Haemophilia (2014), 20, 846–853
DOI: 10.1111/hae.12496
ORIGINAL ARTICLE von Willebrand disease
Safety and efficacy of a von Willebrand factor/factor VIII concentrate (Wilateâ): a single centre experience P . B A T T Y , Y . - H . C H E N , L . B O W L E S , D . P . H A R T , S . P L A T T O N and K . J . P A S I The Royal London Hospital Haemophilia Centre, Barts and The London School of Medicine and Dentistry, The Royal London Hospital, Whitechapel, London E1 1BB, UK
Summary. von Willebrand disease (VWD) is the commonest inherited bleeding disorder. Management of major surgery or bleeding often requires treatment with a plasma-derived (pd) VWF/FVIII containing concentrate. Wilateâ is a dual-virally inactivated pdconcentrate, produced specifically for the treatment of VWD, containing physiological (1:1) ratios of VWF: FVIII. We reviewed efficacy and safety of Wilateâ usage (2007–2012) at our centre including 2 years following product switching the majority of patients. Clinical and laboratory data of all adult patients treated with Wilateâ during the study period were evaluated. Fifty four patients used 3 972 150 IU of Wilateâ (1378 infusions) between 1/3/07 and 1/5/12. Efficacy was rated as being excellent or good in 94% of surgical episodes (n = 70; 34 patients) and 98% of bleeding/traumatic episodes (n = 46; 25 patients). Eight patients (2 636 100 IU) were managed on home
treatment regimens. Two patients switched to Wilateâ prophylaxis in the evaluation period, demonstrating similar efficacy to a previous product. Incremental recoveries (n = 37) were 2.24 IU dL 1 per IU kg 1 for FVIII:C, 2.39 IU dL 1 per IU kg 1 for VWF:Ag and 1.88 IU dL 1 per IU kg 1 for VWF:RCo. Six adverse events occurred in six patients (11.1% patients) over 1378 infusions (0.44%). Half of these were retrospectively felt to be infusion speed related. No notable accumulation of FVIII was seen in patients treated for ≥3 days. There was no treatment failure, thrombosis, transfusion transmitted infection or inhibitory VWF antibodies seen. Our findings confirm safety and efficacy of Wilateâ in an adult VWD population with lack of notable FVIII accumulation.
Introduction
RCo to VWF:Ag and FVIII to VWF, as a result of the manufacturing and viral inactivation processes [5]. Theoretically, the ideal concentrate would have preservation of the structure and function of VWF and FVIII, whilst maintaining the native 1:1 ratio to keep in-vivo pharmacokinetic parameters physiological. From a clinical perspective, however, the key factors in the selection of VWF/FVIII concentrates are efficacy and safety (minimizing risk of viral transmission and inhibitor occurrence) [5]. A pd-albumin free high purity freeze dried VWF/ FVIII containing concentrate, Wilateâ (OctapharmaAG, Lachen, Switzerland) has been available for usage in the United Kingdom since 2007. Plasma is sourced from donors in countries with low variant Creutzfeldt-Jakob disease (vCJD) rates and undergoes two viral inactivation steps. This involves solvent detergent (SD) treatment and terminal dry heating (+100°C for 120 min) of the lyophilized product (PermaHeatTM) to inactivate enveloped and non-enveloped viruses [6]. Wilateâ displays VWF triplet structures
von Willebrand disease (VWD) is the commonest inherited bleeding disorder in the United Kingdom affecting 9377 individuals [1,2]. In patients who are unresponsive to desmopressin (1-deamino-8-D-arginine vasopressin; DDAVP), bleeding following surgery, trauma or spontaneous requires treatment with a von Willebrand factor/Factor VIII (VWF/FVIII) containing concentrate [3]. Although recombinant VWF products are undergoing clinical trials, all currently available concentrates are plasma derived (pd) [4]. Of these concentrates, differences exist in their VWF structure (multimer composition) and ratios of VWF: Correspondence: Professor K John Pasi, Professor of Haemostasis and Thrombosis, The Royal London Hospital Haemophilia Centre, Haematology Day Unit, The Royal London Hospital, Whitechapel, London E1 1BB, UK. Tel.: 0203 594 1869; fax: 0203 594 1859; e-mail: [email protected]
Keywords: bleeding, efficacy, plasma concentrate, prophylaxis, surgery, von Willebrand disease
Accepted after revision 12 June 2014 846
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corresponding with those seen in normal plasma and physiological ratios of VWF to FVIII (1:1) [7,8]. The Royal London Hospital Haemophilia Centre provides comprehensive care to 1185 patients with inherited bleeding disorders, of which 393 (33%) are registered with VWD. Our centre started using Wilateâ in 2007, making an en-masse product switch in May 2010 on the basis of the dual viral inactivation technology and physiological VWF/FVIII product profile. We present our experience of usage and efficacy of this product.
Materials and methods Study design We performed a single centre retrospective review of all clinical and laboratory data of product use since first used in 2007, and for a 2-year period following en-masse product switching in May 2010 (1/3/07–1/5/ 12). Institutional approval was granted by The Royal London Hospital, Clinical Effectiveness Unit as part of clinical audit and service evaluation. The primary outcome measure was efficacy in the management of bleeding and in the peri-operative period. Secondary outcome measures were indications for usage, dosing (IU of VWF:RCo), occurrence of adverse events (immune, infective or thrombotic) and laboratory response values (FVIII:C, VWF:Ag and VWF:RCo incremental recoveries). All patients were diagnosed locally following criteria set out by the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) [9]. All patients > 18 years at the time of first treatment episode with sufficient clinical information to assess treatment efficacy and indication were included. Our experience of usage in a paediatric population is presented as part of a haemophilia network experience in an accompanying manuscript (Khair K., et al. submitted for publication).
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Assessment of efficacy and safety Treatment episodes were defined as being either surgical, bleeding (including trauma), home treatment (prophylaxis or on-demand) or other. Surgical episodes were classified as major, minor or dental. Major surgery was surgery meeting one or more of the following criteria: requirement for general or spinal anaesthesia; opening of a body cavity; orthopaedic intervention to joint or bone; or the potential for significant blood loss [8]. Other surgical procedures were classified as being minor or dental (any oral surgical intervention, requiring local anaesthesia including endodontic, prosthetic, orthodontic or peri-odontic interventions). Bleeding was graded as being major or minor. Major bleeding was bleeding meeting any of the following criteria: requirement for hospital admission; > 48 h of treatment; life threatening or resulting in death or disability. All other bleeding was classified as being minor. Assessments of efficacy for treatment of surgery or bleeding, were made by two investigators using 4-point ordinal scales (excellent, good, moderate or none), adapted and developed from previously published scales (Table 1) [10,11]. All treatment episodes were reviewed for early or late adverse events.
Laboratory assessment and statistical analysis All laboratory measurements of FVIII:C, VWF:Ag and VWF:RCo were performed centrally. Incremental recoveries (IVR) (FVIII:C, VWF:Ag and VWF:RCo) were calculated for all patients with complete laboratory data following first infusion, with samples taken pre and post-infusion (~30 min) as part of routine clinical care. In patients treated over multiple episodes, recovery data were averaged (mean) to account for inter-individual clustering of pharmacokinetic data, to provide a summary measure for analysis [12]. In patients receiving ≥ 3 infusions, trough levels were reviewed to assess for potential FVIII
Table 1. Scales for assessment of efficacy in the treatment of bleeding and surgery. Efficacy Excellent
Good
Bleeding/Trauma Number of infusions ≤ estimated* number required to control that episode. No additional VWF containing concentrate required. 1 –2 (minor) or ≤ 1.5 times (major) infusions greater than estimated* required to control that episode. No additional VWF containing concentrate required.
Moderate
3 or more (minor) or ≥ 1.5 times (major) infusions greater than estimated* required to control that episode. No additional VWF containing concentrate required.
None
Severe uncontrolled bleeding, bleeding intensity unchanged or requirement for additional VWF containing concentrate.
Surgery Blood loss and transfusion requirements similar to (or less than) the non-VWD patient with no additional doses of Wilateâ. Bleeding slightly increased over expectation (≤ 250 mL) for the non-VWD patient, but not clinically significant. No additional doses of Wilateâ and transfusion requirements similar to the non-VWD patient. Blood loss increased (250–500 mL) over expectation for the non-VWD patient. Additional treatment or dose of Wilateâ needed or increased transfusion requirements. Bleeding substantially (>500 mL) increased over expectation for the non-VWD patient not due to a surgical or medical cause. Intervention required; unexpected hypotension or unexpected transfer to intensive care unit due to bleeding; substantially increased transfusion requirements.
*Estimated number of infusions based on the investigator experience with other VWF/FVIII concentrates in the treatment of bleeding and trauma.
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accumulation. Descriptive (mean, median, standard deviation, range, frequencies) and comparative (paired sample t-test) statistics were performed using IBM SPSS version 21 (IBM Corporation, Armonk, New York, USA).
