The Risks of Aprotinin and Tranexamic Acid in Cardiac Surgery: A One-Year Follow-Up of 1188 Consecutive Patients Martin, Klaus MD*; Wiesner, Gunther MD*; Breuer, Tamás MD*†; Lange, Rüdiger MD‡; Tassani, Peter MD* Author(s): Section Editor(s): Houge, Charles W. Jr; London, Martin J.; Levy, Jerrold H. Issue: Publication Type: Publisher: Volume 107(6), December 2008, pp 1783-1790 [Cardiovascular Anesthesiology: Cardiovascular and Thoracic Education: Hemostasis and Transfusion Medicine] © 2008 by International Anesthesia Research Society. From the *Institute of Anesthesiology, German Heart Centre Munich, Munich, Germany; †Department of Cardiology, Semmelweis University, Budapest, Hungary; and ‡Department of Cardiovascular Surgery, German Heart Centre Munich, Munich, Germany. Institution(s): Accepted for publication May 7, 2008. Address correspondence and reprint requests to Klaus Martin, MD, Institute of Anesthesiology, German Heart Centre Munich, Clinic at the Technical University Munich, Lazarettstr. 36. 80636 Munich, Germany. Address e-mail to martin@dhm.mhn.de. Abstract BACKGROUND: Our aim was to investigate postoperative complications and mortality after administration of aprotinin compared to tranexamic acid in an unselected, consecutive cohort. METHODS: Perioperative data from consecutive cardiac surgery patients were prospectively collected between September 2005 and June 2006 in a universityaffiliated clinic (n = 1188). During the first 5 mo, 596 patients received aprotinin (Group A); in the next 5 mo, 592 patients were treated with tranexamic acid (Group T). Except for antifibrinolytic therapy, the anesthetic and surgical protocols remained unchanged. RESULTS: The pre- and intraoperative variables were comparable between the treatment groups. Postoperatively, a significantly higher incidence of seizures was found in Group T (4.6% vs 1.2%, P < 0.001). This difference was also significant in the primary valve surgery and the high risk surgery subgroups (7.9% vs 1.2%, P = 0.003; 7.3% vs 2.4%, P = 0.035, respectively). Persistent atrial fibrillation (7.9% vs 2.3%, P = 0.020) and renal failure (9.7% vs 1.7%, P = 0.002) were also more common in Group T, in the primary valve surgery subgroup. On the contrary, among primary coronary artery bypass surgery patients, there were more acute myocardial infarctions and renal dysfunction in Group A (5.8% vs 2.0%, P = 0.027; 22.5% vs 15.2%, P = 0.036, respectively). The 1-yr mortality was significantly higher after aprotinin treatment in the high risk surgery group (17.7% vs 9.8%, P = 0.034). CONCLUSION: Both antifibrinolytic drugs bear the risk of adverse outcome depending on the type of cardiac surgery. Administration of aprotinin should be avoided in coronary artery bypass graft and high risk patients, whereas administration of tranexamic acid is not recommended in valve surgery. In a retrospective analysis of 4374 patients enrolled in the Multicenter Study of Perioperative Ischemia Research Group international database, aprotinin use was associated with a higher incidence of adverse outcome, (renal, neurological, and cardiac) in patients undergoing primary coronary artery bypass surgery (CABG), compared to patients receiving tranexamic acid, [epsilon]–aminocapronic acid or control group patients.1 From the same database, a 5-yr follow-up was recently published.2 The authors concluded that, with regard to the association between aprotinin, end-organ failure and long-term mortality, the continued use of aprotinin seems not to be prudent. “Safer alternatives,” such as tranexamic acid or [epsilon]aminocapronic acid, should be used during CABG. Both studies had an inconsistent demographic bias, especially concerning the patients’ preoperative risk, and had to be mathematically corrected by propensity score adjustment. The possible influence of unmeasured variables cannot be excluded, and the question remains whether the increased prevalence of adverse outcomes is a consequence of different perioperative risk factors. For many years at our institution aprotinin has been used in almost every patient undergoing cardiac surgery with extracorporeal circulation.3 As a consequence of the serious concerns about the safety of aprotinin, we decided to completely stop using aprotinin in February 2006, and to use tranexamic acid instead, as the antifibrinolytic drug of choice during cardiac surgery. This consequent treatment with one of the antifibrinolytic drugs offered us the opportunity to create two