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Ann Thorac Surg 2004;77:949-950
© 2004 The Society of Thoracic Surgeons
Department of Cardiothoracic Surgery, University Hospital, Linkoping, Sweden SE-581 85
e-mail: rolf.svedjeholm{at}lio.se
The neuroendocrine stress response and activation of several biological cascade systems contribute to the pathophysiology after cardiac surgery. Inhibition of one cascade is unlikely to abolish all adverse effects; and it can be questioned if a single therapeutic intervention can reduce undesirable sequelae significantly. In general surgery, similar issues have been raised and a multimodal approach to enhance clinical outcome has been suggested by Kehlet [1]. The evidence-oriented cardiac surgeon faces other obstacles, including defining accurate criteria, for vital complications such as perioperative myocardial infarction or LV dysfunction. This can explain why the clinical efficacies of many measures that have become routine in cardiac surgery remain to be proven. On the other hand, cardiac surgical literature has not been pampered with adequately powered randomized trials; however, such efforts are not futile. Recently, it was demonstrated that intensive insulin treatment could reduce mortality in a cohort of surgical ICU patients, of which two thirds were cardiac surgical patients [2].
Shernan et al deserve credit for their efforts to assess the clinical usefulness of pexelizumab (P), a recombinant single-chain anti-C5 monoclonal antibody. Experimental evidence suggests that inhibition of C5 cleavage ameliorates the inflammatory response to CPB and reperfusion of ischemic myocardium. A pilot study suggested that these effects translate into improved clinical outcome after CABG with CPB [3]. The authors have now evaluated P in a large randomized clinical trial. The biological assays confirmed that P inhibits complement activation. However, this effect was not associated with the clear-cut clinical benefits that were reported in the pilot study. The heterogeneity brought from mixing CABG and CABG + valve patients operated at 65 centers with different routines, may have contributed to the inconclusive results. Given the circumstances addressed initially, the importance of a homogenous, yet appropriate, study population cannot be overestimated.
The authors address several issues concerning the primary end-point. Exploratory analyses post hoc are acceptable as long as the prespecified end-points have been clearly stated in the protocol. By retrospectively changing criteria for perioperative myocardial infarction, the authors found a reduction in the composite of death/myocardial infarction after isolated CABG in patients receiving a bolus + infusion of P. However, in conflict with the pilot study, no effect of P given as a bolus was detected. The inflammatory response may have been of limited clinical significance while the bolus was effective, or the effect of P may have been diluted by events unrelated to complement activation.
The authors justly point out the potentially untoward effect of P on postoperative infections. This issue must be closely monitored in future trials, which are warranted as a result of the post hoc analyses. Above all, this important contribution highlights the need to review criteria for endpoints that cover some of our most important postoperative complications, such as perioperative myocardial infarction and postoperative heart failure. We need to specify more accurate and uniform criteria, not only to facilitate evaluation of specific treatments but also to allow meaningful comparisons of different studies.
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  R. J. De Silva, A. Vuylsteke, S. J. Fritchley, A. K. Trull, J. J. Dunning, and J. Wallwork APT070 inhibits complement activation during in vitro cardiopulmonary bypass. Eur. J. Cardiothorac. Surg., July 1, 2006; 30(1): 72 - 76. [Abstract] [Full Text] [PDF]
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