Efficacy and Safety of High-Intermediate-Purity VWF/FVIII Concentrates Given Repeatedly to Severe Patients with Von Willebrand Disease: An Italian Cohort Study on 32 Intensively Treated Cases.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4060-4060
Author(s):  
Augusto B. Federici ◽  
Belinda J. Cedron ◽  
Barbara Scimeca ◽  
Maria T. Canciani ◽  
Pier M. Mannucci
Keyword(s):  
Cohort Study ◽  
Side Effects ◽  
Von Willebrand Disease ◽  
Severe Bleeding ◽  
Efficacy And Safety ◽  
Inclusion Criteria ◽  
Mean Values ◽  
On Demand ◽  
Post Infusion

Abstract Background and Objectives. Patients with severe forms of von Willebrand’s disease (VWD) may have frequent episodes of mucocutaneous bleeding and also of hemarthrosis or hematomas. They are usually unresponsive to desmopressin (DDAVP) and must be treated with high- or intermediate-purity VWF/FVIII concentrates (VWFc). Due to the different VWF/FVIII composition of the VWFc, timing and dosage of infusions are still not completely standardized. Aim of this study was to evaluate the efficacy and safety of repeated infusions of VWFc given on demand, for bleeds and surgery, and on secondary long-term prophylaxis to our cohort of severe VWD patients. Design and Methods. This is a cohort study on 473 VWD patients regularly followed up at our Center for more than two years. Inclusion criteria: patients proven to be unresponsive to DDAVP and treated with VWFc with > 25 exposure days (ED)/year (> 50,000 FVIII U/year) during the previous 2 years. All patients were characterized by a bleeding severity score derived from a detailed history of 11 symptoms. Since VWFc available in Italy are still labeled in FVIII IU, patients were given 60 or 40 FVIII IU/Kg of high- (Alphanate, Fanhdi) or intermediate-purity (Haemate-P) in case of on demand or long term prophylaxis, respectively. Efficacy of VWFc used on demand versus prophylaxis (every other day or twice a week) regimens was based on resolution/reduction of bleeds and rated as excellent/good versus partial/poor clinical responses. Safety was measured by monitoring side effects and pre-post infusion FVIII levels during the first two weeks of treatment. Results. 32/473 (7%) patients only met the inclusion criteria. They were severe (bleeding scores >15; VWF:RCo baseline levels <10 U/dL), with confirmed VWD diagnosis (case n) of types 3 (7), 2A (8), 2B (6), 2M (5) and 1 (6). High (n= 9) and intermediate (n=12) VWFc were used on demand therapy in 21 VWD cases. Prophylaxis was started because of recurrent GI bleeds in 7 patients with VWD types 3 (n=1), 2A (n=4), 2M (n=1) and 1 (n=1) and for joint bleeds only in VWD type 3 (n= 4). Total amounts of FVIII:C Units (mean values with ranges ×1000 U/year) transfused were: on demand = 66.4 (51–123); secondary prophylaxis = 297 (117–720). Clinical response was excellent/good in >95%, >85%, >90% surgeries, bleeds, prophylaxis, respectively. Prophylaxis could stop bleeding in 8 patients and largely reduced hospitalization for PRBC transfusions in the remaining 3. As far as safety, FVIII levels were always <180 U/dL during bleeds and prophylaxis and <210 U/dL during surgeries in all intensively treated VWD. No side effects, including thrombosis, were observed Interpretations and Conclusions. High- and intermediate-purity VWFc are effective and safe in severe forms of VWD also in patients exposed to intensive regimens of therapy, on demand or on prophylaxis. The use of pre-post infusion levels of FVIII is very useful to prevent unnecessary treatment with VWFc. Cost-effectiveness of prophylaxis regimens versus on demand therapy should be further investigated in large prospective studies.

