High-dose Prophylaxis Research Articles

The Association of Anticoagulation Intensity with Outcomes in Hospitalized COVID-19 Patients.

Venous thromboembolism (VTE) risk is increased in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A key question was whether increased intensity of anticoagulation would help prevent VTE and improve patient outcomes, including transfer to the intensive care unit (ICU) and mortality. At the start of the coronavirus disease-19 (COVID-19) pandemic, our institution, Boston Medical Center, instituted a VTE risk stratification protocol based on patients' initial D-dimer levels, medical history, and presence of thrombosis to determine whether they should receive standard-dose prophylaxis, high-dose prophylaxis, or therapeutic anticoagulation. We performed a retrospective observational cohort study examining the association of degree of anticoagulation with outcomes in 915 hospitalized COVID-19 patients hospitalized initially on the general inpatient wards between March 1,, 2020, and June 1, 2020. Patients directly hospitalized in the ICU were excluded. Most, 813 patients (89%), in our cohort were on standard-dose prophylaxis; 32 patients (3.5%) received high-dose prophylaxis; 70 patients (7.7%), were treated with therapeutic anticoagulation. VTE occurred in 45 patients (4.9%), and the overall in-hospital mortality rate was 5.4% (49 deaths). On multivariable analysis of clinical outcomes in relation to type of anticoagulation, in the high-dose prophylaxis group, there was a trend towards increased in-hospital mortality (odds ratio 2.4 (0.8-7.5, 95% CI)) and increased ICU transfer (odds ratio 2.2 (0.9-5.7, 95% CI)). Our results suggest that patients receiving high-dose prophylaxis had more severe disease that was not mitigated by intermediate-dose anticoagulation.

Cost-effectiveness analysis of emicizumab prophylaxis in patients with haemophilia A in India.

Emicizumab is the initial subcutaneously administered bispecific antibody approved as a prophylactic treatment for patients with haemophilia A (PwHA). This study assessed the economic evaluation of emicizumab treatment for non-inhibitor severe haemophilia A (HA) patients in India. A Markov model evaluated the cost-effectiveness of emicizumab prophylaxis compared to on-demand therapy (ODT), low-dose prophylaxis (LDP; 1565IU/kg/year), intermediate-dose prophylaxis (IDP; 3915IU/kg/year) and high-dose prophylaxis (HDP; 7125IU/kg/year) for HA patients without factor VIII inhibitors. Inputs from HAVEN-1 and HAVEN-3 trials included transition probabilities of different bleeding types. Costs and benefits were discounted at a 3.5% annual rate. In the base-case analysis, emicizumab was cost-effective compared to HDP, with an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-years (QALY) of Indian rupees (INR) 27,869. Compared to IDP, ODT and LDP, emicizumab prophylaxis could be considered a cost-effective option if the paying threshold is >1 per capita gross domestic product (GDP) with ICER/QALY values of INR 264,592, INR 255,876 and INR 305,398, respectively. One-way sensitivity analysis (OWSA) highlighted emicizumab cost as the parameter with the greatest impact on ICERs. Probabilistic sensitivity analysis (PSA) indicated that emicizumab had a 94.7% and 49.4% probability of being cost-effective at willingness-to-pay (WTP) thresholds of three and two-times per capita GDP. Emicizumab prophylaxis is cost-effective compared to HDP and provides value for money compared to ODT, IDP, and LDP for severe non-inhibitor PwHA in India. Its long-term humanistic, clinical and economic benefits outweigh alternative options, making it a valuable choice in resource-constrained settings.

Management of Severe Hemophilia A: Low-Dose Prophylaxis vs. On-Demand Treatment.

