Original Manuscript Clinical and Applied Thrombosis/Hemostasis ® Clinical Efficacy and Safety of Fanhdi , Volume 28: 1-11 © The Author(s) 2022 a Plasma-Derived VWF/Factor VIII Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/10760296221074348 Concentrate, in von Willebrand Disease journals.sagepub.com/home/cat in Spain: A Retrospective Study Víctor Jiménez-Yuste, MD, PhD1, María Teresa Alvarez-Román, MD1, Ángeles Palomo Bravo, MD2, Bernardo J. Galmes, MD3, Maria del Mar Nieto Hernández, MD4, Olga Benítez Hidalgo, MD5, Cristina Marzo Alonso, MD6, Noelia Florencia Pérez González, MD7, Julia Coll, MD8, Ramiro Núñez, MD9, Marina Carrasco, MD10, Faustino García Candel, MD11, Jose Ramon Gonzalez-Porras, MD12, Carmen Hernández García, MD13, Maria José Varó Castro, MD14, and Roser Mir, PhD15 Abstract Objective: 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. Methods: A retrospective, multicentric, observational study of VWD patients treated with Fanhdi®, a pdVWF/FVIII concen- trate, 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. Results: Seventy-two eligible patients, type 1, 2, 3 VWD (25%/38.9%/36.1%) were treated for spontaneous and traumatic bleed- ing (140 episodes, n = 41 patients), to prevent surgical bleeding (69 episodes, n = 43 patients); and for secondary long-term pro- phylaxis (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. Conclusions: 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. Keywords von willebrand factor, plasma-derived von willebrand factor/factor VIII concentrate, bleeding, surgery, prophylaxis, von willebrand disease 1 Department of Hematology and Hemotherapy, Hospital Universitario La Paz, 11 Autónoma University, Madrid, Spain Hematology and Hemotherapy Service, Hospital Clínico Universitario Virgen 2 Hematology Service, Hospital Materno-Infantil de Málaga, Málaga, Spain Arrixaca, Murcia, Spain 3 12 Hematology Service, Hospital Universitario Son Espases, Palma de Mallorca, Spain Department of Hematology, Hospital Universitario de Salamanca-IBSAL- 4 Hematology and Hemotherapy Service, Complejo Universitario de Jaén, Jaén, Spain USAL, Salamanca, Spain 5 13 Hematology and Hemotherapy Department, Hospital Vall d’Hebron, Hematology and Hemotherapy Service, Hospital de Don Benito-Villanueva, Barcelona, Spain Badajoz, Spain 6 14 Hematology and Hemotherapy Service, Hospital Universitari Arnau de Hematology Service, Hospital Universitario de Albacete, Albacete, Spain 15 Vilanova, Lleida, Spain Scientific and Medical Affairs Department, Grifols, Barcelona, Spain 7 Hematology and Hemotherapy Service, Complejo Universitario Torrecárdenas, Almería, Spain Corresponding Author: 8 Hematology Service, Complejo Hospitalario de Navarra, Pamplona, Spain Dr Víctor Jiménez-Yuste, MD, PhD, Department of Hematology and 9 Hematology Service, Hospital Virgen del Rocío, Sevilla, Spain Hemotherapy, Hospital Universitario La Paz, Paseo de la Castellana, 261, 10 Thrombosis and Hemostasis Unit, Hospital de la Santa Creu i Sant Pau, 28046 Madrid. Barcelona, Spain Email: vjimenezy@salud.madrid.org Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Clinical and Applied Thrombosis/Hemostasis Date received: 28 October 2021; revised: 21 December 2021; accepted: 2 January 2022. Introduction surgical procedures in VWD patients.11 In addition, two retro- spective studies showed excellent or good responses with Von Willebrand disease (VWD) is the most common hereditary Fanhdi® in bleeding episodes (92%-95%), and in surgical pro- blood-clotting disorder. It is caused by a deficiency of von cedures (93%-98%), without reporting adverse reactions Willebrand factor (VWF) and is subdivided into types 1, 2, (AR)15,17 . and 3.1 Type 1 (70%-80% of cases) is characterized by a quan- Although the efficacy and safety of Fanhdi® in VWD has titative deficiency of VWF. Type 2 (20% of cases) is caused by been proven in clinical trials,11,17 studies on its efficacy and dysfunctional VWF that results in a normal or reduced VWF safety in standard clinical practice are limited. Real-world antigen concentration and is further subdivided in 2A, 2B, data covering a broader and more representative patient popula- 2M and 2N subtypes. Type 3 VWD (<5% cases) is the most tion could improve patient management and optimize health- severe form and is due to the absence of circulating VWF and care resources. The study aimed to retrospectively evaluate greatly reduced factor VIII (FVIII) levels.1 VWD prevalence the clinical efficacy and safety of Fanhdi® in routine clinical ranges from 0.1 to 1% of the general population.2,3 In Spain, practice in VWD patients. it is estimated to be 122 patients per million.4 The most common clinical symptoms in VWD patients are