Secondary Long-Term Prophylaxis in Severe Patients with von Willebrand’s Disease: An Italian Cohort Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1782-1782 ◽  
Author(s):  
Augusto B. Federici ◽  
Francesca Gianniello ◽  
Maria T. Canciani ◽  
Pier M. Mannucci
Keyword(s):  
Cohort Study ◽  
Side Effects ◽  
Von Willebrand's Disease ◽  
Packed Red Blood Cells ◽  
Von Willebrand’S Disease ◽  
On Demand ◽  
Before And After ◽  
Type 3 ◽  
Design And Methods

Abstract Background and Objectives. Patients with severe forms of von Willebrand’s disease (VWD) may have frequent episodes of mucocutaneous bleeding and also of hemarthrosis or hematomas. However, little retrospective or prospective data on secondary long term prophylaxis in VWD are available. Aim of this study was to evaluate the efficacy and safety of fixed regimens of prophylaxis with factor VIII/VWF concentrates in our cohort of VWD patients with recurrent joint and gastrointestinal (GI) bleeds. Design and Methods. This is a cohort study on 452 VWD patients regularly followed up at our Center for at least three years. 89/452 cases (20%) were treated with FVIII/VWF concentrates during the last two years because of one or more bleedings and 11/89 (12%) were included in a long term prophylaxis program because of frequent recurrence of bleeds at the same sites. All patients were characterized by a bleeding severity score derived from a detailed history of 11 symptoms. Since concentrates available in Italy are still labelled in FVIII IU, patients were given 40 FVIII IU/Kg of high- (Alphanate, Fanhdi) or intermediate-purity (Haemate-P) concentrates, two times a week (joint bleeds) or every other day (GI bleeds) to maintain FVIII/VWF levels higher than baseline during prophylaxis. Effectiveness of prophylaxis was based on resolution/reduction of bleeding as well as on numbers of transfused packed red blood cells (PRBC) and days of hospitalization. Safety was measured by monitoring side effects and FVIII levels before and after every injection during the first three weeks of prophylaxis. Results. All the 11 patients were severe, as shown by high bleeding scores (> 20) and VWF:RCo baseline levels <10 U/dL. Prophylaxis was started because of GI bleeds in 7 patients with VWD type 3 (n=1), 2A (n=4), 2M (n=1) and 1 (n=1) and for joint bleeds only in VWD type 3 (n= 4). Prophylaxis could stop bleeding in 8 patients and largely reduced hospitalization for PRBC transfusions in the remaining 3. When prophylaxis was compared with previous on demand regimen in all 11 cases, the annual total FVIII IU (x 1000) of concentrate (a) as well as number of PRBC used (b) and days of hospitalization (c) were significantly reduced (mean ± SD, with * p < 0.01): a * = 239±207 versus 385±247; b* = 9±11 versus 3±4; c* = 18±13 versus 4±3. As far as safety, FVIII levels were always <180 U/dL in all VWD and no side effects, including thrombosis, were observed. Interpretations and Conclusions. Secondary long-term prophylaxis by high-and intermediate purity FVIII/VWF concentrates is effective and safe in severe forms of VWD. Cost-effectiveness of these prophylaxis regimens versus on demand therapy should be further investigated in large prospective studies.

Safety and Effectiveness of Desmopressin for the Management of Delivery and Major Surgery in Patients with Mild-Moderate Von Willebrand Disease: Final Analysis of the Prodeswil Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 759-759
Author(s):  
Augusto Bramante Federici ◽  
Giancarlo Castaman ◽  
Alfonso Iorio ◽  
Emily Oliovecchio ◽  
Prodeswil Investigators
Keyword(s):  
Side Effects ◽  
Clinical Efficacy ◽  
Oral Surgery ◽  
Biological Response ◽  
Von Willebrand Disease ◽  
Major Surgery ◽  
Efficacy And Safety ◽  
Inclusion Criteria ◽  
Bleeding Episodes ◽  
Von Willebrand

