Letter by Al-Ruzzeh and Navia Regarding Article, “Safety and Efficacy of Recombinant Activated Factor VII: A Randomized Placebo-Controlled Trial in the Setting of Bleeding After Cardiac Surgery”
To the Editor:
We read with interest the recent article by Gill et al on recombinant factor VIIa (rFVIIa) in cardiac surgery.1 We would like to raise the following issues. The authors’ conclusion that “for the first time, a hemostatic agent has the possibility of being an effective alternative to allogenic transfusion in cardiac surgery patients with uncontrolled postoperative bleeding” is imprecise. The 3 randomization arms in the trial received “allogenic transfusion,” and the concluded beneficial effect of rFVIIa in the trial was that it significantly increased the percentage of patients who avoided transfusions. In other words, rFVIIa was an adjunct, not a replacement or an alternative to transfusion in this trial.
The authors rightly recognize that the rFVIIa group received significantly more transfusions before randomization and discuss this fact in terms of its probable contribution to the numeric increase in serious adverse events. They fail, however, to recognize that the rFVIIa group also received significantly more fresh frozen plasma and platelet transfusions, along with the allogenic blood transfusions, and this difference could have had a major effect on the apparent efficacy of rFVIIa. Likewise, the authors report 43% to 66% use of “antifibrinolytic treatment” in the baseline characteristics of the trial patients without explanation of times, doses, indications of use, or even effects on the trial results. The authors may have adequately standardized the transfusion protocol after randomization; however, they failed to control the events during the initial critical period before randomization in terms of blood and blood product transfusion and antifibrinolytic treatment, which unfortunately may have affected the trial results.
The authors use the reoperation rate as a secondary end point of the trial, although at best it is a surrogate outcome, in which rFVIIa significantly reduced the number of patients requiring reoperations. They fail to inform the reader about the mechanism of surgical decision to take the patient back to the operating room and whether it was standardized among the centers and surgeons who joined the trial. There is no mention of how much the patients bled before going back to the operating room, how long the duration of bleeding was before returning to the operating room, whether they were placed on cardiopulmonary bypass again and heparinized, whether they had any additional procedures at reoperation, and whether the trial protocol continued after they went back to the intensive care unit. They also do not comment on the surgical perception of the cause of bleeding at reoperation. Was the reason poor surgical hemostasis, for which rFVIIa was not likely to have an effect, or generalized coagulopathy with no specific bleeding points identified?
The authors recognize that the study was underpowered to provide any conclusion for the primary end point, the serious adverse outcomes, that they set out to test in the trial. They do not recognize that the trial could not provide a definite conclusion on the secondary end points either, which at best are surrogate outcomes. The percentage of patients who avoided transfusion could have been confounded by the lack of prerandomized standardization, and the reoperation variable was not subject to enough standardization.