Effects of replacement therapies with clotting factors in patients with hemophilia: A systematic review and meta-analysis

Background Different prophylactic and episodic clotting factor treatments are used in the management of hemophilia. A summarize of the evidence is needed inform decision-making. Objective To compare the effects of factor replacement therapies in patients with hemophilia. Methods We performed a systematic search in PubMed, Central Cochrane Library, and Scopus. We included randomized controlled trials (RCTs) published up to December 2020, which compared different factor replacement therapies in patients with hemophilia. Random-effects meta-analyses were performed whenever possible. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The study protocol was registered in PROSPERO (CRD42021225857). Results Nine RCTs were included in this review, of which six compared episodic with prophylactic treatment, all of them performed in patients with hemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means [RM]: 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups (p = 0.003, I2 = 82.9%). In addition, compared to the episodic treatment group, the annualized joint bleeding rate was lower in the low-dose prophylactic group (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic group (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic group (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates (CFCs), assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration. Conclusions Our results suggest that prophylactic treatment (at either low, intermediate, or high doses) is superior to episodic treatment for bleeding prevention. In patients with hemophilia A, the bleeding rate seems to have a dose-response effect. However, no study compared different doses of prophylactic treatment, and all results had a very low certainty of the evidence. Thus, future studies are needed to confirm these results and inform decision making.

Real-World Bleeding Outcomes, Weekly Factor Consumption Doses, Annualized Factor Costs in Severe-Type Patients with Hemophilia a (PwHA) before and after Switching to Extended Half-Life rFVIII-Fc Prophylaxis

Introduction: Stand half-life (SHL) rFVIII had been used in patients with hemophilia A (PwHA) for episodic treatment (ET) and prophylaxis therapy (PT) for years. Extended half-life (EHL) rFVIII had been available since 2014, also available in Taiwan since 2018, and resulted in markedly increased willingness for PT because it reduced injection burden. We aimed to investigate the real-world bleeding outcomes, weekly factor doses, and factor costs of severe-type PwHA with pre-switch SHL rFVIII and post-switch EHL rFVIIIFc prophylaxis in Taiwan, and made a pre-switch and post-switch comparison. Methods and Materials: There were totally 51 non-inhibitor, severe-type PwHA, with complete bleeding records before and after switching from SHL rFVIII to EHL rFVIII-Fc, enrolled from two hemophilia centers during Nov, 2018－July, 2019. Most of them had various degree of one to more major joints arthropathy, except children. The medical charts were retrospective reviewed and data were collected, including body features and factor regimen, etc. Patients' annualized bleeding/joint-bleeding rate (ABR/AJBR), weekly doses (WD), annualized factor costs (AFC) were obtained from the