treatment groups of our consecutive patients without any preselection. In this study, we compared data of a 5-mo period of administering tranexamic acid with data of the preceding 5 mo of aprotinin administration in almost 1200 consecutive adult cardiac surgery patients undergoing extracorporeal circulation with regard to blood loss, cardiac, renal, and neurological complications, as well as 30day, and 1-yr mortality. Although not randomized, this study meets most criteria of a randomized clinical trial without the need to use statistical methods for risk adjustment, in contrast to the other recently published studies on this topic. METHODS The study was approved by the Ethical Committee of the Technical University Munich (Germany); the requirement for written informed consent was waived by the board. After approval, we analyzed the perioperative data of all adult patients undergoing cardiac surgery using cardiopulmonary bypass (CPB) between September 2005 and June 2006 (n = 1239). Patients were excluded if they did not receive any antifibrinolytic therapy, received multiple drugs, or the administered dose of the antifibrinolytic drug was not sufficient according to our institutional protocol (total dose <4 × 106 kallikrein inhibiting units (KIU) aprotinin or 4 g tranexamic acid, respectively). If a patient underwent reoperation for nonbleeding reasons during the same admission, only data of the first operation were included in the analyses. After exclusion, the study cohort contained data of 1188 consecutive patients (Fig. 1). Data of the patients were prospectively collected in the clinical database as part of the national quality assurance project in cardiac anesthesia and surgery. Laboratory values were extracted from the database of the clinical laboratory. Figure 1. Diagram of patient enrollment. CPB, cardiopulmonary bypass. Until February 2006, all patients undergoing cardiac surgery with CPB were treated with full-dose aprotinin (Trasylol; Bayer, Leverkusen, Germany) according to the Hammersmith protocol (Group A). The Hammersmith protocol consists of a bolus of 2 × 106 KIU aprotinin administered at the beginning of CPB, followed by a continuous infusion of 0.5 × 106 KIU/h until chest closure; 2 × 106 KIU is added to the prime of the CPB equipment. From February 2006 onward, aprotinin was completely replaced by tranexamic acid (Cyklokapron; Pfizer, Karlsruhe, Deutschland) (Group T). Tranexamic acid was administered according to the institutional protocol: 2 g was administered at the beginning of CPB and then as a continuous infusion at a rate of 0.5 g/h until chest closure; 2 g was added to the prime of the CPB equipment. We compared perioperative data of the patients from the first 5-mo period of using tranexamic acid (Group T, n = 592) with data of patients from the preceding 5 mo of aprotinin administration (Group A, n = 596). All other aspects of the surgical and anesthetic management remained unchanged. A standard CPB setting was used. After cross-clamping of the aorta, either 1500 mL of cold crystalloid cardioplegic solution (Bretschneider = Custodiol; Köhler Chemie, Alsbach-Hahnlein, Germany) for any surgery involving valves or warm bloodcardioplegia (CABG surgery only) was used for cardiac arrest. Transfusion triggers used were a hematocrit decrease to <18% on CPB or <24% during the postoperative course, or if the patient showed clinical signs indicating the need for a higher oxygen supply. Inotropic support was defined as the continuous infusion of at least two of the following: more than 5 µg · kg · min-1 dopamine or dobutamine, or epinephrine or milrinone, respectively. Vasopressor therapy was defined as the application of norepinephrine of at least 500 µg/h. We analyzed the main demographic data, the medical history data, the intraoperative data, and the type of surgery. Postoperative blood loss was measured as chest-tube output at 6, 12, and 24 h after surgery. The amount of transfused allogenic blood products and reoperation for bleeding were also recorded. Postoperative renal dysfunction required a serum creatinine level of >1.3 mg/dL with an increase over baseline of at least 0.5 mg/dL; renal failure was defined as dysfunction requiring dialysis. Cardiac complications were new persistent atrial fibrillation (new atrial fibrillation continuing until discharge from the intensive care unit), acute myocardial infarction (AMI; new Q-waves, persistent ST-segment or T-wave changes and CK-MB higher than three times