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J Thorac Cardiovasc Surg 2007;133:1242-1251
© 2007 The American Association for Thoracic Surgery
Surgery for Acquired Cardiovascular Disease |
a Multicenter Study of Perioperative Ischemia Research Group, San Bruno, Calif
b Ischemia Research and Education Foundation, San Bruno, Calif
c Departments of Anesthesiology, Ludwig-Maximilians-University, Munich, Germany
d St Michael’s Hospital, University of Toronto, Toronto, Canada
e Montefiore Medical Center, New York, NY
f University of Heidelberg, Germany
g University of Alberta, Edmonton, Alberta, Canada
h Washington University School of Medicine, St Louis, Mo
i Papworth Hospital, Cambridge, United Kingdom
j California Pacific Medical Center Research Institute, San Francisco, Calif
k Department of Laboratory Medicine, University of California School of Medicine, San Francisco, Calif.
Received for publication April 26, 2005; revisions received November 8, 2006; accepted for publication December 6, 2006. * Address for reprints: Elisabeth Ott, MD, c/o Editorial Office, The Ischemia Research and Education Foundation, 1111 Bayhill Drive, Suite 480, San Bruno, CA 94066. (Email: diane{at}iref.org).
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Abstract |
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Methods: A total of 5065 patients undergoing coronary artery bypass graft surgery were analyzed at 70 international medical centers, and from this pool, 3180 patients from the 4 highest enrolling countries were selected. Fatal and nonfatal postoperative ischemic complications related to the heart, brain, kidney, and gastrointestinal tract were assessed by blinded investigators.
Results: In-hospital mortality was 1.5% (9/619) in the United Kingdom, 2.0% (9/444) in Canada, 2.7% (34/1283) in the United States, and 3.8% (32/834) in Germany (P = .03). The rates of the composite outcome (morbidity and mortality) were 12% in the United Kingdom, 16% in Canada, 18% in the United States, and 24% in Germany (P < .001). After adjustment for difference in case-mix (using the European System for Cardiac Operative Risk Evaluation) and practice, country was not an independent predictor for mortality. However, there was an independent effect of country on composite outcome. The practices that were associated with adverse outcomes were the intraoperative use of aprotinin, intraoperative transfusion of fresh-frozen plasma or platelets, lack of use of early postoperative aspirin, and use of postoperative heparin.
Conclusions: Significant between-country differences in perioperative outcome exist and appear to be related to hematologic practices, including administration of antifibrinolytics, fresh-frozen plasma, platelets, heparin, and aspirin. Understanding the mechanisms for these observations and selection of practices associated with improved outcomes may result in significant patient benefit.
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Introduction |
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Consequently, one would expect that case-mix adjusted cardiovascular mortality and morbidity would be similar among high-volume centers, despite national differences in health care systems and reimbursement practices.6-8 However, there are few, if any, comprehensive, international data sets that allow comparison of the effects of country-specific, system-associated factors, such as length of stay, time from diagnosis to surgery, and variations in the pharmacologic management of hemostasis on morbidity and mortality, although these factors vary markedly depending on where CABG surgery is performed.8-13 The primary aim of this analysis was to determine and contrast the adverse vascular outcomes that occurred after CABG surgery among 4 countries; our hypothesis was that vascular outcomes differed among countries. Our secondary hypothesis was that practice pattern differences existed and accounted for between-country differences in outcome. The target population was patients undergoing elective CABG surgery (primary or repeat) or combined CABG-valve surgery (replacement or repair) among institutions of 4 countries, the United States, Canada, the United Kingdom, and Germany. Patients were randomly sampled by center, and a comprehensive set of individual perioperative data were collected, to allow definition of practice by center and by country.
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Materials and Methods |
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Specifically, at each institution, after institutional review board approval, 100 patients were to be enrolled prospectively according to a systematic sampling scheme. To be eligible for enrollment, the patient had to be scheduled to undergo CABG using cardiopulmonary bypass, had to complete the preoperative interview, had to be at least 18 years old, could not be enrolled in another study or clinical trial, and had to give written informed consent.
Clinical Care
Clinical decisions were not controlled by the study protocol, and all patients qualifying for enrollment within the prespecified enrollment period were entered. Of the 5436 patients enrolled, 371 were excluded from the analysis for the following reasons: withdrawal from the study (32 patients), death before surgery (2 patients), cancellation or rescheduling of the surgery (97 patients), change in procedure (132 patients), incomplete data (97 patients), or inadvertent enrollment in another study (11 patients).
