Low-dose Prophylaxis Research Articles

Prophylaxis re-visited: The potential impact of novel factor and non-factor therapies on prophylaxis.

Prophylaxis re-visited: The potential impact of novel factor and non-factor therapies on prophylaxis.

Fluconazole non-susceptible breakthrough candidemia after prolonged low-dose prophylaxis: a prospective FUNGINOS study

ObjectivesBreakthrough candidemia (BTC) on fluconazole was associated with non-susceptible Candida spp. and increased mortality. This nationwide FUNGINOS study analyzed clinical and mycological BTC characteristics. MethodsA 3-year prospective study was conducted in 567 consecutive candidemias. Species identification and antifungal susceptibility testing (CLSI) were performed in the FUNGINOS reference laboratory. Data were analyzed according to STROBE criteria. Results43/576 (8%) BTC occurred: 37/43 (86%) on fluconazole (28 prophylaxis, median 200 mg/day). 21% BTC vs. 23% non-BTC presented severe sepsis/septic shock. Overall mortality was 34% vs. 32%. BTC was associated with gastrointestinal mucositis (multivariate OR 5.25, 95%CI 2.23–12.40, p < 0.001) and graft-versus-host-disease (6.25, 1.00–38.87, p = 0.05), immunosuppression (2.42, 1.03–5.68, p = 0.043), and parenteral nutrition (2.87, 1.44–5.71, p = 0.003). Non-albicans Candida were isolated in 58% BTC vs. 35% non-BTC (p = 0.005). 63% of 16 BTC occurring after 10-day fluconazole were non-susceptible (Candida glabrata, Candida krusei, Candida norvegensis) vs. 19% of 21 BTC (C. glabrata) following shorter exposure (7.10, 1.60–31.30, p = 0.007). Median fluconazole MIC was 4 mg/l vs. 0.25 mg/l (p < 0.001). Ten-day fluconazole exposure predicted non-susceptible BTC with 73% accuracy. ConclusionsOutcomes of BTC and non-BTC were similar. Fluconazole non-susceptible BTC occurred in three out of four cases after prolonged low-dose prophylaxis. This implies reassessment of prophylaxis duration and rapid de-escalation of empirical therapy in BTC after short fluconazole exposure.

Participant experiences of clean intermittent self-catheterisation, urinary tract infections and antibiotic use on the ANTIC trial – A qualitative study

BackgroundRecurrent urinary tract infections are a commonly reported problem in people who use clean intermittent self-catheterisation. Yet there is a lack of knowledge regarding both the impact on people’s lives, the use of prophylactic anti-biotics and perceptions of patients on their use. AimsTo explore the views and experiences of adults who use clean intermittent self-catheterisation for long-term bladder conditions, with a focus on urinary tract infection experience and prophylactic antibiotic use. DesignA qualitative descriptive study. MethodsTwenty-six semi-structured qualitative interviews were conducted with individuals recruited from the ANTIC Trial (Antibiotic treatment for intermittent bladder catheterisation: A randomised controlled trial of once daily prophylaxis). Participants were intermittent self-catheter users aged 18 years or older. Interviews took place between August 2015 and January 2016. Transcript data were analysed thematically. FindingsThree overarching topics were revealed with corresponding themes: the experiences of intermittent self-catheterisation and urinary tract infections (normalisation, perceived burden); attitudes towards antibiotics for urinary tract infection treatment (nonchalant attitudes, ambivalence towards antibiotic resistance); and experiences of low-dose prophylaxis antibiotics (habitual behaviour and supportive accountability). ConclusionThe emotional and practical burden of catheter use and urinary tract infection was considerable. Beliefs pertaining to antibiotic use were based on utility, gravity of need and perceived efficacy. These opinions were often influenced by clinician recommendations.

Prolonged Low-Dose Prophylaxis With Valganciclovir in Cytomegalovirus-Negative Recipients of Kidney Transplants From Cytomegalovirus-Positive Donors Allows Seroconversion and Prevents Cytomegalovirus Disease

