Data from a Spanish hospital suggest off-label rFVIIa use in patients refractory to conventional treatment may reduce transfusion requirements and improve haemostasis.
Raúl Prats Ortega
Hospital Pharmacy Resident
Patricio Mas Serrano
Eduardo Climent Grana
Francisco Martinez Granados
Hospital Pharmacy Resident
Juan Pablo Ordovás Baines
University General Hospital of Alicante
Severe bleeding is an important cause of death. Such bleeding is frequently a combination of surgical/trauma and coagulopathic bleeding.
Bleeding of the latter type is caused by impaired thrombin generation, and has a multifactorial mechanism: impaired hepatic function (low production of coagulation factors), hypothermia and acidosis (which decrease platelet and coagulation-enzyme activity), hyperfibrinolysis, anaemia (which causes low platelet adhesion and aggregation), dilutional coagulopathy (resulting from the dilution of coagulation factors and platelets caused by the infusion of large volumes of blood products, and colloids), and consumption coagulopathy.
Nowadays it is believed that pH is a very important factor in coagulation activity, and that this should be corrected in order to achieve good haemostasis.
Conventional treatments for severe bleeding consist of blood-product infusion (concentrated red blood cell units, fresh frozen plasma units, concentrated platelet units), surgical measures (packing the bleeding area, clamping damaged vessels or inducing localised arterial thrombosis) or pharmacological measures (administration of antifibrinolytic drugs).
Unfortunately, in some cases of severe massive bleeding these measures may fail to arrest coagulopathic bleeding, and patients die despite the massive replacement therapy. However, we now have a new haemostatic agent: recombinant activated factor VII.
Recombinant activated factor VII (rFVIIa, NovoSeven, Novo Nordisk) is an analogue of the physiological coagulation protease. It was approved by the EMEA in February 1996 and by the FDA in March 1999 for treating and preventing haemorrhagic episodes in haemophiliac A and B patients with factor VII and factor IX inhibitors, respectively.
The rFVIIa factor has very weak enzymatic activity while circulating in blood until it binds to tissue actor (TF), which is only exposed at the site of the bleeding. The TF-VIIa complex initiates the coagulation cascade, as a result of which rFVIIa enhances haemostasis at the site of the bleeding by increasing thrombin production.
The rFVIIa factor has a very good safety profile with hardly any adverse events (<1/10,000); reported effects comprise coagulopathic disorders (thromboembolism, disseminated intravascular coagulation), haemorrhage, nausea and pain at the injection site. At first it was thought that rFVIIa would increase the risk of thromboembolism, but localised activation at the site of bleeding could explain the good safety profile of rFVIIa observed in its labelled indication. Thromboembolism is a serious adverse effect, although in clinical practice it is rarely observed, with serious thromboembolic events accounting for fewer than 0.05% of more than 400,000 doses.
Because of the excellent safety profile of rFVIIa and the limited therapeutic options for arresting severe bleeding, recent years have seen increasing off-label use of rFVIIa for treating severe bleeding of several ethiologies when other therapeutic measures have failed. This off-label use is supported by published clinical evidence reporting higher survival rate and a decrease in coagulation factor requirements.
There are several limitations to the theoretical benefits of such off-label use. Available published data are from case reports and case series, and since 2005 there have been a few clinical trials on trauma,[2,3] intracerebral haemorrhage and other ethiologies. Reviewing this published data, we find heterogeneity among patients (in terms of demographics, clinical conditions, doses received, conventional treatment and outcome measures), efficacy results (we have found statistical significance in intracranial haemorrhage but not in trauma[2,3]) and safety (low incidence of thromboembolism for trauma,[1–3] but a high incidence in intracerebral haemorrhage). Results of the clinical trials seem to be contradictory (mainly regarding the safety profile), and there could be a publication bias in the case reports because of the higher proportion of positive findings.
In those published data we find a wide range of doses for rFVIIa (50–120 mcg/kg/dose), and a lack of consensus on the possibility of giving extra doses if the bleeding does not stop. One might think that with the good safety profile and the theoretical mechanism of action this might present a good option for cases of severe bleeding refractory to conventional treatment, but rFVIIa has a high cost: that of each dose ranges from €2,000 to €5,000).
In this clinical scenario, and because of the high cost of treatment and the lack of controlled trials and guidelines, we decided to evaluate the experience in our hospital with rFVIIa in treating severe bleeding in patients with neither congenital haemophilia nor inhibitors to coagulation factors (VII or IX).
We designed a retrospective study that ran from January 2005 to April 2006. Inclusion criteria were patients with severe bleeding who did not respond to conventional treatment and were treated with rFVIIa. Primary outcome was survival at 15 days, secondary outcomes were coagulation test and transfusion requirements (before rFVIIa administration and up to 36 hours afterwards). We also recorded data on demographics, bleeding aetiology, disease severity and rFVIIa dose administered. Statistical comparisons were performed with Wilcoxon’s nonparametric paired test (p < 0.05).
During the study period five patients were included; the mean age was 40 years (16–73 years), and there were four men and one woman. The aetiology of bleeding was as follows: one case of intraperitoneal bleeding secondary to trauma, two cases of high digestive bleeding secondary to chronic hepatopathy, and two cases of post-surgical bleeding. In all cases rFVIIa was administered when the conventional treatment failed. Survival at 15 days was 40% (2/5); causes of death were one each of hypovolaemic shock, multi-organic failure and septic shock. The median number of doses was four (1–9); median dose amount was 6.0 mg (4.8–8.4 mg); and the median interval period was five hours (2–13 h).
Transfusion requirements and coagulation tests before and after (36 h) treatment were as in Table 1.
Treatment with rFVIIa does not show any significant change in either transfusion requirements or coagulation test. Nevertheless, our limited data indicate that treatment with rFVIIa shows a trend (without statistical significance) towards reducing transfusion requirements and improving haemostasis in patients with life-threatening bleeding. We believe further controlled, randomised, double-blind and case-control studies with larger numbers of patients are needed in order to assess the efficacy and safety of rFVIIa and how nonresponding patients would gain more benefit.
1. Martinowitz U, Michaelson M. 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.
2. Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials. J Trauma 2005;59(1):8-18.
3. Rizoli SB, Boffard KD, Rou B, et al. Recombinant activated factor VII as an adjunctive therapy for bleeding control in severe trauma patients with coagulopathy: subgroup analysis from two randomized trials. Crit Care 2006;10(6):R178.
4. Mayer SA, Brun NC, Broderick J, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777-85.