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J Thorac Cardiovasc Surg 2004;128:442-448
© 2004 The American Association for Thoracic Surgery
Surgery for acquired cardiovascular disease |
a Yale University School of Medicine, New Haven, Conn, USA
b Royal College of Surgeons of England, London, UK
c Cardiothoracic Unit, Guy's Hospital, London, UK
d London School of Hygiene and Tropical Medicine, London, United Kingdom
Received for publication December 17, 2003; revisions received March 13, 2004; accepted for publication March 29, 2004.
* Address for reprints: Artyom Sedrakyan, MD, PhD, Health Services Research Unit, London School of Hygiene and Tropical Medicine and Clinical Effectiveness Unit, Royal College of Surgeons of England, 35-43 Lincoln's Inn Fields, London WC2A 3PE, United Kingdom
asedrakyan{at}rcseng.ac.uk
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Abstract |
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METHODS: MEDLINE, EMBASE, and PHARMLINE (1988-2001) and reference lists of relevant articles were searched for coronary artery bypass grafting studies. Criteria for data inclusion were as follows: (1) random allocation of study treatments, (2) placebo control, (3) enrollment only of patients undergoing coronary artery bypass grafting, (4) no combination with another experimental medication or device, and (5) prophylactic and continuous intraoperative use.
RESULTS: Data from 35 coronary artery bypass grafting trials (n = 3879) confirm that aprotinin reduces transfusion requirements (relative risk 0.61, 95% confidence interval 0.58-0.66) relative to placebo, with a 39% risk reduction. Aprotinin therapy was not associated with increased or decreased mortality (relative risk 0.96, 95% confidence interval 0.65-1.40), myocardial infarction (relative risk 0.85, 95% confidence interval 0.63-1.14), or renal failure (relative risk 1.01, 95% confidence interval 0.55-1.83) risk, but it was associated with a reduced risk of stroke (relative risk 0.53, 95% confidence interval 0.31-0.90) and a trend toward reduced atrial fibrillation (relative risk 0.90, 95% confidence interval 0.78-1.03).
CONCLUSIONS: Aprotinin reduces transfusion requirements. Concerns that aprotinin therapy is associated with increased mortality, myocardial infarction, or renal failure risk is not supported by data from published, randomized, placebo-controlled clinical trials. Evidence for a reduced risk of stroke and a tendency toward reduction of atrial fibrillation occurrence was observed in patients who received aprotinin.
A reluctance by surgeons to use aprotinin routinely may result from concerns about the risk of a possible procoagulable state, including such adverse outcomes as myocardial infarction (MI), stroke, and atrial fibrillation, induced by an agent that reduces blood loss. Although some side effects (MI and renal failure) have been reported in the literature,4 evidence supporting these associations is limited and primarily based on case series.5 A recent prospective, uncontrolled, observational study reported that therapy with antifibrinolytic agents including aprotinin was associated with increased mortality,6 whereas a previous literature review analysis7 showed aprotinin use to be associated with decreased mortality. The latter study addressed safety and efficacy of aprotinin use in cardiac surgery by analyzing a mixture of cardiac surgical procedures; the study,7 however, did not address important clinical end points reported in more recent studies, such as stroke8 and atrial fibrillation.9 In addition, numeric discrepancies in the evaluation7 led to the criticism that a more rigorous analysis was required.10
This investigation analyzed the association of aprotinin with mortality, myocardial infarction, renal failure, stroke, and atrial fibrillation by performing a rigorous quantitative overview of all randomized, controlled trials of aprotinin in CABG. As a secondary end point, the relationship of aprotinin administration to the reduced risk of blood transfusion was calculated. The impact of preoperative aspirin use on these clinical outcomes was also evaluated.
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Methods |
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Data collection
For each trial, abstracted data included the frequencies of the events in the aprotinin (full-dose, low-dose, or other) and placebo groups, as well as the numbers of patients randomly allocated to the treatment groups. Information on methodologic quality of the included studies, such as method of randomization, blinding and its methodology, group comparability, and information on similar treatment and follow-up after randomization was also collected. Additional abstracted data included surgical history of the patients (primary CABG trials versus mixed [including both primary and reoperative CABG] trials or only reoperative CABG trials), preoperative (within 7 days) aspirin use, mean age, gender, race, left ventricular ejection fraction, and the publication date. One of the authors (A.S.) abstracted the data, and another author (J.A.E.) participated in adjudication of any discrepancies.