Results A total of 4 346 550 IU of Wilateâ were issued between 1/3/07 and 1/5/12. Data were evaluable for 3 972 150 IU (91.4%) corresponding to 1378 infusions. There was insufficient clinical information regarding the treatment indication or efficacy for 63 000 units (eight treatment episodes, seven patients), with the remainder of data being missing. Fifty four patients (30 male, 24 female) with a median age of 40.2 years (range 19.0–82.3) were treated. Of these patients, 22% (n = 12) had type 1 disease, 60% (n = 32) type 2 disease, 17% (n = 9) type 3 disease and 2% (n = 1) acquired von Willebrand syndrome (AVWS) (Table 2). Indications for the 1378 evaluable infusions included: surgery (n = 150); bleeding (n = 256); home treatment (n = 909) and other (n = 63).
Bleeding and trauma episodes Twenty five patients were treated with 716 850 IU of Wilateâ over 46 bleeding episodes (256 infusions) covering 245 treatment days. 20.0% (n = 5) of patients had type 1 disease, 56.0% (n = 14) type 2 disease, 20.0% (n = 5) type 3 disease and 4.0% (n = 1) AVWS. Twenty five bleeding episodes were classified as major and 21 minor (Table 3). The indication for usage based on the organ system is shown in Fig. 1(a). Four episodes, classified as post-surgical resulted from uncovered surgical intervention at another centre (n = 2) or at the diagnosis of AVWS (n = 2). The
adjusted median number of infusions to treat bleeding was 2 (range 1–9). All major bleeding episodes required ≥ 2 infusions, with an adjusted median of 4 (range 2–9) infusions. Seventeen episodes (37.0%) were treated with a single infusion and all of these were minor in severity. The median loading dose was 2700 IU (range 900–7200) corresponding to 40.2 IU kg 1 (range 11.8–89.0). In patients receiving ≥ 2 doses the median follow-up dose was 2700 IU corresponding to 37.9 IU kg 1 (range 11.8–95.7). Most episodes (89.7%) requiring ≥ 2 doses were treated on once daily dosing. Efficacy was excellent or good in 97.9% of episodes (Table 3). There were three outlying episodes (30, 30 and 80 treatments) involving two patients who were commenced on regular prophylaxis. One patient had moderate efficacy requiring 80 treatments for urological bleeding from underlying inoperable bladder pathology requiring commencement of prophylaxis and a second episode of recurrent bleeding requiring optimization of prophylactic dosing. A second patient had significant and protracted menorrhagia unresponsive to hormonal therapy. Within these treatment episodes both patients were commenced on prophylaxis whilst an inpatient, thus not fulfilling criteria for inclusion within the home treatment group.
Surgical prophylaxis Thirty four patients were treated using 442 800 IU of Wilateâ over 70 surgical episodes (150 infusions) covering 137 treatment days. 29.4% (n = 10) of patients had type 1, 55.9% (n = 19) type 2 and 14.7% (n = 5) type 3 disease. There were 22 major, 29 minor and 19 dental surgical episodes (Table 4). The indication for usage by surgical speciality is shown in Fig. 1(b). The median number of infusions was 1 (range 1–13), with
Table 2. Cohort baseline demographics. Type 1 Number (n) M:F Ratio Age (years) Mean SD Median (range) Weight (kg) Mean SD Median (range) VWF:Ag (IU dL 1) Mean SD Median (range) VWF:Rco (IU dL 1) Mean SD Median (range) FVIII:C (IU dL 1) Mean SD Median (range)
Type 2 (A,B,M,N)
Type 3
46.3 20.3 43.2 (19.0 –80.5)
45.0 17.3 45.7 (19.1 –76.7)
29.9 20.0 22.8 (19.0 –82.3)
41.7* 41.7*
42.7 18.9 40.2 (19.0 –82.3)
68.7 17.0 62.6 (46.6 –100.0)
82.8 21.9 78.5 (51.5 –152.0)
84.9 30.0 70.0 (53.5 –150.0)
84.6* 84.6*
80.0 22.7 75.5 (46.6 –152.0)
23.5 11.1 22.0 (8.7 –45.3)
28.7 14.9 22.3 (8.1 –78.3)
39.2 25.0 30.4 (12.8 –98.3)
6.0 14.4 0.0 (0.0–63.7**) 41.4 22.6 37.0 (11.2 –105.4)
1 1:0
Total
32 17:15
11.1 14.4 2.4 (0.0–34.8)
9 7:2
AVWS
12 5:7
54 30:24
0.0* 0.0*
8.3* 8.3*
22.7 16.0 20.6 (0.0 –78.3)
0.0* 0.0*
0.0* 0.0*
6.0 13.3 0.0 (0.0–63.7)
0.5 0.8 0.0 (0.0–2.0)
2.8* 2.8*
33.4 26.0 27.2 (0.0 –105.4)
*All values are equal. **type 2N. AVWS, Acquired von Willebrand syndrome.
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Table 3. Demographics and efficacy of usage in the treatment of bleeding and trauma.
Episodes (pt) Type 1 Type 2 Type 3 AVWS M:F Age (years) Mean SD Median (range) Weight (kg) Mean SD Median (range) Infusions (n) Mean SD Adjusted* Mean SD Median (range) Adjusted* Median (range) Treatment days Mean SD Adjusted* Mean SD Median (range) Adjusted* Median (range) Loading Dose Mean IU SD Median IU (range) Mean IU kg 1 SD Median IU kg 1 (range) 2nd Dose Episodes Mean IU SD Median IU (range) Mean IU kg 1 SD Median IU kg 1 (range) Initial BD Usage (episodes) Efficacy Excellent Good Moderate None Excellent/Good
Major
Minor
25 (16) 2 (12.5%) 10 (62.5%) 3 (18.8%) 1 (6.3%) 9:7
21 (13) 3 (23.1%) 7 (53.8%) 3 (23.1%) 0 (0.0%) 9:4
46 (25) 5 (20.0%) 14 (56.0%) 5 (20.0%) 1 (4.0%) 15:10
Total
50.0 20.6 46.7 (22.2 –82.3)
37.3 18.8 28.8 (19.0 –74.0)
44.7 20.4 41.7 (19.0 –82.3)
86.9 28.7 76.9 (51.5 –152.0)
80.0 25.5 78.6 (46.6 –137.0)
82.0 26.8 74.0 (46.6 –152.0)
9.2 4.1 5.0 4.0
16.5 2.0 (2.0–80.0) (2.0–9.0)
1.2 0.4 N/A 1.0 (1.0–2.0) N/A
5.6 2.7 2.0 2.0
12.7 2.1 (1.0–80.0) (1.0–9.0)
8.8 4.0 4.0 4.0
15.9 2.0 (2.0–78.0) (2.0–9.0)
1.2 0.4 N/A 1.0 (1.0–2.0) N/A
5.3 2.6 2.0 2.0
12.2 2.0) (1.0–78.0) (1.0–9.0)
3384.0 1140.8 2700 (1800 –7200) 41.7 16.2 42.0 (11.8 –85.1)
2850.0 1167.7 2700 (900 –5400) 38.4 16.3 38.7 (19.2 –89.0)
3140.2 1171.5 2700 (900 –7200) 40.2 16.1 40.2 (11.8 –89.0)
25 3096.0 1326.8 2700 (1800–8100) 37.8 17.6 36.9 (11.8 –95.7) 12.0% (3)
4 2700.0 734.8 2700 (1800–3600) 38.9 12.1 36.2 (27.6 –55.7) 0% (0)
29 3041.4 1259.4 2700 (1800 –8100) 37.9 16.8 36.6 (11.8 –95.7) 10.3% (3)
80.0% (20) 16.0% (4) 4.0% (1) 0% (0) 96.0% (24)
95.2% (20) 4.8% (1) 0% (0) 0% (0) 100% (21)
87.0% (40) 10.9% (5) 2.2% (1) 0.0% (0) 97.9% (45)
All doses stated are IU of VWF:RCo. *Infusion and treatment days adjusted for 3 outliers (30, 30 and 80 infusion), in the major bleeding group who were commenced on regular prophylaxis as an inpatient.
70% (49/70) of surgical episodes managed with a single infusion. The majority of patients undergoing major surgery had type 2 (46%, n = 6) or type 1 disease (39%, n = 5) with only 2 patients (15%) having type 3 disease. Major surgery was managed with a median of 3 infusions over 3 treatment days. 44% (n = 18) of major surgical procedures requiring ≥ 2 infusions were managed initially with twice daily dosing. Minor surgery was managed with a median of 1 infusion and all dental procedures with a single infusion. The median loading dose prior to surgery was 3600 IU (range 1800–7200) corresponding to 42.1 IU kg 1 (range 11.8–117.5). The median followup dose in patients requiring more than one dose (n = 21) was 2700 IU (range 1800–4500) corresponding to 30.6 IU kg 1 (range 17.9–68.2). Efficacy was excellent or good in 94.2% of episodes (Table 4). Four procedures were rated as having moderate efficacy. These episodes required only local treatment or © 2014 John Wiley & Sons Ltd
an additional dose of Wilateâ. A mean dose of 2700 IU (range 1800–5400) corresponding to 37.0 IU kg 1 (range 17.9–89.0), was used in these episodes, similar to the mean for all patients. Two of these patients had post-dose VWF:RCo levels of < 50 IU dL 1, after receiving doses of < 25 IU kg 1, suggesting initial under-treatment rather than impaired efficacy.
