The role of total ankle replacement in patients with haemophilia and end-stage ankle arthropathy: A review.

Haemophilia is the most common X-linked bleeding disorder, affecting over 1 million individuals throughout the world. Patients are subclassified into mild, moderate and severe disease based on per cent factor activity level. Nearly, all patients with haemophilia develop haemophilic arthropathy (HA) by age 30 and HA is known to have a negative impact on physical health subscores in Haem-A-QOL, a validated quality of life scoring system for patients with haemophilia. Unfortunately, many patients progress to end-stage HA of the ankle, which is characterized by pain, contractures, decreased range of motion and muscle atrophy. Ankle arthrodesis (AAD) has been the standard of care in the definitive surgical management of end-stage HA of the ankle. While AAD is a safe surgical procedure known to improve HA-related pain, it decreases functional mobility and has been associated with secondary hindfoot arthritis as well as subtalar degeneration. In recent years, total ankle replacement (TAR) has emerged as an alternative surgical procedure that strives to improve functional mobility, pain and quality of life in end-stage HA of the ankle. However, the safety, durability, and efficacy of this procedure in these patients are unknown. In this review, we analyse the clinical studies investigating TAR in patients with end-stage HA of the ankle. We also discuss important considerations in the perioperative management of patients with haemophilia and compare the risks and benefits of AAD and TAR for patients with end-stage HA of the ankle.

Baby hamster kidney cell-derived recombinant factor VIII: a quarter century of learning and clinical experience.

INTRODUCTION: Management and care of individuals with hemophilia A advanced immensely with the introduction of recombinant factor VIII (rFVIII) replacement products. This review provides a historical overview of rFVIII development with a focus on Bayer's rFVIII (with albumin) and sucrose-formulated rFVIII (rFVIII-FS), the only rFVIII products cloned in baby hamster kidney (BHK) cells with >25 years of proven safety and efficacy. Areas covered: We review the advances in rFVIII technology and the efficacy and safety data for BHK-derived rFVIII/rFVIII-FS from clinical trials, investigator-initiated studies, and observational studies. Innovative products with new treatment potentials (eg, BAY 81-8973 and BAY 94-9027) built on this established safety and efficacy profile are also briefly discussed. The literature search strategy included targeted searches (PubMed) with manual article selection and other product-specific searches. Expert commentary: Development of rFVIII products and related improvements in viral safety and manufacturing efficiency have guaranteed an adequate supply of factor products worldwide and increased prophylaxis use. The net effects have been joint health preservation, reduction in morbidity and mortality, and quality-of-life enhancements. Current treatment challenges include lack of adherence to prophylaxis and inhibitor development; extended-half-life rFVIII products and non-FVIII replacement therapies in development may help overcome these challenges.

Bivariate evaluation of thromboembolism and bleeding in clinical trials of anticoagulants in patients with atrial fibrillation.

Clinical trials of antithrombotic therapy require a cohesive assessment of benefit and risk. A new graphical method to represent the bivariate relation of benefit and risk in trials of antithrombotic drugs is described and illustrated using published data from the four major registration clinical trials of non-vitamin K oral anticoagulants (NOACs) totalling 71,683 patients for prevention of thromboembolic events (TE) in patients with atrial fibrillation (RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE-AF TIMI48). A curve representing a null hypothesis defines a region of benefit on a two-dimensional plane. Trial results are summarised by a rectangle defined by standard 95 % confidence intervals (CI) for thrombosis and bleeding risks. Benefit is judged by whether the confidence rectangle contains the null curve. The treatment effect is measured by the distance from the null curve to the opposing corners of the confidence rectangle (termed "corner distance (CD)"). Across trials NOACs reduced the absolute risk of TE compared to warfarin by 0.30 % (95 % CI: -0.56 % to -0.05 %) and reduced major bleeding by 0.88 % (95 % CI: -1.26 % to -0.51 %). Bivariate evaluation showed NOAC superiority to warfarin overall and elucidated dose differences; low dose edoxaban increased bivariate TE-bleeding risk 0.08 % (CD = -0.85 % to 0.78 %), whereas high dose edoxaban reduced risk 1.41 % (CD = -2.07 % to -0.70 %). In conclusion, bivariate evaluation facilitates visual assessment of the safety-efficacy profile of antithrombotic drugs. Its application to trials in atrial fibrillation found NOACs superior to warfarin without substantial differences between agents.