Mortality reported in all trials included only in-hospital deaths. The criterion for defining MI was "definite MI" report according to Minnesota coding classification,11 or in the absence of such coding information, the reports of "new Q-wave MI." The criterion for defining renal failure was the report of this event as clinical diagnosis. Most of the trials that reported renal failure did not report assessment method. However, trials funded by a pharmaceutical company reported a definition of renal failure as any of the following diagnoses: "anuria," "kidney failure," "acute kidney failure," "kidney tubular necrosis," and "uremia." The criteria for the evaluation of stroke frequency were clinical diagnosis of "stroke" and "severe neurologic deficit." In addition, such diagnoses as "cerebrovascular accident," "cerebral embolism," "cerebral hemorrhage," "cerebral infarct," and "cerebral ischemia" were considered. The definition of atrial fibrillation was based on clinical diagnosis of that event.
Although the methods of ascertainment of the events were not standardized among the trials, within each trial they were applied equally to the treatment groups. Reports and descriptions such as "no major complications were observed in the study" were not considered to represent 0 events. Only explicit description of the absence of any outcome event was considered as 0 events.
Quality of the studies
Methodologic quality of included studies was evaluated according to Jadad and coworkers' criteria,12 which are based on following:
Statistical analysis
The risk estimates for mortality, MI, renal failure, stroke, and atrial fibrillation in the aprotinin and placebo groups were assessed separately. Information from the trials was combined with the general inverse variance-based method,13 which incorporates a fixed-effect model and assumes that studies under examination share a common true effect size, that the sampling distribution of these effects is normal, and that all the variability is due to sampling error (homogeneity assumption). In this model, the weights of individual studies correspond to the inverse of the total variance for each study. Numbers-needed-to-treat and their confidence intervals (CIs) were also calculated using risk difference (RD) analysis. RD statistics were particularly important in the trials with 0 events, in which relative risk (RR) was not estimable. In these instances RD statistics still provided an estimate of uncertainty around 0. On the basis of number-needed-to-treat statistics, number of events averted or induced were calculated per 1000 patients undergoing CABG.
The assumption of homogeneity was tested with the 
2 statistic, formed by summing the weighted difference between each individual estimate and the pooled estimate. This assumption was rejected in only instance of blood transfusion analysis. To account for this, a random effect model was applied to estimate the variance component associated with between-study variation.14 According to this method, the variance for each individual study in the overview is the sum of within- and between-study components of the variance. However, the estimate from this model was not different from a fixed-effect model; thus rejection of homogeneity did not influence the results of the blood transfusion analysis. Only fixed-effect model results are reported in this article.
Sensitivity analyses were performed to evaluate the importance of methodologic quality. This factor was not found to have substantial influence on the results. RevMan 4.1 (Cochrane Collaboration, http://www.cc-ims.net/RevMan) was used for all statistical analyses.
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Results |
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Full-dose aprotinin was used in 29 trials, whereas low-dose or some other dose was used in 12 trials. Both full-dose and low-dose or other dose aprotinin were used in 6 trials. Aspirin use within a 7-day preoperative period was reported in 27 trials. In 14 of these trials, patients receiving aspirin within the 7-day preoperative period were excluded by the investigators, whereas in the other 13 trials, patients were not excluded on the basis of this criterion.
Mortality
Mortality was assessed in 32 randomized trials including 3779 patients (Figure 1; Appendix Table 2, available online). The overall occurrences of death were similar in combined (full-dose, low-dose) aprotinin (2.47%) and placebo (2.40%) groups, and no significant increased risk of mortality was associated with use of aprotinin (RR 0.96, 95% CI 0.65-1.40). RD statistics showed a 0 mortality difference between the groups per 1000 patients undergoing CABG (95% CI –10 to 10).
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Renal failure
Renal failure data were available in 17 trials including 3003 patients (Figure 1; Appendix Table 2, available online). Renal failure incidence also did not vary by study group (aprotinin 1.48%, placebo 1.28%). Meta-analytic estimate for renal failure also did not show increased risk associated with aprotinin therapy (RR 1.01, 95% CI 0.55-1.83). Similarly, RD statistics showed 0 events averted or induced per 1000 patients undergoing CABG when aprotinin was compared with placebo (95% CI –10 to 10).