Prophylactic clotting factor infusion regimens to prevent bleeding and joint deformity has become the standard of care in severe hemophilia A patients. To assess low-dose factor prophylaxis in our population as an alternative approach to managing severe hemophilia A. A prospective cohort study that included 68 hemophilia A patients divided into two groups, i.e., Prophylaxis and on-demand. The two groups were compared for annualized bleeding rate (ABR), hospitalization, units of factor VIII (FVIII) infused, or plasma products transfused, i.e., fresh frozen plasma (FFP) and cryoprecipitate (CP), and development of FVIII inhibitors. Of the 68 patients recruited in this study, 25 (36.7%) were in the prophylaxis group, and 43(63.3%) were in the on-demand group. The on-demand group presented a higher median-IQR ABR [8(20-3) vs. 5(10-1.5), p-value 0.024], several hospitalizations (39.7% vs. 0, p-value0.001), and inhibitor development (9.3% vs. 0, p-value 0.289) compared to the prophylaxis group. The prophylaxis approach demonstrated a significant negative correlation of ABR with FVIII prophylaxis (r=-0484, p=value=0.014). Moreover, no hospitalizations or inhibitor development was observed in the prophylaxis group. The estimated annual consumption of FVIII was 328 IU/kg/year in the on-demand group and 1662.6 IU/kg/year in the prophylaxis group. However, a highly significant difference in plasma product utilization was observed between the two groups, i.e., p-value <0.001 and 0.038 for FFP and CP, respectively. Low-dose factor prophylaxis resulted in improved outcomes compared to on-demand treatment in terms of ABR, joint bleeding, hospitalization, and the development of inhibitors. This treatment approach should be adopted as an economically feasible alternative to high-dose Prophylaxis in resource-constrained countries.

Bone mineral density in haemophilia - a multicentre study evaluating the impact of different replacement regimens.

The aim of this study was to investigate if prophylactic treatment in severe haemophilia impact on bone mineral densisty (BMD) in adults with haemophilia A/B. Subjects with haemophilia (n=120) underwent bone-density measurement and clinical data was collected. BMD in subjects with severe haemophilia on high-dose prophylaxis (n=41) was compared to BMD in subjects with mild haemophilia (n=33) and to severe haemophilia treated with intermediate-dose prophylaxis (n=32) or on-demand replacement therapy (n=14). Subjects with severe haemophilia on high-dose prophylaxis showed BMD at total hip comparable to subjects with mild haemophilia (median BMD 955.8 and 977.4mg/cm2 (P=.17), respectively). No difference in BMD was found related to type of prophylactic regimen (median BMD 955.8 and 942.4mg/cm2 , in high-dose and intermediate dose groups, respectively; P=.70). Subjects with severe disease treated on-demand had significantly lower BMD compared to subjects on a high-dose prophylactic regimen (median BMD 771.8 and 955.8mg/cm2 (P=.001), respectively). BMD decreased significantly with age, regardless of severity of haemophilia disease. In a multivariate analysis, adjusted for disease status and age, type of prophylactic regimen was not significantly associated with osteoporosis development. We show that BMD differs in persons with severe haemophilia on propylaxis as compared to those treated on-demand, but that type of prophylactic regimen does not reflect on BMD. The difference between treatment groups was mainly explained by an age difference between groups. However, patients on prophylaxis displayed a high degree of normal BMD not far from mild haemophilia at comparative age.

POSC83 Estimating the Clinical and Economic Benefits of Optimising Management of Patients with Hemophilia A in Developing Countries

Whilst lifelong high-dose prophylaxis (Px) is considered the optimal standard of care (SOC) for hemophilia A (HA), the perceived high cost and limited access and availability of factor FVIII could limit adoption of high-dose Px. Thus, many developing countries adopt less costly Px management alternatives, including low- and intermediate-dose Px treatment. This study estimates the potential clinical and economic benefits of optimizing Px treatment strategies to improve the SOC in patients with severe HA.

The Impact of Degree of Anticoagulation on Thrombotic and Other Complications in Hospitalized COVID-19 Patients