Other indications Twelve patients were issued with 176 400 IU over 21 other indications (63 infusions): single dose home treatment (n = 10); travel (n = 2); pharmacokinetic studies (n = 2); un-complicated non-instrumented vaginal delivery (n = 2); commencement of prophylaxis (n = 2); test dose following a previous reaction (n = 1); physiotherapy (n = 1) and prior to a surgery that was precipitously cancelled (n = 1). Haemophilia (2014), 20, 846--853
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Treatment episodes
(a) 7
Major
6
Minor
5 4 3 2 1 0
(b) 20 18 16 14 12 10 8 6 4 2 0
Treatment episodes
Major Minor Dental
Fig. 1. (a) Wilateâ usage for the treatment of bleeding/traumatic episodes by organ system. (b) Wilateâ usage in the peri-operative period by surgical specialty.
Home treatment Eight patients received treatment at home on either on-demand or prophylactic regimens. Data were evaluable for 909 infusions covering 2 636 100 IU of concentrate. Four patients were on regular prophylaxis, two on-demand, one targeted prophylaxis and one intermittent prophylaxis/on-demand. The mean dose used in patients on regular prophylaxis was 3000 IU (35.6 IU kg 1) with two treated twice weekly and two-three times weekly. Two patients switched from an alternative VWF/FVIII containing product during the follow-up period demonstrating similar efficacy on prophylaxis to the 6-month period on an alternative product.
Laboratory data Laboratory data were evaluable for 37 patients (type 1 = 9, type 2 = 23, type 3 = 5) over 67 treatment episodes. The mean first dose of Wilateâ used was 42.1 IU kg 1 (range 10.8–117.5). Mean adjusted incremental recoveries (IVR) were 2.24 IU dL 1 per IU kg 1 (95% confidence interval (CI), 2.03–2.45) for FVIII:C, 2.39 IU dL 1 per IU kg 1 (95% CI, 2.16– Haemophilia (2014), 20, 846--853
2.62) for VWF:Ag and 1.88 IU dL 1 per IU kg 1 (95% CI, 1.70–2.06) for VWF:RCo (Table 5). Nineteen patients (26 episodes) received treatment for ≥ 3 days, with data evaluable for 19 episodes (15 patients). The mean maximum FVIII:C trough level seen at all recorded data-points was 143.4 IU dL 1 (range 60.0–318.0). The mean adjusted change in FVIII:C from first to last recorded FVIII:C trough level was + 33.58 IU dL 1 (95% CI, 4.10–63.06, P = 0.028). The mean adjusted change in VWF:Ag from first to last recorded VWF:Ag trough level was +21.60 (95% CI, 9.02–+52.21, P = 0.15).
Safety Six adverse events (six patients) were recorded over the study period. Two were reported as being serious (medically significant) and four non-serious. Symptoms included, shortness of breath (83%), chest tightness (67%), flushing (33%), urticaria (17%) and back pain (17%). Three adverse events (50%) were felt directly related to infusion rate and three occurred following the first infusion. Three patients required medical review, two requir-
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Table 4. Demographics and efficacy of usage in the peri-operative period.
Episodes (pt) Type 1 Type 2 Type 3 M:F Age (years) Mean SD Median (range) Weight (kg) Mean SD Median (range) Infusions (n) Mean SD Median (range) Treatment Days Mean SD Median (range) Loading Dose Mean IU SD Median IU (range) Mean IU kg 1 SD Median IU kg 1 (range) 2nd Dose Episodes Mean IU SD Median IU (range) Mean IU kg 1 SD Median IU kg 1 (range) Initial BD Usage (episodes) Efficacy Excellent Good Moderate None Excellent/Good
Major
Minor
Dental
Total
22 (13) 5 (38.5%) 6 (46.2%) 2 (15.4%) 7:6
29 (20) 5 (25.0%) 12 (60.0%) 3 (15.0%) 10:10
19 (11) 3 (27.3%) 6 (54.5%) 2 (18.2%) 6:5
70 (34) 10 (29.4%) 19 (55.9%) 5 (14.7%) 19:15
48.4 18.8 45.4 (22.7 – 82.4)
43.2 20.8 41.5 (19.0 – 82.3)
43.7 14.1 46.7 (22.0 – 67.2)
44.1 18.3 44.3 (19.0 – 82.3)
73.7 13.7 70.0 (53.5 – 100.0)
81.3 28.0 75.2 (48.4 – 166.0)
78.1 28.3 66.0 (50.0 – 152.0)
78.1 21.9 74.5 (48.4 – 152.0)
4.5 3.7 3.0 (1.0 – 13.0)
1.1 0.3 1.0 (1.0 – 2.0)
1* 1*
2.1 2.6 1.0 (1.0 – 13.0)
3.9 3.3 3.0 (1.0 – 12.0)
1.1 0.3 1.0 (1.0 – 2.0)
1* 1*
2.0 2.3 1.0 (1.0 – 12.0)
3722.7 1528.8 3600 (1800 –7200) 52.1 23.3 51.4 (17.9 –117.5)
3181.0 931.1 3600 (1800 –4500) 41.8 12.8 44.0 (18.8–64.3)
18 2600.0 867.0 2700 (1800 –4500) 36.1 15.3 32.0 (17.9 –68.2) 44.4% (10)
3 2550.0 259.8 2700 (2250 –2700) 31.2 13.5 25.9 (21.1 –46.5) 0.0% (0)
68.2% 18.2% 13.6% 0.0% 86.4%
(15) (4) (3) (0) (19)
2936.8 840.1 2700 (1800 – 4500) 31.44 14.60 25.30 (11.84–70.31) 0
21 2592.9 803.8 2700 (1800 –4500) 35.4 14.8 30.6 (17.9 –68.2) 38.1% (8)
N/A
96.6% (28) 3.4% (1) 0.0% (0) 0.0% (0) 100.0% (29)
94.7% 0.0% 5.3% 0.0% 94.7%
3285.0 1160.3 3600 (1800 –7200) 42.1 18.8 43.0 (11.8 –117.5)
(18) (0) (1) (0) (18)
87.1% 7.1% 5.7% 0.0% 94.2%
(61) (5) (4) (0) (66)
*All episodes were treated with a single infusion. All doses stated are IU of VWF:RCo.
Table 5. Adjusted incremental recovery (IVR) following first treatment dose for surgery or bleeding. FVIII:C IVR (IU dL Type 1 (n = 9) Mean (95% CI) Type 2 (n = 23) Mean (95% CI) Type 3 (n = 5) Mean (95% CI) All patients (n = 37) Mean (95% CI)
1
per IU kg 1)
VWF:Ag IVR (IU dL
per IU kg 1)
VWF:RCo IVR (IU dL
1
per IU kg 1)
1.85 (1.35 –2.36)
1.99 (1.57 –2.41)
1.53 (1.08 –1.98)
2.32 (2.07 –2.56)
2.51 (2.20 –2.81)
1.94 (1.74 –2.14)
2.60 (1.75 –3.45)
2.58 (1.72 –3.43)
2.20 (1.52 –2.88)
2.24 (2.03 –2.45)
2.39 (2.16 –2.62)
1.88 (1.70 –2.06)
ing some form of medical treatment, although none required hospitalization. Both patients with serious adverse events were switched to their previous VWF/FVIII concentrate without re-challenge. Three patients with non-serious adverse events were rechallenged without further reaction. Two switched back to their previous VWF/FVIII containing concentrate at patient request. All adverse events were reported to Octapharma(UK) as part of ongoing pharmacovigilance. There was no treatment failure, thrombosis, infection or inhibitory VWF allo-antibodies recorded. © 2014 John Wiley & Sons Ltd
1
Discussion Usage of Wilate in four prospective phase II and III studies for the treatment of surgery or bleeding in patients > 12 years has been described [8,13]. In these, efficacy was rated excellent or good in 96% of surgical procedures (32 patients, 57 surgeries) and 96% of spontaneous or post-traumatic bleeding episodes (44 patients, 1095 episodes). Efficacy described to date for Wilateâ is similar to that of other VWF/ FVIII containing concentrates [14]. We present a large single centre experience (3 972 150 IU of Wilateâ) in Haemophilia (2014), 20, 846--853
Haemophilia (2014), 20, 846–853
DOI: 10.1111/hae.12496
ORIGINAL ARTICLE von Willebrand disease
Safety and efficacy of a von Willebrand factor/factor VIII concentrate (Wilateâ): a single centre experience P . B A T T Y , Y . - H . C H E N , L . B O W L E S , D . P . H A R T , S . P L A T T O N and K . J . P A S I The Royal London Hospital Haemophilia Centre, Barts and The London School of Medicine and Dentistry, The Royal London Hospital, Whitechapel, London E1 1BB, UK
Summary. von Willebrand disease (VWD) is the commonest inherited bleeding disorder. Management of major surgery or bleeding often requires treatment with a plasma-derived (pd) VWF/FVIII containing concentrate. Wilateâ is a dual-virally inactivated pdconcentrate, produced specifically for the treatment of VWD, containing physiological (1:1) ratios of VWF: FVIII. We reviewed efficacy and safety of Wilateâ usage (2007–2012) at our centre including 2 years following product switching the majority of patients. Clinical and laboratory data of all adult patients treated with Wilateâ during the study period were evaluated. Fifty four patients used 3 972 150 IU of Wilateâ (1378 infusions) between 1/3/07 and 1/5/12. Efficacy was rated as being excellent or good in 94% of surgical episodes (n = 70; 34 patients) and 98% of bleeding/traumatic episodes (n = 46; 25 patients). Eight patients (2 636 100 IU) were managed on home
treatment regimens. Two patients switched to Wilateâ prophylaxis in the evaluation period, demonstrating similar efficacy to a previous product. Incremental recoveries (n = 37) were 2.24 IU dL 1 per IU kg 1 for FVIII:C, 2.39 IU dL 1 per IU kg 1 for VWF:Ag and 1.88 IU dL 1 per IU kg 1 for VWF:RCo. Six adverse events occurred in six patients (11.1% patients) over 1378 infusions (0.44%). Half of these were retrospectively felt to be infusion speed related. No notable accumulation of FVIII was seen in patients treated for ≥3 days. There was no treatment failure, thrombosis, transfusion transmitted infection or inhibitory VWF antibodies seen. Our findings confirm safety and efficacy of Wilateâ in an adult VWD population with lack of notable FVIII accumulation.
