variables were expressed as mean ± SD and compared with the unpaired Student t test. The Fisher exact test was used for categoric variables. Wilcoxon scores were used for categoric variables with an ordinal scale. Discrete variables were expressed as counts and percentages and were compared in terms of relative risks (for surgery vs stenting) with 95% confidence intervals calculated by the formula of Greenland and Robins. 13 All statistical tests were 2-tailed. Event-free survivals were estimated according to the Kaplan-Meier method, and differences were assessed with the log-rank test.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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shows their baseline demographic and angiographic characteristics. As indicated in Table 2, 5 patients (1 assigned to undergo stented angioplasty and 4 assigned to undergo surgery) did not undergo coronary revascularization and instead continuted to receive pharmacologic treatment. The average time elapsed between random assignment and treatment was 27 ± 39 days (range 0-362 days) for the surgical group and 11 ± 16 days (range 0-173 days) for the stent group. Three patients assigned to undergo surgery died while on the waiting list. Six patients allocated to the stent arm crossed over to the surgical treatment arm, whereas 19 patients assigned to surgery were treated with stent implantation. During the initial hospital stay, 14 patients initially assigned to undergo stenting underwent surgical revascularization, 3 urgently and 11 electively, after a complicated or unsatisfactory percutaneous treatment. Similarly, 2 patients who had undergone surgery had further angioplasty during the same hospital stay. Thus 579 patients in the surgical group (95.9%) and 593 patients in the stent group (98.8%) were treated according to the assigned treatment.
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In the first 24 hours after intervention, abnormal creatine kinase MB levels were observed in 61% of the surgical group and 31% of the stent group. Eight patients died in the hospital between 1 and 18 days after the operation. The causes of death were excessive bleeding (1 patient), ventricular fibrillation (n = 2), mesenteric infarction (n = 2), cardiogenic shock (n = 2), and myocardial infarction (n = 1). The overall operative mortality was 1.3%. By comparison, the in-hospital mortality rate in the stented angioplasty group was 1% (n = 6). A total of 571 patients were weaned off the bypass machine, extubated, and discharged from hospital. The lengths of stay were 11.3 ± 9.1 days in the surgical group and 3.4 ± 4.8 days in the stent group.
Outcomes at 30 days after random assignment
At 30 days after random assignment there were a total of 11 deaths, including the 3 deaths of patients on the waiting list. A further 6 patients had a cerebrovascular event (1.0%), and 18 had a myocardial infarction (3.0%). Reintervention was necessary in 1 case (0.2%) by means of bypass surgery and in 1 case (0.2%)by additional angioplasty. The events in the stented angioplasty group were similar: 9 patients died (1.5%, including the 6 in-hospital deaths), 4 patients (0.7%) had a cerebrovascular accident, and 19 patients (3.0%) had a myocardial infarction.
Outcomes at 1 year
The outcomes at 1 year have previously been discussed in detail elsewhere. 12 The primary end-point criterion was met by 157 of 600 patients (26.2%) assigned to undergo stented angioplasty and 74 of 605 patients (12.2%) assigned to undergo bypass surgery (relative risk 2.14; 95% confidence interval 1.66-2.75). There was no significant difference in freedoms from death, stroke, or myocardial infarction between the stent and surgical groups (90.7% vs 91.2%, respectively, relative risk 1.07, 95% confidence interval 0.75-1.52). Of the remaining patients, however, 16.8% in the stent group and 3.5% in the surgical group underwent repeated revascularization, an absolute difference of 13.3%.
Outcomes at 2 years
Events per patient and ranking of clinical events at 2-year follow-up are shown in Table 3. The primary clinical end point (major adverse cardiac and cerebrovascular events) was reached by 92 (15.2%) of the 605 patients assigned to undergo bypass surgery, compared with 183 (30.5%) of the 600 patients assigned to undergo stented angioplasty (relative risk 0.39, 95% confidence interval 0.29-0.53). Freedoms from death, stroke, and myocardial infarction were similar in the surgical and the stented angioplasty groups (89.6% vs 89.2%, respectively, relative risk 0.92, 95% confidence interval 0.62-1.35). The difference in clinical outcomes between the study groups at 2 years was almost entirely due to the need for more repeated revascularizations in the stent group.