BackgroundCytomegalovirus-negative recipients of kidneys from cytomegalovirus (CMV)-positive donors (D+/R−) are at high risk to develop severe clinical manifestations of CMV disease. Long-term data about incidence and timing of CMV seroconversion, CMV disease, and the influence of prolonged valganciclovir prophylaxis on the clinical course of CMV infection are missing. MethodsWe conducted a retrospective long-term study of 89 consecutive CMV D+/R− kidney transplant recipients transplanted between 2003 and 2012. All recipients received valganciclovir prophylaxis after transplantation (median 187 [126-261] days) with a median dose of 213 (181-338) mg/d. Long-term outcome was assessed over a maximum of 10 years post-transplant. ResultsDuring follow-up (median 62 months) 60 of 89 (67%) patients had CMV seroconversion, and 29 of 89 (33%) developed symptomatic CMV disease. In addition, in 38 of the 60 (63%), seroconversion occurred during prophylaxis (median 154 days post-transplant), and in 22 patients, after the end of prophylaxis (median 320 days after transplantation). Baseline characteristics of the 2 groups did not differ significantly. Seroconversion during prophylaxis vs seroconversion after the end of prophylaxis was associated with significantly lower incidence of CMV disease (34% vs 73%, P = .007), less severe CMV disease (16% vs 64%, P < .001), and fewer organ manifestations (26% vs 64%, P = .006). The risk of CMV disease was limited to the first 475 days after transplantation. Valganciclovir resistance occurred in just 1 case (1%). ConclusionsProlonged prophylaxis with low-dose valganciclovir allowed CMV seroconversion during prophylaxis in a high proportion of D+/R− patients. Seroconversion occurred after a median of 154 days and was associated with significantly lower incidence of CMV disease, less severe CMV disease, and fewer CMV complications.

Influence of medical insurance schemes and charity assistance projects on regular prophylaxis treatment of the boys with severe haemophilia A in China.

To explore the influence of medical insurance policy and charity assistance projects on the uptake and discontinuation of regular prophylaxis treatment in Chinese severe haemophilia A children. This retrospective study was conducted on children with severe haemophilia A, who received FVIII prophylaxis treatment at 12 haemophilia centres in China from 1 November 2007 to 31 May 2013. The average duration of prophylaxis treatment received by haemophilia children significantly increased from 16.7weeks in 2008 to 32.8weeks in 2012 (P<.001). The main reason for prophylaxis acceptance included dissatisfaction with previous "on-demand" regimens, availability of improved local medical insurance policies and patient/family awareness of haemophilia. The main reason for subsequent discontinuation of prophylaxis was economic instability. The upper limit of insurance was up to RMB 150000/y (~USD: 22000/y) for 80.1% of the insured patients and would be sufficient to cover the continuous low-dose prophylaxis regimen. However, for many patients the burden of out-of-pocket copayment cost represented a risk for poor adherence to regular prophylaxis. In about two third of the patients, the annual out-of-pocket copayment cost amounted to >50% of their average annual disposable income. Many patients therefore required assistance from the charity assistance projects, but nonadherence remained prevalent. Medical insurance policy and charity assistance projects helped haemophilia children to accept and continue prophylaxis regimens. It was the proportion of the out-of-pocket copayment cost rather than the upper limit of insurance reimbursement that restricted long-term regular low-dose prophylaxis in China.

Recurrent Urinary Tract Infection in Women

The purpose of this review is to discuss the pathophysiology, diagnosis, treatment, and prevention of recurrent urinary tract infection (UTI) in the setting of antimicrobial stewardship. Although recurrent UTI was traditionally thought to occur by repeated ascension of uropathogenic colonizers, newer evidence suggests that a subset of bacteria becomes internalized within uroepithelial cells forming quiescent intracellular reservoirs. These quiescent reservoirs do not elicit an immune response and persist after treatment of acute infection. In time, epithelial turnover results in release of these bacteria potentially leading to recurrent infection. Given the rise in antimicrobial resistance, the concept of antimicrobial stewardship has been developed to promote appropriate use of antimicrobials, improve patient outcomes, decrease microbial resistance, and reduce the spread of infections caused by multidrug-resistant organisms. This has sparked interest in non-antimicrobial measures for UTI prevention. Although cranberry products and probiotics may prevent UTI, the data for their efficacy are limited. Current evidence supports vaginal estrogen use for UTI prevention in postmenopausal women. Daily or post-coital low-dose antimicrobial prophylaxis may also be beneficial, particularly for women who develop UTI despite non-antimicrobial measures. Nevertheless, studies demonstrating the efficacy of antimicrobial prophylaxis are > 10 years old when antibiotic resistance was less common. Prevention of recurrent UTI requires identifying and addressing risk factors for infection. Non-antimicrobial strategies should be recommended whenever possible given increasing antimicrobial resistance. However, more studies are needed to define the ideal populations that may benefit from current non-antimicrobial strategies and to identify other potential ways UTI may be prevented.

