Controversy over ISTH Hemophilia Treatment Guidelines
By Dr. David Clark
From the Summer 2024 newsletter
A controversy over a set of clinical treatment guidelines has been raging for over a year now, but you probably haven’t heard about it. Unfortunately, it has the potential to negatively affect your treatment. We published a piece about the controversy in the Hemophilia News section of the Summer newsletter, but the headline was mistakenly dropped, making it look like it was just part of the preceding article. Here’s the Summer newsletter report followed by an update.
New International Society on Thrombosis and Haemostasis (ISTH) Clinical Guidelines for Hemophilia Treatment
6/19/24 The ISTH has released the “International Society on Thrombosis and Haemostasis Clinical Practice Guideline for Treatment of Congenital Hemophilia A and B Based on the Grading of Recommendations Assessment, Development, and Evaluation methodology.” This has caused a lot of controversy in the hemophilia treatment community. It is different in several aspects from the “WFH Guidelines for the Management of Hemophilia,” 3rd edition, which were published in August 2020. The WFH guideline was consensus-based, being developed by a large panel of hemophilia treaters according to how they actually treat hemophilia. The ISTH document used the GRADE method (Grading of Recommendations Assessment, Development, and Evaluation methodology), which evaluates the scientific reliability of the information on which the guidelines are based. These give different answers.
What the ISTH report actually tells us is that most of the methods used to treat hemophilia haven’t been rigorously tested according to the highest scientific standards. That’s true, and we know it. However, that doesn’t mean that your medical treatment is deficient. As explained by Mannucci in an accompanying article in the same issue of the Journal of Thrombosis and Haemostasis, in the GRADE method, the gold standard is results from randomized clinical trials (RCTs).
While some hemophilia studies are done using RCTs, most are not. That’s not surprising in a small field like hemophilia B. RCTs are expensive, time-consuming and usually require larger numbers of subjects – things that aren’t always available to us. Instead, hemophilia treaters rely more on another important tool that science gives us, scientific reasoning, plus their own experience. They know, even without studies, that getting factor IX into your bloodstream will help minimize your bleeding – and there are lots of ways to do that to accommodate all the variations from patient to patient.
The ISTH report only makes two recommendations for hemophilia B (11 for A). The first is that prophylaxis is recommended over on-demand treatment. We’ve actually been assuming that to be true for a long time (based on scientific reasoning and small non-RCT studies), but it’s nice to have it confirmed (although with only “moderate-certainty evidence” according to ISTH).
The other recommendation for hemophilia B is that prophylaxis can be carried out using plasma-derived products, standard half-life recombinant products or extended half-life (EHL) recombinant products. This is where the potential trouble comes in. According to ISTH, there is not enough scientific evidence to determine which of these three types of products is better, so they can’t recommend one over another. This is one of the ways that science operates that seems to mystify lay people. Note that ISTH is not saying that there is no difference between the three product types; they’re just saying that since the studies haven’t been done, they can’t say whether there is a difference.
This is no problem within the scientific/medical community – we understand what this means. The problem is when something like this gets out into the general population and is misunderstood. You can imagine an insurance company reading the ISTH report and assuming that it is saying that there is no difference among the three types of products: “Hooray! This is what we’ve been waiting for. The ISTH, the most prestigious international organization for hemostasis, says there is no difference. We can quit paying for those expensive EHL products and just give everyone cheaper plasma-derived products. We’ll save tons of money!” People fear that the same could also be true in countries that have national health plans and buy one, or just a few, products for the country’s whole hemophilia B population.
ISTH has written their report very carefully to try to prevent that misunderstanding, but in a society that doesn’t understand or value science, that doesn’t always work. We’ll just have to see what happens. [Rezende SM et al., J Thromb Haemost, online ahead of print 6/19/24; see also Mannucci PM, J Thromb Haemost, online ahead of print 6/19/24 and Ainle FN et al., J Thromb Haemost, online ahead of print 6/20/24]
Background and Update
The draft guidelines were given to the hemophilia community for comment in October 2023. Over 400 comments were received. In a 5/3/24 statement on their website, the World Federation of Hemophilia (WFH) said: “The ISTH guidelines risk setting hemophilia treatment back 30 years.” And further: “These ISTH guidelines may impede patient access to products that can improve outcomes in countries of all socioeconomic strata and thereby harm patients and reverse health equity gains.”
The Medical and Scientific Advisory Council (MASAC) of the National Bleeding Disorders Foundation (NBDF) also stated in MASAC Document #288: “The draft ISTH guidelines for hemophilia treatment do not support the changed treatment paradigm in hemophilia. They are counterproductive toward reaching the goal of zero bleeds, and work against the goals of shared decision making and improved patient-centered outcomes.” ISTH went ahead and published the guidelines on 6/20/24 in their Journal of Thrombosis and Haemostasis.
Criticism of the ISTH guidelines has continued with three recent articles in the WFH’s journal Haemophilia. A group of 44 treaters and other leaders in the hemophilia community, and also on behalf of 14 hemophilia organizations around the world, published a critical appraisal of the ISTH recommendations. Their final conclusion is noteworthy: “These recommendations may mislead healthcare professionals, payers and governments and therefore cannot serve the patient community well. They set back the advances made in haemophilia care because they overlook important available evidence and do not guide clinical practice to contemporary standards.”
They point out that ISTH focused only on annualized bleeding rates (ABRs) and overlooked the benefits of high trough levels and maintenance of healthy joints as well as the ability of the patient to participate in normal activities and enjoy a high quality of life. They also point out the lack of community consensus in developing the ISTH guidelines and the fact that the three people with hemophilia who were originally on the ISTH panel developing the guidelines dropped out and would not let their names be included on the final publication. [Albisetti M et al., Haemophilia, online ahead of print 12/6/24]
Albisetti et al. also point out that the GRADE methodology used by ISTH is not applicable for rare diseases where RCTs are difficult to conduct. In fact, ISTH used a modified GRADE method that takes this into account in their own 2021 guidelines on the treatment of von Willebrand Disease, a less rare disorder. The other Haemophilia paper addresses this in more detail.
Their conclusion is also noteworthy: “The puristic approach taken in the ISTH Guideline development process, without consideration of accepted adaptations to GRADE implementation, created a missed opportunity for progressing haemophilia care, leading to guideline recommendations that have been widely deemed invalid and obsolete by expert healthcare professionals and by those living with the condition, the very people who are expected to implement or bear the impact of the recommendations. Lessons learnt from this comparative analysis should guide future guideline development and encourage collaboration to further advance haemophilia.” [Skinner M et al., Haemophilia, online ahead of print 12/9/24]
The European Association for Haemophilia and Allied Disorders (EAHAD) also published a commentary pointing out that guidelines are only recommendations. They state: “Indeed, meticulous observations and progressive understanding of disease pathophysiology have resulted in significant treatment advances that would not merit an RCT today.” That is, based on our knowledge today, RCTs would not provide us with anything better than we already have. [Chowdary P et al., Haemophilia, online ahead of print 12/6/24]
We don’t know why ISTH did this and whether insurance companies and ministries of health who control which products are available to hemophilia patients will try to restrict care based on the ISTH guidelines. However, the outpouring of criticism against the ISTH guidelines should help provide strong support against product restriction. Hopefully, as Dr. Mannucci says in his commentary, this will all turn out to simply be a “storm in a teacup.”