Stroke
Stroke was reported in 18 trials and evaluated in 2976 patients (Figure 1; Appendix Table 2, available online). Aprotinin use was associated with consistently fewer strokes in most of the individual trials. Stroke occurred in 1.10% of aprotinin and 2.22% of placebo groups. Aprotinin use was associated with a 47% RR reduction (RR 0.53, 95% CI 0.31-0.90) relative to placebo. The exclusion of a trial in which the quality of diagnosis of cerebrovascular accident was questionable and not confirmed in personal communication17 had little influence on the magnitude of the association (RR 0.49). RD statistics showed a 10-event reduction per 1000 patients undergoing CABG treated with aprotinin (95% CI –20, 0) relative to placebo.
Atrial fibrillation
Only 11 studies (Figure 1; Appendix Table 2, available online) involving 2460 patients reported information on atrial fibrillation. The occurrences of atrial fibrillation reported in individual trials were substantial in both aprotinin (22.72%) and placebo (25.00%) groups. A tendency toward risk reduction associated with aprotinin use was observed (RR 0.90, 95% CI 0.78-1.04). RD statistics also showed a tendency toward a more than 30 event reduction (per 1000 CABGs) associated with the use of aprotinin (95% CI –60 to 10).
Blood transfusion
The number of patients who required any blood transfusion was evaluated in 25 trials involving 3430 patients (Figure 1; Appendix Table 2, available online). The use of aprotinin was consistently associated with fewer patients requiring any blood transfusion. Total numbers of patients requiring any blood transfusion were 40.33% in aprotinin and 63.34% in placebo groups. Accordingly, a 39% risk reduction of blood transfusion was associated with use of aprotinin (RR 0.61, 95% CI 0.58-0.66). RD statistics determined that RR of this magnitude corresponded to more than 250 patients prevented from receiving any blood transfusion per 1000 CABG procedures (95% CI –280 to –220).
Events by subgroups of preoperative aspirin use
Subgroup analyses stratified by aspirin use were evaluated in fewer trials (Figure 2). In addition, sufficient numbers of events were available regarding only three outcomes (mortality, MI, and blood transfusion). Presence or absence of aspirin use had no impact on mortality as related to aprotinin therapy. The stratified analysis shows that in trials where aspirin users within 5 to 7 days before surgery were excluded, aprotinin use was associated with statistically significant risk reduction in the occurrence of MI (RR 0.40, 95% CI 0.17-0.92). In trials where aspirin users were not excluded, no difference between aprotinin and placebo groups was observed regarding the occurrence of MI (RR 1.00, 95% CI 0.71-1.40). In addition, fewer patients required blood transfusion in trials where aspirin users were excluded (RR 0.53, 95% CI 0.47-0.60) than in trials where aspirin users were not excluded (RR 0.67, 95% CI 0.61-0.72).
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Discussion |
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Concerns about MI (graft closure) and renal failure may contribute to relative underuse of this medication in CABG. The contention that aprotinin might be associated with MI and renal failure originated when Cosgrove and colleagues4 reported overall 14 MI events among 113 patients treated with aprotinin versus 4 among 56 treated with placebo. Although substantial increase in creatinine was also reported in aprotinin-treated patients, occurrence of renal failure itself was not different between the groups (8 of 133 vs 4 of 56 in the clinical study report). Although a similar trend was reported in another well-known clinical trial,18 evidence linking aprotinin to these side events was limited. Further studies on coagulation monitoring have shown that aprotinin increases the activated clotting time in the Celite-based measurement,19 which could potentially lead to underheparinization and contribute to the observed findings in studies conducted earlier. Although increased or decreased risks of MI and renal failure cannot be definitely excluded (because of wide confidence intervals), our findings should alleviate concerns that aprotinin causes increases in the occurrence of these adverse events.
One previous study attempting to address systematically the issue of mortality and MI found aprotinin to be associated with reduced mortality and slightly higher risk of MI.7 However, the analysis included a mixture of cardiac surgical procedures (mitral valve, aortic valve, coronary bypass, etc). In addition, others have indicated concerns about inaccuracies in patient numbers, discrepancies in odds ratios extracted from individual studies, and inappropriate application of inclusion criteria, casting doubt on conclusions draw from this previous systematic analysis.10 A recent report suggested that antifibrinolytic therapy, including aprotinin, increased mortality among patients undergoing CABG.6 The study used data from studies in which treatment group assignment was not described as randomized or controlled; thus treatment bias or use of antifibrinolytics as rescue therapy, instead of as prophylaxis for bleeding, could well explain the data in this observational study. In our analysis of aprotinin therapy, no decrease or increase in mortality was confirmed; the data showed aprotinin therapy to be associated with a mortality risk ratio of 0.96 (95% CI 0.65, 1.40). In addition, no tendency toward an increased occurrence of MI in aprotinin treated patients was shown, and in fact the opposite tendency was observed.