Bypassing agent prophylaxis in people with hemophilia A or B with inhibitors.

People with hemophilia A or B with inhibitors are at high risk of bleeding complications. Infusion of bypassing agents, such as recombinant activated FVII (rFVIIa) and plasma-derived activated prothrombin complex concentrate, are suggested as alternative therapies to factor VIII (haemophilia A) or IX (haemophilia B) for individuals who no longer respond to these treatments because they develop inhibitory antibodies. The ultimate goal of treatment is to preserve the individual's joints, otherwise destroyed by recurrent bleeds. To assess the effects of bypassing agent prophylaxis to prevent bleeding in people with hemophilia A or B and inhibitors. We searched for relevant studies from the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries (16 February 2017) and bibliographic references of retrieved studies were reviewed for potential articles to be included in the review.Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Coagulopathies Trials Register: 12 December 2016. We included randomized and quasi-randomized controlled studies (cross-over or parallel design) evaluating the effect of prophylaxis treatment with bypassing agents compared with on-demand treatment, or studies evaluating the effects of high-dose compared with low-dose prophylaxis in males of any age with hemophilia with inhibitors. Two authors independently selected studies and extracted data and assessed the risk of bias according to standard Cochrane criteria. They assessed the quality of the evidence using the GRADE criteria. We included four randomized studies (duration 7 to 15 months) involving 116 males. Risk of bias was judged to be high in two studies due to the open-label study design and in one study due to attrition bias.Two studies compared on-demand treatment to prophylaxis with bypassing agents. In one study (34 males) prophylaxis significantly reduced mean overall bleeding rates, MD - 7.27 (95% CI -9.92 to -4.62) (low quality evidence), mean number of overall bleeding events per month, MD -1.10 (95% CI -1.54 to -0.66), mean number of hemarthrosis, MD -6.60 (95% CI -9.32 to -3.88) (low quality evidence) and mean number of joints that had hemarthrosis, MD -0.90 (95% CI -1.36 to -0.44). The meta-analysis did not conclusively demonstrate significant benefit of prophylaxis on health-related quality of life as measured by Haem-A-QoL score, EQ-5D total score and utility score, EQ-5D VAS and SF-36 physical summary and mental summary score (low quality evidence for all health-related quality of life analyses).The remaining two studies compared dose regimens. The results from one study (22 males) did not conclusively demonstrate benefit or harm of high-dose versus low-dose recombinant activated factor VIIa (rFVIIa) as a prophylaxis for overall bleeding rate, MD -0.82 (95% CI -2.27 to 0.63) (moderate quality evidence), target joint bleeding rate, MD -3.20 (95% CI -7.23 to 0.83) (moderate quality evidence) and serious adverse events, RR 9.00 (95% CI, 0.54 to 149.50) (moderate quality evidence).The overall quality of evidence was moderate to low due to imprecision from limited information provided by studies with small sample sizes and incomplete outcome data in one study. The evidence suggests that prophylaxis with bypassing agents may be effective in reducing bleeding in males with hemophilia with inhibitors. However, there is a lack of evidence for the superiority of one agent over the other or for the optimum dosage regimen. Further studies are needed to evaluate the benefits and harms of prophylaxis treatment on health-related quality of life, as well as the effects of dose of bypassing agents on the outcomes.

Efficacy of standard prophylaxis versus on-demand treatment with bayer's sucrose-formulated recombinant FVIII (rFVIII-FS) in Chinese children with severe hemophilia A

ABSTRACTIn China, care of patients with severe hemophilia primarily involves insufficient dosing of on-demand treatment and secondary low-dose prophylaxis (10 IU/kg 2× /wk). We sought to evaluate 3× /wk, standard-dose prophylaxis with sucrose-formulated recombinant factor VIII (rFVIII-FS; Bayer) compared with on-demand treatment in Chinese children with severe hemophilia A. Children and adolescents aged 2–16 years with severe hemophilia A, no inhibitors, and no prophylaxis for >6 consecutive months before study entry were eligible for this 24-week, interventional, sequential-treatment study. Patients received rFVIII-FS on demand for 12 weeks followed by a 12-week prophylaxis period (25 IU/kg 3× /wk). The primary efficacy endpoint was comparison of the annualized bleeding rate (ABR) of all bleeds in the prophylaxis versus on-demand phase. Additional variables included ABR of joint bleeds, school attendance/activity, daily activity, and hemophilia Joint Health Score (HJHS). Thirty patients (median age, 12 years) were treated and analyzed. Compared with on-demand treatment, prophylaxis reduced median (quartile [Q1; Q3]) ABR of all bleeds (57.5 [44.5; 73.9] vs 0 [0; 4.0]) and joint bleeds (34.5 [26.1; 56.5] vs 0 [0; 4.0]). Median (range) total HJHS improved after both the prophylaxis and on-demand phases (8.0 [0–48.0] and 11.0 [0–55.0], respectively) compared with baseline (16.0 [0–56.0]). School attendance/activity and daily activity improved with prophylaxis versus on demand. No inhibitors or treatment-related adverse events were reported. In this first prospective, standard-dose, secondary prophylaxis study in China, rFVIII-FS prophylaxis reduced bleeding and improved health outcomes versus on-demand treatment in children with severe hemophilia A.