mild to moderate mucocutaneous bleeding, epistaxis, bruising, Materials and Methods menorrhagia, gastrointestinal bleeding, and prolonged bleeding after haemostatic challenges. Joint bleeds occur in approximately Study Design half of the patients with type 3 VWD, but also in 5 to 10% of type This was a retrospective, multicentre, observational study of 1 and type 2 patients. Recurrent joint bleeds can result in arthrop- patients diagnosed with VWD that were treated with a athy in VWD patients with FVIII levels <10 IU/dL.1,5,6 pdVWF/FVIII concentrate (Fanhdi®) for acute bleeding epi- VWD treatment is aimed primarily at increasing endogenous sodes, prevention of bleeding during surgery and for prophy- VWF levels using vasopressin analogues, such as desmopressin laxis of bleeding complications. The study was a retrospective (DDAVP), or replacement therapy using FVIII/VWF concen- analysis of clinical data obtained under standard clinical prac- trates.7 DDAVP is effective in some patients with type 1 tice conditions. The study was conducted in full conformity VWD and for some patients with type 2 VWD, whereas with appropriate local laws and regulations and the FVIII/VWF concentrates are the first choice when DDAVP is Declaration of Helsinki. The original protocol was approved ineffective or contraindicated (as in severe type 1, type 2 and by the Institutional Review board/Ethics Committee. type 3 VWD).8,9 Several FVIII/VWF concentrates are commer- cially available with published efficacy and pharmacokinetic (PK) data.10–12 According to the treatment strategy for VWD, Study Drug it is preferred to know the VWF:RCo/FVIII:C ratio to reduce Fanhdi® is a highly purified pdVWF/FVIII concentrate. Due to thrombotic risk due to secondary FVIII elevation after repeated its multimeric structure, the VWF contained is functionally administration.13 active to promote platelet adhesion to subendothelial structures.19 In severe forms of VWD, patients may experience hemarth- The manufacturing process includes heparin affinity chromatog- rosis episodes and severe gastrointestinal bleeding requiring raphy, salt/glycine precipitation, and two virus inactivation steps long-term prophylactic treatment with plasma-derived FVIII (solvent/detergent and heat treatment).15 The von Willebrand concentrates containing VWF (pdVWF/FVIII). The VWD Factor:ristocetin co-factor activity (VWF:RCo) is standardized Prophylaxis Network international study group showed a sig- and individual values are provided for each batch. The concen- nificant reduction in the annualized bleeding rate (ABR) for epi- trate is characterized by a high content in VWF, with a mean staxis, gastrointestinal and joint bleeds after long-term (SD) VWF:RCo/FVIII:C ratio of 1.58 (0.20).16 secondary prophylaxis with FVIII/VWF concentrates.14 Fanhdi® (Grifols, Barcelona, Spain) is a pdVWF/FVIII con- centrate indicated for treatment and prophylaxis of bleeding in Patients haemophilia A patients, and for treatment of bleeding and pro- This retrospective study involved patients with VWD followed phylaxis of surgical bleeding in VWD patients, when desmo- up at their reference center from January 2011 to December pressin is ineffective or contraindicated.11,15–18 PK, efficacy 2017. The protocol was approved by the competent authorities and safety parameters have been evaluated in a prospective, in March 2019 and the study was conducted at the haematology multicentre study to prevent bleeding episodes and during departments of 14 Spanish centers according to current standard Jiménez-Yuste et al. 3 clinical practice. Descriptive data on the efficacy and safety of the treatment, dose per infusion, episode duration, number of Fanhdi® were collected from patients’ medical records between infusions, concomitant treatment, and total dose of the product. July 2019 and February 2020, and were recorded in an elec- tronic case report form. Patients were eligible for the study if they were compliant Safety Assessment with the following inclusion criteria: patients of both sexes Adverse events (AEs) and serious adverse events (SAEs) diagnosed with congenital VWD, according to International recorded in the medical histories were encoded according to Society of Thrombosis and Haemostasis [ISTH] criteria,20 the Medical Dictionary for Regulatory Activities version 22 who have received treatment with Fanhdi® as part of standard (MedDRA®, ICH, Geneva, Switzerland) by system organ clinical practice during the study period, and with the class (SOC). If there was causal relationship between the minimum data available for analysis (ie, at least one set of base- study drug and the event, the AE was labeled as an AR. For line and post-treatment