the upper limit of normal range of our institution protocol, i.e., >80 U/L),29 and heart failure (need for inotropic support and intraaortic ballon pump). Neurological events, defined as new seizure or stroke/transitory ischemic attack, were clinically diagnosed; stroke was confirmed by computed tomography scan. Mortality (all-cause death) was assessed 30 days and 1-yr after surgery. Foreign patients were primarily excluded from follow-up (primary loss). A questionnaire was sent to all patients who were not taking part in routine examination at 1-yr after surgery. If necessary, the patients’ cardiologists or the local authorities were contacted. Nonresponders were also excluded (secondary loss). We analyzed data of the whole cohort together (ALL). For post hoc analysis, this collective was split in three subgroups according to the type of surgery: primary CABG, primary valve surgery (VALVE); i.e., left heart valve surgery (mitral and/or aortic valve), and high risk surgery (HIGH RISK) operations for bleeding, e.g., combined and redo operations, aortic surgery, etc. (Table 1). Table 1. Different Types of Operations in the Study Cohort Continuous data are presented as mean ± sd (SD), categorical variables as number (N), and incidence (%). Parameters were compared between Group A and Group T using Mann-Whitney U-test for continuous variables and [chi]2 test for categorical variables. For [chi]2 analysis, the effective total sample size to achieve a power level of 0.8 ([alpha] = 0.05, estimated effect size = 0.2, df = 1) was 197 (GPOWER for MS-DOS, Franz Faul & Edgar Erdfelder, Bonn, Germany). The difference in mortality between the treatment groups was assessed by Kaplan-Meier analysis and Mantel–Cox log-rank test. The results of the two-sided tests were considered significant if the P value was <0.05. The statistical analyses were performed by SPSS for Windows 14.0 statistical software package (SPSS Inc., Chicago, IL). RESULTS There was similar distribution of type of surgery in the treatment groups (Table 1). The main pre- and intraoperative data are presented in Table 2. The only difference in the entire cohort was that more patients were medicated with clopidogrel in Group A. In the subgroups, we found some minor differences (Table 2.). The 10 most experienced surgeons and anesthesiologists performed 92% and 83% of the operations in Group T, and 93% and 85% in Group A, respectively. Table 2. Preoperative and Operative Data of the Patients In ALL patients, the postoperative blood loss and the postoperative transfusion of red blood cells and fresh frozen plasma were significantly decreased in Group A (Table 3.). Subgroup analyses showed significantly less blood loss after administration of aprotinin at all time points in all subgroups, whereas the amount of transfused blood products was significantly smaller only in the VALVE subgroup postoperatively (Table 3). Table 3. Blood Loss and Transfusion of Blood Products Outcome data of the patients are presented in Table 4. Analyzing ALL patients, the incidences of persistent atrial fibrillation and seizure were significantly higher in Group T; the incidence of AMI was higher in Group A. Subgroup analyses showed that in the primary CABG group there were more AMI and renal dysfunction after aprotinin treatment. Administration of tranexamic acid was associated with a higher incidence of seizure, atrial fibrillation, and renal failure in the VALVE subgroup, and with a higher incidence of seizure in the HIGH RISK patients. Table 4. Outcome Data of the Patients Follow-up for mortality was conducted in 96.5% of the patients. Mortality in ALL patients showed no significant difference between the treatment groups. We have not found any significant difference in 30-day mortality in the subgroups, but 1-yr mortality was significantly higher in the HIGH RISK group after aprotinin treatment (Table 5, Fig. 2). Table 5. Mortality of the Patients Figure 2. Kaplan–Meier analysis of 30-day (A) and 1-yr mortality (B) in the HIGH RISK group. Group tranexamic acid contains 177 patients, group aprotinin contains 166 patients. DISCUSSION As every consecutive patient was included in our analysis, we generated an unselected population with only minor differences in the preoperative and intraoperative data. We assumed that the unmeasured variables were also comparable and therefore, no mathematical adjustment, such as propensity score method, was necessary for further analysis. This is an important difference to