Plasma-derived factor VIII (Octapharma AG)

To evaluate the efficacy and safety of a plasma-derived factor VIII concentrate containing von Willebrand Factor (pdVWF/FVIII) in standard clinical practice in von Willebrand Disease (VWD) patients.

A retrospective, multicentric, observational study of VWD patients treated with Fanhdi ® , a pdVWF/FVIII concentrate, from January 2011 to December 2017 was conducted at 14 centers in Spain. Efficacy and safety were evaluated for acute bleeding episodes, for prevention of bleeding in surgeries, and for secondary long-term prophylaxis.

Seventy-two eligible patients, type 1, 2, 3 VWD (25%/38.9%/36.1%) were treated for spontaneous and traumatic bleeding (140 episodes, n = 41 patients), to prevent surgical bleeding (69 episodes, n = 43 patients); and for secondary long-term prophylaxis (18 programs, n = 13 patients). Replacement therapy with pdVWF/FVIII showed an excellent to good clinical efficacy in 96.7% of the bleeding episodes, 100% during surgical procedures and 100% during prophylaxis. No adverse events (AEs), nor serious AEs related to the product were observed.

Fanhdi ® was effective, safe and well tolerated in the management of bleeding episodes, the prevention of bleeding during surgeries, and for secondary long-term prophylaxis in VWD patients.