Introduction:In hospitalized patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the frequency of venous thromboembolism (VTE) is increased. Retrospective studies suggested that an elevated D-dimer level is associated with increased mortality and predictive of thrombosis in these patients. In the spring of 2020, our institution developed a risk protocol for stratification of hospitalized COVID-19 patients into high, intermediate, or low risk groups, based upon history of thrombosis and D-dimer level. These patients were treated with full-dose anticoagulation, high- or standard-dose prophylaxis, respectively. The goal of this project was to determine the impact of this protocol on VTE frequency, need for intensive care unit (ICU) admission, organ failure and in-hospital mortality while assessing the frequency of hemorrhagic complications when compared to standard prophylactic anticoagulation.Methods:We performed a retrospective chart review of adults hospitalized between March 1 - June 1, 2020 who tested positive for SARS-CoV-2 by nasopharyngeal polymerase chain reaction (PCR). Patients were excluded if they were initially admitted to the ICU. VTE was defined as either a deep vein thrombosis (DVT) on Duplex ultrasound and/or pulmonary embolism (PE) on computed tomography (CT) angiogram. We collected demographic data, medical histories, laboratory and radiologic data on all subjects. Data were analyzed using the Chi Square test and Fisher's Exact Test to establish significant association with clinical outcomes between 3 anticoagulation regimens. Statistical significance was assessed at the p<0.05 level.Results:Data were analyzed from 910 patients; 496 (54.6%) were male and the mean age was 57.8 ± 16.9 years. 419 (46%) subjects were Black, 151 (16.6%) Caucasian, 133 (14.6%) Latinx. Diabetes mellitus (35.3%) and hypertension (59.8%) were common in our cohort as were tobacco (12.6%) and alcohol (20.4%) use. Only 69 (7.6%) were treated with chronic anticoagulation and 216 (23.7%) were on antiplatelet agents. 123 (13.5%) required an ICU transfer and the overall mortality was 5.3%. Most patients, 809 (88.9%), received standard prophylactic anti-coagulation initially (Group A); 32 (3.5%) received high dose prophylaxis (Group B) and 69 (7.6%) received therapeutic dose anticoagulation (Group C). In the entire cohort, 46 (5.1%) developed VTE; 29 (3.6%) in Group A, 2 (6.3%) in Group B, and 15 (22%) in Group C (p<0.0001). ICU admission was required for 102 (12.6%) in Group A, 7 (21.9%) in Group B, and 14 (20.3%) in Group C (p=0.075). 73 ICU patients (8%) required vasopressors, including 57 (7%) in Group A, 6 (18.8%) in Group B and 10 (14.5%) in Group C (p=0.175). 81 ICU patients (8.9%) required mechanical ventilation, including 66 (8.2%) in Group A, 6 (18.8%) in Group B, and 9 (13%) in Group C (p=0.513). One patient in Group B developed an intracerebral hemorrhage. Gastrointestinal hemorrhage occurred in 11 (1.2%) of the cohort; similar rates were observed across treatment arms. The overall in-hospital mortality was 5.3% in this cohort (4.7% in Group A, 12.5% in Group B, and 8.6% in Group C, p=0.064).Conclusion:The rate of VTE in COVID-19 patients receiving any form of anti-coagulation was low. There was an increased rate of VTE, but not rates of ICU admission, mortality, mechanical ventilation nor vasopressor use in those receiving either high dose prophylaxis or therapeutic anticoagulation, suggesting an increased propensity for thrombosis either related to prior thrombotic events or reflected by increased D-dimer levels. These findings need to be confirmed in prospective studies. DisclosuresDiLorenzo: Abbott: Current holder of individual stocks in a privately-held company; Merck & Co: Current holder of individual stocks in a privately-held company; Glaxo Smith Kline: Current holder of individual stocks in a privately-held company. Sloan: Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Stemline: Honoraria. Weinberg: Janssen Pharmaceuticals: Other: Serve on data safety monitoring boards; Merck & Co: Current holder of individual stocks in a privately-held company. Klings: CSL Behring: Other: Consultant; Omeros: Other: Consultant; Bluebird Bio: Other: Consultant; Bayer: Research Funding; Novartis: Research Funding; FORM therapeutics: Research Funding.

Early High-Dose Caffeine Improves Respiratory Outcomes in Preterm Infants

The objective of the study is to determine if early high-dose caffeine (HD) therapy is associated with shorter duration of mechanical ventilation, bronchopulmonary dysplasia (BPD), or decreased need for mechanical ventilation. We conducted a single center, retrospective cohort study of 273 infants less than 32 weeks gestational age (GA). Infants receiving early HD (10 mg/kg/day maintenance) caffeine citrate started within 24 h of life were compared with those receiving LD (6 mg/kg/day) with variable timing of initiation using linear and logistic regression models. The infants in the early HD group had 91.4 (95% confidence interval (CI): −166.6, −16.1; p = 0.018) less hours of mechanical ventilation up to 36 weeks PMA or discharge as compared with the LD group. Moreover, infants in the HD group had 0.37 (95% CI: 0.14, 0.97; p = 0.042) times lower odds of developing moderate/severe BPD compared with the LD group. Infants receiving early HD caffeine had improved respiratory outcomes with no increase in measured comorbidities. Large prospective studies are needed to determine the long-term outcomes of using high-dose caffeine prophylaxis for preterm infants.

