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Anesthesiology and Critical Care Medicine, Englewood Hospital and Medical Center, 350 Engle St, Englewood, NJ 07631
(Email: aryeh.shander{at}ehmc.com; mazyarjr{at}yahoo.com).
Level 1 evidence is seriously lagging behind the wide off-label use of recombinant activated factor VII (rFVIIa) in the control of massive or insurmountable bleeding. Dunkley and colleagues [1] have made a commendable effort in gathering and analyzing the data on nonhemophilia cardiac surgery cases with critical bleeding treated with rFVIIa from a large multicenter registry with financial support from Novo Nordisk. The study faces limitations, many of which are shared with other registries; lack of a control group is perhaps the biggest obstacle in interpreting the data, given the complicated nature of cardiac surgery and the numerous confounding variables and heterogeneous practices. For instance, 15 cases received platelets, fresh frozen plasma (FFP) or cryoprecipitate, but no red blood cells prior to rFVIIa. As an alternative to control, authors have resorted to comparing measurements before and after rFVIIa administration. However, observed improvements can be the result of collective salvage efforts rather than rFVIIa alone. In addition, data on 87% of the cases have been retrospectively collected, which raises the questions of accuracy, especially for response to treatment. With some cases dating back more than 4 years, the potential memory lapse combined with the possible bias toward the treatment can result in inaccuracies. Apart from the old cases, the subjective reporting of this outcome is of significant concern. Although the authors argue that this measure concurs with mortality rates, objective measurements (such as chest tube drainage) would have been more desirable. Finally, lack of set times for measuring blood parameters before and after giving rFVIIa could substantially obscure the causal relationship between the measured values and the treatment.
In a registry, bias can be introduced at many levels including data collection, submission, and analysis. The authors have taken appropriate countermeasures (ie, participating hospitals were required to submit all cases and their adherence was audited). The observed median dose in this study was very close to the dose used in hemophilia patients as well as off-label cases. Interestingly, dose was not associated with outcomes, suggesting the possibility of lower doses being as effective (or less likely, the drug not being effective at all and all the observed improvements being due to other treatments). The observed thromboembolic adverse event rate of 7% in this study is close to the previously reported rates, which is of concern. This rare but significant complication would be acceptable providing rFVIIa had a demonstrable higher benefit. In summary and within constrains of a registry, this study serves to highlight some of the issues facing future trials on rFVIIa, such as defining outcomes and accounting for heterogeneity in practices while suggesting an acceptable safety profile. Although the present study provides a valuable insight, ongoing and future controlled trials will hopefully provide the much needed higher quality evidence for the "off-label" use of rFVIIa.
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