Historical perspective on the treatment of hemophilia: Understanding the value of experience

As we enter into an era of increased scrutiny over healthcare costs and the associated benefits of providing certain treatment regimens, it has become quite evident that health technology assessments (HTA) may make recommendations on how hemophilia treatment is managed.

The question that arises is whether or not the correct evidence is used to justify financial decisions that could significantly impact health outcomes for those living with hemophilia. The unfortunate outcome are assessments derived from data that does not take into consideration decades of real-life treatment experience and the significant quality of life improvements that treatment regimens, such as prophylaxis, provides for patients.

In 1958, a historic paper was published by Biggs and Farlane, who proposed a diagnosis of hemophilia based on the missing amount of factor VIII or IX. Severe hemophilia was characterized by < 1% FVIII or FIX, moderate hemophilia by 1-5%, and mild hemophilia by >5%.

These early laboratory diagnoses were correlated with clinical observation in well-defined patients groups in Sweden. In 1964, Ahlberg published a paper which showed a clear correlation between the severity of hemophilia and the age bleedings started as well as the number of joint bleedings.

This was the main background for healthcare professionals to consider regular infusion with plasma component, later with cryoprecipitate, in order to raise the factor level in severe hemophilia to the level present in moderate hemophilia. This was first offered to patients who had the most frequent bleeds and it clearly was demonstrated to reduce bleeding.

An obvious further development in the treatment regimen of prophylaxis was decreasing the age at which this therapy was started, in order to raise the pre-infusion level above 1%. This led to the effective prevention of bleeding and in fact changed the patient’s diagnosis from severe hemophilia to moderate hemophilia.

Many observational studies have demonstrated with excellent results that this strategy is effective and we now see that patients with severe hemophilia can have a normal life expectancy, reach adulthood with normal or near-normal joints and are fully engaged in activities similar to their peers.

For the hemophilia community, especially in Europe, it is inconceivable that this basic treatment regimen based on a well-defined pathophysiologic concept needs additional proof through randomized controlled trials. However, this discussion is beginning to be raised in several countries. The challenge of performing randomized controlled trials in hemophilia is that the bleeding patterns between patients, even with severe hemophilia, is variable. Disabilities due to complications from bleeding would only become evident after many years of monitoring and follow-up, meaning that patients are put into inevitable situations of additional health complications of joint damage and suffering.

The most significant clinical trial, leading at last to the provision of prophylaxis for children within the United States, was performed by Manco-Johnson and her colleagues (NEJM 2007).  In a direct comparison between prophylactic and intensive on-demand therapy, after a 6 year follow-up period, it was concluded that children who did not experience bleeding were healthier than children who had to suffer bleeding. The latter group experienced more joint abnormalities identified on MRI. In this study no clear correlation was found between the number of bleeds these children had experienced and the severity of joint damage as observed with MRI. This shows the weakness of using only bleeding as a clinical measure to determine outcomes for the patient, particularly over such a relatively short period of time. More randomized controlled clinical trial studies have been published and all show a beneficial outcome for prophylaxis, including the last Cochrane evaluation of the concept of prophylaxis, concluding that prophylaxis provided beneficial outcomes for patients with hemophilia.

Even considering the overwhelming evidence from both these trials and real-life experiences of healthcare professionals providing prophylaxis to their patients, the reality is that we now live in the era of health technology assessments (HTAs), designed to determine the correlation between cost of treatment and outcome. This is especially prevalent when there needs to be a determination of paying for treatment for a growing population of patients with hemophilia.

The hemophilia community has to take an active role in the discussion, but has also has to actively encourage additional data collection and assist in providing them, especially in countries that do not have access to treatment at the same levels as developed countries. Well-defined registries, collecting data in a comparable way, from the diagnosis to the provision of treatment, provide the opportunity to demonstrate that without sufficient treatment, patients with severe hemophilia still struggle with their condition and have a shorter life expectancy. This is not only crucial for individual countries working to improve access to treatment, but also for the collection of prospective data on outcomes in many parts of the world.

Within this area of hemophilia care, the WFH is investigating how to deliver a framework for data collection that will  help the global community gather valuable  data on diagnosis, bleeding scores, treatment regimen, and results of validated outcome assessment tools. Choosing too narrow a focus, as happened in some of the more recent HTAs, negates the many years of real-world experience of those working directly with patient populations who have significantly benefited from prophylaxis. It is our responsibility not to place patients in situations where their quality of life will be put at risk for many years because the main focus is on financial analyses.