chart records of pre-switch 12 months and post-switch at least more-than 6-month until July, 2019. Data from scheduled operation or hospitalization due to trauma or accidence were excluded. Results: There were 8 boys and 43 adults, the median age of all PwHA when switching was 35.6 years (10.5-62). Before switching, these 51 PTP treated with SHL rFVIII who received ET (ET group), irregular prophylaxis (IP group), and regular prophylaxis (RP group) were 19 (37.3%), 7 (13.7%), and 25 (49%), respectively. Bleeding records of 51 PTP treated with SHL rFVIII were traced back with 11.8±0.9 months. After switching to rFVIII-Fc, 3 PwHA receiving ET were excluded, and bleeding records of 48 received RP were obtained with 14.7±4.6 months. Pre-switch and post-switch prophylaxis rate were 62.7% (32/51) and 94.1% (48/51), respectively. For comparison of pre-switch and post-switch outcomes: Median ABR was reduced from 48, 12, and 4 to 1.15, 1.9, and 1.5 for ET, IP, and RP group, respectively. Median AJBR was reduced from 32, 11, and 4 to 0.95, 0.7, and 1.2 for ET, IP, and RP group, respectively. Median WD was increased from 38.4, 52.9, and 63.6 IU/kg/wk to 84.6, 84.5, and 84.9 IU/kg/wk for ET, IP, and RP group, respectively. Median AFC was increased from 4,141,800, 4,064,000 and 5,129,700 NTD to 7,042,325, 5,835,450, and 5,762,810 NTD for ET, IP, and RP group, respectively. Comparing pre-switch and post-switch outcomes of children and adults who received pre-switch and post-switch prophylaxis, median ABR was reduced from 3 and 5 to 1.35 and 1.85 for children and adults, respectively. Median AJBR was reduced from 3 and 4 to 1.35 and 1.15 for children and adults, respectively. Median WD was increased from 58.8 and 58.3 IU/kg/wk to 87.85 and 83.85 IU/kg/wk for children and adults, respectively. Median AFC was increased from 4,104,225 and 5,879,025 NTD to 4,419,800 and 6,024,916 NTD for children and adults, respectively. For all PwHA, zero ABR accounted for 5.9% (3/51) with pre-switch SHL rFVIII treatment and for 20.8% (10/48) with post-switch rFVIII-Fc prophylaxis. Zero AJBR accounted for 9.8% (5/51) with SHL rFVIII treatment and for 33.3% (16/48) with rFVIII-Fc prophylaxis. For PwHA with pre- and post-switch prophylaxis, zero ABR accounted for 12.5% (1/8) and 8.3% (2/24), respectively, for children and adults on SHL rFVIII prophylaxis and 25% (2/8) and 25% (6/24) respectively, for children and adults on rFVIII-Fc prophylaxis. Zero AJBR accounted for 12.5% (1/8) and 16.7% (4/24), respectively, for children and adults on SHL rFVIII prophylaxis and 25% (2/8) and 37.5% (9/24) respectively, for children and adults on rFVIII-Fc prophylaxis. Conclusion: In real-world setting, for pre-switch ET group, switch to rFVIII-Fc prophylaxis made both mean ABR and AJBR reduced >95%, and mean WD increased >50%. For pre-switch IP group, switch to rFVIII-Fc prophylaxis made both mean ABR and AJBR reduced >80%, and mean WD increased >35%. For pre-switch RP group, switch to rFVIII-Fc prophylaxis made both mean ABR and AJBR also reduced >45%, and mean WD increased >20%. The proportions in zero ABR and zero AJBR as post-switch rFVIII-Fc prophylaxis were increased. No matter in ET, IP, or RP group, after switching to RP with rFVIII-Fc, improvement for bleeding outcomes was quite evident. Disclosures No relevant conflicts of interest to declare.