Study Data
For our comparison, we chose the 4 highest enrolling countries to obtain the largest and most homogeneous samples of patients undergoing elective CABG surgery. All surgery in these countries was performed at university or university-affiliated teaching hospitals. The distribution of the patients was as follows: United States (29 centers; n = 1283); Germany (9 centers; n = 834); United Kingdom (7 centers; n = 619); and Canada (8 centers; n = 444).
For each enrolled patient, more than 7500 fields of data were collected, including demographic, historical, clinical, laboratory, electrocardiographic, special testing, resource use, and adverse outcome data. Independent investigators coded all medications received throughout hospitalization from admission to discharge or until death. All data fields for each patient were examined centrally for completeness and accuracy, with all changes documented before formal in-hospital database closure on October 15, 2001.
Measurement of Outcomes
All outcomes were prespecified by protocol and diagnosed by independent and blinded investigators. Fatal and nonfatal outcomes were classified as cardiac (myocardial infarction, heart failure), cerebral (stroke, encephalopathy), renal (dysfunction, failure), gastrointestinal (ischemia, infarction), or other adverse event complications.14 The diagnosis of myocardial infarction required15 the development of new Q waves (as defined by Minnesota Code 1-1-1 up to 1-2-7), new persistent ST-segment or T-wave changes (Minnesota Code 9-2, 4-1, 4-2, 5-1, or 5-2) associated with an elevation of creatine kinase-myocardial band isoenzyme values, or autopsy evidence of acute myocardial infarction. The diagnosis of heart failure required the use of a ventricular assist device, the use of continuous inotropic support for at least 24 hours, or autopsy verification of heart failure. Cerebral outcomes were classified16 as clinically diagnosed stroke or encephalopathy, or computed tomography, magnetic resonance imaging, or autopsy evidence of a focal or global lesion. Renal dysfunction was defined17 as a serum creatinine level of 2.00 mg/dL or greater accompanied by a 0.7 mg/dL or greater increase over baseline; renal failure was defined as dysfunction requiring dialysis or autopsy verification of renal failure. Gastrointestinal ischemia18 was defined as abdominal pain likely associated with bowel ischemia; gastrointestinal infarction was defined by bowel resection or evidence of intestinal infarction on autopsy. In addition, we defined a composite outcome consisting of mortality and/or any of the morbidities: myocardial infarction, congestive heart failure, stroke, encephalopathy, renal dysfunction, renal failure, and gastrointestinal ischemia/infarction.
Statistical Analysis
The prevalence of clinical characteristics and the incidence of individual adverse events comprising the composite outcome (death, myocardial infarction, congestive heart failure, stroke, encephalopathy, renal dysfunction, renal failure, or gastrointestinal ischemia/infarction) among the 4 countries were compared using the chi-square test. Continuous variables (eg, time to surgery and length of hospital stay) were compared using nonparametric tests.
The European System for Cardiac Operative Risk Evaluation (EuroSCORE)19 (one of the most common risk stratification systems for cardiac surgical patients) and other potential risk factors for adverse outcomes were investigated first using univariate logistic regression analysis. All risk factors statistically significant at P less than .20 in univariate analysis were then entered into a multivariate logistic regression model. Stepwise logistic regression was performed, with variables retained that were significant at a 2-tailed nominal P value of less than .05. To investigate the differences among countries, adjusting for their differences in risk profile, separate risk models were developed for mortality, morbidity, early morbidity (within 48 hours postsurgery), and late morbidity (after 48 hours postsurgery). All statistical analyses were performed with SAS Version 8.12 software (SAS Institute, Cary, NC).
The Ischemia Research and Education Foundation provided all funding for execution of the study, collection of the data, and analysis and publication of the findings.
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Results |
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, diabetes, unstable angina, prior CABG, left main coronary artery disease, ejection fraction less than 44%, and non-caucasian ethnicity. U.K. patients had a higher prevalence of heart failure and acute smoking cessation but were the youngest and least likely to have diabetes, unstable angina, left main coronary artery disease, and previous coronary intervention. Angiotensin-converting enzyme inhibitors were used most commonly in Germany and the United States, calcium channel blockers were used most commonly in the United Kingdom and Canada, and antiplatelet medications were used most commonly in the United States and Canada. On the basis of the EuroSCORE, the United Kingdom had the highest proportion of patients in the low-risk group, whereas the United States cohort had the highest proportion in the high-risk group (Figure 1). The differences among countries in the overall distribution of the EuroSCORE were significant (P < .001). In addition, the process of care factors (Table 2) varied considerably among countries.