Introduction
RCo to VWF:Ag and FVIII to VWF, as a result of the manufacturing and viral inactivation processes [5]. Theoretically, the ideal concentrate would have preservation of the structure and function of VWF and FVIII, whilst maintaining the native 1:1 ratio to keep in-vivo pharmacokinetic parameters physiological. From a clinical perspective, however, the key factors in the selection of VWF/FVIII concentrates are efficacy and safety (minimizing risk of viral transmission and inhibitor occurrence) [5]. A pd-albumin free high purity freeze dried VWF/ FVIII containing concentrate, Wilateâ (OctapharmaAG, Lachen, Switzerland) has been available for usage in the United Kingdom since 2007. Plasma is sourced from donors in countries with low variant Creutzfeldt-Jakob disease (vCJD) rates and undergoes two viral inactivation steps. This involves solvent detergent (SD) treatment and terminal dry heating (+100°C for 120 min) of the lyophilized product (PermaHeatTM) to inactivate enveloped and non-enveloped viruses [6]. Wilateâ displays VWF triplet structures
von Willebrand disease (VWD) is the commonest inherited bleeding disorder in the United Kingdom affecting 9377 individuals [1,2]. In patients who are unresponsive to desmopressin (1-deamino-8-D-arginine vasopressin; DDAVP), bleeding following surgery, trauma or spontaneous requires treatment with a von Willebrand factor/Factor VIII (VWF/FVIII) containing concentrate [3]. Although recombinant VWF products are undergoing clinical trials, all currently available concentrates are plasma derived (pd) [4]. Of these concentrates, differences exist in their VWF structure (multimer composition) and ratios of VWF: Correspondence: Professor K John Pasi, Professor of Haemostasis and Thrombosis, The Royal London Hospital Haemophilia Centre, Haematology Day Unit, The Royal London Hospital, Whitechapel, London E1 1BB, UK. Tel.: 0203 594 1869; fax: 0203 594 1859; e-mail: [email protected]
Keywords: bleeding, efficacy, plasma concentrate, prophylaxis, surgery, von Willebrand disease
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We attempted to control for this by defining and using strict efficacy evaluation criteria prior to data analysis. In order to strictly apply these criteria it was necessary to exclude a small number of treatment episodes with insufficient clinical information (1.4% of total usage). However, use of a set of strict criteria did allow us to more objectively compare differing clinical events. To further evaluate the efficacy of any new concentrate a prospective study with rigid criteria is preferable. To this end the international WONDERS study a prospective, open-label, multi-centre, phase III trial of efficacy and safety of Wilateâ in 41 subjects with inherited VWD undergo surgery is ongoing. In summary, our data from a real life, uncontrolled non-study setting confirm that Wilateâ is safe and efficacious. Our efficacy data are comparable to those reported in previous clinical trials of this VWF/FVIII concentrate.
References 1 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood 1987; 69: 454–9. 2 United Kingdom Haemophilia Centres Doctors’ Organisation. Bleeding disorder statistics for April 2011 to March 2012: a report from the national haemophilia database. 1–87. 2012. 3 Pasi KJ, Collins PW, Keeling DM et al. Management of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors’ Organization. Haemophilia 2004; 10: 218–31. 4 Mannucci PM, Kempton C, Millar C et al. Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial. Blood 2013; 122: 648–57. 5 Keeling D, Tait C, Makris M. Guideline on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. A United Kingdom Haemophilia Center Doctors’ Organisation (UKHCDO) guideline approved by the British Committee for Standards in Haematology. Haemophilia 2008; 14: 671–84. 6 Stadler M, Gruber G, Kannicht C et al. Characterisation of a novel high-purity, double virus inactivated von Willebrand Factor and Factor VIII concentrate (Wilate). Biologicals 2006; 34: 281–8. 7 Kessler CM, Friedman K, Schwartz BA, Gill JC, Powell JS. The pharmacokinetic diversity of two von Willebrand factor (VWF)/factor VIII (FVIII) concentrates in subjects with congenital von Willebrand disease. Results from a prospective,
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Acknowledgements We would like to acknowledge the assistance of Heather Williams (Operational Services Manager), for her assistance in compiling the database of treatment issues.
Author contributions PB wrote the first draft paper. DPH, LB and KJP treated the patients. KJP and PB designed the study. SP performed all testing of samples. PB and YHC conducted all data collection and analysis. All authors reviewed and critically edited the manuscript.
Disclosures PB has received an unrestricted research fellowship and travel grants from Octapharma. DPH has received honoraria for lectures and travel grants from Octapharma. KJP has been part of Advisory Boards for Octapharma, received honoraria for lectures and travel grants. YHC, LB and SP state that they had no interests which might be perceived as posing a conflict or bias.
randomised crossover study. Thromb Haemost 2011; 106: 279–88. Windyga J, von Depka-Prondzinski M. Efficacy and safety of a new generation von Willebrand factor/factor VIII concentrate (Wilate(R)) in the management of perioperative haemostasis in von Willebrand disease patients undergoing surgery. Thromb Haemost 2011; 105: 1072–9. Laffan M, Brown SA, Collins PW et al. The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors’ Organization. Haemophilia 2004; 10: 199–217. Ragni MV, Pasi KJ, White GC, Giangrande PL, Courter SG, Tubridy KL. Use of recombinant factor IX in subjects with haemophilia B undergoing surgery. Haemophilia 2002; 8: 91–7. Lillicrap D, Poon MC, Walker I, Xie F, Schwartz BA. Efficacy and safety of the factor VIII/von Willebrand factor concentrate, haemate-P/humate-P: ristocetin cofactor unit dosing in patients with von Willebrand disease. Thromb Haemost 2002; 87: 224– 30. Matthews JN, Altman DG, Campbell MJ, Royston P. Analysis of serial measurements in medical research. BMJ 1990; 300: 230– 5. Berntorp E, Windyga J. Treatment and prevention of acute bleedings in von Willebrand disease–efficacy and safety of Wilate, a new generation von Willebrand factor/ factor VIII concentrate. Haemophilia 2009; 15: 122–30. Federici AB. Management of von Willebrand disease with factor VIII/von Willebrand factor concentrates: results from current studies and surveys. Blood Coagul Fibrinolysis 2005; 16(Suppl 1): S17–21.
15 Franchini M, Makris M, Santagostino E, Coppola A, Mannucci PM. Non-thrombotic-, non-inhibitor-associated adverse reactions to coagulation factor concentrates for treatment of patients with hemophilia and von Willebrand’s disease: a systematic review of prospective studies. Haemophilia 2012; 18: e164–72. 16 Makris M, Colvin B, Gupta V, Shields ML, Smith MP. Venous thrombosis following the use of intermediate purity FVIII concentrate to treat patients with von Willebrand’s disease. Thromb Haemost 2002; 88: 387–8. 17 Mannucci PM. Venous thromboembolism in von Willebrand disease. Thromb Haemost 2002; 88: 378–9. 18 Coppola A, Franchini M, Makris M, Santagostino E, Di MG, Mannucci PM. Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies. Haemophilia 2012; 18: e173–87. 19 Mannucci PM. Treatment of von Willebrand’s Disease. N Engl J Med 2004; 351: 683–94. 20 Raquet E, Stockschlader M, Dickneite G. Repeated infusions of VWF/FVIII concentrate: impact of VWF:FVIII ratio on FVIII trough and peak levels in a rabbit model. Haemophilia 2011; 17: 808–14. 21 Kessler CM, Windyga J, Schwartz BA, Knaub S. Use of objective efficacy criteria for evaluation of von Willebrand factor/ factor VIII concentrates. Blood Coagul Fibrinolysis 2012; 23: 262–7. 22 Berntorp E, Fuchs B, Makris M et al. Third Aland islands conference on von Willebrand disease, 26-28 September 2012: meeting report. Haemophilia 2013; 19(Suppl 3): 1–18.