Baseline VWF:Ag Level and Body Mass Index Are Inverse Influencing Factors of Annualized Total Bleeding Rate and Annualized Joint Bleeding Rate Respectively in Severe-Type Adult Patients with Hemophilia a (PwHA) with Episodic Treatment with rFVIII

Introduction: Bleeding phenotypes of severe-type patients with hemophilia A (PwHA) vary greatly, which influence factor consumption and medical cost. Factors affecting bleeding patterns of PwHA include various procoagulant and anticoagulant factors, joint condition and physical activity, etc. We aimed to investigate clinical factors influencing by-nature bleeding frequency of severe-type PwHA during episodic treatment. Methods and materials: There were 19 non-inhibitor, severe-type, previously treated PwHA aged >20 years, who had at least one to five major joints arthropathy, retrospectively enrolled from two hemophilia centers for analysis. They had been refusing prophylaxis therapy with FVIII product due to heavy burden of frequent intravenous FVIII injection and had long-term episodic treatment. Clinical informations were collected from November 2017 to November 2018, including age, body mass index (BMI), body weight, ABO blood grouping, HCV and HIV infection status, baseline VWF:Ag and VWF:activity, mutation of F8 gene. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR), weekly doses and annualized factor consumption costs (calculated by new Taiwan dollars, NTD) were obtained from the patients' medical records. Results: The PwHA with ABR <24 had significantly lower proportion of blood-group-O patients, higher baseline VWF:Ag and VWF:activity than those with ABR >24.(P-value <0.05) The PwHA with AJBR <13 had significantly higher BMI than those with AJBR >13.(P-value <0.05) There was no significant difference in ABR, AJBR, weekly dose, and annualized factor cost between PwHA with O blood group and non-O blood group. Compared with PwHA with baseline VWF:Ag or VWF:activity <145%, those with baseline VWF:Ag or VWF:activity >145% had significantly older age (34.9 vs 53.2 years, P-value <0.05), higher BMI (25.2 vs 29.9, P-value <0.05), lower ABR (58.2 vs 12.2 per year, P-value<0.01), lower AJBR (46.8 vs 10.8 per year, P-value<0.01), lower weekly dose (42.4 vs 10.6 IU/kg/wk, P-value<0.01), and lower annualized factor consumption costs (4,177,732 vs 1,120,704 NTD, P-value<0.01). Compared with PwHA with BMI <28, those with BMI >28 had significantly lower ABR (58.2 vs 12.2 per year, P-value<0.05), lower AJBR (46.8 vs 10.8 per year, P-value<0.05), higher baseline VWF:activity (94.6% vs 190.2%, P-value <0.05), and lower weekly dose (38.5 vs 17.1 IU/kg/wk, P-value <0.05). By backward-stepwise multivariate linear regression, baseline VWF:Ag and BMI were identified as independent and significant inverse influencing factors for ABR and AJBR, respectively.(P-value <0.05) Conclusion: For severe-type adult PwHA with episodic treatment, baseline VWF:Ag or VWF:activity >145% was associated with lower ABR, AJBR, weekly dose, and annualized factor cost. BMI >28 was associated with lower ABR, AJBR, and weekly dose consumption. Baseline VWF:Ag and BMI were revealed as inverse influencing factors for ABR and AJBR, respectively. The results of our study could be useful for clinicians to have an insight into diversity of bleeding phenotypes of by-nature severe-type PwHA. For developing countries where factor concentrate resources are not enough, these clinical influencing factors might be helpful for the management of therapeutic strategies and resource allocation for severe PwHA. Disclosures No relevant conflicts of interest to declare.

Low dose long-acting factor VIII prophylaxis in pediatric and young adult patients with hemophilia A: Short-term single-center experience from a developing country

Objectives: High dose factor prophylaxis in hemophilia has been proven to prevent joint bleeds in the western world effectively. We look for a cost-effective and feasible way for Indian patients to reduce the dose and frequency of factor infusion. Data on prophylaxis with a low dose, long-acting factor infusion twice a week dosing schedule is limited. The purpose was to study the efficacy and safety of long-acting factor VIII (Eloctate) for secondary/ tertiary prophylaxis in pediatric and young adult patients with moderate and severe hemophilia A. Materials and Methods: Thirty-eight patients with moderate and severe hemophilia A with an age range from 1 to 25 years were included in the study. During the initial 4 months, they received therapeutic doses of ELOCTATE (Factor VIII with Fc Fusion Protein) on an episodic basis after a clinical bleed. In the next 4 months, they received prophylactic intravenous ELOCTATE at the dose of 20 units/kg body weight twice a week. Annual bleeding rates (ABR), school absenteeism, emergency visits, joint scores, and adverse events were compared during both periods. Results: The total number of joint bleeds during the episodic treatment and prophylaxis period was 608 and 67, respectively. ABR was 47.9 during the episodic treatment period and 5.3 during prophylaxis showing an 88.9% reduction in joint bleeds. School/college absenteeism and emergency visits were significantly reduced during prophylaxis. No significant adverse events were noted during prophylaxis. Conclusion: Low dose, twice a week, and long-acting recombinant factor VIII-Fc (Eloctate) prophylaxis can be a reasonable options for patients with hemophilia A in developing countries.

Correlation between Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score and Hemophilia Joint Health Score (HJHS) in patients with hemophilic arthropathy

