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Recombinant FactorVIIa in non-haemophiliacs
- NEVIL P. HUTCHINSON, PRAVEEN D. PRASANNA, S H O Intensive Care (15 November 2006)
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factor VIIa
- Imrat S Sohanpal (4 October 2006)
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NEVIL P. HUTCHINSON, Consultant Cardiac Anaesthetist , PRAVEEN D. PRASANNA, S H O Intensive Care
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Editor - We read with interest the recent paper by Bowles and colleagues on the use of recombinant Factor VIIa in non-haemophiliacs(1). As we all know the off-label use of this drug is rapidly expanding and it is widely recognised that certain preconditions must pertain for rFVIIa to be successful(2. First of all, if the pH is below 7.1 there is virtually no point in giving rFVIIa(3). The protocol being used during the retrospective study period did not take pH into consideration at all and the pH values are not given. Most guidelines, like the new guideline given in Appendix 2, suggest a minimum pH of 7.2 It is also interesting to look at the range of platelet counts in each of the group (survivors and non-survivors) at the time of administration of rFVIIa. These were as low as 16 and 18 in each group and it is not mentioned how many patients in each group had low platelets, because platelet count > 50 IU is a pre-requisite for successful rFVIIa activity(2). Besides platelet count of over 50, pH >7.2, the patient should also have a fibrinogen level >1 g L-1 and a Haematocrit over 0.25(6). Although the “current” protocol (Appendix 2) makes pH >7.2 and keeping platelet count >50 IU explicit, there is only mention of “adequate” treatment with FFP and cryoprecipitate. This begs the question “What is adequate?” This may well explain the “This suggests a physiological difference in terms of capacity to respond to rFVIIa existed at the time of administration of the drug between the two groups of patients and that this difference may have prognostic value. This observation was supported by a difference in the SOFA scores between the two groups.” So, for the above mentioned reasons, it is likely that patients with higher SOFA(Sequential Oragan Failure Assessment) scores i.e. the sicker patients had lower pH and/or suboptimal fibrinogen and possibly low platelet concentrations which might have caused the drug failure in these patients. A further point worth making is about the blood product requirement in the study groups. The authors mention the reduced post-rFVIIa blood product requirements in the survivors and an increase in the non- survivors, however could it be due to the fact that the non-survivor group received fewer blood products pre-rFVIIa (suggesting a possible treatment bias in this group) than the patients who survived? (45 vs. 28; table 3) Furthermore, rFVIIa is unlikely to be worth giving if the patient is profoundly hypothermic. Interestingly, degree of hypothermia was one of the components of the prognostic scoring system in a recent similar trial done prospectively(4). As the authors rightly observed, PT is expected to be shortened, but unrelated to the efficacy of the drug(2). Although these may be useful in following trends related to treatment, especially well after the effect of rFVIIa has worn off, even then we would suggest that a functional measurement of clotting such as thromboelastometry may give better information(5). So far, the best indicator of the efficacy of rFVIIa is the clinical improvement in bleeding(2). We think it is a shame that the appendices were not included in the paper publication as protocols are the key to the success or failure while using drugs such as recombinant FactorVIIa. We disagree with the authors’ conclusion that the SOFA score is likely to have a role in deciding the use of rFVIIa and would urge the use of guidelines based on variables known to be important in the physiology of haemostasis. Despite a growing number of articles in the literature about rFVIIa there is little discussion of the use of alternatives such as prothrombin complex concentrates. These are cheaper and from anecdotal evidence at least (7), equally effective. Why are people not exploring the use of these alternatives? The nature of medical publishing is such that we are unlikely to see articles published proclaiming that “rFVIIa” use is unnecessary, only more and more articles reporting its use, the way in which it is used, how it should be used, etc. thus perpetuating the myth of it’s place in non- haemophiliac bleeding management(8). N. P. Hutchinson* P. D. Prasanna Brighton, UK *E-mail: Nevil.Hutchinson@bsuh.nhs.uk References 1 Bowles KM, Callaghan CJ, Taylor AL, Harris RJ, Pettigrew GJ, Baglin TP, Park GR. Predicting response to recombinant factor VIIa in non- haemophiliac patients with severe haemorrhage. Br J Anaesth 2006; 97: 476- 481 2 Martinowitz U, Michaelson M on behalf of the Israeli Multidisciplinary rFVIIa Task Force. Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force. J Thromb Haemost 2005; 3: 640–8. 3 Meng ZH, Wolberg AS, Monroe DM III, Hoffman M. The effect of temperature and pH on the activity of factor VIIa: implications for the efficacy of high-dose factorVIIa in hypothermic and acidotic patients. J Trauma 2003; 55: 886–91. 4 Biss TT, Hanley JP. Recombinant activated factor VII (rFVIIa/NovoSeven(R)) in intractable haemorrhage: use of a clinical scoring system to predict outcome. Vox Sang 2006; 90: 45–52 5 Soresen B, Ingerslev J. Thromboelastography and recombinant factor VIIa-hemophilia and beyond. Semin Hematol 2004; 41:140-4. 6 Roberts HR, Monroe DM, Escobar MA. Current concepts of hemostasis: Implications for therapy. Anesthesiology 2004; 100(3): 722-730. 7 Schoechl H. Personal communication (2006). 8 Spahn DR, Tucci MA. Is recombinant FVIIa the magic bullet in the treatment of major bleeding? Br J Anaesth 2005; 94(5): 553-555. Conflict of Interest:None declared |
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Imrat S Sohanpal, Anaesthetic Registrar
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Dear Editor I would like to congratulate Dr Bowles and colleagues for a well thought and executed retrospective study on the use of recombinant factor VIIa (rFVIIa) in non-haemophiliac patients. The question the study has identified - when does the use of rFVIIa become futile and how to discriminate between patients that would respond, is of particular importance. But are we being aggressive enough in its use to maximise the benefits of the drug in conjunction with an effective scoring system. An Israeli study by the Multidisciplinary task force (1) looked at 36 trauma patients with a median age of 19.5 all with no previous co- morbidity. Cessation of bleeding as determined by haemodynamic stabilization was achieved in 26 of 36 patients after administration of rFVIIa. 9 out of the 10 patients died within 24 hours due to exsanguination. Those who died had application of all accepted and available surgical measures but mortality in 52% was due to refractory coagulopathic bleeding. A trend towards improved survival was observed in patients who received a higher initial dose (median 120ug/kg) compared to those who received the lower dose of 90ug/kg as per protocol for haemophiliac patients. The main difference between the guidelines used in the Israeli study is that the repeated dose was given 15-20min after the initial dose if there was no response, in comparison to 3 hours. This timing of the second dose in conjunction with the SOFA scoring system could significantly change the outcome in future studies. Although, this study does not break down the number of patients that survived who had the repeated dose, which is unfortunate. I think more questions have been generated than answers in addition to the ones stated by Dr Bowles and colleagues, which seems to be the trend with the use of rFVIIa at present. 1. Should rFVIIa be initially given in higher dose? (120ug/kg instead of 90ug/kg) 2. Should rFVIIa be used earlier in the treatment line before substantial organ failure and refractory coagulopathy develops (Coagulopathy develops early after injury and is present in 25-36% of trauma victims upon admission to the emergency department)(2)? 3. Is there any benefit in using repeated doses in patients with high SOFA scores and if so what duration should be between the doses? The frequently encountered limitations of replacement therapy emphasize the need for additional pro-haemostatic agents. The proposed wonder drug that rFVIIa set out to be I still think is debatable but its proven to be wonderful in a certain group of patients, which is highlighted in the article as an area needed for a large multi-centre prospective study. On the back of this article we are now auditing the use of rFVIIa in our trust retrospectively. This will hopefully give more collectable data, which can be compiled to produce a meta-analysis to achieve greater statistical power. Dr I. S. Sohanpal E-mail: imyso@mac.com 1. Guidelines for the use of recombinant activated factor VII in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa task force. U. Martinowitz and M. Michaelson. Journal of Thrombosis and Haemostasis, 3: 640-648 Jan 2005. 2. Acute Traumatic Coagulopathy. Brohi K. J Trauma 2003; 541: 1127- 30. Conflict of Interest:None declared |
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