Modeling Minimally-Effective FVIII Trough Levels in Hemophilia a Patients on PK-Guided Prophylaxis

Abstract Background: The aim of FVIII prophylaxis in Hemophilia A management is the reduction of risk for any bleed events (BE) in order to preserve long-term joint health and QOL. One proposed measure of the ideal prophylactic outcome is the virtual elimination of all BE not associated with trauma and/or of spontaneous etiology. Given the wide inter-patient variance in PK parameters, long-term prophylaxis outcomes and costs of therapy, PK-guided dosing has become an attractive approach to add more precision to dosing decisions and improve outcomes. Knowledge of the appropriate FVIII trough target for each individual patient to achieve a bleed-free outcome is needed however to design the ideal personalized PK-guided regimen. Objective: Model individual FVIII trough targets for achieving ideal outcomes in hemophilia A patients prescribed PK-guided prophylaxis every third day. Methods: FVIII infusion and BE records, and PK parameters from each subject participating in the 12-month PK-guided dosing arm of the randomized rAHF-PFM prophylaxis study (Valentino et al, 2012) were used to determine the predicted FVIII level at time of each BE. Median and maximum predicted FVIII values at time of spontaneous/non-trauma BE for all sites, and for joint and non-joint sites were estimated per subject. Number (%) of subjects with any spontaneous/non-trauma BE that occurred at predicted FVIII levels (maximum value and/or median value for those with more than one bleed) above and below specific theoretical FVIII trough values was modeled. Results: Of 34 subjects on PK-guided prophylaxis with rAHF-PFM targeting 1% trough every third day, 19 (56%) had no spontaneous BE during one year observation at FVIII levels (median) above the theoretical trough value of 1%. The number (%) of subjects with no spontaneous/non-trauma BE at FVIII levels (median) above the theoretical trough value of 3%, 5%, 10%, 15% and 20% levels increased to 71%, 79%, 31 91%, 97%, and 100%, respectively (Figure 1). All 57 spontaneous/non-trauma BE occurred at predicted FVIII levels ≤30%. Figure 1 Figure 1. Conclusions: Evaluation of individual bleeding events and treatment records for this prophylaxis study population, most of which had pre-established hemophilic arthropathy, suggests that some patients may require higher trough targets to achieve an ideal outcome. Targeting a 1% trough FVIII level every 72 hrs was effective with 56% of subjects achieving a full year with no spontaneous BE. Modeling showed that targeting a 3 - 5% FVIII trough level would have led to more than 75% overall achieving zero spontaneous annual bleed rate (ABR), and that others may have benefitted from trough targets even as high as ≥15%. While this study could not necessarily account for or examine the role of differing levels of physical activity and/or arthropathy on levels of bleeding risk, modeling of FVIII levels post-infusion using individual PK parameters and infusion records along with the contemporaneous overlay of BE should provide valuable insight when designing the optimal, personalized prophylaxis regimen for patients. Valentino LA, Mamonov V, Hellmann A, et al. J Thromb Haemost 2012 Mar; 10(3): 359-67. Disclosures Spotts: Baxter Healthcare Corporation: Employment, Equity Ownership. Pipe:Baxter: Consultancy, Honoraria. Berntorp:Baxter: Honoraria. Collins:Baxter: Consultancy, Honoraria. Oh:Baxter: Employment. Valentino:Baxter: Consultancy, Employment, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biogen: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; GTC Biotherapeutics: Consultancy, Honoraria, Research Funding; rEVO Biologics: Consultancy, Honoraria; Inspiration Bioscience: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

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Real World Use of Extended Half-Life Products and the Impact on Bleeding Events and Joint Health in the United States

Blood ◽

10.1182/blood-2018-99-113956 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1195-1195 ◽

Cited By ~ 1

Author(s):

Lynn M. Malec ◽

Char M Witmer ◽

Julie Jaffray ◽

Peter A. Kouides ◽

Kristina M. Haley ◽

...

Keyword(s):