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). The primary clinical end point had been reached at 2 years by 17 of the 96 patients with diabetes assigned to undergo bypass surgery (17.7%), versus 49 of the 112 assigned to undergo stented angioplasty (43.8%, relative risk 2.47; 95% confidence interval 1.53-3.99). The incidences of death, stroke, and myocardial infarction were similar (14.6% in the surgical group vs 16.1% in the stent group, relative risk 1.10, 95% confidence interval 0.58-2.10). However, the reintervention rate was markedly lower among the patients with diabetes who were treated with surgery than among those who were treated with stented angioplasty (5.2% vs 35.7%, relative risk 6.86, 95% confidence interval 2.82-16.68). This absolute difference in the need for reintervention of 30.5% was also markedly higher than the difference of 19.1% observed for the total group and the absolute difference of 13.2% for the patients without diabetes. |
Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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The ARTS trial allows a direct comparison of two entirely different approaches to coronary revascularization in patients with multivessel coronary artery disease. This trial showed no significant difference in the frequency of death, stroke, and myocardial infarction between surgery and stented angioplasty. It is important to emphasize that in the early postoperative period the mortalities in the two arms were very similar (0.7 % vs 1%). 12 The most significant difference in favor of surgery was related to the need for repeated revascularization at 24 months (14.9% difference). Compared with previous trials with balloon angioplasty alone in a similar population, 5 the need for urgent surgical revascularization after failed or complicated balloon angioplasty had fallen from 4.6% 5 to 0.5%. As noted previously, the difference in clinical outcome at 1 year between the surgical and percutaneous approach has been reduced by approximately 50% relative to other studies. 5 This considerable improvement in the percutaneous approach is due largely to the increased safety and partial prevention of restenosis provided by the stent.
In the ARTS trial the degree of revascularization achieved in the group treated with multivessel stenting is now comparable to that in the surgical cohort. In this trial 2.7 out of 2.8 stenotic lesions detected on the diagnostic angiogram were successfully treated with stented angioplasty, whereas in the Coronary Angioplasty versus Bypass Revascularisation Investigation trial 14 only 2.1 out of 3.4 stenotic lesions were successfully treated, and in the Bypass Angioplasty Revascularization Investigation trial 15 only 1.9 out of 3.5 stenotic lesions were successfully treated. The adequacy of revascularization with surgical techniques in this study in the surgical cohort was very similar: 2.7 out of 2.8 lesions detected were treated with bypass grafts. The aim of surgery is always to achieve complete revascularization.
The ARTS trial was designed in April 1996 and initiated in April 1997; patient recruitment was completed in June 1998. During this period the time that elapsed between random assignment and treatment was approximately three times as long for the surgical cohort as for the stent cohort. Eight major adverse cardiac events occurred in the surgical group during the waiting period, versus 1 in the stent group. There are reports that the waiting list for cardiac surgery is in itself a considerable risk factor for these patients. 16-18 Since 1997, the waiting-time for surgery has been markedly reduced or even eliminated in many countries. It is also worth noting that the in-hospital stay was more than three times as long for patients undergoing surgery as for those undergoing stented angioplasty. This difference has probably not changed substantially.
In the selection of centers for the trial, it was surprising that many centers could not be included because they did not routinely use the internal thoracic artery, not to mention an all-arterial approach. The use of an internal thoracic graft to the left anterior descending and saphenous vein grafts to the remaining vessels that require treatment still appears to be the standard of care, at least in Europe. 19 Adoption of this standard was necessary to ensure a basically similar approach to surgery in all 67 centers.
Evolving technology
There have been new developments in coronary revascularization, such as off-pump surgery, minimally invasive approaches, and new techniques in anesthesiology. 20-23 Although these techniques may affect practice in the future, they did not represent standard practice except at a few centers of excellence. 11,24-25 Thus the surgical data in this trial reflected the standardized approach to bypass surgery in 67 centers in 25 countries, not the standard of total arterial arterialization that might potentially be achieved in some centers of excellence.
However, the same caveats apply to the patients treated with stented angioplasty. Percutaneous stent procedures have also evolved substantially since 1997. Direct stenting without balloon predilatation and intracoronary radiation therapy 26,27 for in-stent restenosis are now part of the cardiologist's armamentarium. It is also worth noting that 40% of the 30-day events in the stent group were due to stent thrombosis, which occurred in 1.1% of the stented lesions but 3% of the patients. These events might have been prevented by the use of a glycoprotein receptor antagonist 28 or heparin-coated stents. 5 Finally, drug-eluting stents may markedly reduce restenosis and the need for repeated revascularization. 29 These therapies, although promising, also cannot yet be considered "standard practice."