Abstract Introduction. Despite the fact that desmopressin (DDAVP) is considered the treatment of choice in the majority of patients with inherited von Willebrand disease (VWD), there are still open questions about the efficacy and safety of the use of DDAVP to manage recurrent bleeding episodes, delivery and major surgery. In fact, to avoid tachyphylaxis and possible side effects with repeated DDAVP injections, VWF concentrates are usually preferred to manage delivery and major surgery also in VWD patients proven to be DDAVP-responsive. No prospective data have been reported so far to correlate biological response with DDAVP clinical efficacy in VWD and guide clinical practice. Design, aims and methods. ProDesWilis an investigator-driven Pro spective study on D esmopressin e fficacy and s afety of patients with inherited von Wil lebrand disease assessed at enrolment for DDAVP biological response during a test-infusion. Inclusion criteria: VWD diagnosis without any age restriction according to bleeding score >4, VWF activity levels <45U/dL, and at least another affected member in the family. DDAVP Biological Response: VWD were classified as complete, partial or no-responders as previously reported (Blood 2008;111:3531). Treatment regimens: DDAVP given intravenously or subcutaneously (0.3 ug/Kg) or by nasal spray (4 ug/Kg) according to preparations available in different countries with or without standard doses of anti-fibrinolytic agents (Epsilon-amino-caproic acid, EACA or tranexamic acid, TA). In case of major surgery, DDAVP was used together with TA using a 3dayOn-4dayOff-3dayOn schedule. DDAVP efficacy-safety evaluated with criteria currently used for VWF concentrates, with poor efficacy defined when VWF concentrates were needed. Patients were prospectively followed up for 24 months by ProDesWil Investigators who reported detailed information about DDAVP therapy used for bleeds, deliveries, oral and minor/major surgeries Results. 268 patients were enrolled in this 24-month prospective study. DDAVP-biological response: 225/268 (85%) patients met inclusion criteria as VWD1(n=184), VWD1C (n=14), VWD2A(n=15), VWD2M(n=12). The 14 VWD1C with accelerated clearance carried C1130F and R1205H mutations. DDAVP biological response was complete, partial and absent in 89%, 10% and 1% of all VWD. DDAVP clinical efficacy and safety: during the 24-month follow-up 84/225 (37.3%) received DDAVP for bleeding episodes (n=104), oral surgeries (n=33), deliveries (n=12), other minor/major surgeries (n=25). Total DDAVP injections were 652 with median, range/episode during bleeds (2,1-12), oral surgeries (1,1-10), deliveries (3,1-13), minor/major surgeries (3.6,1-16). Clinical efficacy was excellent/good in bleeds (93.3%), oral surgery (100%), deliveries (91.7%), minor/major surgeries (92.3%). All VWD treated for oral surgery with (75%) and without (25%) EACA/TA had excelled/good outcomes. Efficacy was rated excellent/good in 96/104 bleeds, with 8 episodes rated poor during menorrhagia (n=4) in 2 VWD1 and 2 VWD2A, during nose (n=2) and gastrointestinal (n=2) bleeds in 3 VWD2A and 1 VWD1C. 11/12 deliveries had excellent/good outcome with poor response in only one VWD1C who required VWF concentrates after caesarean section. All the 11/25 cases with minor surgeries had excellent outcomes. Among the 14/25 major surgeries [abdominal (n=5), hysterectomy (n=3), tonsillectomy (n=3), orthopaedic and others (n=3)] 2 episodes (partial resection of kidney in VWD2A and tonsillectomy in VWD1) were rated poor. Side effects (16 cases) were mainly minor (flushing, headache, tachycardia) with water retention reported only in 2 patients who received >12 doses of DDAVP for delivery or major surgery. Conclusions: DDAVP is an effective, safe and cheap treatment for managing patients with mild-moderate VWD who showed complete biological response to this drug. Therefore, DDAVP must be always recommended as first line therapy in responsive VWD not only in bleeds and oral surgery but also in deliveries and major surgeries. On the other hands, DDAVP should be used with caution in VWD2A and VWD1 with partial response. The additional use of EACA/TA should be considered especially when DDAVP is required for more than 4 days. Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficacy and safety of leflunomide versus cyclophosphamide for initial-onset Takayasu arteritis: a prospective cohort study