Haemophilia (2014), 20, 846--853
DOI: 10.1111/hae.12496
ORIGINAL ARTICLE von Willebrand disease
Safety and efficacy of a von Willebrand factor/factor VIII concentrate (Wilateâ): a single centre experience P . B A T T Y , Y . - H . C H E N , L . B O W L E S , D . P . H A R T , S . P L A T T O N and K . J . P A S I The Royal London Hospital Haemophilia Centre, Barts and The London School of Medicine and Dentistry, The Royal London Hospital, Whitechapel, London E1 1BB, UK
Summary. von Willebrand disease (VWD) is the commonest inherited bleeding disorder. Management of major surgery or bleeding often requires treatment with a plasma-derived (pd) VWF/FVIII containing concentrate. Wilateâ is a dual-virally inactivated pdconcentrate, produced specifically for the treatment of VWD, containing physiological (1:1) ratios of VWF: FVIII. We reviewed efficacy and safety of Wilateâ usage (2007–2012) at our centre including 2 years following product switching the majority of patients. Clinical and laboratory data of all adult patients treated with Wilateâ during the study period were evaluated. Fifty four patients used 3 972 150 IU of Wilateâ (1378 infusions) between 1/3/07 and 1/5/12. Efficacy was rated as being excellent or good in 94% of surgical episodes (n = 70; 34 patients) and 98% of bleeding/traumatic episodes (n = 46; 25 patients). Eight patients (2 636 100 IU) were managed on home
treatment regimens. Two patients switched to Wilateâ prophylaxis in the evaluation period, demonstrating similar efficacy to a previous product. Incremental recoveries (n = 37) were 2.24 IU dL 1 per IU kg 1 for FVIII:C, 2.39 IU dL 1 per IU kg 1 for VWF:Ag and 1.88 IU dL 1 per IU kg 1 for VWF:RCo. Six adverse events occurred in six patients (11.1% patients) over 1378 infusions (0.44%). Half of these were retrospectively felt to be infusion speed related. No notable accumulation of FVIII was seen in patients treated for ≥3 days. There was no treatment failure, thrombosis, transfusion transmitted infection or inhibitory VWF antibodies seen. Our findings confirm safety and efficacy of Wilateâ in an adult VWD population with lack of notable FVIII accumulation.
Introduction
RCo to VWF:Ag and FVIII to VWF, as a result of the manufacturing and viral inactivation processes [5]. Theoretically, the ideal concentrate would have preservation of the structure and function of VWF and FVIII, whilst maintaining the native 1:1 ratio to keep in-vivo pharmacokinetic parameters physiological. From a clinical perspective, however, the key factors in the selection of VWF/FVIII concentrates are efficacy and safety (minimizing risk of viral transmission and inhibitor occurrence) [5]. A pd-albumin free high purity freeze dried VWF/ FVIII containing concentrate, Wilateâ (OctapharmaAG, Lachen, Switzerland) has been available for usage in the United Kingdom since 2007. Plasma is sourced from donors in countries with low variant Creutzfeldt-Jakob disease (vCJD) rates and undergoes two viral inactivation steps. This involves solvent detergent (SD) treatment and terminal dry heating (+100°C for 120 min) of the lyophilized product (PermaHeatTM) to inactivate enveloped and non-enveloped viruses [6]. Wilateâ displays VWF triplet structures
von Willebrand disease (VWD) is the commonest inherited bleeding disorder in the United Kingdom affecting 9377 individuals [1,2]. In patients who are unresponsive to desmopressin (1-deamino-8-D-arginine vasopressin; DDAVP), bleeding following surgery, trauma or spontaneous requires treatment with a von Willebrand factor/Factor VIII (VWF/FVIII) containing concentrate [3]. Although recombinant VWF products are undergoing clinical trials, all currently available concentrates are plasma derived (pd) [4]. Of these concentrates, differences exist in their VWF structure (multimer composition) and ratios of VWF: Correspondence: Professor K John Pasi, Professor of Haemostasis and Thrombosis, The Royal London Hospital Haemophilia Centre, Haematology Day Unit, The Royal London Hospital, Whitechapel, London E1 1BB, UK. Tel.: 0203 594 1869; fax: 0203 594 1859; e-mail: [email protected]
Keywords: bleeding, efficacy, plasma concentrate, prophylaxis, surgery, von Willebrand disease
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corresponding with those seen in normal plasma and physiological ratios of VWF to FVIII (1:1) [7,8]. The Royal London Hospital Haemophilia Centre provides comprehensive care to 1185 patients with inherited bleeding disorders, of which 393 (33%) are registered with VWD. Our centre started using Wilateâ in 2007, making an en-masse product switch in May 2010 on the basis of the dual viral inactivation technology and physiological VWF/FVIII product profile. We present our experience of usage and efficacy of this product.
Materials and methods Study design We performed a single centre retrospective review of all clinical and laboratory data of product use since first used in 2007, and for a 2-year period following en-masse product switching in May 2010 (1/3/07–1/5/ 12). Institutional approval was granted by The Royal London Hospital, Clinical Effectiveness Unit as part of clinical audit and service evaluation. The primary outcome measure was efficacy in the management of bleeding and in the peri-operative period. Secondary outcome measures were indications for usage, dosing (IU of VWF:RCo), occurrence of adverse events (immune, infective or thrombotic) and laboratory response values (FVIII:C, VWF:Ag and VWF:RCo incremental recoveries). All patients were diagnosed locally following criteria set out by the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) [9]. All patients > 18 years at the time of first treatment episode with sufficient clinical information to assess treatment efficacy and indication were included. Our experience of usage in a paediatric population is presented as part of a haemophilia network experience in an accompanying manuscript (Khair K., et al. submitted for publication).
847
Assessment of efficacy and safety Treatment episodes were defined as being either surgical, bleeding (including trauma), home treatment (prophylaxis or on-demand) or other. Surgical episodes were classified as major, minor or dental. Major surgery was surgery meeting one or more of the following criteria: requirement for general or spinal anaesthesia; opening of a body cavity; orthopaedic intervention to joint or bone; or the potential for significant blood loss [8]. Other surgical procedures were classified as being minor or dental (any oral surgical intervention, requiring local anaesthesia including endodontic, prosthetic, orthodontic or peri-odontic interventions). Bleeding was graded as being major or minor. Major bleeding was bleeding meeting any of the following criteria: requirement for hospital admission; > 48 h of treatment; life threatening or resulting in death or disability. All other bleeding was classified as being minor. Assessments of efficacy for treatment of surgery or bleeding, were made by two investigators using 4-point ordinal scales (excellent, good, moderate or none), adapted and developed from previously published scales (Table 1) [10,11]. All treatment episodes were reviewed for early or late adverse events.
Laboratory assessment and statistical analysis All laboratory measurements of FVIII:C, VWF:Ag and VWF:RCo were performed centrally. Incremental recoveries (IVR) (FVIII:C, VWF:Ag and VWF:RCo) were calculated for all patients with complete laboratory data following first infusion, with samples taken pre and post-infusion (~30 min) as part of routine clinical care. In patients treated over multiple episodes, recovery data were averaged (mean) to account for inter-individual clustering of pharmacokinetic data, to provide a summary measure for analysis [12]. In patients receiving ≥ 3 infusions, trough levels were reviewed to assess for potential FVIII
Table 1. Scales for assessment of efficacy in the treatment of bleeding and surgery. Efficacy Excellent
Good
Bleeding/Trauma Number of infusions ≤ estimated* number required to control that episode. No additional VWF containing concentrate required. 1 –2 (minor) or ≤ 1.5 times (major) infusions greater than estimated* required to control that episode. No additional VWF containing concentrate required.
Moderate
3 or more (minor) or ≥ 1.5 times (major) infusions greater than estimated* required to control that episode. No additional VWF containing concentrate required.
None
Severe uncontrolled bleeding, bleeding intensity unchanged or requirement for additional VWF containing concentrate.
Surgery Blood loss and transfusion requirements similar to (or less than) the non-VWD patient with no additional doses of Wilateâ. Bleeding slightly increased over expectation (≤ 250 mL) for the non-VWD patient, but not clinically significant. No additional doses of Wilateâ and transfusion requirements similar to the non-VWD patient. Blood loss increased (250–500 mL) over expectation for the non-VWD patient. Additional treatment or dose of Wilateâ needed or increased transfusion requirements. Bleeding substantially (>500 mL) increased over expectation for the non-VWD patient not due to a surgical or medical cause. Intervention required; unexpected hypotension or unexpected transfer to intensive care unit due to bleeding; substantially increased transfusion requirements.
*Estimated number of infusions based on the investigator experience with other VWF/FVIII concentrates in the treatment of bleeding and trauma.
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accumulation. Descriptive (mean, median, standard deviation, range, frequencies) and comparative (paired sample t-test) statistics were performed using IBM SPSS version 21 (IBM Corporation, Armonk, New York, USA).
