Outcome measures in haemophilia: a systematic review

Abstract

Haemophilia A and B are hereditary X-linked disorders due to deficiency (or absence) of coagulation factor VIII or IX, respectively. Bleeding risk is related to the severity of factor deficiency. Repeated joint bleeding can lead to a severe haemophilic arthropathy resulting in disabilities. Outcome measurements in persons with haemophilia (PWH) have been limited to laboratory evaluation (factor VIII or IX levels) and clinical outcomes (such as bleeding frequency), morbidity (for example linked with arthropathy) and mortality. Due to the new standard of care of PWH, there is a need to consider other outcome measures, such as the early detection and quantification of joint disease, health-related quality of life (QoL) and economic or costutility analyses. To investigate this, we performed a 10-yr systematic overview of outcome measures in haemophilia. Only clinical trials including at least 20 patients with haemophilia A or B were included. To facilitate the search strategy, eight issues of outcome measures were selected: physical scores, imaging technique scores, functional scores, QoL measurement, mortality, bleeding frequency, cost and outcome and bone mineral density. The results of these will be discussed. Clearly defined outcomes in haemophilia care are important for many reasons, to evaluate new treatments, to justify treatment strategies, to allow a good follow-up, to perform studies and to allocate resources. The use of such scoring systems is clearly recommended by experts in haemophilia care. However, most centres do not perform such scores outside clinical trials due to reasons such as lack of time and resources.

Recognizing the need for personalization of haemophilia patient‐reported outcomes in the prophylaxis era

“…The ABR is a measure of bleeding frequency and treatment effectiveness in the clinic, and is often the primary outcome in clinical studies involving PwH [13,14]. With respect to the latter, it has been especially valuable as a means of documenting the superior efficacy of prophylaxis in comparison with on-demand therapy [2,12].…”

“…Moreover, an ABR of 0 in a patient with a sedentary lifestyle is very different from the same ABR in a patient with an active lifestyle. Thus, ABR cannot account for inter-individual variability in bleeding patterns and their functional sequelae, which are dependent on factors such as disease severity, physical activity and age [14,15]. Finally, evaluating ABR in patients with pre-existing severe arthropathy is difficult, as the distinction between a new bleeding event and a flare of arthritis pain cannot be readily assessed [16].…”

“…This limitation stems from the fact that improvements in ABR are comparable across clinical studies evaluating prophylaxis, with all studies showing low mean/median frequencies of bleeding [2,14,[17][18][19]. Thus, using ABR as the sole endpoint to discriminate among prophylactic approaches would require an impractically large patient enrolment to provide statistically meaningful power to discriminate efficacy.…”

“…Two current standards used for research studies include the World Federation of Hemophilia (WFH) Physical Examination Score (aka Gilbert score) and the Haemophilia Joint Health Score (HJHS) [11,14]. These tools assess joint status, incorporating range of motion, pain, deformity and swelling, in the joints most commonly affected by bleeding in haemophilia: the knees, ankles and elbows.…”

“…Various radiographic modalities have been explored as a means to monitor haemophilia and the effects of treatment, including X-rays, magnetic resonance imaging (MRI) and ultrasonography [14]. X-ray imaging has been used for many decades, with results typically classified using the Arnold-Hilgartner system [22] (progressive scale) or the Pettersson score [23] (additive scale).…”