Low-dose prophylaxis for Chinese haemophilia children involving maxillary haemophilic pseudotumours

Low-dose prophylaxis for Chinese haemophilia children involving maxillary haemophilic pseudotumours

Low-dose factor VIII infusion in Chinese adult haemophilia A patients: pharmacokinetics evidence that daily infusion results in higher trough level than with every-other-day infusion with similar factor VIII consumption.

Pharmacokinetics (PK) modelling suggests improvement of trough levels are achieved by using more frequent infusion strategy. However, no clinical study data exists to confirm or quantify improvement in trough level, particularly for low-dose prophylaxis in patients with haemophilia A. To provide evidence that low dose daily (ED) prophylaxis can increase trough levels without increasing FVIII consumption compared to every-other-day (EOD) infusion. A cross-over study on 5 IU kg-1 FVIII daily vs. 10 IU kg-1 EOD infusions, each for 14 days was conducted at the PUMCH-HTC. On the ED schedule, trough (immediate prior to infusion), and peak FVIII:C levels (30 min after infusion) were measured on days 1-5; and trough levels alone on days 7, 9, 11 and 13. For the EOD schedule, troughs, peaks and 4-h postinfusion were measured on day 1; troughs and peaks on days 3, 5, and 7; troughs alone on days 9, 11 and 13 and 24-h postinfusion on days 2, 4 and 6. FVIII inhibitors were assessed on days 0 and 14 during both infusion schedules. Six patients were enrolled. PK evidence showed that daily prophylaxis achieved higher (~2 times) steady-state FVIII trough levels compared to EOD with the same total factor consumption. The daily prophylaxis had good acceptability among patients and reduced chronic pain in the joints in some patients. Our PK study shows low-dose factor VIII daily infusion results in higher trough level than with EOD infusion with similar factor VIII consumption in Chinese adult haemophilia A patients.

411: The impact of low dose versus high dose antibiotic prophylaxis regimens on surgical site infection rates after cesarean delivery

To determine if high dose antibiotic prophylaxis prior to cesarean delivery (CD) decreases the risk of postoperative wound infection compared with low dose. Two preoperative antibiotic regimens were compared: Low dose (cefazolin 1 g unless BMI > 35 kg/m2 then 2 g) and high dose (cefazolin 2 g unless BMI > 35 kg/m2 then 3 g). The primary outcome was surgical site infection (SSI) based on the Centers for Disease Control and Prevention criteria. Sample size of 343 patients per group was calculated for a 50% reduction in risk for SSI. Univariable and multivariable logistic regression analyses were performed and a P<0.05 was considered statistical significant. A total of 730 women were included. Demographics are shown in Table 1. During this period the incidence of SSI was 5%. On univariable analysis, women who had SSI were more likely to be Caucasian, Black, smokers, hypertensive and had a higher estimated blood loss at delivery (Table 2). The rate of SSI did not differ between the low and high dose groups (14/367 (4%) vs 19/365 (5%), P=0.38). The rate of SSI in high vs low remain no different after adjusting for the above covariates (aOR 1.75, 95% CI [0.91-4.40]; (Table 3). Higher dosages of antibiotic prophylaxis did not decrease the rates of SSI compared to the usual doses. Further Level 1 randomized clinical trials are needed to support our observation.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Low dose prophylaxis in Tunisian children with haemophilia.

Low dose prophylaxis could be recommended in countries with limited resources. We report our single centre experience in children with haemophilia. Fifty-five children were included in our study with a weekly median dose of 30 UI kg-1 given once, twice or thrice a week. Age of initiation of prophylaxis is 5.32 years (0.64-11.44). Outcome assessment used were number of bleeding before and after initiating prophylaxis, haemophilia joint health score (HJHS), functional independence score in haemophilia (FISH) and quality of life with the Haemo-QoL. Reduction of number of bleeding was clear in all patients; HJHS, FISH and Haemo-QOL were satisfactory. Low dose prophylaxis is effective and better than on-demand therapy. It should be the starting point for prophylaxis in countries with limited resources.