Challenges of antithrombotic therapy in the management of cardiovascular disease in patients with inherited bleeding disorders: A single-centre experience.

Cardiovascular events in patients with inherited bleeding disorders are challenging to manage. The risk of bleeding secondary to antithrombotic treatment must be balanced against the risk of thrombosis secondary to haemostatic therapy. Patients with inherited bleeding disorders with coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI) or atrial fibrillation (AF) from a single centre (2010-2018) are included. A total of 11 patients undergoing CABG (n=3), PCI (n=5) or with AF (n=3) and a diagnosis of haemophilia A (n=8), haemophilia B (n=1), factor XI deficiency (n=1) and von Willebrand disease (n=1) managed by a multidisciplinary team are reported. In patients undergoing CABG, factor levels were normalized for 7-10days with trough levels of 70-80% with severe patients continuing high-dose factor prophylaxis (trough 20-30%) three weeks post-operatively with daily aspirin. In a patient with mild haemophilia A and an inhibitor, recombinant factor VIIa dosing was monitored with thromboelastometry. For PCI, a 3rd-generation drug-eluting stent with one month of dual antiplatelet therapy in addition to high-dose prophylaxis as needed was preferred. Patients with AF and severe haemophilia did not receive antithrombotic treatment, and a thrombin generation assay was used to guide heparin dosing in mild haemophilia. Our experience demonstrates the importance of interdisciplinary communication to identify strategies that decrease the risk of bleeding and thrombosis. The use of extended, increased intensity prophylaxis facilitated antiplatelet therapy. Global assays may help balance the intensity of haemostatic and antithrombotic treatment.

Guideline-Discordant Preoperative Gentamicin Dosing and the Risk of Gentamicin Associated Nephrotoxicity in Urologic Surgery

ObjectiveTo determine the rate of and predictors for guideline-discordant preoperative gentamicin dosing in urologic surgery and to assess the risk of nephrotoxicity in patients who receive the recommended high-dose prophylaxis. Materials and MethodsWe retrospectively reviewed all adult patients who received preoperative gentamicin for urologic surgery from January 1, 2017 - October 3, 2019. Doses were categorized as guideline-concordant or -discordant using a cutoff of 4.5 mg/kg dosing weight. We used multivariable logistic regression to identify predictors for guideline-discordant dosing. Postoperative kidney injury was assessed using RIFLE criteria. ResultsAmong 2134 patients, 89% received a preoperative dose ≤ 4.5 mg/kg. Older age (70+ years) and endoscopic surgery were significant risk factors for guideline-discordant dosing (OR 2.54, P< 0.001; OR 6.21, P<0.001). Among 735 patients with complete data, there was no significant difference in the risk of kidney injury between those who received a dose less than 4.5 mg/kg and those who received a higher dose (OR 0.89, 95% CI: 0.26 – 2.99, P = 0.75). ConclusionPreoperative gentamicin is commonly administered at lower than recommended doses for urologic surgery. Older age and endoscopic surgery are significant predictors of guideline-discordant dosing. The risk of kidney injury following high-dose preoperative gentamicin for urologic procedures is likely comparable to the risk at lower doses.

Low Dose Factor VIII Prophylaxis in Hemophilia: Indian Perspective

Important complications of hemophilia are bleeding and joint deformity. Episodic treatment of hemophilia with Factor VIII arrests bleeding but not joint deformity. Thus there is a need to administer Factor VIII prophylactically to prevent bleeding and joint deformity. Apart from high dose prophylaxis practised in developing countries, low dose prophylaxis with 10-15 IU/ kg body weight twice/thrice a week is found to be quite effective in resource limited tropical country like India. Significant reduction in musculo-skeletal, visceral bleeding and joint deformity has been observed from various centres in India. Country wide awareness, including at district level, has happened now in India. Factor VIII is more freely supplied by Govt. agencies n o w.