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Early Outcomes (Within 48 Hours)
There were 338 patients with adverse events within 48 hours after surgery. After adjustment for significant confounders (admission, preoperative, and intraoperative factors, including the EuroSCORE), country no longer had an independent effect on the risk of the composite outcome within 48 hours. Reversible risk factors for early composite outcome were the use of aprotinin and transfusion of fresh-frozen plasma (Table 5,
Figure 2).
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Late Outcomes (After 48 Hours)
Patients with early composite outcomes were excluded in analyses of the factors associated with the risk of late composite outcome. Early postoperative use (within 48 hours) of aspirin was associated with a reduced risk of late outcomes, whereas use of intravenous heparin increased the risk (Table 6). The use of aspirin was most prevalent in Canada (83%), followed by the United Kingdom (70%), the United States (67%), and Germany (42%) (Figure 3). The administration of heparin was most prevalent in Germany (75%), followed by Canada (40%), the United Kingdom (17%), and the United States (15%).
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There were significant inter-country differences in all intraoperative and postoperative time-related factors (Table 2). The United Kingdom had the shortest median bypass and crossclamp times (71 minutes and 38 minutes, respectively) in contrast with the United States (104 minutes and 69 minutes, respectively) and Germany (98 minutes and 58 minutes, respectively). After correction for the number of bypass grafts, these times remained longer in the United States and Germany than in the United Kingdom or Canada.
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Discussion |
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Transfusion practices for red blood cells and blood products have been reported to vary widely between institutions and countries,20-22 ranging from 0% to 97% for fresh-frozen plasma. Prophylactic plasma administration has not been shown to reduce red cell transfusion,23-29 and recent studies have reported an independent risk of stroke and death after platelet or plasma transfusions.20,30 The association between blood product transfusion, aprotinin use, or aspirin administration and adverse outcome in our study suggests that the complex interaction of factors affecting blood coagulation and hemostasis may play an important role in clinical outcome.
We found that the use of aprotinin and fresh-frozen plasma was more prevalent among German centers, despite relatively little difference in blood loss compared with the other 3 countries studied. It is possible that frozen plasma administration, in combination with aprotinin, may have conferred additional risk. Although the large majority of randomized studies comparing aprotinin with placebo or other antifibrinolytic agents have not suggested additional risk with aprotinin, 6 recent investigations reported that the use of aprotinin is associated with increased adverse outcomes.31-36 Therefore, our findings raise questions regarding the optimal hematologic management of patients who undergo CABG in general and the coincident use of aprotinin with frozen plasma, platelets, or other prothrombotic agents.
Geographic variability has been reported to exist for cost, length of stay, volume, and access to and adverse events after CABG surgery,35,37,38 although no previous studies have prospectively evaluated the processes of care and outcomes in the range of countries examined in this investigation. Peterson and colleagues39 found that the hospital at which CABG surgery was performed was the strongest predictor of prolonged stay, although there was also limited correlation between mortality and other outcomes.
The waiting list time may impact outcome in that a country with a longer list time (eg, the United Kingdom) may effectively exclude sicker patients. On the other hand, longer wait times also have been shown to result in clinical deterioration, which could then predispose to worse outcomes in those patients waiting longer.40 However, we found no substantial differences among the countries regarding acute or chronic disease severity at the time of surgery, suggesting that if wait time did play a role, its effects may have been mitigated.
This study has some limitations. The patient selection procedures may not be representative of the countries studied, although the average volume of cardiac cases in centers that participated in EPI-II exceeded 1200 patients per year. We chose the EuroSCORE for risk adjustment because it is an established index using data from European patients. Although some studies have suggested that the EuroSCORE can accurately predict short and long-term outcomes in North American patients, it is possible that it is less accurate in our non-European cohort. There may have been changes in the frequency of CABG surgery or the use of alternative techniques since completion of study enrollment, but the lack of major changes in the management of patients undergoing CABG with cardiopulmonary bypass makes our data current and applicable to this population. Finally, despite prospective data collection, it is possible that unmeasured confounders may exist that could have affected either the risk adjustment or the strength of the outcome associations.