2020 ◽  
Vol 12 ◽  
pp. 1759720X2093011
Author(s):  
Sun Ying ◽  
Cui Xiaomeng ◽  
Dai Xiaomin ◽  
Lin Jiang ◽  
Lv Peng ◽  
...  
Keyword(s):  
Cohort Study ◽  
Side Effects ◽  
Treatment Response ◽  
Takayasu Arteritis ◽  
Propensity Scores ◽  
Reproductive Toxicity ◽  
Efficacy And Safety ◽  
Effectiveness Rate ◽  
Initial Onset ◽  
Active Disease

Background: Leflunomide (LEF) has been considered as an alternative treatment for Takayasu arteritis (TA); however, data on its efficacy are still scanty. Objective: To investigate the efficacy and safety of LEF versus cyclophosphamide (CYC) for initial-onset TA. Methods: Initial-onset TA patients with active disease were enrolled in this research. Patients enrolled from 1 January 2009 to 31 December 2015 were treated with glucocorticoids and CYC, while patients enrolled from 1 January 2016 to 31 October 2018 received glucocorticoids and LEF. Treatment response including complete remission (CR), partial remission (PR), and effectiveness rate (ER) and side effects were evaluated at 6 and 12 months. Results and conclusion: In total, 92 patients were enrolled. A total of 47 patients were treated with LEF, while 45 patients were treated with CYC. The CR and ER rates were 75.55%, and 88.89% at 6 months, and 85.37% and 95.12% at 12 months in the LEF group. The CR and ER rates were 39.02% and 70.73% at 6 months, and 56.41% and 82.05% at 12 months in the CYC group. The CR rate was significantly higher in the LEF group than in the CYC group both at 6 months (75.61% versus 38.24%, p < 0.01) and 12 months (77.42% versus 53.33%, p < 0.05) after adjustment for propensity scores. The incidence of side effects in the LEF group was much lower than that in the CYC group (21.28% versus 44.44%). In conclusion, LEF provided a better treatment response, along with lower reproductive toxicity, compared with CYC in initial-onset TA.

Efficacy and safety of percutaneous administration of dihydrotestosterone in children of different genetic backgrounds with micropenis

2017 ◽  
Vol 30 (12) ◽  
Author(s):  
Dan Xu ◽  
Liangsheng Lu ◽  
Li Xi ◽  
Ruoqian Cheng ◽  
Zhou Pei ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Side Effects ◽  
Low Doses ◽  
Efficacy And Safety ◽  
Short Term ◽  
Term Study ◽  
Long Term Study ◽  
Percutaneous Administration ◽  
Open Prospective Study

AbstractBackground:Exogenous androgen supplement is an optional treatment for micropenis; however, its use in childhood is controversial due to potential side effects.Methods:Twenty-three children (mean age: 4.07±3.4 years) with micropenis of unknown causes harboring the 46,XY karyotype were recruited in an open prospective study. Androgen receptor (Results:Two patients were found withConclusions:Short term and local application of DHT at low doses in patients with micropenis could accelerate penile growth effectively without evident side effects; however, precautions still need be taken due to the paucity of long term study and the lack of ideal DHT dosage.