Board Of Directors ◽

Real World ◽

Research Funding ◽

Hemophilia A ◽

Advisory Board ◽

Hemophilia B ◽

Severe Hemophilia ◽

Bleeding Events ◽

On Demand ◽

Joint Health

Abstract Background : The hemophilia treatment landscape has evolved substantially in the last several years with the approval of extended half-life (EHL) products which reduce the burden of prophylaxis. Data reported from the American Thrombosis and Hemostasis Network (ATHN) as of June 2017 indicate that 21% of patients with moderate or severe hemophilia A, and 42% of patients with moderate or severe hemophilia B, receive prophylaxis utilizing an EHL. As new treatments become available and are adopted into practice, it is important to recognize the need for evaluation of efficacy, safety, and economic impact of their use outside of the clinical trial setting. We aimed to characterize the real world impact of EHL products by collecting detailed information on bleeding rates, joint health and quality of life amongst patients cared for at ATHN-affiliated Hemophilia Treatment Centers. We hypothesized that use of EHL products were utilized in at least 30% of patients and would lead to decreased ABRs and improved joint health. To date 67 of a planned 135 subjects have been enrolled, constituting this interim analysis. Methods:Subjects were recruited from seven U.S. Hemophilia Treatment Centers. Subjects with severe hemophilia A or B ≤ 30 years of age on prophylaxis or demand therapy were eligible for enrollment. Subjects excluded from study were those with a recent joint bleed (within the last 2 weeks) or those unwilling to complete all elements of the study. Data were collected during a one-time encounter concurrent with an appointment for clinical evaluation, including demographic information, treatment regimen, product type, frequency, location and severity of all bleeds, Hemophilia Joint Health Scores (HJHS), and Quality of life (QoL). Bleeding rates in subjects receiving prophylaxis were compared with those receiving on demand therapy by type treatment, EHL vs standard half-life (SHL), and by hemophilia type. Severity of bleeding events (mild, moderate, or severe) and HJHS were compared by prophylaxis groups. Results: A total of 67 patients were enrolled and eligible for analysis. This included 58 subjects with severe hemophilia A, and 9 subjects with severe hemophilia B. The mean age of the cohort was 15 years (median 12 years, IQR 8 - 21 years). For these patients whose race information was known, 89.1% were Caucasian, 3.3% African-American, 3.3% Asian, and 4.7% were of mixed or 'other' race. Eleven out of 61 (18.0%) subjects with known ethnicity were Hispanic. Among 59 patients whose treatment type were available, the majority were on prophylaxis (n=53; 89.8%) as compared to on demand therapy (n=6; 10.2%). The average annualized bleeding rate (ABR) was 2.8 amongst all individuals. As expected, the ABR was substantially lower in those receiving prophylaxis (ABR=1.0) as compared to on demand therapy (ABR=18.6) (p<0.001). Additionally, HJHS in those receiving prophylaxis was lower (mean HJHS= 3.9), meaning less evidence of joint damage, than in those receiving demand therapy (mean HJHS= 8.8) (p=0.162). For patients with severe hemophilia A, the ABR was lower in those individuals receiving EHL (ABR= 0.5) versus SHL (ABR= 1.5), although this did not reach statistical significance (p=0.136). All subjects with severe hemophilia B enrolled to date receive EHL products (n=9) therefore no comparison of ABR could be made between EHL and SHL products; the ABR in this group was 0.9. In patients with severe hemophilia A, there was a higher HJHS for those receiving EHL (mean HJHS= 7.0) versus those receiving SHL (mean HJHS = 2.1) (p=0.053). For patients with severe hemophilia B, all of whom received EHL, the mean HJHS was lower than in the hemophilia A cohort (mean HJHS=1.2). Conclusions: We report real-world bleeding events and joint health in patients with severe hemophilia A and B utilizing EHL and SHL products across a wide U.S. geographic distribution. As anticipated, there is substantial bleed reduction with prophylaxis versus on demand therapy. In our severe hemophilia A cohort, the ABR for patients receiving EHL products was similar to ABRs reported in clinical trials, suggesting clinical trial data may be reflective of real world use. Patients with severe hemophilia A receiving EHL for prophylaxis had a lower ABR than those receiving SHL, although the early impact is not reflected in the HJHS score. Longer follow-up will be necessary to determine the impact of EHL on HJHS. Disclosures Malec: Bioverativ: Research Funding; Bayer: Consultancy; Bioverativ: Consultancy; Shire: Consultancy. Jaffray:Octapharma: Consultancy; Bayer: Consultancy; CSL Behring: Consultancy, Research Funding. Kouides:UniQure: Other: DSMB; Octapharma: Research Funding. Sidonio:Octapharma: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; CSL Behring: Other: Advisory Board; Shire: Other: Advisory Board, Research Funding; Novo Nordisk: Other: Advisory Board; Kedrion: Research Funding; Biomarin: Other: Advisory Board; Grifols: Other: Advisory Board, Research Funding; Bioverativ: Other: Advisory Board, Research Funding; Uniqure: Other: Advisory Board. Abshire:CSL: Consultancy; Shire: Consultancy; Novo Nordisk: Other: DSMB. White:Asklepios: Other: Scientific Advisory Board; Novo Nordisk: Consultancy; Shire: Other: Physician Leadership Group; Bayer: Other: GRAC; Bioverativ: Other: DSMB; Biomarin: Other: DSMB; Invitrox: Other: Scientific Advisory Board; Pfizer: Equity Ownership. Ragni:CSL Behring: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; SPARK: Consultancy, Research Funding; Shire: Research Funding; Bioverativ: Consultancy, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Sangamo: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees.

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Bone and Joint Health Markers in Persons with Hemophilia A (PwHA) Treated with Emicizumab in HAVEN 3

Blood ◽

10.1182/blood-2019-123689 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 626-626 ◽

Cited By ~ 1

Author(s):

Anna Kiialainen ◽

Markus Niggli ◽

Christine L. Kempton ◽

Giancarlo Castaman ◽

Tiffany Y. Chang ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Study Entry ◽