data, and one safety data record). all AEs, the following data were recorded: onset date, duration, Patients were excluded from the study if they were not compli- intensity (mild, moderate, severe), action taken by the physi- ant with any of the inclusion criteria. cian, and the outcome. Immunogenicity assessment was aimed at determining the occurrence of hypersensitivity, infu- sion reactions, alloimmunity, and inhibitor development. Data Collection Thrombogenicity was assessed by the occurrence of thrombotic Demographics and clinical baseline data were collected includ- events associated with Fanhdi®. ing VWD familiar history, levels of factor VIII activity (FVIII: C), VWF:RCo, von Willebrand Factor antigen (VWF:Ag), von Willebrand Factor collagen binding assay (VWF:CB), previous Sample Size exposure to any VWF concentrate and presence of VWF inhib- The estimated sample size was the approximate number of itors. Bleeding episodes were classified by type, spontaneous or patients in Spain who may have been treated with Fanhdi® traumatic, and were defined by anatomical site. Surgery proce- during the study period. All efficacy analyses were performed dures were classified as major or minor and the time between on a single sample of assessable patients who met all the inclu- start of treatment and surgery was recorded. In major surgeries, sion criteria. Safety population consisted of enrolled patients it was likely that patients required more than three days of sub- who were treated as part of standard clinical practice and who stitutive therapy, while in minor surgeries, less than three days met inclusion criteria. of substitutive therapy was expected, and probably treatment with one or two doses was enough. Statistical Analysis Efficacy Assessment Categorical variables were presented by absolute and relative frequencies. Continuous variables were described using The primary endpoint was to assess the efficacy of pdVWF/ means, standard deviations, medians, 25th-75th interquartile FVIII concentrate treatment in three clinical situations: bleeding (IQR) ranges, and mean 95% confidence intervals (CI). episodes, prevention of surgical bleeding and secondary long- Efficacy variables were analysed using paired Student’s t or term prophylaxis. For each clinical situation, efficacy in achiev- non-parametric tests (U Mann-Whitney), when applicable. ing haemostasis was analysed by describing the clinical varia- Statistical significance was set as p < 0.05. SAS software, bles of the episodes and according to the efficacy scale at the version 9.4 (SAS, Cary, NC, USA) was used for statistical investigator’s discretion: (1) Excellent, haemostasis comparable analyses. to expectation, with no other associated bleeding cause and no increase of pdVWF/FVIII dose (2) Good, slightly below expec- tation, with no other associated bleeding cause and requiring a Results low increase in pdVWF/FVIII dose; (3) Poor, reduced haemo- stasis compared to expectation, with no other associated bleed- Baseline Patient Characteristics and Disease Activity ing cause and requiring a significant increase in pdVWF/FVIII Seventy-two of the 83 recruited patients with VWD met the dose; (4) No response, severe bleeding despite pdVWF/FVIII inclusion criteria and were the evaluable population for the therapy, requiring a significant increase in pdVWF/FVIII dose study. Fanhdi® was used in a total of 227 episodes: for treating and/or an alternative therapy to control bleeding. bleeding (140 episodes, n = 41 patients), for the prevention of For secondary long-term prophylaxis, the number of bleed- surgical bleeding (69 episodes, n = 43 patients), and for secon- ing episodes per year, the length of hospital stays and the dary long-term prophylaxis (18 programs, n = 13 patients) number of red blood cells (RBC) transfusions were compared (Figure 1). before and after the prophylaxis period to assess if prophylactic Baseline patient characteristics are shown in Table 1. treatment reduces bleeding compared to baseline values. Overall, of the 72 assessable patients, 28 were male (38.9%) The secondary efficacy endpoint was the treatment charac- and 44 female (61.1%). Most were adults (median [IQR] age terization for each clinical situation: regimen and duration of 32 [4-89] years), and the main VWD types diagnosed were 4 Clinical and Applied Thrombosis/Hemostasis Figure 1. Flow diagram showing the distribution of patients in the study. Two different populations comprised the study: evaluable and safety populations. Table 1. Demographic and baseline patient characteristics. Type of VWD Diagnosed Type 2, n = 28a TOTAL, Type 2B, Type 2N, n = 72 Type 1, n = 18 Type 2A, n = 17 n=6 n=3 Type 3, n = 26 Demographic