Dosing of thromboprophylaxis and mortality in critically ill COVID-19 patients

BackgroundA substantial proportion of critically ill COVID-19 patients develop thromboembolic complications, but it is unclear whether higher doses of thromboprophylaxis are associated with lower mortality rates. The purpose of the study was to evaluate the association between initial dosing strategy of thromboprophylaxis in critically ill COVID-19 patients and the risk of death, thromboembolism, and bleeding.MethodIn this retrospective study, all critically ill COVID-19 patients admitted to two intensive care units in March and April 2020 were eligible. Patients were categorized into three groups according to initial daily dose of thromboprophylaxis: low (2500–4500 IU tinzaparin or 2500–5000 IU dalteparin), medium (> 4500 IU but < 175 IU/kilogram, kg, of body weight tinzaparin or > 5000 IU but < 200 IU/kg of body weight dalteparin), and high dose (≥ 175 IU/kg of body weight tinzaparin or ≥ 200 IU/kg of body weight dalteparin). Thromboprophylaxis dosage was based on local standardized recommendations, not on degree of critical illness or risk of thrombosis. Cox proportional hazards regression was used to estimate hazard ratios with corresponding 95% confidence intervals of death within 28 days from ICU admission. Multivariable models were adjusted for sex, age, body mass index, Simplified Acute Physiology Score III, invasive respiratory support, and initial dosing strategy of thromboprophylaxis.ResultsA total of 152 patients were included: 67 received low-, 48 medium-, and 37 high-dose thromboprophylaxis. Baseline characteristics did not differ between groups. For patients who received high-dose prophylaxis, mortality was lower (13.5%) compared to those who received medium dose (25.0%) or low dose (38.8%), p = 0.02. The hazard ratio of death was 0.33 (95% confidence intervals 0.13–0.87) among those who received high dose, and 0.88 (95% confidence intervals 0.43–1.83) among those who received medium dose, as compared to those who received low-dose thromboprophylaxis. There were fewer thromboembolic events in the high (2.7%) vs medium (18.8%) and low-dose thromboprophylaxis (17.9%) groups, p = 0.04.ConclusionsAmong critically ill COVID-19 patients with respiratory failure, high-dose thromboprophylaxis was associated with a lower risk of death and a lower cumulative incidence of thromboembolic events compared with lower doses.Trial registrationClinicaltrials.gov NCT04412304 June 2, 2020, retrospectively registered.

Ischemic-hemorrhagic stroke in patients with Covid-19

Coronavirus associated severe acute respiratory syndrome (SARS-CoV-2) causes a worldwide syndrome called Covid-19 that has caused 5,940,441 infections and 362,813 deaths until May 2020. In moderate and severe stages of the infection a generalized swelling, cytokine storm and an increment of the heart damage biomarkers occur. In addition, a relation between Covid-19 and neurological symptoms have been suggested. The results of autopsies suggest thrombotic microangiopathy in multiple organs. We present 2 cases of patients infected with severe Covid-19 that were hospitalized in the Reanimation Unit that presented cerebrovascular symptoms and died afterwards. A high dose prophylaxis with antithrombotic medication is recommended in patients affected by moderate to severe Covid-19.

Impact of central nervous system (CNS) prophylaxis on the incidence of CNS relapse in patients with high-risk diffuse large B cell/follicular grade 3B lymphoma

Although overall survival in diffuse large B cell lymphomas (DLBCL) has improved, central nervous system (CNS) relapse is still a fatal complication of DLBCL. For this reason, CNS prophylaxis is recommended for patients at high risk of CNS disease. However, no consensus exists on definition of high-risk patient and optimal CNS prophylaxis. Systemic high-dose methotrexate in combination with R-CHOP has been suggested as a potential prophylactic method, since methotrexate penetrates the blood-brain barrier and achieves high concentration in the CNS. In this retrospective analysis, we report treatment outcome of 95 high-risk DLBCL/FL grade 3B patients treated with R-CHOP or its derivatives with (N = 57) or without (N = 38) CNS prophylaxis. At a median follow-up time (51 months), CNS relapses were detected in twelve patients (12.6%). Ten out of twelve (83%) of CNS events were confined to CNS system only. Median overall survival after CNS relapse was 9 months. Five-year isolated CNS relapse rates were 5% in the prophylaxis group and 26% in the group without prophylaxis. These findings suggest that high-dose methotrexate-containing prophylaxis decreases the risk of CNS failure.