Type I ◽

Healthy Individuals ◽

Advisory Committees ◽

Joint Health ◽

Equity Ownership

Introduction Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that restores the function of missing activated factor VIII (FVIII) by bridging activated FIX and FX in persons with hemophilia A (PwHA). Prophylaxis with emicizumab once weekly or every two weeks resulted in significant reductions in bleeds, including joint bleeds, and a favorable safety profile in PwHA without FVIII inhibitors in the HAVEN 3 study (NCT02847637; Mahlangu et al. 2018). Recurrent joint bleeds in PwHA can lead to hemophilic arthropathy, and hemophilia A has been associated with decreased bone mineral density (Kempton et al. 2014). To explore the potential effect of emicizumab prophylaxis on bone and joint health beyond bleed prevention, we measured joint health scores and bone and joint biomarkers in HAVEN 3. Methods Hemophilia joint health scores (HJHS; v2.1) were evaluated at baseline and Week 49 of emicizumab prophylaxis in 107 PwHA in HAVEN 3. Biomarkers of bone formation (osteocalcin [OC], N-terminal propeptide of type I procollagen [P1NP]), bone resorption (C-terminal telopeptide of type I collagen [CTX-I]), osteoblasts (osteoprotegerin), osteoclastogenesis (soluble receptor activator of nuclear factor- kappaB Ligand [sRANKL]), cartilage turnover (cartilage oligomeric matrix protein [COMP]), and inflammation (interleukin 1 beta, interleukin 6, and tumor necrosis factor) were measured in 117 PwHA (Table 1) receiving emicizumab at baseline and after 3, 6, 12, and 18 months of treatment. In all, 94 of 117 PwHA with samples for biomarker analysis were part of the HJHS evaluation. Results PwHA previously on FVIII prophylaxis and those with no target joints at study entry had lower (indicating healthier) HJHS scores at baseline. Mean improvements from baseline of −2.25 (95% confidence interval [CI]: −4.12, −0.39) in total HJHS and −2.23 (95% CI: −4.07, −0.38) in HJHS joint-specific domain (excluding gait) were observed after 49 weeks of emicizumab prophylaxis in PwHA with one or more target joints at study entry (n=71). Improvement was consistent across HJHS for different locations (knee, ankle, elbow). No significant differences in the measured biomarkers between PwHA previously on FVIII prophylaxis or on on-demand treatment, or in those with or without target joints, were seen at baseline. Mean baseline values of most bone and joint biomarkers were within normal ranges, or similar to published levels in healthy individuals, although large variability was observed between individuals. None of the measured biomarkers changed significantly during emicizumab prophylaxis. Higher OC, P1NP, and CTX-I levels were observed in adolescent vs adult PwHA at all time points, which is consistent with reported increases of these biomarkers during skeletal growth. Data suggest a potential association of COMP levels with HJHS scores at baseline (Pearson correlation coefficient 0.46, p=0.0001). Data on two additional cartilage biomarkers, CTX-II (C-terminal telopeptide of type II collagen) and CS-846 (a chondroitin sulfate epitope) are being generated. Conclusions Reduction in joint bleeds was previously reported in HAVEN 3, including over 99% target joint resolution with long-term follow up (Callaghan et al. 2019). This analysis provides further evidence of the positive effect of emicizumab on joint health, showing significant and clinically relevant improvements in HJHS (defined as a ≥2-point reduction in HJHS joints domain [Kuijlaars et al. 2017]) after as few as 49 weeks of emicizumab prophylaxis. The biomarkers measured in blood as surrogates of bone and joint health did not show significant changes over the first 18 months of emicizumab prophylaxis. This may reflect heterogeneity between individuals, and effects on the measured biomarkers by factors other than joint health. However, improvement in bone and joint biomarkers would have been unexpected as the observed means at baseline were already similar to levels reported in healthy individuals. Although data from animal models have suggested that FVIII may play a role in bone health beyond protection against bleeds, in this study we observed no indication of worsening in any of the measured bone and joint health markers that might have resulted from reduced exposure to FVIII in PwHA who switched to emicizumab prophylaxis. Additional data are needed to better understand the long-term effect of emicizumab prophylaxis on bone and joint health. Disclosures Kiialainen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Niggli:F. Hoffmann-La Roche Ltd: Employment. Kempton:Novo Nordisk: Research Funding; Octapharma: Honoraria; Pfizer: Honoraria; Genentech, Inc.: Honoraria. Castaman:Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Uniqure: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Werfen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda (SHIRE): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chang:Genentech/Roche: Equity Ownership; Genentech, Inc.: Employment. Paz-Priel:Genentech, Inc.: Employment. Adamkewicz:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. Levy:F. Hoffman La Roche: Equity Ownership; Genentech, Inc: Employment.

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High Diagnostic Utility of Second-Day Factor VIII Levels to Assess Pediatric Hemophilia A Pharmacokinetics

Blood ◽

10.1182/blood.v120.21.3368.3368 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3368-3368

Author(s):

Jacqueline F. Morrison ◽

Rachael F. Grace ◽

Kapil Saxena ◽

Ellis J. Neufeld

Keyword(s):

Factor Viii ◽

Graphical Models ◽

Research Funding ◽

Hemophilia A ◽

Bleeding Risk ◽

Fixed Dose ◽

Time Interval ◽

Post Dose ◽

Least Squares Fit ◽

Post Infusion

Abstract Abstract 3368 Background: The role of pharmacokinetic (PK) assessment of factor VIII (fVIII) plasma levels in hemophilia A patients (pts) is evolving. For two decades at our center and many others, full or “modified” PK studies were based on multiple levels drawn before and for several hours following infusion. This required IV access for frequent sampling as well as substantial staff, patient, and parent time. A practical consequence was that PK assessment was reserved for pts with concern for poor factor survival. Recently Björkman, Collins et al reported use of population-based PK sampling to obtain accurate half-life (t1/2) determination by limited blood sampling (2 levels only, 12–36 hours post dose, “Day 2”) in adults with hemophilia A [Haemophilia 16:597, 2010]. The aim of this study was to evaluate the applicability and practical use of these principles in a large pediatric hemophilia clinic, with a long-term goal of individualizing factor VIII dosing. Methods: For this IRB-approved chart review, 27 pts were identified through Hemophilia Center records and a hospital EMR search strategy, who had fVIII PK studies since 2002 at Boston Children's Hospital. Four of 27 had an inhibitor at the time of assessment and were excluded from analysis. Maximum post-infusion fVIII concentrations (Cmax) were estimated from the TCI Works Program [Björkman, Haemophilia 17:e239, 2011]. Graphical and statistical analyses were conducted in GraphPad Prism 5.01. Graphical models in Prism used non-linear least squares fit to a one phase exponential decay curve with the “terminal plateau” parameter arbitrarily constrained to 0.5% (0.005U/ml fVIII) for severe hemophilia A. Results: Forty sets of PK studies were analyzed from 23 pts, median age 7.9 years, and including 8/23 patients (35%) with former inhibitors. The median z-score for BMI was +0.3; obesity was rare. All FDA approved recombinant fVIII brands were represented. The average t1/2 of fVIII in our pts was 6.8 ± 2.1 hours. 52% (12/23) of patients had PK values only within the first 8 hours after an infusion (plus pre-infusion “trough”). Eight non-inhibitor pts contributed multiple sets of PK to the study, over a maximum time interval of 8 years, with negligible variability over time. Due to the commonly observed rapid early fVIII clearance (“biphasic kinetics”), estimates of t1/2 based on Day 2 time points (after 12–24 h when available) are longer than estimates based on points within the first several hrs post infusion (“Day 1”) for pts in which both “Days” were available. Figure A demonstrates this effect in one pt, and shows t1/2 estimated from early vs. late samples. An example of Day 2 sampling alone is shown in Figure B. Conclusions: Second-day fVIII sampling shows promise in pediatric hemophilia A pts as published for adult pts. Testing our entire prophylaxis population by this method has significant implications for individualized vs. fixed dose prophylactic dosing strategies. In non-inhibitor pts, our center has historically used every-other-day prophylactic fVIII dosing at 25 U/kg usually not modified for individual PK. The recognition that Day 2 sampling is equal or superior to detailed first-day testing could result in manifold improvements in (a) pt satisfaction; (b) ability to test all prophylaxis pts rather than those with perceived bleeding risk; (c) ability to individualize treatment models based on PK assessments; (d) reduced testing cost per pt; and (e) potential large savings on a population basis for factor utilization. Individualized dose tailoring and kinetic analyses offer the potential for better pt health and decreased cost of hemophilia treatment. Disclosures: Saxena: Bayer: Research Funding; Novo Nordisk: Research Funding. Neufeld:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bayer: DSMB membership, DSMB membership Other; Baxter: Research Funding.