Background Hemophilic arthropathy, a condition manifested as joint destruction due to spontaneous joint bleeding, is one complication of hemophiliac patients. Early detection and intervention may improve the outcome, in which ultrasonography can be an ideal modality with the introduction of HEAD-US (Hemophilia Early Arthropathy Detection with Ultrasound) protocol. Studies have shown US benefit in hemophiliac patients, including its potential as an alternative for the Hemophiliac Joint Health Score (HJHS) system. However, many of the studies were conducted in countries with better management of hemophilia using prophylaxis treatment. It is unclear whether HEAD-US has a correlation with HJHS in countries using episodic treatment only, like in Indonesia. Purpose This study aimed to explore the correlation between HEAD-US and HJHS in hemophiliac patients with joint problems in Indonesia. Materials and methods A cross-sectional correlation study between HEAD-US and HJHS was performed with primary data collected from 120 hemophilic patients. US examination was performed on elbow, knee and ankle joints using the HEAD-US scoring method by a musculoskeletal radiologist. HJHS examination was conducted by a trained physiotherapist and a medical rehabilitation specialist. All examiner is member of multidisciplinary Hemophiliac Management Team in Cipto Mangunkusumo General Hospital in Jakarta, Indonesia. Results The mean age of the participant was 9.3 (5–14) years old. The median score of HEAD-US was 8 (1–28) with most of the joint abnormalities found on the ankles. The median score of HJHS was 3 (0–35), with most joint abnormalities found on the knees. There was a moderate correlation between HEAD-US and HJHS score (p < 0.05, r = 0.65). Conclusion HEAD-US shows a moderate correlation to HJHS in hemophiliac patients who received episodic treatment. HEAD-US can provide additional value in the anatomical evaluation of the joint and could be complementary to HJHS in assessing the joint status in hemophilic patient

Economic Analysis of an Ambulatory Care Service Delivery Model for Hemophilia a Patients; A Cost Minimization Study

Aim: This study aimed to perform an economic evaluation of Hemophilia ambulatory service delivery model (HASDM) comparing to the traditional home-episodic treatment model. Study Design: Tehran university of medical science, department pharmacoeconomics and pharmaceutical administration, between Jun 2016 and September 2018. Methods: A cost-minimization analysis (CMA) was conducted for evaluating potential savings of HASDM in comparison to the traditional home-episodic treatment model. The main cost of regular episodic service delivery, basic arm, consists of the cost of recombinant factor VIII (FVIII). In the comparator arm, HASDM, the costs of HASDM for 1660 hemophilia A patients (HAPs) in Tehran were calculated. One-way sensitivity analysis was done to investigate the robustness of the results and to investigate the impact of uncertainty in the percentage of mistakes in bleeding sensation. Results: There were 1660 patients with severe Hemophilia A (PWSHA) in Tehran in 2018. The mean utilization of annual per patient FVIII was 44814 international units (IUs) in Iran. The total annual cost of FVIII concentrate for 1660 hemophilic patients in Tehran was estimated at $ 11,001,816. The cost of running HASDM, personal, and equipment is equal to $ 580,956. The cost of FVIII in HASDM would be $ 4,004,661. Therefore, the total cost of HASDM is estimated at $ 4,585,617. The amount of savings was $ 6,416,199. Sensitivity analysis indicated the robustness of the results up to 94.64% of the variation in the model parameters. Conclusions: HASDM, compared to episodic model, can save 58.32% of the funding for controlling bleeding in HAPs annually. This can save more than 38 times of HAPs annual cost over their lifetime.

Early Prophylaxis Provides Continued Joint Protection in Severe Hemophilia A: Results of the Joint Outcome Continuation Study