recently published retrospective studies.1,2,5–7 The efficacy of antifibrinolytic drugs on blood loss and perioperative transfusion of donor blood has been described.8 The blood-sparing effect of aprotinin was often superior to that of tranexamic acid 9,10 and aminocapronic acid, but not always.6,11,12 Our data showed that patients receiving aprotinin during cardiac surgery had significantly lower postoperative blood loss compared to patients receiving tranexamic acid. This benefit was detected in the entire cohort and all subgroups, but it had no effect on the amount of transfusion in the CABG and HIGH RISK patients. Thus, it is still questionable whether the statistically smaller blood loss in Group A is really clinically relevant. Besides the well documented reduction of blood loss, antifibrinolytic drugs might have some unexpected effects, which were often not assessed in the studies focusing on postoperative blood loss and transfusion rates only. Some investigators have demonstrated that aprotinin decreases mortality in cardiac surgery 13 and reduces the incidences of stroke or encephalopathy.14,15 Others have demonstrated an increased risk of myocardial infarction, stroke or encephalopathy, renal failure,1 renal failure only,5 and even mortality.2 The latter publications have received an enormous public reaction and even the Food Drug Administration has questioned the use of aprotinin.* These studies are still under discussion due to the statistically significant differences in baseline characteristics which had to be corrected by propensity score adjustment. This always leaves unanswered questions about an unmeasured selection which might have led to the higher incidences of adverse outcomes.16 As previously described, aprotinin has a high affinity to the kidneys and may lead to disturbances in kinin-synthesis and release, renal afferent vasoconstriction, and macroand microvascular thrombosis.17,18 The phenomenon of arterial vasoconstriction with a probable intravascular thrombosis has also been observed in an animal model in the coronary 19 and femoral arteries.20 However, the underlying mechanism is still unclear. In our study, there was neither a difference in postoperative renal dysfunction nor in the requirement for dialysis between the two treatment groups of the entire population. We set the criteria for postoperative renal dysfunction at a low serum creatinine level, (>1.3 mg/dL = 115 µmol/L) accompanied by an increase from baseline (>=0.5 mg/dL = 44 µmol/L) to detect even milder forms of dysfunction. The overall incidence of dialysis between 5%–6% is well within the range of the literature,1,5 especially in view of the inclusion of high risk patients in our cohort. Contrary to the results of Group ALL, we found a significantly higher rate of renal dysfunction with aprotinin in the CABG subgroup. Although not reaching significance, the percentage of renal failure was twofold compared to Group T. Our data support previous findings of an increased risk of renal complications in patients receiving aprotinin during primary CABG surgery.1,5 The CABG and HIGH RISK subgroups were defined by similar criteria as in other studies, which described higher incidences of myocardial infarction 1 and death after aprotinin.2† Two recently published retrospective analyses of large CABG cohorts also reported, an increased risk for in-hospital death 6 and reduced long-term survival 7 among aprotinin recipients. We recorded a higher rate of myocardial infarctions in the CABG patients as well. Additionally, there was a tendency for more short-term mortalities in both CABG and HIGH RISK subgroups. The lack of significance might be related to the limited number of patients and fatal events. Nevertheless, 1-yr mortality was significantly increased after aprotinin treatment in the HIGH RISK patients. The finding of an increased mortality with aprotinin in patients at high risk for bleeding is in agreement with the results of the interim analyses of the BART study, which led to the suspension of marketing aprotinin.