Lessons from a systematic literature review of the effectiveness of recombinant factor VIIa in acquired haemophilia
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To conduct a systematic review of the literature reporting efficacy and safety of recombinant factor VIIa (rFVIIa) for the treatment of bleeding in acquired haemophilia and, if data permitted, undertake a meta-analysis of the current evidence. MEDLINE®, Embase®, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for all studies on rFVIIa treatment in acquired haemophilia. Heterogeneity of included studies was measured using the inconsistency index (I2). Of the 2353 publications screened, 290 potentially relevant references were identified: 12 studies published in 32 publications met inclusion criteria. In total, 1244 patients and 1714 bleeds were included (671 patients received rFVIIa treatment for 1063 bleeds). In seven of 12 studies, the initial dose of Recombinant FVIIa was 90 ± 10 μg/kg. Recombinant FVIIa was used as first-line therapy in the majority of cases. Median number of doses administered ranged from 10 to 28. Between 68 and 74% of bleeds were spontaneous, whereas 4–50% were traumatic. Thirty-nine to 90% of bleeds were severe. Haemostatic effectiveness was > 90% in 5/6 studies for both patient and bleed level. Recombinant FVIIa had a favourable safety profile with low risk of general adverse events and thromboembolic-associated events. The heterogeneity of the studies and data precluded a meta-analysis. Recombinant FVIIa demonstrated effectiveness for the treatment of bleeds and had a good safety profile. It is apparent from these data that there is a need for more standardised measures of clinical effectiveness in acquired haemophilia to enable comparison and pooling of results in the future.
KeywordsAcquired haemophilia Bleeding rFVIIa Systematic review Effectiveness Safety
The authors would like to thank PAREXEL for performing the systematic review and tentative meta-analysis. Editorial and writing assistance was provided by Sharon Eastwood (DPhil) of Fishawack Communications Ltd and was financially supported by Novo Nordisk in compliance with international guidelines for good publication practice. The authors would also like to thank Soraya Benchikh el Fegoun of Novo Nordisk Health Care AG for her contributions to this project and comments during the development of the manuscript.
Both authors directed and critically evaluated the performance of the systematic review and tentative meta-analysis. Both authors also wrote and edited the manuscript and reviewed and approved the final submitted version.
This study received financial support from Novo Nordisk.
Compliance with ethical standards
Conflict of interest
Andreas Tiede has received grants and personal fees for lectures and consultancy from Novo Nordisk. Andrew Worster has acted as a consultant for Novo Nordisk. The authors received an unrestricted grant from Novo Nordisk for editorial support during the development of the manuscript.
For this type of study, ethical approval is not required.
For this type of study, formal consent is not required.
- 1.Collins PW, Hirsch S, Baglin TP, Dolan G, Hanley J, Makris M, Keeling DM, Liesner R, Brown SA, Hay CR, Organisation UKHCD (2007) Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors’ Organisation. Blood 109(5):1870–1877. https://doi.org/10.1182/blood-2006-06-029850 CrossRefPubMedGoogle Scholar
- 2.Borg JY, Guillet B, Le Cam-Duchez V, Goudemand J, Levesque H, Group SS (2013) Outcome of acquired haemophilia in France: the prospective SACHA (Surveillance des Auto antiCorps au cours de l'Hemophilie Acquise) registry. Haemophilia 19(4):564–570. https://doi.org/10.1111/hae.12138 CrossRefPubMedGoogle Scholar
- 3.Knoebl P, Marco P, Baudo F, Collins P, Huth-Kuhne A, Nemes L, Pellegrini F, Tengborn L, Levesque H, Contributors ER (2012) Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost 10(4):622–631. https://doi.org/10.1111/j.1538-7836.2012.04654.x CrossRefPubMedGoogle Scholar
- 4.Tiede A, Klamroth R, Scharf RE, Trappe RU, Holstein K, Huth-Kuhne A, Gottstein S, Geisen U, Schenk J, Scholz U, Schilling K, Neumeister P, Miesbach W, Manner D, Greil R, von Auer C, Krause M, Leimkuhler K, Kalus U, Blumtritt JM, Werwitzke S, Budde E, Koch A, Knobl P (2015) Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study. Blood 125(7):1091–1097. https://doi.org/10.1182/blood-2014-07-587089 CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Giangrande P (2012) Acquired hemophilia. Treatment of Hemophilia 38:1–7Google Scholar