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A Phase 1/2 Trial of Investigational Spk-8011 in Hemophilia a Demonstrates Durable Expression and Prevention of Bleeds

Blood ◽

10.1182/blood-2018-99-115495 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 487-487 ◽

Cited By ~ 15

Author(s):

Katherine A. High ◽

Lindsey A. George ◽

M. Elaine Eyster ◽

Spencer K. Sullivan ◽

Margaret V. Ragni ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Bleeding Events ◽

Advisory Committees ◽

Dose Cohort ◽

Post Infusion ◽

Equity Ownership ◽

Dose Dependent

Abstract Gene transfer for hemophilia A offers the potential for a one-time disease altering treatment, eliminating the risk of bleeds while freeing patients from the burden of lifelong chronic therapy. SPK-8011 consists of a bioengineered AAV capsid expressing B domain-deleted factor VIII (FVIII) under the control of a liver-specific promoter. In pre-clinical studies, we showed a dose-dependent increase in circulating FVIII levels in non-human primates infused with SPK-8011. We conducted a Phase I/II study of SPK-8011 in 12 men (ages 18-52 years) with severe (n=11) or moderately severe (n=1) hemophilia A. Prior to gene therapy, 8/12 subjects were on prophylaxis, and 4/12 received on-demand treatment. Subjects were enrolled in 1 of 3 dose cohorts, 5E11 vg/kg (n=2), 1E12(n=3), or 2E12(N=7). Safety analysis showed no inhibitor formation. A single serious adverse event (SAE) was reported, associated with an immune response to AAV capsid characterized by simultaneous decline in FVIII, transaminase elevation peaking at Grade 2, and development of positive IFN-g ELISPOTs to capsid was observed beginning at week 6.5 after vector infusion. The asymptomatic transaminase elevation did not respond promptly to initiation of oral steroids and the subject received two infusions of IV methylprednisolone in hospital, thereby fulfilling SAE criteria. The SAE has resolved. All vector doses led to expression of FVIII levels adequate to prevent bleeding and allow cessation of prophylaxis. Across the 12 subjects at 3 doses, there was a 97% reduction in annualized bleeding rate (ABR), and a 97% reduction in annualized infusion rate (AIR). In the 5E11 dose cohort, mean FVIII levels beginning 12 weeks post vector infusion are 13%, with no bleeding events, no elevated transaminase levels, no use of steroids, and stable FVIII expression out to 66 weeks (ongoing). In the 1E12 dose cohort, mean FVIII levels are 15% beginning at 12 weeks post-infusion and stable out to 46 weeks (ongoing). The first subject in the 1E12 dose infused a single dose of factor concentrate for a spontaneous joint bleed at day 159, and the second received multiple infusions for a traumatic bleed beginning at day 195. Declining FVIII levels triggered initiation of a course of tapering steroids in both subjects, at 12 and 7 weeks post vector infusion respectively, which led to stabilization of FVIII levels. The third subject has had no bleeding and did not receive factor infusions or steroids. In the 2E12 (highest) dose cohort, 5/7 subjects currently have FVIII levels 16-49%; their mean FVIII level beginning 12 weeks post-infusion is 30%. No bleeds have been reported among these subjects beginning 4 weeks post vector infusion. Additionally, 5/7 subjects in the 2E12 dose cohort received a course of steroids, initiated at 6-11 weeks post vector infusion, for one or more of the following: declining FVIII levels, rise in ALT above subject baseline, or elevated IFN-g ELISPOTs to AAV capsid. Steroid initiation normalized ALT levels and extinguished the ELISPOT signal in all cases; 2 subjects showed limited stabilization of FVIII levels, which fell to <6% likely due to the immune response. For one of these, no bleeds have been reported through 12 weeks of follow up; the other has had 4 bleeds through 37 weeks of observation. Our data indicate that the kinetics of SPK-8011 expression are similar to those observed with investigational SPK-9001 for hemophilia B. All subjects demonstrated durable transgene expression for up to 66 weeks post vector administration (data cutoff 7/13/18). On cumulative follow up of 345 weeks, SPK-8011 demonstrated a favorable safety profile with no evidence of FVIII inhibitor formation, a single SAE, and 2/12 subjects who experienced ALT elevation above the upper limit of normal that resolved with steroid initiation. Data from the 5E11 (lowest) dose cohort are consistent with published natural history data indicating FVIII:C 12% is adequate to prevent spontaneous bleeding events. Given that 2 subjects in the 2E12 dose cohort lost some FVIII expression, which then stabilized on steroids, and 5/7 subjects in this cohort required steroids, prophylactic steroids may be warranted. We conclude that infusion of SPK-8011 in 12 subjects with severe or moderately severe hemophilia A resulted in safe, durable, dose-dependent FVIII expression resulting in an excellent preliminary efficacy profile with an overall 97% reduction in ABR and AIR. Disclosures High: Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties. George:University of Pennsylvania: Equity Ownership; Pfizer: Consultancy. Ragni:CSL Behring: Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sangamo: Research Funding; Shire: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Bioverativ: Consultancy, Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees; SPARK: Consultancy, Research Funding. Croteau:Novo Nordisk: Consultancy; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Tremeau Pharmaceuticals: Consultancy; Genetech: Consultancy, Research Funding; CSL-Behring: Consultancy; Catalyst Biosciences: Consultancy; Bioveritiv: Consultancy; Biomarin: Consultancy; Bayer: Consultancy; Baxalta/Shire: Consultancy, Research Funding. Joseney-Antoine:Spark Therapeutics: Employment. Macdougall:Spark Therapeutics: Employment. Tompkins:Spark Therapeutics: Employment. Hait:Spark Therapeutics: Employment. Couto:Spark Therapeutics: Employment. Bassiri:Spark Therapeutics: Employment. Valentino:Spark Therapeutics: Employment. Carr:Spark Therapeutics: Employment. Hui:Spark Therapeutics: Employment. Wachtel:Spark Therapeutics: Employment. Takefman:Spark Therapeutics: Employment. Mingozzi:Spark Therapeutics, Inc.: Employment. Anguela:Spark Therapeutics, Inc.: Employment. Reape:Spark Therapeutics: Employment.