The Efficacy of Recombinant FVIII Low-Dose Prophylaxis in Chinese Pediatric Patients With Severe Hemophilia A: A Retrospective Analysis From the ReCARE Study

This study explores the efficacy of recombinant factor VIII (rFVIII) low-dose prophylaxis in Chinese pediatric patients with severe hemophilia A from the Retrospective Study in Chinese Pediatric Hemophilia A Patients With rFVIII Contained Regular Prophylaxis (ReCARE) population. This is additional analysis of the multicenter, retrospective ReCARE study, in which the annual bleeding rate (ABR), annual joint bleeding rate (AJBR), and safety of >12-week, low dose (10-30 IU/kg/wk) rFVIII prophylaxis divided into primary, secondary, and tertiary groups based on the joint status and joint bleeding history were analyzed. A total of 57 patients (median age: 8.2 [0.4-17.3] years) from the ReCARE study receiving primary (n = 3), secondary (n = 21), and tertiary (n = 33) prophylaxes were included. Low-dose prophylaxis had significant bleeding reduction in all 3 groups compared to the baseline ( S = 408.5, P < .001), with median ABR rates of -4.0 (-8.0 to -3.1), -4.0 (-24.0 to 8.0), and -13.9 (-110.6 to 20.6) in the primary, secondary, and tertiary groups, respectively, with a significant difference between the secondary and tertiary groups ( P = .008). Median AJBR reduction rates were -2.3 (-6.3 to 8.4) and -14.9 (-61.5 to 19.1) in the secondary and tertiary groups, respectively. But there was no significant difference in AJBRs between the secondary and tertiary groups ( P = .061), which was related to damaged joint status. Hence, longer prophylaxis was associated with better prevention of joint bleeding ( P = .024). Despite significant ABR/AJBR reduction in all 3 groups, the efficacy of the primary prophylaxis was better than the secondary and tertiary prophylaxes.

Intermediate-Dose Tertiary Prophylaxis Show a Better Joint Protection in Adults with Severe Hemophilia Than Low-Dose Patterns

Background and Introduction:Prophylaxis treatment is considered optimal care for patients with severe hemophilia during childhood to prevent bleeding and reduce the incidence of joint disability. However, tertiary prophylaxis may also benefit Adults with Severe Hemophilia, but the optimal dose tailoring of FVIII is still unknown. We initiated a study to compare the low-dose and intermediate-dose regimen for tertiary prophylaxis in adults with severe hemophilia A.Methods:Patients with severe hemophilia A (F VIII < 1%) born between January, 1978, and January, 1988, who were treated at the hemophilia treatment centre at Nanfang hospital and treatment data available were eligible for enrollment in the study. The main exclusion criteria were a history of FVIII inhibitor (titer ≥ 0.6BU [Bethesda unit]), detectable FVIII inhibitors at screening (titer ≥ 0.4 BU), chronic liver disease, immunodficiency, another hemostatic defect and the need for major surgery. A total of 40 adults with severe hemophilia were enrolled, including 25 patients with low-dose prophylaxis (5-10 IU/kg twice a week) and 15 patients with intermediate-dose prophylaxis ( FVIII 15-20 IU/kg twice a week). Breakthrough acute bleedings were treated according to the regular practice and guidelines.Results:The study was conducted over a 2-year period (January 2014 to December 2015).Compared to low-dose prophylaxis group, Intermediate-dose tertiary prophylaxis group reduced the annual number of total and joint bleeds (median 13 vs 5.5 and median 10 vs 4; P= 0.001, respectively), and annual target joint bleeding rate were also significantly lower (median 8 vs. 3.5, P =0.002). The breakthrough bleeding events were largely lower in intermediate-dose group than in low-dose group (P=0.03). After prophylaxis, the FISH score in Intermediate-dose group increased from median 21 (range 15-28) to median 24 (range 17-28) (P=0.02) and in low-dose group from median 22 (range 14-28) to median 24 (range 14-28) (P=0.02) respectively. The improvement of FISH score were different between two groups (P=0.04). Meanwhile, The Health-related Qualityof life (HRQoL) in patients with severe hemophilia were measured by the SF-36. The SF-36 score showed better results in terms of overall perceived health status between patients with Intermediate-dose and with low-dose prophylaxis (P < 0.01).Conclusion:Compared to low-dose prophylaxis, Intermediate-dose tertiary prophylaxis may show a better joint protection in Adults with Severe Hemophilia, for Intermediate-dose regimen not only means less joint bleeding, but also helps joint function restore and Quality of life improvement. Our study established that Intermediate-dose tertiary prophylaxis may be a better choice for adults in a number of hemophilia treatment centers in China. DisclosuresNo relevant conflicts of interest to declare.