‡ Another major finding of our study is the much higher rate of seizures after administration of tranexamic acid. Tranexamic acid has been shown to have an epileptogenic effect if it is applied topically to the cortex,21,22 intrathecally 23 or even IV in animals.22 The suspected mechanism is a [gamma]-aminobutyric acid-driven inhibition of the central nervous system.24 Some neurosurgical studies have shown a higher incidence of cerebral vasospasm after topical use of tranexamic acid in patients suffering from subarachnoid hemorrhage,25 and also in an animal model.26 Our finding might be related to tranexamic acid-induced vasoconstriction and to concomitant microcirculatory disturbances. The pathomechanism of seizures detected in our study is not yet determined. They occurred almost exclusively after open heart surgery, in VALVE and HIGH RISK patients receiving tranexamic acid. Therefore, it seems reasonable that this complication was associated with the different management of these patients. One possible explanation is the electrolyte change due to the administration of crystalloid cardioplegia during valve surgery; another is the possible effect of microbubbles, which inevitably remain after closing the heart. Additionally, in the VALVE subgroup, the tranexamic acid patients had renal failure and persistent atrial fibrillation more frequently. These complications might have resulted in the tendency towards more short-term mortalities in this subgroup after tranexamic acid treatment. Since there are no large studies focusing on the safety of tranexamic acid, especially in valve surgery, this should be a topic of future research. LIMITATIONS Our study compared data of two chronologically close patient cohorts. Therefore, the risk of unrecognized changes in practice is reduced to a minimum, but it cannot be excluded completely. However, due to the study design and the fact that the known variables were comparable, we assumed that the groups matched well and the unknown variables were also comparable. There were a considerable number of consecutive patients in total and the sample size exceeded the calculated sample size for a power of 0.8 in all the subgroups. However, we cannot exclude that the study did not have enough power to detect all the differences between the treatment groups. Comparative trials powered for important clinical end-points are needed before any antifibrinolytic drug is routinely prescribed for a large number of patients.27 Although we made multiple comparisons in our analyses, we did not adjust the P value because doing so would have increased the chance of making Type II errors.28 Since our focus was on the possible side effects of antifibrinolytics, this appeared not to be prudent. Nevertheless, even with correction for multiple comparisons, the increased rate of seizures with tranexamic acid in valve surgery is a main finding of our study. CONCLUSIONS The blood-sparing effect of aprotinin after cardiac surgery was superior to that of tranexamic acid, but the clinical relevance of this remains questionable. The benefit of the blood-sparing effect has to be balanced against the potential risks of antifibrinolytic drugs. Aprotinin was associated with a higher incidence of complications after primary CABG surgery and a higher 1-yr mortality in HIGH RISK patients compared to tranexamic acid. In addition, this is the first study reporting the detrimental effects of tranexamic acid after valve surgery. Our results show that both antifibrinolytic drugs bear risks of adverse effects that might worsen outcome. Administration of aprotinin should be avoided in CABG and HIGH RISK patients. Tranexamic acid should not be used in open heart procedures until the mechanism of the side effects is clear. REFERENCES 1. Mangano DT, Tudor IC, Dietzel C; Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353–65 [Context Link] 2. Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, Hoeft A, Fontes ML, Hillel Z, Ott E, Titov T, Dietzel C, Levin J. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 2007;297:471–9 [Context Link] 3. Dietrich W, Ebell A, Busley R, Boulesteix AL. Aprotinin and anaphylaxis: analysis of 12,403 exposures to aprotinin in cardiac surgery. Ann Thorac Surg 2007;84:1144–50 [Context Link] 4. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function: measured and estimated glomerular filtration rate. N Engl J Med 2006;354:2473–83 5. Karkouti K, Beattie WS, Dattilo KM, McCluskey SA, Ghannam M, Hamdy A, Wijeysundera DN, Fedorko L, Yau TM. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion 2006;46:327–38 [Context Link] 6. Schneeweiss S, Seeger JD, Landon J, Walker AM. Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med 2008;358: 771–83 [Context Link] 7. Shaw AD, Stafford-Smith M, White WD, Phillips-Bute B, Swaminathan M, Milano C, Welsby IJ, Aronson S, Mathew JP, Peterson ED, Newman MF. The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008;358: 784–93 [Context Link] 8. Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987;2:1289–91 [Context Link] 9. Diprose P, Herbertson MJ, O’Shaughnessy D, Deakin CD, Gill RS. Reducing allogeneic transfusion in cardiac surgery: a randomized double-blind placebo-controlled trial of antifibrinolytic therapies used in addition to intra-operative cell salvage. Br J Anaesth 2005;94:271–8 [Context Link] 10. Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med 2007;356:2301–11 [Context Link] 11. Munoz JJ, Birkmeyer NJ, Birkmeyer JD, O’Connor GT, Dacey LJ. Is epsilonaminocaproic acid as effective as aprotinin in reducing bleeding with cardiac surgery?: a meta-analysis. Circulation 1999;99:81–9 [Context Link] 12. Henry DA, Carless P, Moxey A, O’connell D, Stokes B, McClelland B, Laupacis A, Fergusson D. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007;17: CD001886 [Context Link] 13. Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJ, Briet E, Buller HR. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a metaanalysis of clinically relevant endpoints. Lancet 1999;354:1940–7 [Context Link] 14. Murkin JM. Attenuation of neurologic injury during cardiac surgery. Ann Thorac Surg 2001;72:S1838–S1844 [Context Link] 15. Harmon DC, Ghori KG, Eustace NP, O’Callaghan SJ, O’Donnell AP, Shorten GD. Aprotinin decreases the incidence of cognitive deficit following CABG and cardiopulmonary bypass: a pilot randomized controlled study. Can J Anaesth 2004;51:1002–9 [Context Link] 16. Byar DP. Problems with using observational databases to compare treatments. Stat Med 1991;10:663–6 [Context Link] 17. Kramer HJ, Moch T, von Sicherer L, Dusing R. Effects of aprotinin on renal function and urinary prostaglandin excretion in conscious rats after acute salt loading. Clin Sci (Lond) 1979;56:547–53 [Context Link] 18. Vio CP, Oestreicher E, Olavarria V, Velarde V, Mayfield RK, Jaffa AA. Cellular distribution of exogenous aprotinin in the rat kidney. Biol Chem 1998;379:1271–7 [Context Link] 19. Ülker S, McKeown PP, Bayraktutan U. Aprotinin impairs coronary endothelial function and down-regulates endothelial NOS in rat coronary microvascular endothelial cells. Cardiovasc Res 2002;55:830–7 [Context Link] 20. Samama CM, Mazoyer E, Bruneval P, Ciostek P, Bonnin P, Bonneau M, Roussi J, Bailliart O, Pignaud G, Viars P. Aprotinin could promote arterial thrombosis in pigs: a prospective randomized, blind study. Thromb Haemost 1994;71:663–9 [Context Link] 21. Pellegrini A, Giaretta D, Chemello R, Zanotto L, Testa G. Feline generalized epilepsy induced by tranexamic acid (AMCA). Epilepsia 1982;23:35–45 [Context Link] 22. Yamaura A, Nakamura T, Makino H, Hagihara Y. Cerebral complication of antifibrinolytic therapy in the treatment of ruptured intracranial aneurysm. Animal experiment and a review of literature. Eur Neurol 1980;19:77–84 [Context Link] 23. de Leede-van der Maarl MG, Hilkens P, Bosch F. The epileptogenic effect of tranexamic acid. J Neurol 1999;246:843 [Context Link] 24. Furtmuller R, Schlag MG, Berger M, Hopf R, Huck S, Sieghart W, Redl H. Tranexamic acid, a widely used antifibrinolytic agent, causes convulsions by a gamma-aminobutyric acid(A) receptor antagonistic effect. J Pharmacol Exp Ther 2002;301: 168–73 [Context Link] 25. Tsementzis SA, Meyer CH, Hitchcock ER. Cerebral blood flow in patients with a subarachnoid haemorrhage during treatment with tranexamic acid. Neurochirurgia (Stuttg) 1992;35:74–8 [Context Link] 26. Iplikcioglu AC, Berkman MZ. The effect of short-term antifibrinolytic therapy on experimental vasospasm. Surg Neurol 2003;59:10–6 [Context Link] 27. Ray WA. Learning from aprotinin-mandatory trials of comparative efficacy and safety needed. N Engl J Med 2008;358:840–2 [Context Link] 28. Feise RJ. Do multiple outcome measures require p-value adjustment? BMC Med Res Methodol 2002;2:8 [Context Link] 29. Califf RM, Abdelmeguid AE, Kuntz RE, Popma JJ, Davidson CJ, Cohen EA, Kleiman NS, Mahaffey KW, Topol EJ, Pepine CJ, Lipicky RJ, Granger CB, Harrington RA, Tardiff BE, Crenshaw BS, Bauman RP, Zuckerman BD, Chaitman BR, Bittl JA, Ohman EM. Myonecrosis after revascularization procedures. J Am Coll Cardiol 1998;31:241–51 [Context Link] *www.fda.gov/bbs/topics/NEWS/2006/NEW01472.html , last accessed March 27, 2008. [Context Link] †www.fda.gov/cder/drug/early_comm/aprotinin.htm , last accessed March 27, 2008. [Context Link] ‡www.fda.gov/cder/drug/infopage/aprotinin/default.htm , last accessed March 27, 2008. [Context Link]