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Impact of Hemophilia a Inhibitor on Joint Health and Health-Related Quality of Life from the Hemophilia Utilization Group Studies Part VIII in the U.S

Blood ◽

10.1182/blood-2020-142947 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Megan M. Ullman ◽

Marilyn J Manco-Johnson ◽

Jonathan C. Roberts ◽

Nicole Crook ◽

Rahul Khairnar ◽

...

Keyword(s):

Research Funding ◽

Hemophilia A ◽

Publicly Traded ◽

Active Inhibitor ◽

Adult Participants ◽

Younger Age ◽

Related Quality ◽

Joint Health ◽

Health Related

Introduction: Persons with hemophilia A (PwHA) and Factor VIII inhibitors experience significant economic burden associated with high treatment costs and compromised physical and psychosocial health. Few studies have compared burden of illness for PwHA with active inhibitors to those with tolerized or no inhibitor. We describe clinical and treatment outcomes, and health-related quality of life (HRQoL) in PwHA with and without inhibitors using the Hemophilia Utilization Group Studies Part VIII (HUGS VIII) baseline cross-sectional data. Methods: HUGS VIII prospectively examines the cost and burden of hemophilia care, including HRQoL, arthropathy, and psychosocial impact in PwHA aged ≥2 years. The study enrolled PwHA with inhibitors and without inhibitor at a 1:2 ratio. Participants were classified to three groups: 1) active inhibitor (FVIII≥1.0 Bethesda Units within six months of data extraction), 2) presumably tolerized inhibitor (history of immune tolerance induction, ITI, and using factor VIII for prophylaxis), and 3) no inhibitor. Parents/adult participants completed a standardized interview at enrollment (baseline) to collect sociodemographic and clinical data, self-reported pain, joint health, and HRQoL measured by the EQ-5D-3L. Clinical chart review documented hemophilic severity, inhibitor level and treatment regimen. Associations between participants' characteristics and inhibitor status were assessed using Chi-square tests. Results: Data from 73 participants with complete baseline information were analyzed. Mean age was 24.8 (standard deviation (SD)=14.1) years, 65.8% were adults, 87.7% had severe hemophilia A, and 87.1% self-reported receiving prophylactic treatment. The three groups of participants were: non-inhibitor (n=42, 57.5%); tolerized inhibitor (n=23, 31.5%); and active inhibitor (n=8, 11.0%). Mean age among the tolerized inhibitor group was significantly younger (17.3, SD=9.3 years) than active inhibitor (22.6, SD=20.4) or non-inhibitor groups (29.3, SD=13.3), p=0.02. Among individuals with inhibitors, 78.6% had undergone ITI which was successful in 72.2%. Adult participants/parents in the active inhibitor group reported a lower rate of full-time employment (42.9%) compared to the non-inhibitor (58.5%) or tolerized inhibitor (55.7%) groups, p=0.03. Compared to those without inhibitors or tolerized inhibitors, those with active inhibitors showed lower HRQoL with lower covariates adjusted mean EQ-5D Visual Analogue Scale (73.1 vs. 83.6, 80.2, P=0.21) or index score (0.80 vs. 0.87, 0.88, P=0.57). Participants with active inhibitors and those without inhibitors were more likely to report having joint pain (85.7%, 75.6% non-inhibitors, vs. 59.1% tolerized inhibitors, p=0.26), or very stiff joints upon arising (71.4%, 73.2%, vs. 27.3%, p=0.002) or during the day (71.4%, 63.4% vs. 27.3%, p=0.01) than those with a tolerized inhibitor, likely due to younger age and earlier institution of long-term effective prophylaxis after ITI. Conclusions: While the study is limited to a small sample with a skew to younger age in persons with tolerized inhibitors, preliminary analyses indicate that individuals with active inhibitors experienced greater negative impacts on employment and HRQoL than PwHA with no or tolerized inhibitors. Younger persons with tolerized inhibitors showed better joint health (less pain, stiffness) than older persons with active or no inhibitor. Future research using longitudinal data on these participants will examine whether individuals in the tolerized inhibitor group with successful ITI continue with long-term prophylaxis and achieve positive joint health outcomes. Disclosures Roberts: uniQure: Consultancy; Takeda: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Novo Nordisk: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau. Khairnar:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Wu:Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., and Octapharma USA, Inc.: Research Funding. Carrasco:Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., and Octapharma USA, Inc.: Research Funding. Curtis:Bayer: Consultancy; USC Hemophilia Utilization Group Study (HUGS): Consultancy; Novo Nordisk: Consultancy; Patient Reported Outcomes, Burdens and Experiences: Consultancy. Tran:Bioverativ: Consultancy; Novo Nordisk: Consultancy; Bayer: Consultancy; Takeda: Consultancy. Nichol:Pfizer: Research Funding; Octapharma: Research Funding; CSL Behring: Research Funding; Global Blood Therapeutics: Research Funding; Baxalta US Inc., Bannockburn, IL (a Takeda Company): Research Funding; Genentech Inc.: Research Funding.

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Benefits of Ehl Factor VIII Replacement Therapy in Hemophilia: Observations on Coverage, Physical Activity and Phisiotherapy

Blood ◽

10.1182/blood-2019-125651 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2455-2455

Author(s):

Felipe Querol ◽

Sofía Pérez-Alenda ◽

Juan Eduardo Megias ◽

Juan José Carrasco ◽

Marta Aguilar ◽

...