Sex, male/female 28/44 8/10 7/10 2/4 1/2 9/17 Age, years 32 (16.5-50) 39 (20-66) 35 (22-60) 33 (14-38) 21 (18-36) 24 (12-37) Weight, kg 64 (48-75) 65 (58-79) 62 (48-75) 66.5 53.1 52.9 (54-79) (36-67.5) (31.60-68.50) Clinical data Positive VWD familiar history, n (%) 30 (41.7) 6 (33.3) 6 (35.3) 2 (33.3) 0 (0.0) 14 (53.8) FVIII:C, IU/dL 25 (5-48) 44 (20-64.2) 48 (23.5-52) 42 (28-52) 36.3 (26-39) 4 (1.9-13.6) VWF:RCo, IU/dL 12.8 22.9 13.7 (4.2-16) 17 87 (75-160) 3.3 (0.85-8.75) (4.2-23.9) (10.4-40.7) (15-27.7) VWF:Ag, IU/dL 16 16 (11.6-40) 30.7 31 81 (77-182) 3.1 (0.95-9.95) (6.8-38.25) (20.85-39.95) (19-37.5) VWF:CB, IU/dL 6.5 (3-168.5) n/a 6.5 (6-7) n/a 65 (65-65) 6 (0-272) Previous exposition VWF 28 (38.9) 5 (27.8) 3 (17.6) 1 (16.7) 1 (33.3) 17 (65.4) concentrate, n (%) Previous VWF inhibitors, n (%) 1 (1.4) 0 (0) 0 (0) 0 (0) 0 (0) 1 (3.8) a Type 2M, n = 0; Percentages based on n = 72 assessable patients. There were two patients with type 2 diagnosed, but with subtype not reported. Data are expressed are n (%) or median (IQR). FVIII:C, factor VIII activity; VWF:RCo, von Willebrand Factor:ristocetin co-factor activity; VWF:Ag, von Willebrand Factor antigen; VWF:CB, von Willebrand Factor collagen binding assay. n/a: not available. Table 2. Management of bleeding episodes according to VWD types diagnosed. VWD typea, n (%) Treatment, median (IQR) Episode Outcome, Type Type durationb, Treatment Median Concomitant Excellent/Good, All Type 1 2A 2B Type 3 days durationc, days Infusions dose, IU/Kg Total dose, IU treatment, n (%) n (%) All bleeding 140 19 35 11 67 2 (1-6) 2 (1-6) 2 (1-6) 39 (30-50) 2500 60 (42.9) 138 (98.6) episodes (100) (13.6) (25) (7.9) (47.9) (1500-11000) By type Spontaneous 106 13 29 8 (72) 48 2 (1-6) 2 (1-8) 2 (1-7) 40 (30-50) 3000 45 (42.5) 105 (99) (75.7) (68.4) (82.9) (71.6) (2000-12000) Traumatic 34 6 6 3 19 1 (1-5) 1 (1-4) 1 (1-4) 37 2000 15 (44.1) 33 (97) (24.3) (31.6) (17.1) (27.3) (28.4) (30-47.6) (500-4000) By anatomical site Epistaxis 45 7 17 1 (9.1) 20 1 (1-3) 1 (1-2) 1 (1-2) 48 (40-50) 2000 17 (37.8) 45 (100) (32.1) (36.8) (48.6) (29.9) (1500-3000) Gastrointestinal 22 4 8 0 (0) 2 (3) 3 (2-10) 15.50 (6-36) 11 31.25 18250 10 (45.5) 21 (95.5) bleedingd (15.7) (21.1) (22.9) (6-18) (26-39) (6000-33000) Gingival bleeding 21 (15) 3 4 4 10 1 (1-2) 1 (1-2) 1 (1-2) 32.5 2000 9 (42.9) 21 (100) (15.8) (11.4) (36.4) (14.9) (30-37) (1500-2500) Muscular 17 0 (0) 1 (5.9) 3 13 7 (1.5-11.5) 8 (2-10) 8 (2-10) 50 (50-59) 12000 10 (58.8) 17 (100) haematoma (12.1) (17.6) (76.5) (4000-30000) Joint 9 (6.4) 0 (0) 2 (5.7) 0 (0) 7 10 (5-17) 6 (2-17) 6 (3-10) 37 12000 4 (44.4) 9 (100) hemarthrosis (10.4) (30-37.7) (2500-35000) Other 5 (3.6) 1 (5.3) 0 (0) 0 (0) 4 (6) 8.5 (5.5-12) 4 (4-4) 4 (4-4) 34.5 2000 2 (40) 5 (100) haematomas (29-43) (2000-4000) Menorrhagia 2 (1.4) 0 (0) 0 (0) 0 (0) 2 (3) 3 (1-5) 2.5 (1- 4) 3.5 (1-6) 30 (30-30) 10000 2 (50) 2 (100) (2000-18000) Othere 19 4 3 (8.6) 3 9 n/a n/a n/a n/a n/a n/a n/a (13.6) (21.1) (27.3) (13.4) a No patients with subtype 2M and subtype 2N reported any bleeding episode. b Episode duration was calculated by number of days between the end and the start date of the episode. c Treatment duration was calculated as the number of days between the end and the start of the treatment. d There were eight gastrointestinal bleeding episodes related to one patient whose subtype 2 was not reported. e List of n = 19 other localizations reported: birth (n = 2); bleeding in surgical wound (n = 2), contusion (n = 2), haemorrhagic corpus luteal (n = 1), caesarean (n = 1), swelling (n = 2), tongue bleeding (n = 2), tonsil (n = 2); haemoptysis (n = 1), muscular stretch (n = 1), oral mucosa (n = 1), head trauma (n = 1) and upper eyelid (n = 1). Data are expressed as n (%) or median (IQR). Percentages based on number of cases in each row. n/a: not available. 5 6 Clinical and Applied Thrombosis/Hemostasis Figure 2. Global clinical efficacy of treatment (%) with Fanhdi® in bleeding episodes, surgeries and secondary long-term prophylaxis, in total study cohort and according to type VWD diagnosed. Total number of episodes reported for (A) bleeding were Excellent (n = 73), Good (n = 65), Poor (n = 1) and No response (n = 1); for (B) prevention of surgical bleeding: Excellent (n = 35), Good (n = 35), and No response (n = 1) and for (C) secondary long-term prophylaxis: Excellent (n = 10) and Good (n = 8). type 3 (36.1%), type 1 (25%) and subtype 2A (23.6%). One (major surgery, n = 20; minor surgery, n = 49) (Table 3). The type 3 VWD patient was under treatment with Fanhdi® as 34.8% of the patients were diagnosed with type 1 VWD, part of standard clinical practice and developed inhibitors while 34.7% corresponded to type 2 