Results A total of 4 346 550 IU of Wilateâ were issued between 1/3/07 and 1/5/12. Data were evaluable for 3 972 150 IU (91.4%) corresponding to 1378 infusions. There was insufficient clinical information regarding the treatment indication or efficacy for 63 000 units (eight treatment episodes, seven patients), with the remainder of data being missing. Fifty four patients (30 male, 24 female) with a median age of 40.2 years (range 19.0–82.3) were treated. Of these patients, 22% (n = 12) had type 1 disease, 60% (n = 32) type 2 disease, 17% (n = 9) type 3 disease and 2% (n = 1) acquired von Willebrand syndrome (AVWS) (Table 2). Indications for the 1378 evaluable infusions included: surgery (n = 150); bleeding (n = 256); home treatment (n = 909) and other (n = 63).
Bleeding and trauma episodes Twenty five patients were treated with 716 850 IU of Wilateâ over 46 bleeding episodes (256 infusions) covering 245 treatment days. 20.0% (n = 5) of patients had type 1 disease, 56.0% (n = 14) type 2 disease, 20.0% (n = 5) type 3 disease and 4.0% (n = 1) AVWS. Twenty five bleeding episodes were classified as major and 21 minor (Table 3). The indication for usage based on the organ system is shown in Fig. 1(a). Four episodes, classified as post-surgical resulted from uncovered surgical intervention at another centre (n = 2) or at the diagnosis of AVWS (n = 2). The
adjusted median number of infusions to treat bleeding was 2 (range 1–9). All major bleeding episodes required ≥ 2 infusions, with an adjusted median of 4 (range 2–9) infusions. Seventeen episodes (37.0%) were treated with a single infusion and all of these were minor in severity. The median loading dose was 2700 IU (range 900–7200) corresponding to 40.2 IU kg 1 (range 11.8–89.0). In patients receiving ≥ 2 doses the median follow-up dose was 2700 IU corresponding to 37.9 IU kg 1 (range 11.8–95.7). Most episodes (89.7%) requiring ≥ 2 doses were treated on once daily dosing. Efficacy was excellent or good in 97.9% of episodes (Table 3). There were three outlying episodes (30, 30 and 80 treatments) involving two patients who were commenced on regular prophylaxis. One patient had moderate efficacy requiring 80 treatments for urological bleeding from underlying inoperable bladder pathology requiring commencement of prophylaxis and a second episode of recurrent bleeding requiring optimization of prophylactic dosing. A second patient had significant and protracted menorrhagia unresponsive to hormonal therapy. Within these treatment episodes both patients were commenced on prophylaxis whilst an inpatient, thus not fulfilling criteria for inclusion within the home treatment group.
Surgical prophylaxis Thirty four patients were treated using 442 800 IU of Wilateâ over 70 surgical episodes (150 infusions) covering 137 treatment days. 29.4% (n = 10) of patients had type 1, 55.9% (n = 19) type 2 and 14.7% (n = 5) type 3 disease. There were 22 major, 29 minor and 19 dental surgical episodes (Table 4). The indication for usage by surgical speciality is shown in Fig. 1(b). The median number of infusions was 1 (range 1–13), with
Table 2. Cohort baseline demographics. Type 1 Number (n) M:F Ratio Age (years) Mean SD Median (range) Weight (kg) Mean SD Median (range) VWF:Ag (IU dL 1) Mean SD Median (range) VWF:Rco (IU dL 1) Mean SD Median (range) FVIII:C (IU dL 1) Mean SD Median (range)
Type 2 (A,B,M,N)
Type 3
46.3 20.3 43.2 (19.0 –80.5)
45.0 17.3 45.7 (19.1 –76.7)
29.9 20.0 22.8 (19.0 –82.3)
41.7* 41.7*
42.7 18.9 40.2 (19.0 –82.3)
68.7 17.0 62.6 (46.6 –100.0)
82.8 21.9 78.5 (51.5 –152.0)
84.9 30.0 70.0 (53.5 –150.0)
84.6* 84.6*
80.0 22.7 75.5 (46.6 –152.0)
23.5 11.1 22.0 (8.7 –45.3)
28.7 14.9 22.3 (8.1 –78.3)
39.2 25.0 30.4 (12.8 –98.3)
6.0 14.4 0.0 (0.0–63.7**) 41.4 22.6 37.0 (11.2 –105.4)
1 1:0
Total
32 17:15
11.1 14.4 2.4 (0.0–34.8)
9 7:2
AVWS
12 5:7
54 30:24
0.0* 0.0*
8.3* 8.3*
22.7 16.0 20.6 (0.0 –78.3)
0.0* 0.0*
0.0* 0.0*
6.0 13.3 0.0 (0.0–63.7)
0.5 0.8 0.0 (0.0–2.0)
2.8* 2.8*
33.4 26.0 27.2 (0.0 –105.4)
*All values are equal. **type 2N. AVWS, Acquired von Willebrand syndrome.
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Table 3. Demographics and efficacy of usage in the treatment of bleeding and trauma.
Episodes (pt) Type 1 Type 2 Type 3 AVWS M:F Age (years) Mean SD Median (range) Weight (kg) Mean SD Median (range) Infusions (n) Mean SD Adjusted* Mean SD Median (range) Adjusted* Median (range) Treatment days Mean SD Adjusted* Mean SD Median (range) Adjusted* Median (range) Loading Dose Mean IU SD Median IU (range) Mean IU kg 1 SD Median IU kg 1 (range) 2nd Dose Episodes Mean IU SD Median IU (range) Mean IU kg 1 SD Median IU kg 1 (range) Initial BD Usage (episodes) Efficacy Excellent Good Moderate None Excellent/Good
Major
Minor
25 (16) 2 (12.5%) 10 (62.5%) 3 (18.8%) 1 (6.3%) 9:7
21 (13) 3 (23.1%) 7 (53.8%) 3 (23.1%) 0 (0.0%) 9:4
46 (25) 5 (20.0%) 14 (56.0%) 5 (20.0%) 1 (4.0%) 15:10
Total
50.0 20.6 46.7 (22.2 –82.3)
37.3 18.8 28.8 (19.0 –74.0)
44.7 20.4 41.7 (19.0 –82.3)
86.9 28.7 76.9 (51.5 –152.0)
80.0 25.5 78.6 (46.6 –137.0)
82.0 26.8 74.0 (46.6 –152.0)
9.2 4.1 5.0 4.0
16.5 2.0 (2.0–80.0) (2.0–9.0)
1.2 0.4 N/A 1.0 (1.0–2.0) N/A
5.6 2.7 2.0 2.0
12.7 2.1 (1.0–80.0) (1.0–9.0)
8.8 4.0 4.0 4.0
15.9 2.0 (2.0–78.0) (2.0–9.0)
1.2 0.4 N/A 1.0 (1.0–2.0) N/A
5.3 2.6 2.0 2.0
12.2 2.0) (1.0–78.0) (1.0–9.0)
3384.0 1140.8 2700 (1800 –7200) 41.7 16.2 42.0 (11.8 –85.1)
2850.0 1167.7 2700 (900 –5400) 38.4 16.3 38.7 (19.2 –89.0)
3140.2 1171.5 2700 (900 –7200) 40.2 16.1 40.2 (11.8 –89.0)
25 3096.0 1326.8 2700 (1800–8100) 37.8 17.6 36.9 (11.8 –95.7) 12.0% (3)
4 2700.0 734.8 2700 (1800–3600) 38.9 12.1 36.2 (27.6 –55.7) 0% (0)
29 3041.4 1259.4 2700 (1800 –8100) 37.9 16.8 36.6 (11.8 –95.7) 10.3% (3)
80.0% (20) 16.0% (4) 4.0% (1) 0% (0) 96.0% (24)
95.2% (20) 4.8% (1) 0% (0) 0% (0) 100% (21)
87.0% (40) 10.9% (5) 2.2% (1) 0.0% (0) 97.9% (45)
All doses stated are IU of VWF:RCo. *Infusion and treatment days adjusted for 3 outliers (30, 30 and 80 infusion), in the major bleeding group who were commenced on regular prophylaxis as an inpatient.
70% (49/70) of surgical episodes managed with a single infusion. The majority of patients undergoing major surgery had type 2 (46%, n = 6) or type 1 disease (39%, n = 5) with only 2 patients (15%) having type 3 disease. Major surgery was managed with a median of 3 infusions over 3 treatment days. 44% (n = 18) of major surgical procedures requiring ≥ 2 infusions were managed initially with twice daily dosing. Minor surgery was managed with a median of 1 infusion and all dental procedures with a single infusion. The median loading dose prior to surgery was 3600 IU (range 1800–7200) corresponding to 42.1 IU kg 1 (range 11.8–117.5). The median followup dose in patients requiring more than one dose (n = 21) was 2700 IU (range 1800–4500) corresponding to 30.6 IU kg 1 (range 17.9–68.2). Efficacy was excellent or good in 94.2% of episodes (Table 4). Four procedures were rated as having moderate efficacy. These episodes required only local treatment or © 2014 John Wiley & Sons Ltd
an additional dose of Wilateâ. A mean dose of 2700 IU (range 1800–5400) corresponding to 37.0 IU kg 1 (range 17.9–89.0), was used in these episodes, similar to the mean for all patients. Two of these patients had post-dose VWF:RCo levels of < 50 IU dL 1, after receiving doses of < 25 IU kg 1, suggesting initial under-treatment rather than impaired efficacy.