Keyword(s):

Physical Activity ◽

Replacement Therapy ◽

Half Life ◽

Research Funding ◽

Hemophilia A ◽

Vigorous Physical Activity ◽

Bleeding Events ◽

Haemophilic Arthropathy ◽

Post Infusion ◽

Trough Levels

Introduction: Prevention of haemophilic arthropathy and quality of life´s (QoL) improvement are still the main goals in the haemophilia community. Haemophilic arthropathy is the result of clinical and subclinical bleeding during everyday activities and/or traumatic situations. Prophylaxis with extended half-life (EHL) factor replacement therapy is understood as an improvement solution for factor VIII (FVIII) PK properties, as half-life (T1/2) and area under the curve (AUC), however few real world data are yet available. EHL improved pharmacokinetic (PK) properties might directly drive into a reduction of the bleeding risk during physical activity (both therapeutical or leisure) for a longer period of time, allowing an increase in QoL. World Health Organization (WHO) has set recommendations focused on the benefits of moderate and intense physical activity to improve joint health as well as to prevent common pathologies (obesity, diabetes, hypertension, cancer, depression, anxiety) and even the risk of death (since the absence of physical activity is the 4th factor risk worldwide). The aim of this study was to define a safe program of physical activity, sport and physiotherapy along the time according the PK profile of patients treated with the EHL rurioctocog alfa pegol. Materials and methods: PK parameters (infusion frequency, dosage, T½, peak level, trough level at 24, 48 and 72 hours (NV24/NV48 and NV72), and time to reach 5%, 2% and 1% FVIII levels (T5,T2 and T1) were analyzed in patients with hemophilia A after switching from an standard half-life (SHL) FVIII to the EHL (rurioctocg alfa pegol) FVIII replacement therapy. Tailored physical activity and physiotherapy programmes in place during SHL treatment were re-evaluated after switching to the EHL according the new individual PK profile. The Functional Independence Score in Hemophilia (FISH) form was used to measure ambulation. Results: Ten patients with hemophilia A (9 severe and 1 moderate) with a mean age of 34.49 (9.46) were analyzed. All the PK parameters evaluated showed a significant statistical improvement after the switch from an SHL to this FVIII EHL (Figure 1, A.). Specifically, higher T½, peak levels and trough levels were achieved using a lower dosage and infusion frequency (Figure 1, B). After switching to the EHL, FVIII trough levels were higher than 5% until 3.4 days (81.5 hours) (Figure 1, C) post-infusion. This allowed us to establish a physiotherapy program as well as an intense-moderate physical activity program in patients without clinical evidence of bleeding events (Figure 1, D). The potentiation physical program to develop muscle tone for elbows, knees and ankles was authorized until the third day of EHL FVIII post-infusion. However, during SHL treatment, vigorous physical activity was never performed after 24 hours of FVIII post-infusion. No joint bleeding events appeared during everyday physical activities nor during physiotherapy programs aimed to maintain joint trajectory and muscle power. Regarding ambulation (FISH), all patients had hemophilic arthropathy in one joint. The results in the item "Run" were: 3 points for 3 patients (activity non comparable to normal activity), 2 points for 3 patients (requires an orthesis) and 1 point for 4 patients (activity not feasible). Conclusions: EHL FVIII replacement with rurioctocog alfa pegol improved significantly all PK parameters compared to SHL factors. The administration of this EHL allows moderate and vigorous physical activity after more than 72 hours post-infusion, due to higher FVIII coverage along the time. Disclosures Querol: Baxalta US INC.: Research Funding. Pérez-Alenda:Baxalta US INC.: Research Funding. Megias:Baxalta US INC.: Research Funding; Grifols: Research Funding. Carrasco:Baxalta US INC.: Research Funding. Cid:Novo Nordisk: Honoraria; Shire, a Takeda company: Honoraria. Bonanad Boix:Baxalta US INC.: Research Funding.

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Management Strategies in Persons with Inherited Hemophilia Requiring Antithrombotic Therapy: A Scoping Review

Blood ◽

10.1182/blood-2021-148903 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3191-3191

Author(s):

Kelsey Uminski ◽

Yan Xu ◽

Amin Zahrai ◽

Amanda Hodgson ◽

Lisa Duffett ◽

...

Keyword(s):