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Conclusions |
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Appendix |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsAppendixReferences |
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The following institutions and persons coordinated the Multicenter Study of Perioperative Ischemia EPI-II study. Study Chairman—D. Mangano; Senior Editor—J. Levin, L. Saidman; Study Design and Analysis Center: Ischemia Research and Education Foundation—P. Barash, C. Dietzel, A. Herskowitz, Y. Miao, I. C. Tudor; Editorial/Administrative Group—D. Beatty, I. Lei, B. Xavier.
The following institutions and persons participated in the Multicenter Study of Perioperative Ischemia EPI-II Study. Centers and investigators: United States—University of Chicago, Weiss Memorial Hospital—S. Aronson; Beth Israel Hospital—M. Comunale; Massachusetts General—M. D’Ambra; University of Rochester—M. Eaton; Baystate Medical Center—R. Engelman; Baylor College of Medicine—J. Fitch; Duke Medical Center—K. Grichnik; UTHSCSA-Audie Murphy VA, UTHSCSA-University Hospital—C. B. Hantler; St Luke’s Roosevelt Hospital—Z. Hillel; New York University Medical Center—M. Kanchuger, J. Ostrowski; Stanford University Medical Center—C. M. Mangano; Yale University School of Medicine—J. Mathew, M. Fontes, P. Barash; University of Wisconsin—M. McSweeney, R. Wolman; University of Arkansas for Medical Sciences—C. A. Napolitano; Discovery Alliance, Inc.—L. A. Nesbitt; VA Medical Center, Milwaukee—N. Nijhawan; Texas Heart Institute, Mercy Medical Center—N. Nussmeier; University of Texas Medical School, Houston—E. G. Pivalizza; University of Arizona—S. Polson; Emory University Hospital—J. Ramsay; Kaiser Foundation Hospital—G. Roach; Thomas Jefferson University Hospital, MCP Hahnemann University Hospital—N. Schwann; VAMC Houston—S. Shenaq; Maimonides Medical Center—K. Shevde; Mt Sinai Medical Center—L. Shore-Lesserson, D. Bronheim; University of Michigan—J. Wahr; University of Washington—B. Spiess; VA Medical Center, SF—A. Wallace; Austria—University of Graz—H. Metzler; Canada—University of British Columbia—D. Ansley, J. P. O’Connor; The Toronto Hospital—D. Cheng; Laval Hospital, Quebec—D. Côte; Health Sciences Centre-University of Manitoba—P. Duke; University of Ottawa Heart Institute—J. Y. Dupuis, M. Hynes; University of Alberta Hospital—B. Finegan; Montreal Heart Institute—R. Martineau, P. Couture; St Michael’s Hospital, University of Toronto—D. Mazer; Colombia—Fundacion Clinico Shaio—J. C. Villalba, M. E. Colmenares; France—CHRU Le Bocage—C. Girard; Hospital Pasteur—C. Isetta; Germany—Universität W
..rzburg—C. A. Greim, N. Roewer; Universität Bonn—A. Hoeft; University of Halle—R. Loeb, J. Radke; Westfalische Wilhelms-Universität Munster—T. Mollhoff; Universität Heidelberg—J. Motsch, E. Martin; Ludwig-Maximillians Universität—E. Ott; Ludwig-Maximillians Universität—P. Ueberfuhr (Department of Cardiac Surgery); Universität Krankenhaus Eppendorf—J. Scholz, P. Tonner; Georg-August Universität Göttingen—H. Sonntag; Hungary—Orszagos Kardiologiai Intezet—A. Szekely; India—Escorts Heart Institute—R. Juneja; Apollo Hospital—G. Mani; Israel—Hadassah University Hospital—B. Drenger, Y. Gozal, E. Elami; Italy—San Raffaele Hospital, Universita de Milano—C. Tommasino; Mexico—Instituto Nacional de Cardiologia—P. Luna; The Netherlands—University Hospital Maastricht—P. Roekaerts, S. DeLange; Poland—Institute of Cardiology—R. Pfitzner; Romania—Institute of Cardiology—D. Filipescu; Thailand—Siriraj Hospital—U. Prakanrattana; United Kingdom—Glenfield Hospital—D. J. R. Duthie; St. Thomas’ Hospital—R.O. Feneck; The Cardiothoracic Centre, Liverpool—M. A. Fox; South Cleveland Hospital—J. D. Park; Southhampton General Hospital—D. Smith; Manchester Royal Infirmary—A. Vohra; Papworth Hospital—R. D. Latimer, A. Vuylsteke.
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Acknowledgments |
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