doi: 10.1161/CIRCULATIONAHA.107.756478
(Circulation. 2008;117:e476.)
© 2008 American Heart Association, Inc.
Correspondence |
Response to Letters Regarding Article "Aprotinin Does Not Increase the Risk of Renal Failure in Cardiac Surgery Patients"
Providence Health System, Portland, Ore
Cardiac, Vascular, and Thoracic Surgeons, Inc, Cincinnati, Ohio
TriHealth (Bethesda North and Good Samaritan Hospitals), Cincinnati, Ohio
We would like to thank Drs Karkouti, Beattie, Bouchard, Mathew, Metha, Agoustides, Landis, Taylor, and Poston for their interest in our study1 and their comments. We agree wholeheartedly with Drs Landis, Taylor, and Poston. We also agree with Dr Agoustides that the inclusion of angiotensin-converting enzyme inhibitor therapy and detailed dose information for aprotinin would lend further discrimination to our model. Unfortunately, although we wished to include such potential confounders in our analysis, these variables were not available in our dataset.
We applaud Drs Bouchard, Mathew, and Metha for pointing out the universal flaw of this sort of research: that is, the lack of a uniform definition of clinically significant renal dysfunction. Retrospective analyses do not allow for the inclusion of >6 hours of oliguria, although prospective trials might. Because Mangano et al2 and Karkouti et al3 used differing definitions of renal dysfunction based on either an absolute or defined percentage rise from baseline creatinine, we could not possibly render a valid comparison. However, both definitions included dialysis-dependent renal failure, a definitive outcome that we did compare. Notably, it was the renal failure outcome that caught the initial attention of the Food and Drug Administration.
Drs Karkouti and Beattie apparently misunderstood the principal conclusion of our article. The principal conclusion was not that "observational studies assessing the risks of aprotinin in cardiac surgery may be unduly influenced by selection bias" as they state in their letter. Although we agree with their statement about observational studies, the principal conclusion of our article was that aprotinin is not associated with an increased risk of new-onset dialysis-dependent renal failure.
We do agree that we may have partially misquoted the results of their original article,3 which stated that that "aprotinin may be associated with renal dysfunction." In reality, their published definition of renal dysfunction not only included an increase in serum creatinine, but also "a new requirement for dialysis support." It is the explicit inclusion of dialysis support to the renal dysfunction lexicon that piqued the keen interest of the Food and Drug Administration, clinicians, and the media worldwide. Collectively, these interested parties took the findings of Karkouti et al3 as a confirmation of the study by Mangano et al,2 which purported to show that "aprotinin was associated with a dose-dependent doubling to tripling in the risk of renal failure requiring dialysis." Without the inclusion of "dialysis dependent renal support," all that the article by Karkouti et al reveals is a numerically significant and previously known transient rise in serum creatinine, which has questionable meaning in terms of clinical outcomes. In fact, as Dr Karkouti himself has recently written, "Whether aprotinin causes renal toxicity or a benign, transient biochemical abnormality, however, is untested and a matter of much controversy."4 If there was absolutely no association between dialysis-dependent renal failure and aprotinin in the study by Karkouti et al, the authors should have explicitly stated that fact. They did not do so. Notably, 2 recent5,6 (and one forthcoming7) articles support our, and now Dr Karkouti’s, mutual conclusion that aprotinin does not cause dialysis-dependent renal failure.
Transfusions are more than an outcome end point; they are a risk variable, or confounder of risk. Most transfusions in cardiac surgery patients are given in the immediate postoperative period, usually within 48 hours of surgery.8 Therefore, inclusion of this largely perioperative variable would be valid even in the eyes of Drs Karkouti and Beattie, as they suggest in their letter. Thus, rather than masking" a potential detrimental effect of aprotinin, inclusion of this largely perioperative variable should further elucidate the safety of this drug in terms of renal failure.
Just because transfusions may be given in the intra- or postoperative period does not make transfusion an outcome without associated consequence. If transfusions were an outcome, why does this outcome never occur in Jehovah’s Witness patients? If transfusions are not an outcome confounder then why have they been shown to be independently associated with increased rates of death, increased infection, increased length of stay, and even renal failure? In fact, Dr Mangano himself showed that postoperative red blood cell transfusion in entirely stable coronary artery bypass grafting patients was associated with significant increases in myocardial infarction, wound infection, renal dysfunction, and renal failure requiring dialysis.9 In that study, Dr Mangano and his coauthors concluded "postoperative [red blood cell] transfusion is associated with an increased risk for cardiac, renal and infectious morbidity."
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Acknowledgments |
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Disclosures
None.
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References |
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 Top References |
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1. Furnary AP, Wu Y, Hiratzka LF, Grunkemeier GL, Page US 3rd. Aprotinin does not increase the risk of renal failure in cardiac surgery patients. Circulation. 2007; 116 (suppl I): I-127–I-133.[CrossRef][Medline] [Order article via Infotrieve]
2. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med. 2006; 354: 353–365.
3. Karkouti K, Beattie WS, Dattilo KM, McCluskey SA, Ghannam M, Hamdy A, Wijeysundera D, Fedorko L, Yau TM. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion. 2006; 46: 327–338.[CrossRef][Medline] [Order article via Infotrieve]
4. Karkouti K, McCluskey SA. Perioperative blood conservation: the experts, the elephants, the clinicians, and the gauntlet. Can J Anesth. 2007; 54: 11:861–867.
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6. Mouton R, Finch D, Davies I, Binks A, Zacharowski K. Effect of aprotinin on renal dysfunction in patients undergoing on-pump and off-pump cardiac surgery: a retrospective observational study. Lancet. 2008; 371: 9611.
7. Pagano D, Howell NJ, Freemantle N, Cunningham D, Bonser RS, Graham TR, Mascaro J, Rooney SJ, Wilson IC, Cramb R, Keogh BE. Bleeding in cardiac surgery: the use of aprotinin does not affect survival. J Thorac Cardiovasc Surg. 2008; 135: 495–502.
8. Snyder-Ramos SA, Moehnle P, Weng YS, Boettiger BW, Kulier A, Levin J, Mangano DT. Ongoing variability in transfusion practices in cardiac surgery despite established guidelines. Blood. 2005; 106: 947. Abstract.
9. Moehnle P, Snyder-Ramos SA, Weng YS, Kulier A, Boettiger BW, Wang S, Levin J, Mangano DT. Morbid risks of unnecessary red blood cell transfusion in stable coronary artery bypass graft patients. Blood. 2005; 106: 427. Abstract.
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