Venous Thromboembolism ◽

Coronary Artery ◽

Scoping Review ◽

Research Funding ◽

Hemophilia A ◽

Management Strategies ◽

Practice Variation ◽

Cardiovascular Disorders ◽

Bleeding Events

Abstract Background: Cardiovascular disorders (CVD) and venous thromboembolism (VTE) are increasingly reported in people with hemophilia (PWH) whose life expectancy has improved dramatically over the past decades. While management of thrombotic events among PWH requires navigating the delicate balance between recurrent ischemic events and hemorrhage, current practices are highly variable and largely informed by expert opinion. Objective: We sought to examine and summarize what is known about the management, practice variation and outcomes of PWH requiring antithrombotic therapy (ATT) for cardiovascular disorders (CVD) or venous thromboembolism (VTE). We also aimed to identify current knowledge and practice gaps in the management of CVD and VTE in PWH. Methods: We conducted a scoping review guided by Arksey and O'Malley (2002), and Levac et al.'s (2010) methodological frameworks. We also adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). A search strategy, developed iteratively in collaboration with a medical librarian, was performed on MEDLINE, EMBASE, and Scopus from inception to May 3, 2021. Studies of any design, published in English or French, in full-text or abstract, were included if they reported on more than two patients with inherited hemophilia A or B requiring ATT for CVD or VTE. Following eligibility assessment in duplicate, data from each study was charted by two independent reviewers to report the type of research designs, population, geographical location, interventions, and outcomes. Conflicts were resolved by consensus. We conducted a descriptive analysis and narrative synthesis to identify common themes and knowledge gaps. Results: We screened 3929 articles and selected 38 studies for inclusion (23 full-text and 15 abstracts). Published studies were largely retrospective (28/38, 73.7%), single center (25/38, 65.8%), and from Europe (25/38, 65.8%). A total of 567 patients with hemophilia A or B were reported. Common indications for ATT use included: coronary artery disease (26/38, 68.4%), including a history of percutaneous coronary intervention or coronary artery bypass procedures (14/38, 36.8%), atrial fibrillation (13/38, 34.2%), VTE treatment or prevention (10/38, 26.3%), cerebrovascular disease (9/38, 23.7%) and valvular heart disease (7/38, 18.4%). ATT included single antiplatelet therapy (28/38, 73.7%), heparins (21/38, 55.3%), dual antiplatelet therapy (19/38, 50%), vitamin K antagonists (10/38, 26.3%), and direct oral anticoagulants (5/38, 13.2%). The use of hemostatic therapies, either on-demand or prophylactically, was reported in 36 studies (94.7%). Clotting factors concentrates were used in 35 studies (92.1%). Other agents included desmopressin (2/38, 5.2%) and emicizumab (1/38, 2.6%). Only 19 studies (50%) reported target factor levels (peak and/or trough) while on ATT. Outcomes related to bleeding while on ATT were described in 36 studies (94.7%). Bleeding events resulting in a change in hemostatic regimen occurred in 9 studies (25%), while bleeding resulting in a change or discontinuation of ATT occurred in 10 studies (27.8%). In 10 studies (26.3%), no pathologic bleeding was observed in PWH on ATT. Four key themes were generated iteratively to describe the observed wide practice variation in the management of PWH requiring ATT: (1) Deviation from established and evolving CVD/VTE-related standards of care; (2) Difficulty weighing competing bleeding and thrombotic risks; (3) Advocacy for individualized strategies and multidisciplinary care; and (4) Absence of high-quality and long-term data for PWH. Discussion and Conclusion: Our scoping review highlights unmet needs in the management of an aging population of PWH with increasing prevalence of CVD and VTE. Management patterns are inconsistent and diverge from those of non-hemophilic patients. Current literature provides limited information on key issues such as hemostatic regimen, target factor levels, bleeding events and long-term outcomes. Prospective, clinically actionable data are needed to inform optimal and evidence-based management strategies of CVD and VTE in PWH. Higher quality data should culminate in much needed guidelines co-produced with patient partners and medical experts in hemophilia, CVD, and VTE. Disclosures Khalife: Pfizer Canada: Honoraria, Research Funding; Canadian Hemophilia Society: Research Funding.

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Pharmacokinetic Parameter Driven Outcomes Model Predicts a Reduction in Bleeding Events Associated with BAY 81-8973 Versus Antihemophilic Factor (Recombinant) Plasma/Albumin- Free Method in a Chinese Healthcare Setting

10.21203/rs.3.rs-1159955/v1 ◽

2022 ◽

Author(s):

Rong Chen ◽

Dmitry Gultyaev ◽

Johanna Lister ◽

Rong Han ◽

Nan Hu ◽

...

Keyword(s):

Hemophilia A ◽

Cost Savings ◽

Standard Of Care ◽

Healthcare Setting ◽

Bleeding Events ◽

Plasma Albumin ◽

Lifetime Horizon ◽

Life Years ◽

Antihemophilic Factor

Abstract Background: Long-term prophylactic therapy is considered the standard of care for hemophilia A patients. This study models the long-term clinical and cost outcomes of two factor VIII (FVIII) products using a pharmacokinetic (PK) simulation model in a Chinese population. Methods: Head-to-head PK profile data of BAY 81-8973 (KOVALTRY®) and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, ADVATE®) were applied to a two-state (alive and dead) Markov model to simulate blood FVIII concentrations at a steady state in prophylactically-treated patients with hemophilia A. Worsening of the Pettersson score was simulated and decline was associated with the probability of having orthopaedic surgery. The only difference between the compounds was FVIII concentration at a given time; each subject was treated with 25 IU/kg every 3 days. The model used a lifetime horizon, with cycle lengths of 1 year. Results: Cumulative bleeding events, joint bleeding events, and major bleeding events were reduced by 19.3%, 9.3% and 19.3%, respectively for BAY 81-8973 compared to rAHF-PFM. Hospitalizations and hospitalization days were also reduced by 19.3% for BAY 81-8973 compared to rAHF-PFM. BAY 81-8973 resulted in both cost savings and a gain in quality adjusted life years (QALYs) compared to rAHF-PFM. Conclusion: Based on modeled head-to-head comparisons, differences in PK-properties between BAY 81-8973 and rAHF-PFM result in a reduced number of bleeding events, leading to reduced costs and increased quality of life for BAY 81-8973. These results should be used to inform clinical practice in China when caring for patients with severe hemophilia A.

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Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽

10.1182/blood-2019-126659 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1126-1126

Author(s):

Karen L. Zimowski ◽

Glaivy M. Batsuli ◽

Paulette Bryant ◽

Jenny McDaniel ◽

Kelly Tickle ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Severe Bleeding ◽