VWD and 27.5% were against VWF prior to study initiation. After immune tolerance type 3 VWD. The main surgical procedures reported were induction success, inhibitors were eradicated, and the patient tooth extraction (n = 15), arthrocentesis (n = 3), caesarean continued on-demand treatment with Fanhdi®. section (n = 3), colonoscopy with biopsy (n = 3), maxillofacial surgery (n = 3) and vaginal birth with episiotomy (n = 3). In major surgeries, the median preoperative dose was 40 Bleeding Episodes (33-50) IU/Kg. Median drug exposure after major surgery Forty-one patients were treated for a total of 140 bleeding epi- was 4.5 (2-8.5) days and patients were treated with a median sodes. Almost half of the registered bleeding episodes (47.9%) postoperative dose of 40 (30-50) IU/Kg of pdVWF/FVIII con- corresponded to type 3 VWD patients. Most of the bleeding epi- centrate. Patients who underwent minor surgery procedures sodes (75.7%) were spontaneous and the rest (24.3%) were were treated with a median preoperative and postoperative traumatic. The most frequent localization was epistaxis (n = dose of 30 IU/Kg and a shorter drug exposure, 1 (1-3) days, 45, 32%), followed by gastrointestinal (n = 22, 15.7%) and gin- than in major surgeries. Twenty-nine (42.6%) episodes of sur- gival bleeding, (n = 21, 15%) (Table 2). gical bleeding required concomitant treatment: RBC concen- The treatment of bleeding episodes lasted a median of two trates, iron, antifibrinolytic and antithrombotic preparations. days and 2 (1-6) infusions. Treatment duration of gastrointesti- Remarkably, only two units of RBC concentrates were used. nal bleeding was extended beyond the episode duration to Overall, global clinical efficacy of treatment with Fanhdi® prevent any possible recurrent bleeding. Patients were treated for the prevention of surgical bleeding yielded 50.7% excellent with 39 (30-50) IU/Kg of pdVWF/FVIII concentrate and the ratings in 35 procedures, 47.8% good ratings in 33 procedures median dose per patient/year was 50 (35-118 IU/Kg). Sixty and 1.4% no response ratings in one procedure. Remarkably, in (42.9%) bleeding episodes required concomitant treatment: type 3 patients, the percentage of patients with an excellent and iron, antifibrinolytic preparations and RBC concentrates good response reached 68.4% and 31.6%, respectively (Table 2). Remarkably, only three units of RBC concentrates (Figure 2B). One episode (1.4%) was rated as no response in were used. the prevention of surgical bleeding, in a type 2B patient. Overall, global clinical efficacy of the treatment achieved an excellent rating in 52.1% (73 episodes), good in 46.4% (65 epi- sodes), poor in 0.7% (1 episode) and no response in 0.7% Efficacy Assessment on Secondary Long-Term (1 episode) (Figure 2A). Importantly, efficacy in type 3 VWD patients was rated as excellent (68.7%), and good in 31.3% of Prophylaxis the episodes. Two episodes (1.4%) were classified as poor or Thirteen patients were treated in 18 secondary long-term pro- no response to the treatment, in two type 2A VWD patients. phylaxis programs (Table 4). Eleven patients (84.6%) were diagnosed with the severe form, type 3 VWD, and two patients (15.4%) were type 1. The main reasons for initiating the pro- Prevention of Surgical Bleeding phylaxis programs were acute bleeding control (28%), preg- Forty-three patients were treated with pdVWF/FVIII concen- nancy (28%) and hemarthrosis (17%). The most common trate for the prevention of surgical bleeding in 69 instances bleeding locations (in >5% of the cases) were epistaxis (39.6%), gingival (22.9%), joints (10.4%) and gastrointestinal Excellent/ Good, Outcome, (8.3%). The pdVWF/FVIII concentrate regimen was 3 days/ n (%) 68 (98.6) 20 (100) week in 66.7% of patients with a median (IQR) treatment dura- 48 (98) tion of 119 (67-433) days. Patients received a median dose per infusion of 2000 (1088-3000) IU of Fanhdi®. treatmentb, n (%) Concomitant There were no statistically significant differences between the mean (SD) number of bleeding episodes per year before 29 (42.6) 21 (43.8) (1.3 [1.6]; n = 14) and during the secondary long-term prophy- 8 (40) laxis periods (0.6 [1.1]; n = 14) (absolute change 0.7 [2]; 95% 9000 (3000-19500) CI [-0.43, -1.87]; P = 0.20). Hospital stay duration was not sig- 3000 (2000-9500) 3000 (2000-7500) Total dose, IU nificantly different between the year before prophylaxis (0.7 [2.2] days; n = 10) and during the prophylaxis period (0.9 [2.8] days; n = 10). Similarly, the number of RBC transfusions revealed no differences between the groups. Overall, global clinical efficacy of Fanhdi® was excellent in 32.3 (24.2-40) postoperative dose, IU/Kg Median 40 (30-50) 30 (24-35) the 55.6% of the secondary-long term prophylaxis programs (n Treatment, median (IQR) = 10) and good in the 44.4% of them (n = 8) (Table 4). Efficacy of treatment in type 3 VWD patients yielded an excellent and N° of infusions good efficacy ratings of 50% each, similar to the overall effi- cacy in the whole study cohort (Figure 2C). 