Initial High-Dose Prophylaxis and Extended Taper for Mushroom Keratoplasty in Vascularized Herpetic Scars

To report the outcomes of initial high-dose and extended taper of antiviral and steroid prophylaxis for the treatment of eyes with high-risk vascularized herpetic corneal scars that underwent 2-piece mushroom keratoplasty (MK). Prospective interventional case series. In this single-center study, 52 consecutive eyes with vascularized (≥2 quadrants) herpetic corneal scars underwent 2-piece microkeratome-assisted MK. Initial high-dose and extended taper of combined oral and topical antiviral and steroid prophylaxis was administered. Outcome measures were best spectacle-corrected visual acuity (BSCVA), refractive astigmatism (RA), endothelial cell density, immunologic rejection, herpetic recurrence, and graft failure rates. Excluding patients with vision-impairing comorbidities, baseline BSCVA (1.73 ± 0.67 logMAR) significantly improved annually during the first 2 years (P < .001, P= .016), reaching 0.17 ± 0.18 logMAR at year 2, and remaining stable up to 10 years (P= .662). At 2 years, 86% of eyes saw ≥20/40, 55% saw ≥20/25, and 18% saw ≥20/20 Snellen BSCVA. RA exceeded 4.5 diopters in 7% of cases after wound revision for high-degree astigmatism in 7 cases. Endothelial cell loss was 40.9% at 1 year with an annual decline of 3.1% over 10 years. The 10-year cumulative risk for immunologic rejection, herpetic recurrence, and graft failure was 9.7%, 7.8%, and 7.6%, respectively. Initial high dose and extended taper of antiviral and steroid prophylaxis for MK in high-risk, vascularized herpetic corneal scars achieves clinical outcomes that remain stable for up to 10 years after surgery with minimal risk of immunologic rejection, herpetic recurrence and graft failure.

Model‐based evaluation of low‐dose factor VIII prophylaxis in haemophilia A

The optimal treatment modality for haemophilia A is lifelong prophylaxis which is expensive and may not be implementable everywhere where factor VIII (FVIII) availability is limited. A less costly alternative to prophylaxis is low-dose prophylaxis (LDP) which was compared to conventional prophylaxis in this model-based simulation study. To explore whether LDP is motivated where standard prophylaxis is not implementable, including evaluating LDP efficacy compared to high-dose prophylaxis and investigating the potential economic benefit of individualized dosing. For a virtual adult haemophilia A population, FVIII activity levels were simulated following alternative treatment regimens, based on a published population PK model. The regimens included very LDP, LDP and conventional prophylaxis twice and thrice weekly. The annual probability of bleeding was predicted based on the weekly time spent below 1IU/dL, using a previously published relationship. Additionally, PK-based dose individualization was evaluated to determine FVIII savings using Bayesian forecasting. A treatment regimen of 10IU/kg administered thrice weekly cost 75% less than a standard high-dose regimen and was predicted to have a 5% higher median probability of annual bleeds. PK-based dose individualization may result in further cost-savings, but implementation needs benefit versus feasibility consideration. Based on simulations, a promising LDP regimen was identified that decreased treatment costs compared with standard high-dose prophylaxis at a small increase in bleeding risk. The results indicate that LDP is advocated where the standard-of-care is on-demand treatment; however, the results should be considered in the context of any limitations of the applied models.

Long-term clinical and economic outcomes in previously untreated paediatric patients with severe haemophilia A: A nationwide real-world study with 700 person-years.

For previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI). From the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use. Using linear mixed models, we analysed longitudinal clinical outcome data. To analyse skewed cost data, including zero costs, we applied hurdle regression. All 62 patients received early regular prophylaxis; totally, they have had treatment for nearly 700 patient-years. The median age of starting home treatment was 1.1years. The mean (SD) annual treatment costs (€perkg) were 4391€ (3852). For ages 1-3, ITI comprised over half of the costs; in other groups, prophylactic FVIII treatment dominated. With these high costs, however, clinical outcomes were desirable; median (IQR) ABR was low at 0.19 (0.07-0.46) and so was AJBR at 0.06 (0-0.24). Thirteen (21%) patients developed a clinically significant inhibitor, 10 (16%) with a high titre. All ITIs were successful. The mean costs for ITI were 383448€ (259085). The expected ITI payback period was 1.81 (95% CI 0.62-12.12) years. Early high-dose prophylaxis leads to excellent long-term clinical outcomes, and early childhood ITI therapy seems to turn cost-neutral generally already in 2years.

