Outcomes for studies assessing the efficacy of hemostatic therapies in persons with congenital bleeding disorders

Abstract

Introduction Management strategies and hemostatic treatments to achieve control of bleeding are relevant across many disease areas. Identification of primary outcomes for studies assessing hemostatic intervention was the objective of a National Heart, Lung and Blood Institute (NHLBI) sponsored multidisciplinary initiative. The aim of this report is to summarize the evidence reviewed, and the outcomes identified by the subgroup tasked to assess outcomes for inherited bleeding disorders. Methods The subgroup decided to focus on haemophilia, the prototypal congenital bleeding disorder and the one with the largest available body of evidence. MEDLINE, EMBASE and PsycINFO, The Cochrane Review, CINAHL, and Web of Science were searched for systematic and narrative reviews on outcomes used in haemophilia clinical trials. Three different clinical goals were identified as typical objectives of future research. Results Out of 1322 unique citations, 24 reviews published in the period 2002–2019 were included. We identified 113 outcome measures, categorized in 6 domains: health‐related quality of life (HRQoL), comorbidities and mortality, overall physical functioning and participation, bleeding and hemostasis, joint health, and costs and resource use. Three different clinical goals were identified as typical objectives of future research: Episodic ‘on demand’ replacement therapy, prevention of bleeding (Prophylaxis), and long‐term and overall impact of bleeding. For each of these scenarios, specific outcomes were recommended. Conclusions Primary outcomes for clinical trials assessing the efficacy of hemostatic treatment in achieving control, prevention and limiting long‐term consequences of bleeding in inherited bleeding disorders are suggested, and their strength and limitations discussed.

Recommended primary outcomes for clinical trials evaluating hemostatic blood products and agents in patients with bleeding: Proceedings of a National Heart Lung and Blood Institute and US Department of Defense Consensus Conference

“…47 There is a body of evidence linking the bleeding rate to the progression of joint disease as measured by joint scores. 49,50 For the long-term and overall impact of bleeding, which is the ultimate goal in patients with inherited bleeding disorders, the recommended primary outcome is a composite of joint function (measured via an objective clinical scale or a patient reported functional score), 8 chronic pain (measured via a validated scale), 51 and health-related quality of life (both generic and specific) 9 as proposed in a core outcome set for hemophilia gene therapy trials. 49,52…”

“…9,47 For the treatment of acute bleeding or for the prevention of surgical bleeding, the recommended primary outcome is a composite scoring system 47,48 incorporating the number of infusions required, rating on a clinical scale, and need for reintervention. 49 These outcomes have been successfully used to evaluate replacement therapy over several decades and recommended by the International Society on Thrombosis and Hemostasis Scientific Subcommittee on Factor VIII and IX. 48 For the prevention of bleeding events, the recommended primary outcome is an annualized bleeding rate, quantifying the number of bleeding events over a period of time.…”

“…For the prevention of bleeding events, the recommended primary outcome is an annualized bleeding rate, quantifying the number of bleeding events over a period of time 47 . There is a body of evidence linking the bleeding rate to the progression of joint disease as measured by joint scores 49,50 …”

User-Centered Development and Testing of the Online Patient-Reported Outcomes, Burdens, and Experiences (PROBE) Survey and the myPROBE App and Integration With the Canadian Bleeding Disorder Registry: Mixed Methods Study

“…The quality of life of people living with hemophilia and the burden of the disease are also affected by other aspects, for example, the burden of adhering to a regular prophylactic regimen and comorbidities, particularly bleeding-related arthropathy and transfusion-transmitted infections with hepatitis B virus, hepatitis C virus, or HIV [ 4 ]. Outcome assessment in hemophilia often comprises clinical measures, such as number of target joints, number of emergency room visits, and hospital length of stay [ 5 ]. In recent years, patient-reported outcomes (PROs) have been increasingly used to measure additional metrics that capture a patient’s perspective of their own health [ 6 , 7 ].…”