5 (2.5-8) 3 (1-7) 2 (1-4) Safety Assessment Treatment duration, days Overall, there was a total of 15 AEs, reported by eight (11.1%) patients during the study period. By intensity, only three AEs (23.1%) were reported as severe: anaemia (n = 2) and infectious 4.5 (2-8.5) mononucleosis (n = 1), while the rest of them (76.9%) were 1 (1-5) 1 (1-3) mild or moderate. Most common AEs by SOC were gastrointes- tinal disorders (33.3%), infections and infestations (20%), blood 30 (24.2-41.7) Preoperative dose, IU/Kg 35 (30-45) 40 (33-50) and lymphatic system disorders (13.3%) and respiratory system disorders (13.3%). There were no patients who discontinued or reduced their dose due to an AE and all patients recovered without complications. All AEs with known outcomes were non- 19 (27.5) 14 (28.6) Type 3 5 (25) related to study drug, therefore no patients experienced a con- firmed AR. No deaths were reported during the study period. Data are expressed as n (%) or median (IQR). Percentages based on number of cases in each row. There were no patients with subtype 2M diagnosed and two patients with subtype not reported. Type 2N Five AEs were related to immunogenicity, being infections and 5 (7.2) 3 (6.1) 2 (10) infestations (n = 3) and respiratory disorders (n = 2). No throm- There was one major surgical bleeding with use of concomitant treatment not reported. botic events were associated with the use of Fanhdi®. Type 2B 2 (2.9) Table 3. Prevention of surgical bleeding according to type of VWD diagnosed. 1 (5) 1 (2) VWD typea, n (%) Discussion Type 2A 17 (24.6) 12 (24.5) We investigated the use of a pdVWF/FVIII concentrate, 5 (25) Fanhdi®, in standard clinical practice over a period of seven years in 72 well-characterized patients. This large retrospective study was conducted in 14 centers in Spain and proved that the Type 1 24 (34.8) 18 (36.7) concentrate was safe and effective for treating bleeding epi- 6 (30) sodes, prevention of surgical bleeding, and for secondary long- term prophylaxis in a real-world setting. 69 (100) In our study, the patient distribution was well-balanced All 20 (29) 49 (71) among all VWD types: type 1, 25%; type 2, 39% and type 3, 36%. Although the prevalence of VWD types 2 and 3 is All surgical bleeding lower in the general population (20% and <5%, respectively), the higher proportion observed in the current study was Classification expected, since eligible patients were those treated with a Minor Major pdVWF/FVIII concentrate. In our study, two (2.8%) patients presented previous alloantibodies against VWF. Although the b a 7 8 Clinical and Applied Thrombosis/Hemostasis Table 4. Clinical data of von Willebrand disease (VWD) patients enrolled into each secondary long-term prophylaxis program. Patient VWD Follow-up, Reason to Frequency, days per Mean dose per number type Sex Age days prophylaxis week infusion, IU Outcome 1 3 F 39 234 Pregnancy 10 days/month 3000 Excellent 930 Pregnancy 3 3000 Excellent 699 Pregnancy 3 2721 Excellent 189 Ovarian cyst 3 1500 Excellent 81 Haematoma 3 3000 Excellent 131 Pregnancy 3 3000 Excellent 2 3 M 58 219 Gingivorrhagia 3 3000 Excellent 3 3 M 34 2095 Acute bleeding 3 3000 Excellent controla 4 1 F 8 91 Acute bleeding 3 500 Excellent controla 5 1 M 4 193 Acute bleeding 2 500 Good controla 6 3 F 9 2515 Acute bleeding 3 625 Good controla 7 3 M 20 2556 Acute bleeding 3 1500 Good controla 8 3 M 21 220 Hemarthrosis 3 2000 Excellent 9 3 F 32 – Hemarthrosis 3 2000 Good 10 3 F 49 – Hemarthrosis 2 2000 Good 11 3 F 26 286 Pregnancy Every other day 2000 Good 12 3 F 9 2771 Otherb 1 1088 Good 13 3 F 8 1638 Otherb 2 500 Good a Acute bleeding control is referred to the following locations: epistaxis (n = 3), digestive tract (n = 2), head skin wound (n = 1), gingival bleeding (n = 1) and lip wound (n = 1). b Other is referred to the following locations: gastrointestinal (n = 2), vaginal bleeding (n = 1), and frontal haematoma (n = 1). exposure to a VWF/FVIII concentrate may be associated with DDAVP. In agreement with the recommended dosages for allergic events and lack of hemostatic response in these the management of bleeding in surgical procedures,1 the patients,21 these clinical events were not identified. pdVWF/FVIII postoperative doses for major and minor sur- In patients treated for bleeding episodes, global clinical effi- geries were 40 IU/Kg and 30 IU/Kg, respectively. cacy was achieved