Diabetes
This study corroborates the findings of the Bypass Angioplasty Revascularization Investigation trial with respect to the adverse clinical impact of diabetes in patients undergoing percutaneous coronary interventions. On the basis of these data, it seems that bypass surgery is clearly the preferred approach for the treatment of patients with diabetes who have multivessel disease. For patients without diabetes the choice represents a series of trade-offs. There was no difference at 2 years in terms of death, myocardial infarction, or cerebrovascular accident between surgery and stented angioplasty. However, there was a substantially greater need for repeated interventions in the stent group, with the associated need for rehospitalization. On the other hand, surgery was associated with a longer initial hospital stay, a prolonged period of recovery, and greater costs. These trade-offs should be presented to the patient, and the best approach for each individual patient should be chosen after careful consideration of all the facts.
Limitations of the study
Because of strict inclusion and exclusion criteria, patients treated in this study represent a small segment of patients treated by the study surgeons. Surgeons often operate on patients with more extensive disease than reported on in this study, and most randomized trials recruit eligible patients who represent only a small fraction of the population amenable to surgical revascularization. In this trial a prospective universe analysis showed that in any given week between 0% and 33% of patients with multivessel disease at the participating institution were actually enrolled in the ARTS trial. This wide range is attributable both to the restrictive eligibility criteria for the study and to local logistic considerations. In essence, these trials should be viewed as scientific experience testing concepts, expanding our knowledge of the field of revascularization and unraveling the need for improvement.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Sponsor
Cordis Corporation, a Johnson & Johnson Company, Miami Lakes, Fla.
Safety and data monitoring
Stuart Pocock, professor of medical statistics, London School of Hygiene & Tropical Medicine; Tom Ryan, professor of medicine, Boston University School of Medicine; and Ken Taylor, professor of surgery, Imperial College of Science, Technology, and Medicine at Hammersmith Hospital.
Board of governors
Marvin Woodall (international vice president, Johnson & Johnson, NJ); Brian Firth (vice president, worldwide medical affairs and health economics, Cordis Corporation, Fla); Felix Unger (professor of cardiac surgery, European Heart Institute, Austria); Patrick Serruys (chair of executive steering committee, professor of interventional cardiology, The Netherlands); and Paul Hugenholtz (past president European Society of Cardiology, The Netherlands).
Executive steering committee
This committee is composed of a subgroup of investigators and representatives of both the sponsor and the coordinating center.
Surgery
Felix Unger, Salzburg, Austria (chair); Lex van Herwerden, Rotterdam, The Netherlands; Friedrich Mohr, Leipzig, Germany; Jochen Cremer, Kiel, Germany; and Gusta Petterson, Copenhagen, Denmark.
Interventional cardiology
Patrick Serruys, Rotterdam, The Netherlands (chair); Rudiger Simon, Kiel, Germany; William Wijns, Aalst, Belgium; Hans Bonnier, Eindhoven, The Netherlands; Antonio Colombo, Milan, Italy; and Marie-Claude Morice, Antony, France.
Outside representatives
O. Madonna (Cordis Corporation, Fla); and G. A. van Es (Cardialysis BV, The Netherlands).
Critical event committee
J. J. Bredee (The Netherlands); O. Hess (Switzerland); W. J. Morshuis (The Netherlands); and W. Wijns (chair, Belgium).
Angiographic committee
M. van den Brand (chair, The Netherlands); B. Rensing (The Netherlands); and C. van de Wiel (The Netherlands).
Electrocardiographic core laboratory
All ECGs collected for the study are assessed by an independent core laboratory located at Cardialysis, Rotterdam, The Netherlands.
Data Coordinating Center
The Data Coordinating Center is located at Cardialysis, Rotterdam, The Netherlands (H. Hennessey, A. M. Hoogenboom, M. Kuypers, M. A. Morel, and V. de Valk). The trial is being monitored by Parexel (I. Kuit). Data analysis has been carried out by W. Lindeboom.
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Appendix 2 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Acknowledgments |
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References |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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