Is Continuous Low-Dose Prophylaxis Superior to On-Demand Treatment for Patients with Hemophilia?

Long-term (or continuous) prophylaxis is generally accepted as the best form of treatment for patients with severe hemophilia A and B. Results of recent prospective, randomized clinical trials, as well as observational studies performed in the last decades, have provided strong and convincing evidence that continuous prophylaxis leads to reduction in the number of bleeding episodes, better joint status and improved health-related quality of life as compared with on-demand (or episodic) treatment. Nevertheless, many questions regarding long-term prophylaxis still remain open, for instance: when should prophylaxis be started (before or after the first joint bleeding), what is the optimal dosage to replace the missing factor, when should discontinuation of long-term prophylaxis be considered, what is the best way to measure the outcome of prophylaxis, etc. Moreover, there are numerous obstacles to widespread use of prophylactic therapy. The most challenging seem to be adequate venous access (particularly in younger patients) and patients' adherence. The crucial barrier to long-term prophylaxis is, however, the remarkably high cost of clotting factor concentrates. For most countries high-dose or intermediate-dose prophylaxis regimens are not affordable due to lack of economic resources. So, is continuous prophylaxis reserved exclusively for wealthy societies? Fortunately, there is an increasing body of evidence to suggest that low-dose prophylaxis offers significant benefits over on-demand treatment with comparable amounts of factor concentrate (and much lower amounts if compared with intermediate or high-dose prophylaxis regimens). The aim of this article is to discuss the clinical and economical aspects of continuous prophylaxis in hemophilia with emphasis on the low-dose regimens.

Various regimens for prophylactic treatment of patients with haemophilia.

Haemophilia prophylaxis is superior to on-demand treatment to prevent joint damage. 'High-dose prophylaxis' as used in Sweden is more effective in preventing arthropathy than an 'intermediate-dose regimen' (the Netherlands) and the Canadian tailored primary prophylaxis. Prophylaxis may reduce the risk of developing inhibitors. There is no difference in inhibitor risk between plasma derived and recombinant factor VIII (rFVIII) products but the Rodin study showed increased risk with second-generation rFVIII products. MRI is a new and very sensitive tool to detect the symptoms of early arthropathy but some results (soft tissue changes in 'bleed-free joints') still need to be investigated. Ultrasound is a very helpful method to aid diagnosis especially during the acute phase of a bleed. The risk of infection with central venous access remains a matter of debate. A fully implanted central venous access device (CVAD) has a significant lower risk of infection compared to external CVADs. Patient's age under 6yr and inhibitor presence are additional risk factors for infections. The role of arteriovenous fistulae needs to be investigated because significant complications have been reported. Disease-specific quality of life instruments are complementary to generic instruments evaluating QoL in patients with haemophilia and have become important health outcome measures.

Long-Term Outcomes Of a Small Cohort At a Single Canadian Centre Of Severe Subunit A FXIII Deficient Patients (F13A1: c.691-1G>A) Treated Prophylactically With Fibrogammin P