To our knowledge, this is the first systematic analysis study to report that substantial stroke reduction benefits could theoretically be associated with aprotinin use, supporting an observation originally published by Levy et al.2 The current analysis indicates that approximately 10 cerebrovascular accidents can be averted per 1000 patients undergoing CABG when aprotinin is used. A number of theories describing the effect of aprotinin on risk of stroke have been discussed. As early as 1994, Murkin and associates20 reported that serine protease inhibitors such as aprotinin may have cerebroprotective effects and proposed that aprotinin could prevent or ameliorate the initial endothelial response in the presence of ischemic cerebral injury and could improve the outcome after cerebral ischemia. Later, Smith and Muhlbaier5 also reported a tendency toward stroke reduction in a combined analysis of US aprotinin trials. In a review study, Royston21 also reported that anti-inflammatory actions and modifications in vascular tone associated with aprotinin therapy may be related to improved outcome by reducing the occurrence of permanent neurologic deficit or stroke after heart operations. A recent retrospective analysis of a cardiac surgery population at high risk for stroke8 observed a significant decrease in the occurrence of stroke among patients administered full-dose aprotinin relative to the placebo group. Our investigation provides additional data describing the cerebrovascular effect of aprotinin. The tendency toward a reduction in atrial fibrillation associated with aprotinin, supporting clinical data published previously,9,22 provides another possible mechanism. Atrial fibrillation is associated with a higher risk of cerebrovascular accidents, particularly in the early postoperative period, so the tendency toward prevention of approximately 30 atrial fibrillations per 1000 patients undergoing CABG could potentially contribute to the observation of fewer strokes associated with aprotinin.
In our study, the number of patients averted from receiving any blood transfusion when treated with aprotinin was accurately quantified. Although blood transfusion benefits associated with aprotinin have been reported at length,1-4 a summary estimate with the large population (n = 3430) generated in this study has not been reported previously in the literature. These data demonstrate that relative to placebo approximately 250 of 1000 patients undergoing CABG could theoretically be prevented from any blood transfusion if treated with aprotinin.
Subgroup analysis of patients enrolled in the trials in which aspirin users were excluded showed aprotinin therapy to have no influence on mortality; however, a reduction in the occurrence of MI was observed. The reduction in MI is likely to result from some aspect of aprotinin action other than its ability to reduce blood transfusion requirements. However, these findings should be interpreted with caution, because fewer patients were enrolled in these trials. Similarly, we found that neither full-dose regimen nor low-dose regimen was associated with more frequent adverse events relative to placebo (data not included). Although full-dose aprotinin seemed to be associated with a higher reduction in the transfusion requirements (RR 0.59, 95% CI 0.55-0.64) than low-dose aprotinin (RR 0.65, 95% CI 0.59-0.72), comparison of these two regimens is a question of its own, and these results need to be confirmed in a more specific meta-analyses that also include trials without a placebo arm that directly compare these regimens.
Conclusions
Aprotinin substantially decreases transfusion requirements in patients undergoing CABG. The concern that aprotinin therapy is associated with increased risk of mortality, MI, or renal failure is not supported by data from published, randomized, placebo-controlled clinical trials. For stroke, evidence of a reduced risk associated with aprotinin therapy was shown. A tendency toward reduction in atrial fibrillation occurrence associated with aprotinin use was observed. The balance of effects is positive with aprotinin use.