Background: The Joint Outcome Study (JOS) was a randomized controlled trial showing that, in severe hemophilia A, prophylactic factor VIII every other day starting prior to age 30 months leads to better joint outcomes at age 6 years than enhanced episodic treatment with factor VIII for bleeding1. After conclusion of the JOS, all participants were encouraged to continue on, or to transition to, prophylaxis. Here we describe the results of the Joint Outcome Continuation Study (JOS-C), which followed the participants of the JOS to age 18 years. Methods: All participants of the JOS were eligible for the JOS-C. MRIs of 6 index joints (right and left ankles, knees, and elbows), index joint physical exam scores using the Colorado Haemophilia Paediatric Joint Physical Examination Scale2 , estimates of joint bleeding episodes, and surgery information were collected. The primary endpoint, as in the initial JOS analysis, was evidence of hemophilia-related osteochondral joint damage on MRI, scored using the extended MRI scale3. Results: Of the 65 previous participants of the JOS, 37 gave informed consent for the JOS-C study, including 18 initially randomized to prophylaxis prior to age 30 months ("early prophylaxis"), and 19 initially randomized to enhanced episodic treatment who started prophylaxis at a mean age of 7.5 years (median 6.1, range 2.7-17.1, "delayed prophylaxis"). All initially on prophylaxis in the JOS continued on prophylaxis through the JOS-C. One participant (early prophylaxis arm) failed to complete an MRI, and four others (2 early and 2 delayed prophylaxis) had their MRIs excluded for technical reasons. Four participants (3 early prophylaxis and 1 delayed prophylaxis) developed high titer inhibitors during or shortly after the JOS and were analyzed separately. Osteochondral joint damage was defined as evidence of osteochondral damage on MRI or a need for joint surgery. The relative risk of osteochondral damage in those on delayed prophylaxis as compared to those on early prophylaxis was 6.5 (95% CI 1.3, 33.6; p=0.029). At age 18, 67% of those on early prophylaxis, and only 24% of those on delayed prophylaxis had zero index joints with osteochondral damage (Figure 1). Twenty-five percent of early prophylaxis and 47% of delayed prophylaxis participants had osteochondral damage to more than one joint. Most participants had some soft tissue changes on MRI, defined as effusion, synovial hypertrophy, or hemosiderin deposition. There was no difference in risk of soft tissue damage between initial treatment groups (p=0.48). Osteochondral damage scores were available for 3 patients with inhibitors: two with refractory inhibitors had osteochondral changes on at least one joint, and one with an inhibitor that tolerized within 3 months had no osteochondral damage. Total physical exam scores were also higher in the delayed prophylaxis arm (mean 22.6, standard deviation (SD) 15.5) than in the early prophylaxis arm (mean 16.2, SD 10.5), but this difference was not statistically significant (p=0.19). Conclusion: The JOS-C demonstrates that, in severe hemophilia A, initiation of prophylaxis prior to age 30 months provides continued protection against joint damage throughout childhood. Those who started on prophylaxis later in childhood had higher risk of joint damage at age 18. Initiation of factor VIII prophylaxis in the toddler years is critical to preventing osteochondral joint damage and should not be delayed. ReferencesManco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-544.Hacker MR, Funk SM, Manco-Johnson MJ. The Colorado Haemophilia Paediatric Joint Physical Examination Scale: normal values and interrater reliability. Haemophilia. 2007;13(1):71-78.Hong W, Raunig D, Lundin B. SPINART study: validation of the extended magnetic resonance imaging scale for evaluation of joint status in adult patients with severe haemophilia A using baseline data. Haemophilia. 2016;22(6):e519-e526. Figure 1: Percentage of participants with zero joints with osteochondral damage at JOS exit (age 6 years) and JOS-C exit (age 18 years), excluding participants with inhibitors. Disclosures Warren: Bayer Healthcare: Research Funding; HTRS/Novo Nordisk: Research Funding; Bayer Hemophilia Awards Program Fellowship Project Award: Research Funding; CSL Behring Heimburger Award: Research Funding. Shapiro:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Prometic Life Sciences: Consultancy, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Bio Products Laboratory: Consultancy; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Sangamo Biosciences: Consultancy; Octapharma: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; OPKO: Research Funding; BioMarin: Research Funding. Recht:Shire: Research Funding; Biogen: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees. Manco-Johnson:Bayer AG: Honoraria, Research Funding; Novo Nordisk: Honoraria; Biogentek: Honoraria; CSL Behring: Honoraria; Baxalta, now part of Shire: Honoraria.

Current trends in drugs avoided in pregnancy

During pregnancy several drugs are having contraindication, hence their use is less and dangerous to mother along with fetus .Drugs play an important role in improving the health and promoting well-being. However to produce desired effect, they have to be safe, efficacious and have to be used rationally. During pregnancy medication is less preferred but in some times cannot be escaped to treat the ailments in mother. Avoiding medications may be desirable, it is often not possible and may be dangerous because some women enter pregnancy medical conditions that require continuous and episodic treatment (e.g. asthma, hypertension, epilepsy). So here we discussed the medication that can be used safely during pregnancy along with unsafe and highly contraindicated for both mother and fetus. Certain drugs given during pregnancy may prove harmful to unborn child is one of the classical problem in the medical treatment. The main purpose of this review is to prepare a list of safe medications which can be taken during pregnancy with unsafe and highly contraindicated drugs. And also a quick reference for health care professionals. Keyboard: Current, Pregnancy, Drugs, Fetus