in the 98.5% of the cases (excellent, 52.1%; Although secondary long-term prophylaxis is not the current good, 46.4%). Clinical responses rated as excellent increased to standard of care in VWD, it is currently recommended for 68.7% in type 3 patients. This result supports the use of the patients with severe VWD and frequent bleeds23,24 to avoid pdVWF/FVIII concentrate in patients with severe forms of the development of arthropathies and to improve quality of VWD who are at a greater risk of experiencing life-threatening life.14,16,18,25 Here, we reported an efficacy rate of excellent/ bleeding. As expected, epistaxis and gingival bleeding needed good in 100% of the prophylaxis programs in severe VWD the fewest number of infusions, whereas gastrointestinal bleed- patients. No secondary prophylaxis programs were rated as ing, muscular haematomas and joint hemarthrosis required poor or no response. Additionally, most of these patients higher numbers. In all cases, this treatment regimen effectively were diagnosed with the severe form, type 3 VWD. Fanhdi® controlled bleeding episodes and the haemostatic effect was was administered three times per week to control bleeding. similar to that reported elsewhere.11,12,16,17 Overall, patients Patient’s bleeding history is a critical step to define the required a median dose of 39 IU/Kg to stop bleeding after fol- severity of a bleeding disorder.26 The use of secondary long- lowing standard recommended dosages for this indication.4,8 term prophylaxis with pdVWF/FVIII concentrates in type 3 The efficacy of Fanhdi® was also assessed in major and VWD patients has shown a reduction in ABR for epistaxis, gas- minor surgeries. Clinical efficacy was rated as excellent trointestinal, joint bleeding and menorrhagia.14,16,18 However, (50.7% of procedures), and good (47.8% of procedures), yield- our results did not reveal either a reduction in the number of ing a total efficacy of 98.5% in these surgical procedures. bleeding episodes per year or in hospital stay duration. This Similarly, previous retrospective studies with pdVWF/FVIII could be explained by the small sample size of the cohort concentrates showed comparable efficacy rates.12,15,17,22 included in secondary prophylaxis programs, and considering Remarkably, in type 3 VWD patients, clinical efficacy rated the observed absolute decrease in the number of bleeding epi- as excellent increased up to 68.4%. This finding supports the sodes per year, a clinical effect could be confirmed in a larger use of pdVWF/FVIII concentrate replacement therapy in population. Furthermore, our study population did not show a those patients who are lacking VWF and are unresponsive to frequent bleeding phenotype, as measured by the number of Jiménez-Yuste et al. 9 bleeding episodes (1.3 episodes/year) compared with patients preparation of this manuscript, under the direction of the authors. from previous trials, who showed one bleeding episode per The authors wish to thank all the patients who contributed to this study. month,14 or three or more recurrent bleeds at the same site.25 Despite the low frequency of bleeding episodes, secondary Author Contribution long-term prophylaxis was deemed necessary since many V. Jiménez-Yuste: conceptualization, methodology, data curation, patients with type 3 severe form of VWD may develop gastro- resources, formal analysis and investigation; R. Mir: conceptualization, intestinal and joint bleeding, and prophylaxis should be initiated project administration, supervision, and visualization; M.T. before joint disease development.27 Alvarez-Román, O. Benitez Hidalgo, N.F. Pérez González, Regarding safety, Fanhdi® showed a good safety profile R. Núñez, J.R. Gonzalez-Porras, C. Marzo, M. J. Varó Castro, which aligned with reports for other pdVWF/FVIII concen- A. Palomo Bravo, C. Hernández-García, J. Coll, M. Carrasco, M.M. Nieto Hernández, F. García Candel, and B. J. Galmes: data curation, trates.22 There were no AEs, SAEs or discontinuations related investigation and resources. All authors critically revised, edited and to the pdVWF/FVIII concentrate. The most common AEs approved the final manuscript. were mild to moderate gastrointestinal disorders. As VWF facil- itates platelet aggregation and thrombus formation, it has been Declaration of Conflicting Interests suggested that there might be an increased risk associated with venous thrombosis after repeated infusions.28,29 Notably, there The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: R. were no thrombotic events associated with the use of the study Mir is full-time employee of Grifols and has no other competing inter- drug. Regarding immunogenicity, 5 to 10% of type 3 VWD ests to