- 7.Baudo F, Collins P, Huth-Kuhne A, Levesque H, Marco P, Nemes L, Pellegrini F, Tengborn L, Knoebl P, Er c (2012) Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood 120(1):39–46. https://doi.org/10.1182/blood-2012-02-408930 CrossRefPubMedGoogle Scholar
- 8.Huth-Kuhne A, Baudo F, Collins P, Ingerslev J, Kessler CM, Levesque H, Castellano ME, Shima M, St-Louis J (2009) International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica 94(4):566–575. https://doi.org/10.3324/haematol.2008.001743 CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Novo Nordisk (2016) NovoSeven (eptacog alfa). Summary of Product Characteristics.Google Scholar
- 11.Khan KS, ter Riet G, Glanville J, Sowden AJ, Kleijnen J (2001) Undertaking systematic reviews of research on effectiveness. CRD’s guidance for those carrying out or commissioning reviews. CRD Report Number 4 (2nd Edition)Google Scholar
- 12.Higgins JPT, Green Se (2011) Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]Google Scholar
- 18.Ma AD, Kessler CM, Al-Mondhiry HAB, Fisher M, Gut RZ, Cooper DL (2012) Use of recombinant factor VIIa (rFVIIa) for acute bleeding episodes in acquired hemophilia: final analysis from the Hemostasis and Thrombosis Research Society (HTRS) Registry AH Study. Blood 120(21):4624Google Scholar
- 19.Kessler CM, Ma AD, Al-Mondhiry HA, Gut RZ, Cooper DL (2016) Assessment of acquired hemophilia patient demographics in the United States: the Hemostasis and Thrombosis Research Society Registry. Blood Coagul Fibrinolysis 27(7):761–769. https://doi.org/10.1097/MBC.0000000000000582 CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Ma AD, Kessler CM, Al-Mondhiry HA, Gut RZ, Cooper DL (2016) Use of recombinant activated factor VII for acute bleeding episodes in acquired hemophilia: final analysis from the Hemostasis and Thrombosis Research Society Registry acquired hemophilia study. Blood Coagul Fibrinolysis 27(7):753–760. https://doi.org/10.1097/MBC.0000000000000471 CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Seita I, Amano K, Higasa S, Sawada A, Kuwahara M, Shima M (2013) Treatment of acute bleeding episodes in acquired haemophilia with recombinant activated factor VII (rFVIIa): analysis from 10-year Japanese postmarketing surveillance. J Thromb Haemost 11(Suppl. 2):119Google Scholar
- 22.Amano K, Seita I, Higasa S, Sawada A, Kuwahara M, Shima M (2017) Treatment of acute bleeding in acquired haemophilia A with recombinant activated factor VII: analysis of 10-year Japanese postmarketing surveillance data. Haemophilia 23(1):50–58. https://doi.org/10.1111/hae.13033 CrossRefPubMedGoogle Scholar
- 23.Luis A, Alejandro A, Pierdominicci M, Azzaro S, Cermelj M, Bernard H (2010) Acquired haemophilia A (AHA): management profiles in Argentina. Haemophilia 16(Suppl 4):2Google Scholar
- 24.GTH Registry (data on file) (2016) GTH Registry on acquired haemophilia: a management of bleeds.Google Scholar
- 27.Scharf RE, Bomke B, Seidel H, Gheisari R, Scharf MA, Hoffmann T (2011) Improved prognosis of acquired hemophilia A: a 10-year experience. Blood 118:21Google Scholar
- 28.Lentz SR, Tandra A, Gut RZ, Cooper DL (2014) A novel supplemental approach to capturing post-marketing safety information on recombinant factor VIIa in acquired hemophilia: the Acquired Hemophilia Surveillance project. J Blood Med 5:1–3. https://doi.org/10.2147/JBM.S55216 CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Zhang XH, Zhu XL, Niu T, Sun J, Liu H, Feng R, Yang LH, Wei Q, Ma QH, Wang QM, Feng FE, Fu HX, Mo XD, Lv M, Huang XJ (2015) Combination of FVIII and low-dose rFVIIa improves haemostasis in acquired haemophilia A patients: a collaborative controlled study. Thromb Res 135(5):835–840. https://doi.org/10.1016/j.thromres.2015.02.029 CrossRefPubMedGoogle Scholar
- 31.Scharf RE, Gheisari R, Bomke B, Hoffmann T (2011) Improved prognosis of acquired hemophilia A (AHA): results of the Duesseldorf monocenter study. J Thromb Haemost 9(Suppl. 2):921Google Scholar
- 33.Kruse-Jarres R, St-Louis J, Greist A, Shapiro A, Smith H, Chowdary P, Drebes A, Gomperts E, Bourgeois C, Mo M, Novack A, Farin H, Ewenstein B (2015) Efficacy and safety of OBI-1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A. Haemophilia 21(2):162–170. https://doi.org/10.1111/hae.12627 CrossRefPubMedGoogle Scholar
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