Extended FIX Preventive Therapy May Not Ease Pain, Study Finds
Chronic pain and a reliance on pain killers remains high among adult men with severe hemophilia B after two years on preventive treatment with extended half-life recombinant factor IX — even with a lesser bleeding frequency and fewer repeated joint bleeds, a real-world study from Ireland reports.
These findings call for careful surveillance of patients using preventive therapy, and the need for multidisciplinary teams in their care.
The study, “Recombinant factor IX-Fc fusion protein in severe hemophilia B: Patient-reported outcomes and health-related quality of life,” was published in the journal Research and Practice in Thrombosis and Haemostasis.
Hemophilia B, an inherited blood disorder, is caused by the lack of functional factor IX (FIX), an essential blood clotting protein.
Prophylactic, or preventive, treatments that provide the missing FIX to patients with hemophilia B are currently considered a gold standard in preventing spontaneous bleeding episodes.
The first therapies to replace the missing FIX — called standard half-life FIX (SHL-FIX) — had, as their name suggests, a shorter half-life, meaning it took less time for their levels to drop to half after being administered. For this reason, they had to be given to patients frequently (every two to three days).
Extended half-life FIX (EHL-FIX) products have a longer half-life than SHL-FIX, needing to be administered once every week, or every other week, to be effective.
In 2017, all severe hemophilia B patients in Ireland switched from SHL products to Alprolix, an EHL containing a recombinant, or man-made version, of FIX (rFIX).
The drop in infusion frequency, along with the longer half-life of EHL products was found to improve patients’ health-related quality of life in some clinical trials. But data from real-world use is limited.
Adults with severe hemophilia B who switched from SHL products to EHL rFIX prophylaxis, being followed at the National Coagulation Centre in Dublin, were invited to complete a hemophilia-specific questionnaire, called Patient Reported Outcomes Burdens and Experience (PROBE). Questionnaires were given at the time of the switch and again two years later.
The PROBE questionnaire consists of 29 questions and assesses measures important for patient’s health status and quality of life.
The European Quality of Life 5-Dimensions 5-Level questionnaire (EQ-5D-5L) is part of the PROBE survey. EQ-5D-5L is a standardized (non-hemophilia specific) measure of overall health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Its score goes up to one, corresponding to the best possible health state; scores below zero reflect the worse possible state.
An additional self-rating visual analog scale (VAS) was also used as part of this last assessment on the day of evaluation. Its scores can range from zero to 100, in which 100 means best health imaginable and zero the worst.
In total, 23 men with severe hemophilia B and a median age of 47 were included in the analysis. Notably, not all answered every question.
Results showed no significant changes in EQ-5D-5L scores before rFIX use and two years later (median of 0.76 vs. 0.77). Over 70% of patients reported no or slight problems overall in their health.
An improvement in median EQ-5D-5L scores was seen among the subgroup of patients who switched from episodic treatment with SHL to regular preventive therapy with EHL rFIX, with scores increasing from 0.62 to 0.76.
Pain and mobility had the lowest scores at both evaluation time-points, and these scores were considerably worse among the hemophilia B patients when compared with an Irish male population.
The EQ VAS score was similar at both evaluation time-points, with a median score of 72.5 before the switch and 75 two years later.
Chronic pain was reduced by 9% after two years of preventive treatment with rFIX. Despite this drop, however, the rate of chronic pain was still deemed high — at 74% — affecting several aspects of patients’ daily life.
The number of affected daily living tasks, however, were significantly reduced — by 25% — after two years of preventive treatment with rFIX. The greatest improvements were seen in performance of heavy domestic tasks (17%), walking (13%), bending (13%), and going up stairs (13%).
However, getting up from a sitting position, sexual intimacy, doing light domestic tasks, and getting in and out of a car, was seen as worsening over this time.
Patients reported a 19% increase in acute pain during the second year of treatment with rFIX, but no link was established between acute pain and the number of bleeds. Acute pain also had a detrimental impact on a variety of daily living activities, such as walking (86%), engaging in general activities (71%), life enjoyment (57%), mood (50%), and sleep (50%).
A majority of patients (86%) required pain relief medications the year before switching to rFIX, but even more (95%) relied on them during the second year of post-switch treatment.
Common health problems after two years of preventive treatment with rFIX included arthritis (44%), anxiety and depression (28%), high blood pressure (28%), and gingivitis, a mild form of gum disease (17%).
The proportion of patients reporting target joints — joints in which three or more bleeds occurred in the past six-months — dropped significantly from 48% at treatment switch to 10% two years later.
More than half of the patients (52%) required a mobility aid/assistive device at some point in the year before switching treatment. During the second year of rFIX, there was a 22% increase in the use of these assistive devices, particularly of orthotic shoes or inserts.
The annualized bleeding rate (ABR) dropped significantly after switching to rFIX preventive therapy, with 86% of the patients reporting fewer than three bleeds a year, compared with 50% before the switch. The proportion of patients with zero bleeds also increased, from 9% to 32%.
These findings confirm the effectiveness of rFIX preventive therapy in reducing bleed frequency and target joints in patients with severe hemophilia B, the researchers noted.
However, they also highlight the “high rates of chronic pain and analgesia [pain relief] use in this population, … and the need for a sustained multidisciplinary approach in hemophilia health care,” they added.