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 used as a replacement therapy in VWD patients requiring prophylactic treatment during surgeries.8 We report 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, non-controlled, multicentre study in patients with type 1, 2 and 3 VWD, who were unresponsive to DDAVP. The study was 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 the drug began prior to the procedure and continued until healing occurred. The patients received the most 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 and minor. In major 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 form were 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 Shapiro-Wilk 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 surgical or invasive procedures. As shown in Table 1, nine of these procedures were major and five were minor. During surgery period, patients received a median (min-max range) dose of 44.3 (30.9-78.4) IU/kg FVIII and 61.7 (45.3-102.4) IU/kg VWF:RCo, for minor surgeries, and 89.5 (53.1-128.6) IU/kg FVIII and 137.0 (104.2-193.4) IU/kg VWF:RCo, for major surgeries. During the post-surgery period, minor surgeries were treated with 30.6 (19.6-41.7) IU/kg FVIII and 43.6 (25.6-61.7) IU/kg VWF:RCo; and major surgeries with 245.0 (12.5-520.7) IU/kg FVIII and 416.9 (24.6-924.1) IU/kg VWF:RCo. Median drug exposure after major surgery was seven (2-16) days, and one (1-2) days for minor. A patient with type 3 VWD, who underwent major surgery, a tibial cyst curettage with cancellous bone allograft, needed the highest total dose and number of infusions. After the surgery, the patient continued with prophylaxis treatment. By contrast, the lowest total dose and number of infusions were administered to a type 1 VWD patient who underwent a minor surgery procedure. To ensure adequate haemostasis during the surgical procedure, FVIII:C and VWF:RCo activity as well as VWF:Ag levels were monitored. Our results reported that FVIII:C activity increased from a median (min-max range) of 42 (1.7-100) IU/dl pre-infusion to 139 (98-213) IU/dl 30 minutes after the infusion, P < .01 (Figure 1A). VWF:RCo activity increased from 7 (below detection limit - 66) IU/dl pre-infusion to 103.7 (36-161) IU/dl post-infusion, P < .05 (Figure 1B). VWF:Ag levels increased from 12 (0-92) IU/dl pre-infusion to 165 (93-245) IU/dl post-infusion, P < .01. (Figure 1C). The mean FVIII recovery was 1.54 (IU/dl)/IU/Kg and for VWF:RCo was 1.17 (IU/dl)/IU/Kg. FVIII:C, VWF:RCo and VWF:Ag reached > 50% post-infusion and during the surgery period, ensuring the correction of the haemostasis parameters. During postoperative period, FVIII:C and VWF:RCo activity were analysed to ensure an haemostasis similar to the expected for patients without known bleeding disorders. According to VWD management guidelines from the National Heart, Lung and Blood Institute (NHLBI) Expert Panel,2 to maintain haemostasis in VWD patients after surgical procedures, it is recommended to achieve trough VWF:RCo and FVIII:C activity higher than 50 IU/dl for 7–14 days in major surgeries, and at least 30 IU/dl for 1–5 days in minor surgeries.2, 9 In our study, all patients achieved mean values over 50% of FVIII:C activity after surgery and postoperative periods (Figure 1A). There were no patients who received thromboprophylaxis treatment in the post-operative period. Three out of 14 (21.4%) patients were treated with the antifibrinolytic agent tranexamic acid. At the end of the follow-up, differences from pre-infusion values were not significant. In two surgical procedures (14.3%), bleeding length was greater than expected. Two patients lost more blood than expected during postoperative period. At the end of the follow-up period, three patients (21.4%) lost an amount of blood greater than expected and one patient required blood derivate transfusions. There were no complications (bleeding, infections, pain) during surgery or postoperative period and only one complication (7.1%) was observed at the last visit. The haemostasis achievement with the pdVWF/FVIII concentrate was assessed by the investigator during surgery and at the early postoperative period and was rated as excellent in 71.4% (n = 10), good in 14.3% (n = 2) and moderate in 14.3% (n = 2) of the procedures. Overall, global clinical efficacy achieved an excellent rate in 64.3% (9 procedures) of the surgery procedures, good in 21.4% (three procedures), poor in 7.1% (one procedure) and not known in 7.1% (one procedure). Therefore, it was rated as excellent or good in 85.7% (CI 95%: ± 28.5%) of the major and minor surgeries (Table 1). These findings were in line with the preliminary results of the current study8 and with other pdVWF/FVIII concentrates, which reported similar efficacy rates.9, 10 The safety results showed no clinically significant alterations in the vital signs and no patients developed antibodies anti-FVIII or anti-VWF during the follow-up. In addition, no significant differences in laboratory parameters, physical examination or in the clinical status of the patient were reported. A total of four mild or moderate non-serious AEs in two patients were reported: phlebitis, seroma, anaemia and hypotension. There were no SAEs, discontinuations due to AEs, or deaths during the study period. Likewise, Fanhdi® showed a good clinical safety profile, consistent with other retrospective studies.7 Limitations of the study were the small sample size considering the duration of the study, the time needed for patient recruitment and the effort for data generation and collection. In addition, the study was designed as an open, non-controlled study without paediatric patients. Finally, our study was designed prior to the most recent guidelines for diagnosis and management of VWD. Further studies on the use of Fanhdi® in standard clinical practice will be needed. In conclusion, the data collected in the final report confirmed the safety and efficacy of Fanhdi® in various subtypes of severe VWD patients undergoing surgical or invasive procedures. Therefore, Fanhdi® ensured an adequate replacement therapy in case of bleedings or as a prophylaxis for major and minor surgeries. Eugenio Rosado, PhD, and Jordi Bozzo, PhD, CMPP (Grifols) are acknowledged for medical writing and editorial support in the preparation of this manuscript. The authors wish to thank all the patients who contributed to this study. Carmen Altisent is acknowledged for her expert contribution to the acquisition of data. This study was supported by Grifols, manufacturer of the pdVWF/FVIII concentrate (Fanhdi®). L.N., E.M., C.G., M.T., A.P. are full-time employees of Grifols. V.J-Y. received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Takeda, Bayer, CSL-Behring, Grifols, Novo Nordisk, Sobi, Octapharma, BioMarin, Sanofi and Pfizer. M-T. A-R. received reimbursement for attending symposia and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Takeda, Bayer, CSL-Behring, Grifols, Novo Nordisk, Sobi, Octapharma, BioMarin, Novartis, Amgen and Pfizer. A.B.F. is involved in the advisory boards of Baxalta-Shire, CSL-Behring, Grifols, Kedrion, LFB, and Octapharma with honoraria related to vWD. S.H. has received speaker fees from Baxter, Grifols, Novo Nordisk, Pfizer, Takeda, Sobi and Roche; honorarium for advisory boards from Grifols, Takeda, Sobi, Octapharma and Roche.Reimbursement for attending congresses from Baxter, Bayer, Grifols, Novo Nordisk, Octapharma and Pfizer. A.B.F. has been involved in advisory boards of Baxalta, Shire, Takeda, CSL-Behring, Grifols, Kedrion, LFB and Octapharma with honoraria related to VWD. The remaining authors stated that they had no interests which might be perceived as posing a conflict or bias. The data that support the findings of this study are available from the corresponding author upon reasonable request.