Other indications Twelve patients were issued with 176 400 IU over 21 other indications (63 infusions): single dose home treatment (n = 10); travel (n = 2); pharmacokinetic studies (n = 2); un-complicated non-instrumented vaginal delivery (n = 2); commencement of prophylaxis (n = 2); test dose following a previous reaction (n = 1); physiotherapy (n = 1) and prior to a surgery that was precipitously cancelled (n = 1). Haemophilia (2014), 20, 846--853
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Treatment episodes
(a) 7
Major
6
Minor
5 4 3 2 1 0
(b) 20 18 16 14 12 10 8 6 4 2 0
Treatment episodes
Major Minor Dental
Fig. 1. (a) Wilateâ usage for the treatment of bleeding/traumatic episodes by organ system. (b) Wilateâ usage in the peri-operative period by surgical specialty.
Home treatment Eight patients received treatment at home on either on-demand or prophylactic regimens. Data were evaluable for 909 infusions covering 2 636 100 IU of concentrate. Four patients were on regular prophylaxis, two on-demand, one targeted prophylaxis and one intermittent prophylaxis/on-demand. The mean dose used in patients on regular prophylaxis was 3000 IU (35.6 IU kg 1) with two treated twice weekly and two-three times weekly. Two patients switched from an alternative VWF/FVIII containing product during the follow-up period demonstrating similar efficacy on prophylaxis to the 6-month period on an alternative product.
Laboratory data Laboratory data were evaluable for 37 patients (type 1 = 9, type 2 = 23, type 3 = 5) over 67 treatment episodes. The mean first dose of Wilateâ used was 42.1 IU kg 1 (range 10.8–117.5). Mean adjusted incremental recoveries (IVR) were 2.24 IU dL 1 per IU kg 1 (95% confidence interval (CI), 2.03–2.45) for FVIII:C, 2.39 IU dL 1 per IU kg 1 (95% CI, 2.16– Haemophilia (2014), 20, 846--853
2.62) for VWF:Ag and 1.88 IU dL 1 per IU kg 1 (95% CI, 1.70–2.06) for VWF:RCo (Table 5). Nineteen patients (26 episodes) received treatment for ≥ 3 days, with data evaluable for 19 episodes (15 patients). The mean maximum FVIII:C trough level seen at all recorded data-points was 143.4 IU dL 1 (range 60.0–318.0). The mean adjusted change in FVIII:C from first to last recorded FVIII:C trough level was + 33.58 IU dL 1 (95% CI, 4.10–63.06, P = 0.028). The mean adjusted change in VWF:Ag from first to last recorded VWF:Ag trough level was +21.60 (95% CI, 9.02–+52.21, P = 0.15).
Safety Six adverse events (six patients) were recorded over the study period. Two were reported as being serious (medically significant) and four non-serious. Symptoms included, shortness of breath (83%), chest tightness (67%), flushing (33%), urticaria (17%) and back pain (17%). Three adverse events (50%) were felt directly related to infusion rate and three occurred following the first infusion. Three patients required medical review, two requir-
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851
Table 4. Demographics and efficacy of usage in the peri-operative period.
Episodes (pt) Type 1 Type 2 Type 3 M:F Age (years) Mean SD Median (range) Weight (kg) Mean SD Median (range) Infusions (n) Mean SD Median (range) Treatment Days Mean SD Median (range) Loading Dose Mean IU SD Median IU (range) Mean IU kg 1 SD Median IU kg 1 (range) 2nd Dose Episodes Mean IU SD Median IU (range) Mean IU kg 1 SD Median IU kg 1 (range) Initial BD Usage (episodes) Efficacy Excellent Good Moderate None Excellent/Good
Major
Minor
Dental
Total
22 (13) 5 (38.5%) 6 (46.2%) 2 (15.4%) 7:6
29 (20) 5 (25.0%) 12 (60.0%) 3 (15.0%) 10:10
19 (11) 3 (27.3%) 6 (54.5%) 2 (18.2%) 6:5
70 (34) 10 (29.4%) 19 (55.9%) 5 (14.7%) 19:15
48.4 18.8 45.4 (22.7 – 82.4)
43.2 20.8 41.5 (19.0 – 82.3)
43.7 14.1 46.7 (22.0 – 67.2)
44.1 18.3 44.3 (19.0 – 82.3)
73.7 13.7 70.0 (53.5 – 100.0)
81.3 28.0 75.2 (48.4 – 166.0)
78.1 28.3 66.0 (50.0 – 152.0)
78.1 21.9 74.5 (48.4 – 152.0)
4.5 3.7 3.0 (1.0 – 13.0)
1.1 0.3 1.0 (1.0 – 2.0)
1* 1*
2.1 2.6 1.0 (1.0 – 13.0)
3.9 3.3 3.0 (1.0 – 12.0)
1.1 0.3 1.0 (1.0 – 2.0)
1* 1*
2.0 2.3 1.0 (1.0 – 12.0)
3722.7 1528.8 3600 (1800 –7200) 52.1 23.3 51.4 (17.9 –117.5)
3181.0 931.1 3600 (1800 –4500) 41.8 12.8 44.0 (18.8–64.3)
18 2600.0 867.0 2700 (1800 –4500) 36.1 15.3 32.0 (17.9 –68.2) 44.4% (10)
3 2550.0 259.8 2700 (2250 –2700) 31.2 13.5 25.9 (21.1 –46.5) 0.0% (0)
68.2% 18.2% 13.6% 0.0% 86.4%
(15) (4) (3) (0) (19)
2936.8 840.1 2700 (1800 – 4500) 31.44 14.60 25.30 (11.84–70.31) 0
21 2592.9 803.8 2700 (1800 –4500) 35.4 14.8 30.6 (17.9 –68.2) 38.1% (8)
N/A
96.6% (28) 3.4% (1) 0.0% (0) 0.0% (0) 100.0% (29)
94.7% 0.0% 5.3% 0.0% 94.7%
3285.0 1160.3 3600 (1800 –7200) 42.1 18.8 43.0 (11.8 –117.5)
(18) (0) (1) (0) (18)
87.1% 7.1% 5.7% 0.0% 94.2%
(61) (5) (4) (0) (66)
*All episodes were treated with a single infusion. All doses stated are IU of VWF:RCo.
Table 5. Adjusted incremental recovery (IVR) following first treatment dose for surgery or bleeding. FVIII:C IVR (IU dL Type 1 (n = 9) Mean (95% CI) Type 2 (n = 23) Mean (95% CI) Type 3 (n = 5) Mean (95% CI) All patients (n = 37) Mean (95% CI)
1
per IU kg 1)
VWF:Ag IVR (IU dL
per IU kg 1)
VWF:RCo IVR (IU dL
1
per IU kg 1)
1.85 (1.35 –2.36)
1.99 (1.57 –2.41)
1.53 (1.08 –1.98)
2.32 (2.07 –2.56)
2.51 (2.20 –2.81)
1.94 (1.74 –2.14)
2.60 (1.75 –3.45)
2.58 (1.72 –3.43)
2.20 (1.52 –2.88)
2.24 (2.03 –2.45)
2.39 (2.16 –2.62)
1.88 (1.70 –2.06)
ing some form of medical treatment, although none required hospitalization. Both patients with serious adverse events were switched to their previous VWF/FVIII concentrate without re-challenge. Three patients with non-serious adverse events were rechallenged without further reaction. Two switched back to their previous VWF/FVIII containing concentrate at patient request. All adverse events were reported to Octapharma(UK) as part of ongoing pharmacovigilance. There was no treatment failure, thrombosis, infection or inhibitory VWF allo-antibodies recorded. © 2014 John Wiley & Sons Ltd
1
Discussion Usage of Wilate in four prospective phase II and III studies for the treatment of surgery or bleeding in patients > 12 years has been described [8,13]. In these, efficacy was rated excellent or good in 96% of surgical procedures (32 patients, 57 surgeries) and 96% of spontaneous or post-traumatic bleeding episodes (44 patients, 1095 episodes). Efficacy described to date for Wilateâ is similar to that of other VWF/ FVIII containing concentrates [14]. We present a large single centre experience (3 972 150 IU of Wilateâ) in Haemophilia (2014), 20, 846--853
Haemophilia (2014), 20, 846–853
DOI: 10.1111/hae.12496
ORIGINAL ARTICLE von Willebrand disease
Safety and efficacy of a von Willebrand factor/factor VIII concentrate (Wilateâ): a single centre experience P . B A T T Y , Y . - H . C H E N , L . B O W L E S , D . P . H A R T , S . P L A T T O N and K . J . P A S I The Royal London Hospital Haemophilia Centre, Barts and The London School of Medicine and Dentistry, The Royal London Hospital, Whitechapel, London E1 1BB, UK
Summary. von Willebrand disease (VWD) is the commonest inherited bleeding disorder. Management of major surgery or bleeding often requires treatment with a plasma-derived (pd) VWF/FVIII containing concentrate. Wilateâ is a dual-virally inactivated pdconcentrate, produced specifically for the treatment of VWD, containing physiological (1:1) ratios of VWF: FVIII. We reviewed efficacy and safety of Wilateâ usage (2007–2012) at our centre including 2 years following product switching the majority of patients. Clinical and laboratory data of all adult patients treated with Wilateâ during the study period were evaluated. Fifty four patients used 3 972 150 IU of Wilateâ (1378 infusions) between 1/3/07 and 1/5/12. Efficacy was rated as being excellent or good in 94% of surgical episodes (n = 70; 34 patients) and 98% of bleeding/traumatic episodes (n = 46; 25 patients). Eight patients (2 636 100 IU) were managed on home
treatment regimens. Two patients switched to Wilateâ prophylaxis in the evaluation period, demonstrating similar efficacy to a previous product. Incremental recoveries (n = 37) were 2.24 IU dL 1 per IU kg 1 for FVIII:C, 2.39 IU dL 1 per IU kg 1 for VWF:Ag and 1.88 IU dL 1 per IU kg 1 for VWF:RCo. Six adverse events occurred in six patients (11.1% patients) over 1378 infusions (0.44%). Half of these were retrospectively felt to be infusion speed related. No notable accumulation of FVIII was seen in patients treated for ≥3 days. There was no treatment failure, thrombosis, transfusion transmitted infection or inhibitory VWF antibodies seen. Our findings confirm safety and efficacy of Wilateâ in an adult VWD population with lack of notable FVIII accumulation.