Low Dose Secondary/Tertiary Prophylaxis Is Feasible and Effective in Resource Limited Setting in South India for Children with Hemophilia

Prophylaxis for Hemophilia is globally accepted as a treatment strategy compared to on-demand therapy in the care of persons with hemophilia (PwH) . Prophylaxis is rarely practized in low and middle income countries due to several reasons such as ill-affordability of clotting factor concentrates ( CFCs), lack of awareness, absence of comprehensive / home care infrastructure and misconcepts regarding treatment among general population.The South Indian state of Kerala had been providing CFCs free of cost for on-demand treatment. A recent initiative was started in Hemophilia Treatment Centre(HTC), Aluva , Ernakulam district to provide secondary/tertiary prophylaxis free of cost to children with severe hemophilia (Factor level <1%, aged 5-15 yrs) as a joint effort from HTC and the local government.A clinical audit was done in 11 children at this center for a period of twelve months (6 months retrospectively for on-demand treatment and 6 months prospectively for prophylactic treatment). Among all patients with severe hemophilia, eight have Hemophilia A and the remaining three have Hemophilia B. They were previously treated with CFCs/plasma/cryoprecipitate, a few of them had established joint disease and all of them had absence of inhibitors. These children were initiated on low dose prophylaxis with plasma derived CFCs. Factor VIII concentrate was given at a dose of 20-40 U/kg in 2 divided doses per week for Hemophilia A and Factor IX concentrate at 25-40 U/Kg once a week for Hemophilia B. Outcomes were measured at two time points - at the end of secondary/tertiary prophylactic treatment period and at the end of preceding six months of on-demand treatment. The variables taken as outcome measures were changes in bleed rates, Hemophilia joint health score (HJHS), Functional independence score in Hemophilia (FISH), hospitalization rates and school absenteeism.A reduction in the bleed rate was seen from the transition of on demand treatment to secondary/tertiary prophylactic treatment (14.9 vs 0.91, p 0.005). Similar reductions were seen for hospitalization rates (12.45 vs 2.36 days, p 0.005) and school absenteeism (78.55 vs 1.27 days, p 0.01) respectively(Fig 1 a). FISH and HJHS scores were either maintained or improved during the prophylaxis period.(Fig 1b, 1c). None of the children developed inhibitors during the study period. The estimated cost of CFCs for on demand treatment per patient was 1314.4 USD and 1691.8USD during prophylaxis. The factor consumption for on demand treatment for 6 months was 968.24 IU/Kg and that of secondary/tertiary prophylaxis was 1077.96 IU/Kg respectively.We conclude that low dose prophylaxis for severe Hemophilia in a developing economy is feasible and has marked clinical benefits with greater well-being when compared to on demand therapy. In countries with resource constraints low dose secondary/tertiary prophylaxis should be considered as a therapeutic option over on demand therapy for children with severe Hemophilia in the light of its potential benefits . [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Anticoagulation Prophylaxis in Asparaginase-Based Therapy in Adults with Acute Lymphoblastic Leukemia