Clinical Efficacy and Safety Versus Biological Response of Desmopressin (DDAVP) In Inherited Von Willebrand Disease (VWD) Types 1 and 2: Initial Results From the International Study Group on DDAVP In VWD In a Cohort of 229 Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 238-238
Author(s):  
Augusto B. Federici ◽  
Alfonso Iorio ◽  
Giancarlo Castaman
Keyword(s):  
Clinical Efficacy ◽  
Demographic Data ◽  
Biological Response ◽  
Working Party ◽  
Von Willebrand Disease ◽  
Efficacy And Safety ◽  
Inclusion Criteria ◽  
Excessive Bleeding ◽  
Baseline Levels ◽  
Von Willebrand

Abstract Abstract 238 Background: Desmopressin (DDAVP) is the treatment of choice for most patients with mild-moderate forms of von Willebrand Disease (VWD) because it can induce the release of von Willebrand Factor (VWF) from cellular compartments. However, despite the widespread use of DDAVP since 1977, there are only a few prospective clinical trials aimed at determining benefits and limits of this approach. Aims and design of the study: To correlate efficacy and safety with biological response of DDAVP in a large cohort of VWD1 and VWD2 patients followed-up for 24 months in a prospective observational study organized on behalf of the Working Party on DDAVP in VWD of the ISTH-SSC on VWF and of Italian Association of Hemophilia Centers (AICE). The study is registered at the EMEA with number EudraCT-2005-004496-38. Patients and Methods: VWD patients were enrolled after obtaining Ethical approval from local IRB. Inclusion criteria: inherited VWD without any age restriction, with previous diagnosis of VWD1 and VWD2 according to ISTH recommendations. Biological response: At enrollment patients were exposed to 0.3 ug/kg DDAVP intravenous injection and to blood withdrawal for measuring VWF/FVIII activities before and after 0.5, 1, 2 and 4 hours. Complete: both VWF:RCo and FVIII:C >50 IU/dL at 2 hours; partial: VWF:RCo or FVIII:C <50 IU/dL but increased at least 3-fold; absent: neither criterion. Clinical Response. Excellent: no excessive bleeding; Good: excess bleeding without need for VWF concentrate; Poor: excess bleeding with need for VWF concentrate. Statistical analyses were performed only on confirmed patients after the blind and independent evaluation by 2 members of the Steering Committee on these criteria: VWD=baseline levels of VWF:RCo <55 U/dL; VWD2= baseline VWF:RCo/Ag ratio≤ 0.6; VWD1 accelerated clearance: rapid increase of VWF:RCo/FVIII after 0.5–1 hrs with return to baseline levels after 2–4 hrs. Results: 229/268 (85%) patients enrolled at 13 participating Centers in Argentina, Brazil, Canada, Germany, Italy and Hungary were found to meet the inclusion criteria. Demographic data and lab tests (mean+SD) at baseline were as follows: Among VWD2, VWD2A(n=15), VWD2B(n=1), VWD2M(n=12), VWD2N(n=3) were identified. Biological response was complete, partial and absent in 89%, 10% and 1% of VWD and correlated with baseline levels of VWF:RCo<30 U/dL (Fisher's exact =0.001). Among VWD1, those (n=15) with C1130F and R1205H mutations showed accelerated clearance. During the 24-month follow-up, 62/86 (72%) patients received >1 injection of DDAVP for bleedings (n=102), deliveries (n=13), dental extractions (n=27), minor/major surgeries (n=46). Total number of injections was 652 with median, range/episode during bleedings (2,1-12), deliveries (3,1-3), dental extractions (1,1-6), surgeries (3.6,1-11). Clinical efficacy was excellent/good in bleedings (92%), deliveries (85%), dental extractions (100%), surgeries (91%). Poor efficacy was observed in 6 cases with VWD2A (n=4) during GI bleedings (n=3) or abdominal surgery (n=1) and VWD1 (n=2) during deliveries and surgery. Side effects observed in 16 patients were mainly minor, such as headache, facial flushing and tachycardia; water retention was reported in 2 cases (1 delivery, 1 surgery) only after >6 injections of the drug. Conclusions: Based on the results of this prospective clinical trial, we confirm that DDAVP is an effective and safe drug at low costs for managing patients with VWD1 and VWD2 once tested for their biological response: therefore it should be always considered as the first approach during bleedings and major/minor surgeries in responsive VWD patients. Disclosures: Federici: CSL Behring: Honoraria, Research Funding.

