We wanted to find evidence on the effectiveness of recombinant factor VIIa (containing no human proteins) as compared to concentrates derived from plasma for treating acute bleeding episodes in people with haemophilia with inhibitors.
Haemophilia is an inherited bleeding disorder caused by a lack of a clotting factor and is characterised by bleeding into the joints. It is treated by injecting a drug containing the missing clotting factor into veins. In some individuals with haemophilia, this factor is seen by the body as a foreign protein when it is injected and the body produces an antibody (inhibitor) that destroys the factor. In this way these people become resistant to treatment. Once someone with haemophilia develops an inhibitor, they are treated to remove the antibody (immunotolerance induction) and for acute bleeding episodes. Treatment for bleeding episodes is with one of two available bypassing agents, recombinant activated factor VIIa (Novoseven®) or human activated prothrombin complex concentrate (FEIBA®). It is not known if one of these products is better than the other. We searched for trials comparing the effectiveness (time until bleeding stops, effect on joint motion, need for re-treatment) and safety of Novoseven® and FEIBA® in people with haemophilia with inhibitors during episodes of acute bleeding.
The evidence is current to: 23 September 2015.
The review included two trials with 69 people (aged one to 55 years) with severe haemophilia with inhibitors. Both trials compared recombinant factor VIIa with activated prothrombin complex concentrate and people were selected for one treatment or the other randomly.
We found two clinical trials comparing Novoseven® and FEIBA®. The trials did not show a difference in how well the two products worked and both were tolerated equally well with no clotting complications. We conclude that both recombinant factor VIIa and plasma-derived concentrates can be used to treat bleeds in people with haemophilia and inhibitors.
Quality of the evidence
There were some major problems with regards to the way both trials were designed, in relation to knowing which treatment group each person was in (both before the trial was started and during) and also how missing results were handled.
Based on the separate analysis of the two available randomised trials, recombinant factor VIIa and activated prothrombin complex concentrate were found to be similar in efficacy and safety. However, there is a need for further, well-designed, adequately-powered, randomised controlled trials to assess the relative benefits and risks of using recombinant factor VIIa compared to human plasma-derived concentrates in people with haemophilia with inhibitors. It is advisable that researchers in the field define commonly agreed objective outcome measures in order to enable the pooling of their results, thus increasing the power of comparisons. To date, data could not be combined in a formal meta-analysis. For the same reason reporting concordant and discordant pairs in cross-over trials is recommended.
In people with haemophilia, therapeutic clotting agents might be recognised as a foreign protein and induce anti-factor VIII antibodies, known as 'inhibitors'. Drugs insensitive to such antibodies, either recombinant or plasma-derived, are called factor VIII 'by-passing' agents and used for treatment of bleeding in people with inhibitors.
To determine the clinical effectiveness of recombinant factor VIIa concentrate compared to plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors.
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Coagulopathies Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.
Date of the most recent search of the Group's Coagulopathies Trials Register: 23 September 2015.
Randomised and quasi-randomised controlled clinical trials comparing recombinant factor VIIa concentrate to human plasma-derived concentrates (high-dose human or recombinant factor VIII or factor IX concentrate; non-activated prothrombin complex concentrates; activated prothrombin complex concentrates) in people with haemophilia. Comparisons with animal-derived products were excluded.
Two authors independently assessed the trials (eligibility and risk of bias) and extracted data. No combined meta-analyses were performed due to the unavailability of outcomes and comparisons common to the included trials.
A total of 15 trials were identified, two of which (with data for a total of 69 participants) were eligible for analysis. Both trials showed methodological flaws and did not show superiority of one treatment over the other. Both the treatments showed that recombinant factor VIIa and activated prothrombin complex concentrate appeared to have a similar haemostatic effect in both trials, without increasing thromboembolic risk.