▪Background:Venous thromboembolism (VTE) is a well-known complication in adults receiving asparaginase (ASNase) based intensification chemotherapy for acute lymphoblastic leukemia (ALL). We previously reported a high VTE rate in patients receiving a modified Dana Farber Cancer Institute (DFCI) intensification phase, which included weekly ASNase. We report thrombosis rates during induction and the results using two different dosing schedules of enoxaparin as primary VTE prophylaxis in adults treated with the same protocol.Methods:We reviewed pts who received induction chemotherapy, without VTE prophylaxis, using DFCI protocol (containing one dose of ASNase) between 2012-2016. Pts achieving complete remission (CR) subsequently received weekly ASNase-based modified DFCI intensification phase for at least 7 cycles (21 weeks) with VTE prophylaxis, using two dosing schedules in consecutive cohorts: A. Low-dose group received enoxaparin 40 mg subcutaneously (SC) daily for patients weighing < 80 kg and 60 mg daily for those ≥ 80 kg; B. Dose-escalated group received enoxaparin 1 mg/kg SC daily (rounded to the nearest 20 mg).VTE rates were calculated for pts during induction and intensification phase (low-dose and escalated dose prophylaxis). Results were compared to a similar group of 99 pts previously treated with the same DFCI protocol who did not receive VTE prophylaxis during intensification. Patients not achieving CR, relapsing, undergoing alloSCT after induction, not completing at least 21 weeks of intensification phase or developing VTE before induction were not included.Results:The VTE rate during induction (n-=144) was 2.8%. Of 111 pts who received intensification prophylaxis, the overall VTE rate was 19.8% (p<0.001 compared to induction). Of 41 patients who received low-dose prophylaxis, the VTE rate was 26.8%, while the VTE rate in the dose-escalated prophylaxis group was 15.7%. This compared to a 27.3% rate in the historical non-prophylaxis group (Table 1). There was no significant difference among intensification groups (no prophylaxis, low-dose, and dose-escalated) with respect to median age, gender, weight and number of treatment cycles.The actual mean dose of enoxaparin in the low-dose prophylaxis group was 0.62 mg/kg, as compared to 0.90 mg/kg in the dose-escalated group. There were no major bleeding complications observed in the prophylaxis groups. The minor bleeding rate in the entire prophylaxis cohort was 4.5% (5/111), and was similar between the low-dose and escalated dose groups. Sites of VTE in the prophylaxis groups included lower extremity (11 cases), sagittal sinus (3), subclavian line related (5), pulmonary embolism (9), and cardiac thrombus (1); some patients had more than one site involved.Conclusions:Our data confirmed a high VTE rate during intensification, even with prophylaxis. Dose-escalation of enoxaparin to 1 mg/kg was safe with a trend toward reduction in VTE rates, particularly in patients weighing > 80 kg; however, a larger cohort would be needed to determine if this difference is significant. The use of novel anticoagulants in this setting could be considered. [Display omitted] DisclosuresSchuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Schimmer:Novartis: Honoraria.

Modelling lifelong effects of different prophylactic treatment strategies for severe haemophilia A.

Lifelong prophylactic replacement therapy with clotting factor concentrates is recommended for severe haemophilia. The prophylactic dose determines both clinical outcome and treatment cost. In the absence of clinical studies, computer simulation was used to explore lifelong effects and clotting factor consumption for various prophylactic dose levels, and optimize strategies for switching between prophylactic and on-demand treatment. Individual patients' lifetime joint bleeds, radiological arthropathy (Pettersson score, 0-78) and consumption were simulated for each treatment strategy. Treatment effectiveness (expressed as % of patients maintaining a lifetime Pettersson score ≤14) and clotting factor consumption were modelled for lifelong prophylaxis at dose levels 1000-4500 IU kg(-1) year(-1) , for on-demand treatment and for switching strategies. Treatment efficiency (consumption per unit of effectiveness) was used to compare strategies. Compared to lifelong on-demand treatment, lifelong prophylaxis at 1000 IU kg(-1) year(-1) increased effectiveness from 21 to 36%, at an additional consumption of 0.9 × 10(6) IU kg(-1) . For lifelong prophylaxis, each additional 1000 IU kg(-1) year(-1) resulted in a proportional increase in consumption by ±5 × 10(6) IU kg(-1) but a less than proportional reduction in arthropathy by ±50%; consequently, increasing consumption progressively diminished treatment efficiency. Switching strategies slightly reduce effectiveness and consumption. Optimum switching criteria were similar across prophylactic dose levels. According to the simulation model, low-dose prophylaxis (1000 IU kg(-1) year(-1) ) improved outcome at a limited increase in consumption compared to on-demand treatment. Increasing prophylactic dose further improved health outcomes, but at decreasing efficiency. Optimal prophylactic dose should therefore be selected balancing acceptable health impact and available budget.

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.

Safety of using escalated doses of enoxaparin prophylaxis in adults with acute lymphoblastic leukemia receiving asparaginase-based intensification therapy.