scholarly journals Cost-Effectiveness of Long-Term Prophylaxis Versus on-Demand Treatment with Von Willebrand Factor Concentrate in Severe Inherited Von Willebrand Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-5
Author(s):  
Anushka Bhaskar ◽  
Nathan T. Connell
Keyword(s):  
Von Willebrand Disease ◽  
Base Case ◽  
Case Scenario ◽  
On Demand ◽  
Bleeding Episodes ◽  
The Cost ◽  
Von Willebrand ◽  
Mean Cost ◽  
Prophylaxis Strategy

Introduction: von Willebrand Disease (VWD) is the most common inherited bleeding disorder with significant variability in clinical phenotype. Patients with the most severe forms of VWD suffer from frequent bleeding complications including mucosal bleeding, gastrointestinal hemorrhage, hemarthrosis, and muscle hematomas. Long-term prophylaxis with von Willebrand factor (VWF) concentrate has been shown to reduce the frequency of bleeding episodes, but higher costs associated with regular VWF concentrate administration remains a barrier to access. Methods: We constructed a Markov state transition model to compare the cost-effectiveness of on-demand treatment (ODT) with long-term prophylaxis (PRO) from a United States (US) societal perspective with costs inflated to 2020 US dollars using the Consumer Price Index. Cycle-length was one month with a one-year time horizon and during each cycle, patients could experience either major (hemarthrosis, gastrointestinal bleeding, muscle hematoma), minor (epistaxis, other mucosal bleeding), or no bleeding. Model inputs for event probabilities, costs, and utility were obtained from previously published literature; while there are no specific utility data for these treatment strategies in VWD patients, we assumed they would be similar to published age-specific utilities used in hemophilia analyses and performed sensitivity analyses to assess these assumptions. The base case scenario was modeled on a 70 kg patient with severe VWD receiving plasma-derived VWF concentrate. In the PRO strategy, patients received 60 units/kg every 3 days. ODT patients were only treated for specific bleeding events (minor bleeding: 60 units/kg every 12 hours for 3 days in the outpatient setting; major bleeding: VWF concentrate 60 units/kg every 12 hours for 5 days in the hospital). Microsimulation of 1000 trials was performed using to calculate mean quality-adjusted life-years (QALYs) and costs associated with the two treatment strategies. TreeAge Pro 2017 (TreeAge Software, Williamstown, MA) was used to construct the model and perform analyses. Results: In the base-case scenario using plasma-derived VWF concentrate, on-demand treatment resulted in a mean cost of US$1,140,586 (± $65,215) generating 0.52 QALYs (±0.01) while the prophylaxis strategy resulted in a mean cost of US$918,329 (± $94,983) generating 0.8 QALYs (±0.04). The microsimulation was repeated to reflect the cost of recombinant VWF concentrate for prophylaxis and a single dose of recombinant factor VIII. Using recombinant VWF, on-demand treatment resulted in a mean cost of US$1,568,005 (± $94206) and generated 0.52 QALYs (±0.01) while the prophylaxis strategy resulted in a mean cost of US$1,343,715 (± $124,974) and generated 0.8 QALYs (±0.04). One-way sensitivity analysis of model inputs showed this result to be robust, as prophylaxis remained the preferred strategy at a willingness to pay (WTP) threshold of US$150,000/QALY for both plasma-derived and recombinant therapies (Figure). Conclusions: With greater effectiveness and lower total societal health care costs, the prophylaxis strategy dominated the on-demand treatment strategy. While the cost of long-term prophylaxis is primarily due to the high cost of VWF concentrate every 3 days, this strategy results in significantly fewer bleeding episodes per year resulting in more QALYs. Our findings suggest that when compared to on-demand treatment, long-term prophylaxis with VWF concentrate is a cost-effective strategy in patients with severe forms of VWD, which helps to avoid expensive hospitalizations and decreased quality of life due to bleeding episodes and their complications. Figure 1 Disclosures No relevant conflicts of interest to declare.

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