Electronic letters to:

Research:
David Henry, MBChB, Paul Carless, BHSc MMedS, Dean Fergusson, PhD MHA, and Andreas Laupacis, MD MSc
The safety of aprotinin and lysine-derived antifibrinolytic drugs in cardiac surgery: a meta-analysis
CMAJ 2009; 180: 183-193 [Abstract] [Full text] [PDF]
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Electronic letters published:

[Read eLetter] Meta-analysis of Antifibrinolytic Use in Cardiac Surgery
Abe DeAnda   (3 February 2009)
[Read eLetter] Aprotinin and mortality in cardiac surgery
Neil Blumberg   (22 January 2009)

Meta-analysis of Antifibrinolytic Use in Cardiac Surgery 3 February 2009
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Abe DeAnda
Montefiore Medical Center

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Re: Meta-analysis of Antifibrinolytic Use in Cardiac Surgery

adeanda{at}montefiore.org Abe DeAnda

To the Editor:

I congratulate Henry et al. for a well-presented meta-analysis of the impact of antifibrinolytic therapy in cardiac surgery [1]. This issue continues to come up as practitioners and clinicians react to the findings of the BART trial [2]. The authors raise some points that merit further discussion. First, in this study (and similar to their previous meta- analysis [3]), the mortality risk of aprotinin never reaches statistical significance with all confidence intervals including unity. Given that placebo-controlled studies have shown a benefit of aprotinin (as well as the lysine analogues), would it be fair to say that aprotinin by itself does not increase mortality, but the other antifibrinolytics do a better job in reducing mortality? Second, the difference in interpretation in two meta-analyses [1,3] reminds us that even with evidence-based medicine, the evidence and resulting practice may change. Finally, the decision for early release publication of this study on the eve of Health Canada’s review of the BART data may raise a few eyebrows.

1. Henry D, Carless P, Fergusson D, Laupacis A. The safety of aprotinin and lysine-derived antifibrinolytic drugs in cardiac surgery: a meta-analysis. CMAJ 2009; 180(2):183-93. Epub 2008 Dec 2. 2. Fergusson DA, Hebert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358:2319 -31. 3. Henry DA, Carless PA, Moxey AJ, O’Connell D, Stokes BJ, McClelland B, Laupacis A, Fergusson D. Anti-fibrinolytic use for minimizing perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2007; 4:CD001886.

Conflict of Interest:

None declared
Aprotinin and mortality in cardiac surgery 22 January 2009
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Neil Blumberg
University of Rochester Medical Center

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Re: Aprotinin and mortality in cardiac surgery

neil_blumberg{at}urmc.rochester.edu Neil Blumberg

Aprotinin administration is associated with a tendency toward increased mortality as compared with other anti-fibrinolytics in Henry and colleagues’s recent meta-analysis. We would like to suggest a possible confounding factor that may contribute to this excess of deaths, and reduced bleeding, observed in aprotinin treated patients. Platelet transfusions are quite frequently administered to high risk patients undergoing cardiac surgery in the absence of evidence based indications. This appears to have been the case in one recent study.(1) Only 9.5-12.1% of patients experienced massive hemorrhage, yet 28-37% of patients received platelet transfusions.

Platelet transfusions are potentially pro-inflammatory,(2) pro- thrombotic,(3, 4) and may be associated with increased mortality.(5) One reason aprotinin is associated with increased mortality might be increased hemostatic efficacy, combined with increased thrombosis due to prophylactic co-administration of platelet transfusions. If so, aprotinin, contrary to current thinking, may be safe and effective, but only if platelet transfusions are not given concomitantly. The role of platelet transfusions as a contributing cause of increased mortality in studies of aprotinin merits further investigation.

1. Fergusson DA, Hebert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008;358(22):2319-31. 2. Khan SY, Kelher MR, Heal JM, et al. Soluble CD40 ligand accumulates in stored blood components, primes neutrophils through CD40, and is a potential cofactor in the development of transfusion-related acute lung injury. Blood 2006;108(7):2455-62. 3. Cook D, Crowther M, Meade M, et al. Deep venous thrombosis in medical- surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med 2005;33(7):1565-71. 4. Khorana AA, Francis CW, Blumberg N, Culakova E, Refaai MA, Lyman GH. Blood transfusions, thrombosis, and mortality in hospitalized patients with cancer. Arch Intern Med 2008;168(21):2377-81. 5. Spiess BD, Royston, D., Levy J.H., Fitch, J., Dietrich, W., Body, S., Murkin, J., Nadel, A. Platelet transfusions during coronary artery bypass graft surgery are associated with serious adverse outcomes. Transfusion 2004;44:1143-8.

Authors:

Neil Blumberg MD and Joanna M. Heal MBBS, MRCP, Clinical Laboratories and Transfusion Medicine Service, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642

Conflict of Interest:

NB served as a paid consultant to Bayer regarding transfusion risks and aprotinin