declare. V. Jiménez-Yuste received reimbursement for attending patients may develop alloantibodies against VWF presenting symposia/congresses and/or honoraria for speaking and/or honoraria as a lack of haemostatic response or even anaphylactic reac- for consulting, and/or funds for research from Shire, Bayer, tions.21 Remarkably, immunogenicity related AEs were CSL-Behring, Grifols, Novo Nordisk, Sobi, Octapharma, BioMarin, mainly mild infections and respiratory disorders, not associated Sanofi and Pfizer. M.T. Alvarez-Román received reimbursement for with inhibitor development, hypersensitivity or infusion reac- attending symposia and/or honoraria for speaking and/or honoraria tions. Altogether, safety results confirmed that the pdVWF/ for consulting, and/or funds for research from Takeda, Bayer, FVIII concentrate was well tolerated in VWD patients. CSL-Behring, Grifols, Novo Nordisk, Sobi, Octapharma, BioMarin, One of the strengths of this real-world evidence study is that Novartis, Amgen and Pfizer. O. Benítez Hidalgo received reimburse- supports the use of Fanhdi® in a more representative and real- ment for attending symposia/congresses and/or honoraria for speaking and/or advisory boards from Bayer, CSL-Behring, Takeda, Sobi and istic population than in a randomized controlled trial, and dem- Pfizer. R. Núñez reports personal fees or consulting services for onstrated the product safety and effectiveness in standard Novonordisk, Bayer, Takeda, Roche, Pfizer, CSL Behring and Sobi. clinical practice. In addition, we showed the breakdown of effi- J.R. Gonzalez-Porras reports financial activities outside the submitted cacy in terms of excellent and good responses, whereas previ- work: fees for consulting services by Amgen, Novartis, Sobi, ous studies using pdVWF/FVIII concentrates reported Grifols, and CSL Behring, and speaking honoraria from excellent/good responses lumped together.16,30,31 Limitations NovoNordisk, Shire, Sobi, Roche, Daiichi Sankyo, Pfizer, Amgen, of the study must be acknowledged. First, the small sample Novartis. N.F. Pérez González, C. Marzo Alonso, A. Palomo Bravo, size of the cohort of patients included in secondary prophylaxis C. Hernández García, J. Coll, M. Carrasco, M.M. Nieto Hernández, programs made it difficult to generate robust results. Second, B. J Galmes, M.J. Varó Castro and F. García Candel have no conflict due to the retrospective nature of the study, some data such of interest to declare. as the subtype of VWD reported, or specific AE characteristics, were missing in some patients. Third, the study intended to Funding include PK values such as FVIII:C activity, VWF:RCo, The author(s) disclosed receipt of the following financial support for and VWF:Ag levels for each clinical situation. Unfortunately, the research, authorship, and/or publication of this article: This work these data were not available to perform a formal analysis. was supported by Grifols, manufacturer of the pdVWF/FVIII, Fanhdi®. Conclusion Data Availability The data that support the findings of this study are available from the Fanhdi®, a highly purified pdVWF/FVIII concentrate with a corresponding author upon reasonable request. high content of active VWF, has been proven to be effective, safe and well-tolerated in the management of bleeding episodes, Presentations at Meetings the prevention of excessive bleeding during major and minor The manuscript has been presented, in the form of an abstract, at the surgical procedures, and for secondary long-term prophylaxis meetings EAHAD Feb 5 to 7, 2020 and ISTH July 12 to 14, 2020, in patients with VWD in Spain. and presented orally at the SETH/SEHH congress Oct 20 to 24, 2020. Acknowledgements Ethical Approval Eugenio Rosado, PhD and Jordi Bozzo, PhD CMPP (Grifols) are Ethical approval to report this study was obtained from the ethics com- acknowledged for medical writing and editorial support in the mittee of Hospital Universitario la Paz (ID number: HULP PI-3597). 10 Clinical and Applied Thrombosis/Hemostasis Informed Consent 14. Holm E, Abshire TC, Bowen J, et al. Changes in bleeding patterns Informed consent for patient information to be published in this article in von willebrand disease after institution of long-term replace- was not obtained because of the retrospective nature of the study. ment therapy: results from the von Willebrand disease prophylaxis network. Blood Coagul Fibrinolysis. 2015;26(4):383-388. doi: 10. 1097/mbc.0000000000000257 References 15. Federici AB, Baudo F, Caracciolo C, et al. Clinical efficacy of highly purified, doubly virus-inactivated factor VIII/von 1. Leebeek FW, Eikenboom JC. Von willebrand’s disease. 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