IntroductionFactor XIII (FXIII) deficiency is an extremely rare autosomal recessive bleeding disorder with a reported prevalence of 1 in 5 million people worldwide. The adult hemophilia clinic in St. John's, NL, Canada manages 5 patients with severe FXIII deficiency and 1 heterozygote. 3 of the 5 severe FXIII patients are siblings. Another sister died of intracranial hemorrhage after trauma. These 3 FXIII patients were also found to have a FXII deficiency, and were described in 1970 in Pediatrics by Mary Hanna shortly after their diagnosis. All 5 of the patients in our cohort report a very strongly positive bleeding history prior to beginning prophylaxis with Fibrogammin P at a dose of 10 U/kg every 3-4 weeks. One heterozygote patient has so far had minimal bleeding. Here we report the bleeding scores of the 5 severely deficient patients prior to and after beginning prophylaxis with Fibrogammin P in 1996. A recombinant FXIII A-subunit concentrate was licensed in Canada in 2012. Therefore treating clinicians now have a choice of therapy for their patients. This product recommends prophylaxis at a dose of 35 U/kg. This product is considerably more expensive than the plasma-derived product currently used. Fibrogammin P is not currently licensed in Canada. MethodsBleeding scores are an important tool to quantify the bleeding history of a patient. The bleeding score that was used to score this FXIII cohort is the MCMDM–1VWD. A study by Bowman et al. calculated the bleeding scores of 100 healthy subjects (35 males, 65 females. These subjects were found to have a mean bleeding score of 0.16 with a standard deviation of 1.7. A bleeding score of equal to or greater than 4 is considered abnormal. ResultsThe bleeding scores of our cohort ranged from 19 to 29 with a mean score of 23.7 prior to starting prophylaxis with Fibrogammin P. Four out of five patients reported significant umbilical cord bleeding, 1 or more episode of intracranial hemorrhage, hemarthrosis, or at least 1 major bleed post surgery prior to starting prophylaxis on Fibrogammi P. After starting Fibrogammin P, patients report very little bleeding, and score in the normal range for the period they have been on prophylaxis. These patients were exposed to hepatitis B and C, but not HIV through prior exposure to blood products. There were no further seroconversions since starting therapy with Fibrogammin P. Three of these patients underwent 7 surgeries, receiving either 10-20 U/kg of Fibrogammin either 1 or 2 days prior to surgery and 10 U/kg for 5 days post-surgery. Patients and physicians reported very satisfactory outcomes. Only one patient had a breakthrough bleed on prophylaxis. He required a transfusion of packed cells and an extra treatment of Fibrogammin P for significant rectal bleeding due to internal hemorrhoids. In this very small group of patients no clinically significant inhibitor to FXIII has been documented. DiscussionSome studies reported in the literature suggest that it is important to keep FXIII levels above 10% to prevent spontaneous hemorrhage. Although our patients are doing well, we know their trough FXIII levels run from 0.2 to 0.5%. Choosing the optimal dose and optimal therapy for these patients is now more nuanced. As patients have had good outcomes to date on low dose Fibrogammin prophylaxis, switching to either high dose prophylaxis with Fibrogammin or recombinant FXIII to keep trough FXIII levels above 10% will result in approximately a 4 or 38.5-fold increase in cost respectively for prophylaxis alone. These estimations do not include any extra therapy required. On the other hand it is essential to make every effort to prevent intracranial hemorrhage. Disclosures:No relevant conflicts of interest to declare.

Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s

AbstractProphylactic treatment in severe hemophilia is very effective but is limited by cost issues. The implementation of 2 different prophylactic regimens in The Netherlands and Sweden since the 1970s may be considered a natural experiment. We compared the costs and outcomes of Dutch intermediate- and Swedish high-dose prophylactic regimens for patients with severe hemophilia (factor VIII/IX < 1 IU/dL) born between 1970 and 1994, using prospective standardized outcome assessment and retrospective collection of cost data. Seventy-eight Dutch and 50 Swedish patients, median age 24 years (range, 14-37 years), were included. Intermediate-dose prophylaxis used less factor concentrate (median: Netherlands, 2100 IU/kg per year [interquartile range (IQR), 1400-2900 IU/kg per year] vs Sweden, 4000 IU/kg per year [IQR, 3000-4900 IU/kg per year]); (P < .01). Clinical outcome was slightly inferior for the intermediate-dose regimen (P < .01) for 5-year bleeding (median, 1.3 [IQR, 0.8-2.7] vs 0 [IQR, 0.0-2.0] joint bleeds/y) and joint health (Haemophilia Joint Health Score >10 of 144 points in 46% vs 11% of participants), although social participation and quality of life were similar. Annual total costs were 66% higher for high-dose prophylaxis (mean, 180 [95% confidence interval, 163 - 196] × US$1000 for Dutch vs 298 [95% confidence interval, 271-325]) × US$1000 for Swedish patients; (P < .01). At group level, the incremental benefits of high-dose prophylaxis appear limited. At the patient level, prophylaxis should be tailored individually, and many patients may do well receiving lower doses of concentrate without compromising safety.