Efficacy and safety evaluation of Fanhdi(R), a plasma-derived factor VIII/von Willebrand factor concentrate, in Von Willebrand's disease patients undergoing surgery or invasive procedures: A prospective clinical study

Dear Editor, Von Willebrand’s disease (VWD) is the most common hereditary blood-clotting disorder caused by a deficiency of von Willebrand Factor (VWF) and characterized by a defective platelet adhesion and aggregation.1 Replacement therapy with plasma-derived von Willebrand factor-containing factor VIII concentrate (pdVWF/FVIII) is indicated as treatment of choice for surgical and invasive procedures in adult and paediatric patients with severe VWD, when desmopressin (DDAVP) is either ineffective or contraindicated.2,3 The presence of functional VWF is estimated by the VWF:RCo/FVIII:C ratio and may vary among pdVWF/FVIII concentrates.4 Fanhdi® (Instituto Grifols S.A., Barcelona, Spain) is a pdVWF/FVIII concentrate characterized by a high content in VWF, with a VWF:RCo/FVIII:C ratio of 1.58±.20.5 Clinical efficacy of Fanhdi® has been assessed extensively in VWD patients, to prevent recurrent bleedings in the management of surgery.5–7 However, the available data is retrospective and the only prospective study supporting its use reported interim results only.8 The preliminary interim analysis showed that Fanhdi® could be successfully usedas a replacement therapy inVWDpatients requiring prophylactic treatmentduring surgeries.8 Wereport here the final efficacy and safety analysis of this multicentre prospective clinical trial. The aim of our study was to evaluate the safety and efficacy of Fanhdi® in the prevention and control of bleedings in VWD patients undergoing invasive or surgical procedures. This was an open, noncontrolled,multicentre study inpatientswith type1, 2 and3VWD,who wereunresponsive toDDAVP. The studywas conducted at four centres in Spain, one in the UK and one in Italy, between December 2000 and April 2008. Fanhdi® was administered as prophylactic treatment and the administration of thedrugbeganprior to the procedure and continued until healing occurred. The patients received themost appropriate dose according to investigator’s discretion to ensure coagulant factor VIII (FVIII:C) and VWF:ristocetin co-factor (VWF:RCo) activities of at least 80–100% within 1 hour of administration, generally between 40 and 60 IU VWF:RCo/kg. Surgical invasive procedures were classified into two groups, major andminor. Inmajor surgeries, patients required more than three days of substitutive therapy, while in minor surgeries, treatment with one or two doses were enough. The study included patients older than 12 years, with severe hereditary VWD, with low levels of VWF (VWF:RCo < 15 IU/dl) at the recruitment visit that underwent surgical or invasive procedure and who had previously presented bleeding episodes and required treatment with VWF concentrates unresponsive to DDAVP challenge or not indicated. Each patient signed a written informed consent form before participating in the study. The trial was performed according to the principles of the Declaration of Helsinki, Good Clinical Practice of the International Council for Harmonization (ICH) and current legal local laws and regulations. The clinical trial protocol and informed consent formwere reviewed and approved by the Institutional Review Board/Independent Ethics Committee of each participating research trial site. To evaluate the clinical efficacy of Fanhdi®, the following variables were considered: duration and severity of bleeding, blood loss, haemostasis achievement, correction of the haemostatic parameters (FVIII:C, VWF:RCo and VWF antigen [VWF:Ag]) and global clinical efficacy. Haemostasis achievement was evaluated during surgery and in the postoperative period as excellent (haemostasis achieved), good (slight oozing), moderate (moderate bleeding), poor (minimum control of bleeding) or none: severe uncontrolled bleeding. Global clinical efficacy was considered as excellent (accurate haemostasis, bleeding controlled early and transfusion as expected), good (slight oozing, haemorrhage length, severity and transfusion as expected); moderate (bleeding persists, great loss of blood, transfusion as expected); poor (minimum haemostasis, increased bleeding time, additional doses needed) or none (uncontrolled bleeding, excessive blood loss, high doses of blood derivative products). To evaluate clinical safety, changes in vital signs, presence of anti-FVIII and anti-VWF inhibitors, laboratory parameters, physical examination, clinical status of the patient and assessment of adverse events (AEs) and serious adverse events (SAEs) were evaluated. When values were not normally distributed according to ShapiroWilk Normality test (P < .001), Wilcoxon test was used to analyse quantitative variables. Otherwise, a paired Student t-test was used. P value < .05 indicated that statistically significant differences were demonstrated. Eleven patients (five women, six men) with a median weight of 70.0 kg (range 50–100) and a median age of 44 years (range 29– 73) were enrolled in the study: three type 1, five type 2A, two type 2B and one type 3. All received at least one dose of Fanhdi® for 14