Aprotinin; An economy of truth?

Abstract

To the Editor: I write to comment on the editorials by Drs Sundt1Sundt T.M. The demise of aprotinin: Our share of the blame.J Thorac Cardiovasc Surg. 2008; 135: 729-731Abstract Full Text Full Text PDF Scopus (10) Google Scholar (April 2008) and Westaby2Westaby S. Aprotinin: Twenty-five years of claim and counterclaim.J Thorac Cardiovasc Surg. 2008; 135: 487-491Abstract Full Text Full Text PDF Scopus (17) Google Scholar (March 2008). Dr Sundt is perceptive but fails to consider that the observational studies suggesting a danger with aprotinin may have had bias in the analysis. At the advisory committee meeting of the Food and Drug Administration (FDA) held on September 12, 2007, Dr Mangano allowed the FDA access to the McSPI (Multicenter Study of Perioperative Ischemia) data set. Whereas Mangano and colleagues3Mangano D.T. Tudor I.C. Dietzel C. The risk associated with aprotinin in cardiac surgery.N Engl J Med. 2006; 354: 353-365Crossref Scopus (909) Google Scholar used a propensity score that was based on likelihood of bleeding, the FDA reanalysis of these data used stratification according to risk of adverse outcome. The FDA analysis showed no increases in relative risks (RRs) for death (RR 0.91, 95% confidence interval [CI] 0.54–1.53), heart failure (RR 1.05, 95% CI 0.75–1.47), myocardial infarction (RR 1.10, 95% CI 0.88—1.39), or renal dysfunction (RR 1.26, 95% CI 0.76–2.11) when data from 1222 aprotinin-treated patients were compared with those of 1307 patients who did not receive the drug.4Levenson.ppt & Cyns.ppt in Cardiovascular and Renal Drugs Advisory Committee (CRDAC) in Joint Session with the Drug Safety and Risk Management Advisory Committee (DSaRM). Slides Found at www.fda.gov/ohrms/dockets/ac/07/slides2007-4316s1-00-index.htm. Accessed July 5th 2008.Google Scholar At the same FDA meeting, Dr Karkouti, who used matching of pairs of data, showed that the inclusion into the model of cardiopulmonary bypass variables (time and circulatory arrest) and transfusion (>4 units of red blood cells and fresh-frozen plasma) removed the statistical effects of aprotinin on renal function.4Levenson.ppt & Cyns.ppt in Cardiovascular and Renal Drugs Advisory Committee (CRDAC) in Joint Session with the Drug Safety and Risk Management Advisory Committee (DSaRM). Slides Found at www.fda.gov/ohrms/dockets/ac/07/slides2007-4316s1-00-index.htm. Accessed July 5th 2008.Google Scholar The Toronto data have never shown any other mortality or morbidity risk. Dr Funary also presented the North West Consortium analysis, which showed that any apparent effect of aprotinin on adverse outcome is lost when red blood cell transfusion numbers are included as a confounding variable.5Furnary A.P. Wu Y. Hiratzka L.F. Grunkemeier G.L. Page 3rd, U.S. Aprotinin does not increase the risk of renal failure in cardiac surgery patients.Circulation. 2007; 116: I127-I133Google Scholar In the article from Shaw and colleagues6Shaw A.D. Stafford-Smith M. White W.D. Phillips-Bute B. Swaminathan M. Milano C. et al.The effect of aprotinin on outcome after coronary-artery bypass grafting.N Engl J Med. 2008; 358: 784-793Crossref Scopus (165) Google Scholar of the Duke University Medical Center, the populations of patients receiving aprotinin or ε-aminocaproic acid (EACA) were hugely different. No matter how clever the statistical modeling, clinicians will recognize that there must be differences in management and outcome between a patient with isolated myocardial ischemia undergoing primary, elective revascularization (given EACA) and one undergoing a nonelective reoperation for heart failure associated with valve pathology (who would likely receive aprotinin in about 70%-80% of cases worldwide). Despite this, Shaw and colleagues6Shaw A.D. Stafford-Smith M. White W.D. Phillips-Bute B. Swaminathan M. Milano C. et al.The effect of aprotinin on outcome after coronary-artery bypass grafting.N Engl J Med. 2008; 358: 784-793Crossref Scopus (165) Google Scholar concluded that aprotinin use was the factor associated with mortality when comparing data from 1343 aprotinin-treated patients with those from 6776 given EACA and 2029 given neither therapy. Two aspects may lead the interested reader to question this conclusion. First, the propensity analysis did not include red blood cell transfusion numbers as a factor (transfusion was graded as either yes or no). More worrisome is that a matched-pairs analysis was relegated to the supplementary data available online from the New England Journal of Medicine. In this analysis, which included 1992 patients with comparable risks, aprotinin showed no effects on 30-day (P = .58) and 1-year mortalities (P = .36) relative to EACA. Thus if propensity scoring is achieved by linear regression, and confounding variables known to be associated with adverse outcomes are excluded, then observational studies show aprotinin to be a dangerous drug. Aprotinin is not seen to be dangerous, however, when the analysis is performed with matching or stratification of risk and known confounders are included.