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Acknowledgments |
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L. R. Sajja, G. Mannam, R. M. Chakravarthi, S. Sompalli, S. K. Naidu, B. Somaraju, and R. R. Penumatsa Coronary artery bypass grafting with or without cardiopulmonary bypass in patients with preoperative non-dialysis dependent renal insufficiency: A randomized study J. Thorac. Cardiovasc. Surg., February 1, 2007; 133(2): 378 - 388. [Abstract] [Full Text] [PDF]
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J. M. Murkin, S. J. Adams, R. J. Novick, M. Quantz, D. Bainbridge, I. Iglesias, A. Cleland, B. Schaefer, B. Irwin, and S. Fox Monitoring Brain Oxygen Saturation During Coronary Bypass Surgery: A Randomized, Prospective Study Anesth. Analg., January 1, 2007; 104(1): 51 - 58. [Abstract] [Full Text] [PDF]
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 A. Ronald and J. Dunning Does use of aprotinin decrease the incidence of stroke and neurological complications in adult patients undergoing cardiac surgery? Interactive CardioVascular and Thoracic Surgery, December 1, 2006; 5(6): 767 - 773. [Abstract] [Full Text] [PDF]
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S. C. Body and C. D. Mazer Pro: Aprotinin Has a Good Efficacy and Safety Profile Relative to Other Alternatives for Prevention of Bleeding in Cardiac Surgery Anesth. Analg., December 1, 2006; 103(6): 1354 - 1359. [Full Text] [PDF]
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W. Dietrich, R. Busley, and M. Kriner High-Dose Aprotinin in Cardiac Surgery: Is High-Dose High Enough?: An Analysis of 8281 Cardiac Surgical Patients Treated with Aprotinin Anesth. Analg., November 1, 2006; 103(5): 1074 - 1081. [Abstract] [Full Text] [PDF]
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D. Royston, J. H. Levy, J. Fitch, W. Dietrich, S. C. Body, J. M. Murkin, B. D. Spiess, and A. Nadel Full-Dose Aprotinin Use in Coronary Artery Bypass Graft Surgery: An Analysis of Perioperative Pharmacotherapy and Patient Outcomes Anesth. Analg., November 1, 2006; 103(5): 1082 - 1088. [Abstract] [Full Text] [PDF]
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A. Sedrakyan, A. Wu, G. Sedrakyan, M. Diener-West, M. Tranquilli, and J. Elefteriades Aprotinin use in thoracic aortic surgery: Safety and outcomes J. Thorac. Cardiovasc. Surg., October 1, 2006; 132(4): 909 - 917. [Abstract] [Full Text] [PDF]
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 B. Bidstrup Who Reviews the Reviewers? Asian Cardiovasc Thorac Ann, October 1, 2006; 14(5): 357 - 358. [Full Text] [PDF]
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K. G. Shann, D. S. Likosky, J. M. Murkin, R. A. Baker, Y. R. Baribeau, G. R. DeFoe, T. A. Dickinson, T. J. Gardner, H. P. Grocott, G. T. O'Connor, et al. An evidence-based review of the practice of cardiopulmonary bypass in adults: A focus on neurologic injury, glycemic control, hemodilution, and the inflammatory response. J. Thorac. Cardiovasc. Surg., August 1, 2006; 132(2): 283 - 290.e3. [Full Text] [PDF]
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C. W. Hogue Jr, C. A. Palin, and J. E. Arrowsmith Cardiopulmonary bypass management and neurologic outcomes: an evidence-based appraisal of current practices. Anesth. Analg., July 1, 2006; 103(1): 21 - 37. [Abstract] [Full Text] [PDF]
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J. R. S. Day, R. C. Landis, and K. M. Taylor Aprotinin and the protease-activated receptor 1 thrombin receptor: antithrombosis, inflammation, and stroke reduction. Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2006; 10(2): 132 - 142. [Abstract] [PDF]
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D. J. Kozik and J. S. Tweddell Characterizing the Inflammatory Response to Cardiopulmonary Bypass in Children Ann. Thorac. Surg., June 1, 2006; 81(6): S2347 - S2354. [Abstract] [Full Text] [PDF]
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V. A. Ferraris, C. R. Bridges, R. P. Anderson, for the Blood Conservation Guideline, J. R. Brown, N. J.O. Birkmeyer, G. T. O'Connor, J. H. Levy, J. G. Ramsay, R. A. Guyton, et al. Aprotinin in cardiac surgery. N. Engl. J. Med., May 4, 2006; 354(18): 1953 - 1957. [Full Text] [PDF]
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D. M. Arnold, D. A. Fergusson, A. K.C. Chan, R. J. Cook, G. A. Fraser, W. Lim, M. A. Blajchman, and D. J. Cook Avoiding transfusions in children undergoing cardiac surgery: a meta-analysis of randomized trials of aprotinin. Anesth. Analg., March 1, 2006; 102(3): 731 - 737. [Abstract] [Full Text] [PDF]