141 Background: Venous thromboembolism (VTE) is a known complication in adults receiving asparaginase (ASNase) for acute lymphoblastic leukemia (ALL). We previously reported a 27.3% VTE rate in patients (pts) receiving a modified Dana Farber Cancer Institute (DFCI).We report updated results using two different dosing of enoxaparin as primary VTE prophylaxis. Methods: 62 pts ALL in complete remission, who were treated with a weekly ASNase-based DFCI intensification phase for at least 7 cycles (21 weeks) and received prophylaxis with enoxaparin targeted to 1 mg/kg subcutaneously (SC) daily (escalated dose group), were evaluated . Results were compared to a similar group of 41 patients who had received enoxaparin 40 mg for patients weighing less than 80 kg, and 60 mg for those 80 kg and above (low-dose group), and to a similar group of 99 pts previously treated with the same DFCI protocol without anticoagulation prophylaxis. Results: The actual mean dose of enoxaparin in the low-dose prophylaxis group was 0.62 mg/kg, as compared to 0.88 mg/kg in the escalated dose group. There were no major bleeding complications observed in the prophylaxis groups. The minor bleeding rate in the entire prophylaxis cohort was 4.8% (5/103), and was similar between the low-dose and escalated dosing groups. The VTE entire cohort that received prophylaxis was 20% (21/103). The VTE rates for all groups as shown in the table. Conclusions: Overall use of prophylactic enoxaparin during intensification in adults with ALL receiving ASNase was safe; escalating the enoxaparin dose to 1 mg/kg, did not increase the number of bleeding events. There was a trend toward a lower rate of VTE using dose-escalated enoxaparin, particularly in patients weighing &lt; 80 kg. [Table: see text]

Comparison of Short-Term Tertiary Prophylaxis at Low-Dose and Intermediate-Dose for Adults with Severe Hemophilia a in China

▪Background: Low-dose prophylaxis and intermediate-dose prophylaxis in hemophilia A both had been proved in reducing bleedings in some developing country, but there was rare attention in terms of the Health-related Quality of life (HRQoL) and patients' adherence. So we initiated a retrospective study to compare the differecen between low-dose and intermediate-dose regimen of tertiary prophylaxis for adults with severe hemophilia A.Methods: Data collected from the hemophilia treatment centre at Nanfang hospital from July 2010 to February 2015(median 2 years of follow-up), a total of 40 adult patients with severe hemophilia A (FVIII < 1%) who are receiving prophylaxis treatment≥1 year and treatment data available were eligible for enrollment in the study, including 25 patients in low-dose regimen(F‡[8-15 IU/kg 1-2times weekly or weekly<30IU/kg), and 15 patients in intermediate-dose regimen( F‡[ 15-20 IU/kg 2-3 times weekly or weekly≥40IU/kg and <75 IU/kg). Collect the data with patients' characteristics, previous condition and treatment, annual total bleeding rate(ABR). Use SF36 to evaluate patients' quality of life, use the difference between the beginning of this study and one year ago of SF36 score to represent the improvement of quality of life. Use "hemophilia bleeding and factor injection record handbook" to collect information about patients' bleeding and injection record, use HO's measuring method to evaluate adherence.Results: 1. There were no statistical differences between two groups in age, weight, age at first bleeding, age at first treatment, family history of hemophilia and history of hepatitis.(the range of P-value was 0.221-1.000). 2.The Health-related Quality of life (HRQoL) in patients with severe hemophilia A were measured by the SF-36. Only on bodily pain(P=0.965) and vitality(P=0.101)the differences did not exist between two groups ,beyond that intermediate-dose group were better in other aspects(included total SF36, physical functioning, role-physical, general health, social functioning, role-emotional and mental health) than low-dose group(the range of P-value was 0.000-0.045, P<0.05),which inferred that the improvement of quality of life was better in patients in intermediate-dose group. 3. Used HO's measuring method for adherence to evaluate the 40 patients in two groups. The dosage and dosing intervals adherence of low-dose group were 78.6A88.5 respectively, while the intermediate-dose group were 90.3A95.2 respectively, the differences in dosage and dosing intervals adherence between two groups were statistically significant(P=0.003). Intermediate-dose prophylaxis treatment reduced the annual total bleeding rate(ABR) than the low-dose group(median 13 vs. 5.5,P=0.000), while poor dosage adherence correlates with more ABR(B=-0.555,P=0.000), which meant worse adherence was association with much bleeding, but there was no correlation between dosing intervals adherence and ABR(B=0.171,P=0.507).Conclusion: 1. Compared to low-dose regimen, intermediate-dose regimen for short-term tertiary prophylaxis in adults with severe hemophilia A would improve quality of life. 2.Patients in intermediate-dose prophylaxis regimen had better adherence than low-dose regimen. There are negative correlation between dosage adherence and ABR, which means poor adherence lead to more bleeding events, while there's no correlation between dosing intervals adherence and ABR. DisclosuresNo relevant conflicts of interest to declare.