The Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) (Institute for Quality and Economics in the Health Care System) in Germany recently issued a report on haemophilia treatment. The full report and an executive summary may be found on the organisation’s website although it is currently only available in German.
IQWiG is an independent institution, which evaluates therapies with respect to efficacy, safety and costs in a similar way to the National Institute for Excellence and Clinical Evaluation (NICE) in the United Kingdom. This report was apparently commissioned by the German Ministry of Health. The report will clearly have a major impact in Germany as the conclusions will be noted by the health insurance companies, which pay for haemophilia treatment. The report is also likely to be read with interest by health care commissioners in other European countries and so we felt it would be helpful to provide a commentary on the EHC website.
The review had three objectives:
- Review evidence-based studies of treatment of haemophilia patients with severe haemophilia A or B and compare different regimes (on demand versus (vs) prophylactic treatment; plasma derived factors vs recombinant factors; doses employed);
- Compare outcomes on prophylaxis vs on demand long term treatment; and
- Consider whether patient treatment guidelines in Germany are evidence-based.
Several sources were taken into account in drafting this report, which does not bear the names of any specific authors. The views of physicians from treatment centres in Germany were sought with regard to their current clinical practice. Two independent advisors were involved in drafting the report (one physician working in a haemophilia treatment centre and one working for a health insurance company). A total of 13 guidelines from various bodies such as the World Federation of Hemophilia (WFH), the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) and the outcome of the Kreuth III initiave were reviewed and cited although most were specifically excluded from consideration in drafting the conclusions as they were not considered to be sufficiently evidence–based.
The most important conclusions for a wider readership of this 275-page report are those which relate to the value of prophylaxis in children and adults with haemophilia A and B. On a positive note, the report endorsed the value of prophylaxis in children and adolescents in controlling bleeds, although the report state that there was no proven benefit in terms of quality of life or overall mortality. Note that these conclusions only refer to haemophilia A, as the report specifically notes that there are no data from randomized studies in patients with haemophilia B. The report is also supportive of prophylaxis in adults, as it is accepted as proven that this prevents joint bleeds (although not necessarily progression of established joint damage). A descriptive analysis is included of studies and recommendations relating to plasma-derived and recombinant products, but no final preference is expressed for either class of product.
A significant limitation of this review is that consideration was restricted to controlled clinical trials, which include at least 50 patients. Many other studies are cited in the list of references but were not actually taken into consideration in drafting the final conclusions. The number of such studies in haemophilia is very limited but includes the joint outcome study led by Dr Manco-Johnson in the USA as well as the ESPRIT (1) and SPINART (2) studies. Although randomized controlled studies are generally regarded as the gold standard for proving a hypothesis, such studies are very difficult to conduct in haemophilia where patient numbers are very limited and there may well be genuine ethical problems in comparing a potential new therapy to placebo or even standard therapy. This is a particular problem in haemophilia B, where numbers are even more limited. We have encountered this problem in the field of haemophilia before, most memorably in the case of the 2005 Cochrane review of prophylaxis in haemophilia. This effectively concluded that there was no evidence that prophylaxis in haemophilia was effective because there were no data from randomized controlled studies at that time. It is manifestly impractical to completely disregard the results of non-randomized studies or indeed years of clinical experience. The British Medical Journal published a now-famous article some years ago to ram home this message (3). This paper pointed out that the efficacy of parachutes cannot be regarded as proven as no-one has conducted a formal study comparing the survival of subjects jumping out of a plane with and without one!
Authors of the commentary:
Prof Paul Giangrande, Chair EHC Medical Advisory Group
Prof Michael Makris, Member EHC Medical Advisory Group
Prof Flora Peyvandi, Member EHC Medical Advisory Group
References:
(1) Gringeri, A. et al. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 9(4):700-10 [2011].
(2) Manco-Johnson, MJ et al. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART). J Thromb Haemost 11(6):1119-27 [2013].
(3) Smith, G.C.S.; Pell, J.P. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ 327: 1459-1461 [2003].
Jim is aged 66 and has Haemophilia A with a high titer inhibitor which he developed at age 14.
Maria Elisa Mancuso (MD, PhD) is a Haematologist and works as a Senior Haematology Consultant at the Center for Thrombosis and Haemorrhagic Diseases of IRCCS Humanitas Research Hospital in Rozzano, Milan, Italy. She is Adjunct Clinical Professor at Humanitas University. She obtained a post-degree in Clinical and Experimental Haematology and a PhD in Clinical Methodology. She is involved in clinical research and has published several original articles in peer-reviewed journals a The Lancet, Blood, Journal of Thrombosis and Haemostasis, Haematologica, Thrombosis and Haemostasis, British Journal of Haematology and Haemophilia. She is reviewer for several peer-reviewed journals and member of the Editorial Board of JTH. She is a member of several scientific societies (ISTH, WFH, ASH, EAHAD, SISET, AICE) and was a medical member of the Inhibitor Working Group of the European Hemophilia Consortium. She is co-chair of the ADVANCE Study Group. She has acted also as co-chair of the Scientific and Standardization Subcommittee of ISTH on FVIII, FIX and rare bleeding disorders. She has been involved as principal and co-investigator in several clinical trials, and she takes care of both children and adults with hemophilia and other congenital bleeding disorders with a specific scientific interest in novel therapies, prophylaxis, inhibitors, and chronic hepatitis C.
As a patient with factor II deficiency, the diagnostic and treatment of rare bleeding disorders is a matter dear to my heart. My motivation to participate in the work of the ERIN committee is to improve both diagnostic and treatment for patients with rare bleeding disorders across Europe.
Economist and financial expert by profession, executive coach and trainer by passion and haemophilia advocate by every drop of my blood through my son (who has severe haemophilia A with inhibitors). Bringing a good decade of practical experience from the corporate insurance world, laser focus, growth mindset and resilience from my own experience, offering you anything I can just do, in hope that together we can make life more fulfilled for those impacted by bleeding disorders.
Amy Owen-Wyard is a Registered Mental Health Nurse. With experience working with children, young people, their families and adults with severe and enduring mental health conditions. Amy was also involved in a service improvement to provide a holistic care approach for those in general hospitals to support both their mental and physical health, whilst sharing her expertise and knowledge in mental health with the wider multidisciplinary team.