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J. R.S. Day, D. O. Haskard, K. M. Taylor, and R. C. Landis Effect of Aprotinin and Recombinant Variants on Platelet Protease-Activated Receptor 1 Activation Ann. Thorac. Surg., February 1, 2006; 81(2): 619 - 624. [Abstract] [Full Text] [PDF]
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D. T. Mangano, I. C. Tudor, C. Dietzel, and the Multicenter Study of Perioperative Ischemia Re The Risk Associated with Aprotinin in Cardiac Surgery N. Engl. J. Med., January 26, 2006; 354(4): 353 - 365. [Abstract] [Full Text] [PDF]
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M. Carrier Invited commentary Ann. Thorac. Surg., January 1, 2006; 81(1): 84 - 84. [Full Text] [PDF]
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J. R.S. Day, K. M. Taylor, E. A. Lidington, J. C. Mason, D. O. Haskard, A. M. Randi, and R. C. Landis Aprotinin inhibits proinflammatory activation of endothelial cells by thrombin through the protease-activated receptor 1 J. Thorac. Cardiovasc. Surg., January 1, 2006; 131(1): 21 - 27. [Abstract] [Full Text] [PDF]
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T. Shiga, Z. Wajima, T. Inoue, and A. Sakamoto Aprotinin in Major Orthopedic Surgery: A Systematic Review of Randomized Controlled Trials Anesth. Analg., December 1, 2005; 101(6): 1602 - 1607. [Abstract] [Full Text] [PDF]
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E. H. Kincaid, D. A. Ashburn, J. R. Hoyle, M. G. Reichert, J. W. Hammon, and N. D. Kon Does the Combination of Aprotinin and Angiotensin-Converting Enzyme Inhibitor Cause Renal Failure After Cardiac Surgery? Ann. Thorac. Surg., October 1, 2005; 80(4): 1388 - 1393. [Abstract] [Full Text] [PDF]
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 T. O. Morgan Cost, quality, and risk: Measuring and stopping the hidden costs of coronary artery bypass graft surgery Am. J. Health Syst. Pharm., September 15, 2005; 62(18_Supplement_4): S2 - S5. [Abstract] [Full Text] [PDF]
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L. Engles Review and application of serine protease inhibition in coronary artery bypass graft surgery Am. J. Health Syst. Pharm., September 15, 2005; 62(18_Supplement_4): S9 - S14. [Abstract] [Full Text] [PDF]
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J. H. Levy Overview of clinical efficacy and safety of pharmacologic strategies for blood conservation Am. J. Health Syst. Pharm., September 15, 2005; 62(18_Supplement_4): S15 - S19. [Abstract] [Full Text] [PDF]
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A. Sedrakyan Improving clinical outcomes in coronary artery bypass graft surgery Am. J. Health Syst. Pharm., September 15, 2005; 62(18_Supplement_4): S19 - S23. [Abstract] [Full Text] [PDF]
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G. Lindvall, U. Sartipy, and J. van der Linden Aprotinin Reduces Bleeding and Blood Product Use in Patients Treated With Clopidogrel Before Coronary Artery Bypass Grafting Ann. Thorac. Surg., September 1, 2005; 80(3): 922 - 927. [Abstract] [Full Text] [PDF]
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A. Kher, K. K. Meldrum, K. L. Hile, M. Wang, B. M. Tsai, M. W. Turrentine, J. W. Brown, and D. R. Meldrum Aprotinin improves kidney function and decreases tubular cell apoptosis and proapoptotic signaling after renal ischemia-reperfusion J. Thorac. Cardiovasc. Surg., September 1, 2005; 130(3): 662 - 662. [Abstract] [Full Text] [PDF]
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J. van der Linden, G. Lindvall, and U. Sartipy Aprotinin Decreases Postoperative Bleeding and Number of Transfusions in Patients on Clopidogrel Undergoing Coronary Artery Bypass Graft Surgery: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial Circulation, August 30, 2005; 112(9_suppl): I-276 - I-280. [Abstract] [Full Text] [PDF]
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J. C.J. Sun, M. A. Crowther, T. E. Warkentin, A. Lamy, and K. H.T. Teoh Should Aspirin Be Discontinued Before Coronary Artery Bypass Surgery? Circulation, August 16, 2005; 112(7): e85 - e90. [Full Text] [PDF]
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E. L. Gillespie, K. A. Gryskiewicz, C. M. White, J. Kluger, C. Humphrey, S. Horowitz, and C. I. Coleman Effect of aprotinin on the frequency of postoperative atrial fibrillation or flutter Am. J. Health Syst. Pharm., July 1, 2005; 62(13): 1370 - 1374. [Abstract] [Full Text] [PDF]
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L. Englberger and T. Carrel Reply to Shrivastava and Akowuah Eur. J. Cardiothorac. Surg., January 1, 2005; 27(1): 177 - 177. [Full Text] [PDF]
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