Severe Hemophilia ◽

Bleeding Events ◽

Advisory Committees ◽

Acute Bleeding ◽

Fviii Activity ◽

Bleeding Episodes

Introduction : Emicizumab is a novel humanized bispecific antibody that mimics the function of activated coagulation factor VIII (fVIII). It has significantly changed the management of patients with hemophilia A and inhibitors by achieving baseline hemostatic control. Based on the HAVEN studies, emicizumab markedly reduces annualized bleeding rates and is FDA-approved for prophylaxis in hemophilia A patients of all ages, regardless of inhibitor status. In the HAVEN2 interim analysis, only 3/57 pediatric patients receiving emicizumab prophylaxis required treatment for an acute bleeding event after a 9-week median observation time. We report 3 patients with severe hemophilia A and a history of inhibitors receiving emicizumab prophylaxis with severe or refractory bleeding episodes to highlight the importance of vigilance and surveillance of children with severe hemophilia A on emicizumab. Methods: This retrospective analysis includes patients between 0-21 years of age with severe hemophilia A (fVIII activity < 1%) receiving emicizumab prophylaxis and admitted for the management of an acute bleeding episode following emicizumab's FDA approval in November 2017. Patients were followed at the Pediatric Hemophilia Treatment Center at the Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory and the St. Jude Affiliate Clinic at Novant Health Hemby Children's Hospital. Data collected included demographics, past medical history including inhibitor status, bleeding history, and treatment modalities, and details regarding the presentation, management, and outcome of acute severe bleeding events. Due to the nature of the study, descriptive statistics were primarily used for data analysis. Results: Three patients with severe hemophilia A receiving emicizumab prophylaxis were admitted for the management of 4 severe bleeding episodes. All patients had a history of a fVIII inhibitor. Three of the 4 bleeding episodes were trauma-induced while 1 occurred spontaneously. For the traumatic episodes, all patients presented with worsening symptoms approximately 1 week following the inciting event. All patients had a normal aPTT at the time of presentation, ruling out a significant anti-drug antibody (emicizumab level not available). A patient with a low-titer inhibitor developed an epidural hematoma following a trampoline injury and was treated with continuous infusion of recombinant factor VIII (rfVIII), adjusting the rate to achieve chromogenic fVIII activity of 100% for 14 days. Following 14 days, he was started on rfVIII 50 IU/kg Q12 hours with a goal fVIII activity of 50%. His rfVIII dosing interval was gradually weaned to every other day while in inpatient rehabilitation. As outlined in Table 1, the remaining 3 bleeding events were initially managed with recombinant activated factor VII (rfVIIa) dosed at 80-90 mcg/kg/dose with escalating frequency for an average of 8 days. However, due to lack of improvement, treatment was changed to low-dose activated prothrombin complex concentrates (aPCC; 10-15 IU/kg/dose Q12-24 hours for an average of 7 days). In all 3 of these events, the hematomas improved after treatment with aPCC. No patient experienced thrombotic microangiopathy, thrombosis, or had evidence of DIC while receiving these treatment regimens. Discussion/Conclusion: Pharmacokinetic analysis of emicizumab suggests that following the standard 4-week loading phase, trough plasma emicizumab concentrations obtained prior to a 1.5 mg/kg once weekly maintenance dose correlates with at least 10-15 IU/dL equivalent fVIII activity. This degree of thrombin generation should be sufficient to prevent severe spontaneous bleeding episodes in most patients. However it does not preclude significant trauma-induced bleeding or spontaneous bleeding in inhibitor patients. Based on our cases, providers should maintain a high index of suspicion for acute bleeding in patients receiving emicizumab prophylaxis. Serious bleeding events, although rare, may have a more insidious onset in patients receiving emicizumab. Furthermore, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Our cases suggest that low-dose aPCC or continuous infusion fVIII may be feasible options for treating acute bleeding events in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis. Disclosures Zimowski: Pfizer: Research Funding; National Hemophilia Foundation: Other: Medical Loan Reimbursement, Research Funding. Batsuli:Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees. Bryant:Novo Nordisk: Other: PI on Novo Nordisk sponsored Studies. McDaniel:Genentech: Membership on an entity's Board of Directors or advisory committees. Tickle:National Hemophilia Foundation: Research Funding. Meeks:Bayer: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Sidonio:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

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Antithrombotic Treatment and Outcomes of Splanchnic Vein Thrombosis in an International Prospective Registry: Results of 2-Year Follow-up

Blood ◽

10.1182/blood.v124.21.592.592 ◽

2014 ◽

Vol 124 (21) ◽

pp. 592-592

Author(s):

Walter Ageno ◽

Nicoletta Riva ◽

Sam Schulman ◽

Jan Beyer-Westendorf ◽

Soo-Mee Bang ◽

...

Keyword(s):

Risk Factors ◽

Major Bleeding ◽

Research Funding ◽

Bleeding Events ◽

Primary Analysis ◽

Vascular Events ◽

Vein Thrombosis ◽

Cirrhotic Patients

Abstract Background: Little information is available on the long-term clinical outcome of patients with splanchnic vein thrombosis (SVT). We aimed to assess incidence rates of bleeding, recurrence, and mortality in a large prospective cohort of SVT patients after a 2-year follow-up. Methods: Consecutive SVT patients were enrolled in a multicenter international registry, from 2008 to 2012. Information was gathered on baseline characteristics, risk factors and therapeutic strategies. Clinical outcomes (major bleeding; vascular events, defined as venous or arterial thrombosis, and mortality) during follow-up were collected and reviewed by a Central Adjudication Committee. Major bleeding was defined using the ISTH definition plus the need for hospitalization. The primary analysis was performed up to the first adjudicated major bleeding or thrombotic event. Results: 604 patients from 31 centers were enrolled in this study, 21 (3.5%) were lost to follow-up. Median follow-up duration was 2 years (IQR 1-2). Median age was 54 years (range 16-85); 62.6% were males. Most common risk factors were liver cirrhosis in 27.8% of patients and solid cancer in 22.3%. Portal vein was the most common site of thrombosis. 139 patients were not anticoagulated; 175 received parenteral anticoagulants only (median duration 5.8 months, IQR 3-12) and 290 were started on vitamin K antagonists (median duration 24 months, IQR 7-24). According to the primary analysis, 103 events occurred during follow-up: 35 major bleeding events (3.8/100 patient-years [pt-y]; 95%CI, 2.7-5.2), 2 of which were fatal bleeding, and 68 thrombotic events (7.3/100 pt-y; 95%CI 5.8-9.3), 9 of which were vascular deaths. All-cause mortality occurred in 106 patients (10.3/100 pt-y; 95% CI 8.5-12.5). The incidence of major bleeding events was 4.0/100 pt-y in patients on anticoagulant drugs and 3.4/100 pt-y in patients not receiving anticoagulants. The incidence of vascular events was 5.6/100 pt-y and 9.7/100 pt-y, respectively. Major bleeding and vascular event rates were highest in cirrhotic patients (10.0/100 pt-y and 11.3/100 pt-y, respectively), and lowest in the subgroup of non-malignant non-cirrhotic patients (1.8/100 pt-y and 5.6/100 pt-y, respectively). Conclusions: SVT patients have a non-negligible long-term risk of both bleeding and thrombotic events, but this risk varies according to the pathogenesis of SVT. Anticoagulant treatment is associated with a reduced incidence of thrombotic events without apparently resulting in an increased risk of bleeding. Funding: The study was funded by a grant from Pfizer Canada to ISTH Disclosures Ageno: Bayer Healthcare: Research Funding. Schulman:Bayer HealthCare: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding. Beyer-Westendorf:Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Boehringer: Honoraria, Research Funding.

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