Introduction
RCo to VWF:Ag and FVIII to VWF, as a result of the manufacturing and viral inactivation processes [5]. Theoretically, the ideal concentrate would have preservation of the structure and function of VWF and FVIII, whilst maintaining the native 1:1 ratio to keep in-vivo pharmacokinetic parameters physiological. From a clinical perspective, however, the key factors in the selection of VWF/FVIII concentrates are efficacy and safety (minimizing risk of viral transmission and inhibitor occurrence) [5]. A pd-albumin free high purity freeze dried VWF/ FVIII containing concentrate, Wilateâ (OctapharmaAG, Lachen, Switzerland) has been available for usage in the United Kingdom since 2007. Plasma is sourced from donors in countries with low variant Creutzfeldt-Jakob disease (vCJD) rates and undergoes two viral inactivation steps. This involves solvent detergent (SD) treatment and terminal dry heating (+100°C for 120 min) of the lyophilized product (PermaHeatTM) to inactivate enveloped and non-enveloped viruses [6]. Wilateâ displays VWF triplet structures
von Willebrand disease (VWD) is the commonest inherited bleeding disorder in the United Kingdom affecting 9377 individuals [1,2]. In patients who are unresponsive to desmopressin (1-deamino-8-D-arginine vasopressin; DDAVP), bleeding following surgery, trauma or spontaneous requires treatment with a von Willebrand factor/Factor VIII (VWF/FVIII) containing concentrate [3]. Although recombinant VWF products are undergoing clinical trials, all currently available concentrates are plasma derived (pd) [4]. Of these concentrates, differences exist in their VWF structure (multimer composition) and ratios of VWF: Correspondence: Professor K John Pasi, Professor of Haemostasis and Thrombosis, The Royal London Hospital Haemophilia Centre, Haematology Day Unit, The Royal London Hospital, Whitechapel, London E1 1BB, UK. Tel.: 0203 594 1869; fax: 0203 594 1859; e-mail: [email protected]
Keywords: bleeding, efficacy, plasma concentrate, prophylaxis, surgery, von Willebrand disease
Accepted after revision 12 June 2014 846
© 2014 John Wiley & Sons Ltd
WILATE REAL-LIFE ADULT AUDIT AND EVALUATION
We attempted to control for this by defining and using strict efficacy evaluation criteria prior to data analysis. In order to strictly apply these criteria it was necessary to exclude a small number of treatment episodes with insufficient clinical information (1.4% of total usage). However, use of a set of strict criteria did allow us to more objectively compare differing clinical events. To further evaluate the efficacy of any new concentrate a prospective study with rigid criteria is preferable. To this end the international WONDERS study a prospective, open-label, multi-centre, phase III trial of efficacy and safety of Wilateâ in 41 subjects with inherited VWD undergo surgery is ongoing. In summary, our data from a real life, uncontrolled non-study setting confirm that Wilateâ is safe and efficacious. Our efficacy data are comparable to those reported in previous clinical trials of this VWF/FVIII concentrate.
References 1 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood 1987; 69: 454–9. 2 United Kingdom Haemophilia Centres Doctors’ Organisation. Bleeding disorder statistics for April 2011 to March 2012: a report from the national haemophilia database. 1–87. 2012. 3 Pasi KJ, Collins PW, Keeling DM et al. Management of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors’ Organization. Haemophilia 2004; 10: 218–31. 4 Mannucci PM, Kempton C, Millar C et al. Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial. Blood 2013; 122: 648–57. 5 Keeling D, Tait C, Makris M. Guideline on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. A United Kingdom Haemophilia Center Doctors’ Organisation (UKHCDO) guideline approved by the British Committee for Standards in Haematology. Haemophilia 2008; 14: 671–84. 6 Stadler M, Gruber G, Kannicht C et al. Characterisation of a novel high-purity, double virus inactivated von Willebrand Factor and Factor VIII concentrate (Wilate). Biologicals 2006; 34: 281–8. 7 Kessler CM, Friedman K, Schwartz BA, Gill JC, Powell JS. The pharmacokinetic diversity of two von Willebrand factor (VWF)/factor VIII (FVIII) concentrates in subjects with congenital von Willebrand disease. Results from a prospective,
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Acknowledgements We would like to acknowledge the assistance of Heather Williams (Operational Services Manager), for her assistance in compiling the database of treatment issues.
Author contributions PB wrote the first draft paper. DPH, LB and KJP treated the patients. KJP and PB designed the study. SP performed all testing of samples. PB and YHC conducted all data collection and analysis. All authors reviewed and critically edited the manuscript.
Disclosures PB has received an unrestricted research fellowship and travel grants from Octapharma. DPH has received honoraria for lectures and travel grants from Octapharma. KJP has been part of Advisory Boards for Octapharma, received honoraria for lectures and travel grants. YHC, LB and SP state that they had no interests which might be perceived as posing a conflict or bias.
randomised crossover study. Thromb Haemost 2011; 106: 279–88. Windyga J, von Depka-Prondzinski M. Efficacy and safety of a new generation von Willebrand factor/factor VIII concentrate (Wilate(R)) in the management of perioperative haemostasis in von Willebrand disease patients undergoing surgery. Thromb Haemost 2011; 105: 1072–9. Laffan M, Brown SA, Collins PW et al. The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors’ Organization. Haemophilia 2004; 10: 199–217. Ragni MV, Pasi KJ, White GC, Giangrande PL, Courter SG, Tubridy KL. Use of recombinant factor IX in subjects with haemophilia B undergoing surgery. Haemophilia 2002; 8: 91–7. Lillicrap D, Poon MC, Walker I, Xie F, Schwartz BA. Efficacy and safety of the factor VIII/von Willebrand factor concentrate, haemate-P/humate-P: ristocetin cofactor unit dosing in patients with von Willebrand disease. Thromb Haemost 2002; 87: 224– 30. Matthews JN, Altman DG, Campbell MJ, Royston P. Analysis of serial measurements in medical research. BMJ 1990; 300: 230– 5. Berntorp E, Windyga J. Treatment and prevention of acute bleedings in von Willebrand disease–efficacy and safety of Wilate, a new generation von Willebrand factor/ factor VIII concentrate. Haemophilia 2009; 15: 122–30. Federici AB. Management of von Willebrand disease with factor VIII/von Willebrand factor concentrates: results from current studies and surveys. Blood Coagul Fibrinolysis 2005; 16(Suppl 1): S17–21.
15 Franchini M, Makris M, Santagostino E, Coppola A, Mannucci PM. Non-thrombotic-, non-inhibitor-associated adverse reactions to coagulation factor concentrates for treatment of patients with hemophilia and von Willebrand’s disease: a systematic review of prospective studies. Haemophilia 2012; 18: e164–72. 16 Makris M, Colvin B, Gupta V, Shields ML, Smith MP. Venous thrombosis following the use of intermediate purity FVIII concentrate to treat patients with von Willebrand’s disease. Thromb Haemost 2002; 88: 387–8. 17 Mannucci PM. Venous thromboembolism in von Willebrand disease. Thromb Haemost 2002; 88: 378–9. 18 Coppola A, Franchini M, Makris M, Santagostino E, Di MG, Mannucci PM. Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies. Haemophilia 2012; 18: e173–87. 19 Mannucci PM. Treatment of von Willebrand’s Disease. N Engl J Med 2004; 351: 683–94. 20 Raquet E, Stockschlader M, Dickneite G. Repeated infusions of VWF/FVIII concentrate: impact of VWF:FVIII ratio on FVIII trough and peak levels in a rabbit model. Haemophilia 2011; 17: 808–14. 21 Kessler CM, Windyga J, Schwartz BA, Knaub S. Use of objective efficacy criteria for evaluation of von Willebrand factor/ factor VIII concentrates. Blood Coagul Fibrinolysis 2012; 23: 262–7. 22 Berntorp E, Fuchs B, Makris M et al. Third Aland islands conference on von Willebrand disease, 26-28 September 2012: meeting report. Haemophilia 2013; 19(Suppl 3): 1–18.
Haemophilia (2014), 20, 846--853
