The Impact of Pharmacokinetic-Guided Prophylaxis on Clinical Outcomes and Healthcare Resource Utilization in Hemophilia A Patients: Real-World Evidence from the CHESS II Study.

From Europe PMC via Jisc Publications RouterHistory: ppub 2022-01-01, epub 2022-09-19Publication status: PublishedBackground: Using a pharmacokinetic (PK)-guided approach to personalize the dose and frequency of prophylactic treatment can help achieve and maintain targeted factor VIII (FVIII) trough levels in patients with hemophilia A. Objective: Investigate clinical and healthcare resource use outcomes in patients with hemophilia A treated with or without PK-guided prophylaxis using data from the Cost of Haemophilia in Europe: A Socioeconomic Survey (CHESS) II database. Methods: CHESS II was a cross-sectional, retrospective, burden-of-illness study incorporating data from eight European countries. Patients were eligible for this analysis if they were male, ≥18 years of age, and diagnosed with congenital hemophilia A of any severity. The clinical endpoints included annualized bleeding rate (ABR), presence and number of problem/target joints, and occurrence of joint surgeries. Healthcare resource utilization endpoints included the number of hematologist consultations and bleed-related hospitalizations or emergency department admissions. Data from November 2018 to October 2020 were included and were stratified according to treatment regimen and use of PK-guided dosing. Results: Altogether, 281 patients on prophylaxis had available FVIII trough level data. Mean (SD) age was 35.7 (13.8) years. A specific FVIII trough level was targeted in 120 (42.7%) patients and 47 (39.2%) received PK-guided dosing. Patients receiving PK-guided dosing had a mean (SD) ABR of 2.8 (2.1) and target joint number of 0.5 (0.7), compared with 3.9 (2.7) and 0.9 (1.4), respectively, for patients receiving non-PK-guided treatment. The mean (SD) number of hematologist consultations was 7.1 (5.3) for patients receiving PK-guided dosing versus 10.7 (5.7) for those who were not. A higher proportion of patients in the non-PK-guided group required hospitalization during their lifetime compared with the PK-guided group.ConclusionThis analysis of real-world data suggests that PK-guided dosing for prophylaxis has a beneficial impact on clinical and healthcare resource utilization outcomes in patients with hemophilia A

Carbohydrate dose influences liver and muscle glycogenoxidation and performance during prolonged exercise

This study investigated the effect of carbohydrate (CHO) dose and composi-tion on fuel selection during exercise, specifically exogenous and endogenous(liver and muscle) CHO oxidation. Ten trained males cycled in a double-blindrandomized order on 5 occasions at 77%_VO2maxfor 2 h, followed by a30-min time-trial (TT) while ingesting either 60 g�h�1(LG) or 75 g�h�113C-glucose (HG), 90 g�h�1(LGF) or 112.5 g�h�113C-glucose-13C-fructose ([2:1]HGF) or placebo. CHO doses met or exceed reported intestinal transportersaturation for glucose and fructose. Indirect calorimetry and stable mass iso-tope [13C] tracer techniques were utilized to determine fuel use. TT perfor-mance was 93% “likely/probable” to be improved with LGF compared withthe other CHO doses. Exogenous CHO oxidation was higher for LGF andHGF compared with LG and HG (ES>1.34,P<0.01), with the relative con-tribution of LGF (24.5�5.3%)moderatelyhigher than HGF (20.6�6.2%,ES=0.68). Increasing CHO dose beyond intestinal saturation increased abso-lute (29.2�28.6 g�h�1,ES=1.28,P=0.06) and relative muscle glycogenutilization (9.2�6.9%, ES=1.68,P=0.014) for glucose-fructose ingestion.Absolute muscle glycogen oxidation between LG and HG was not significantlydifferent, but wasmoderatelyhigher for HG (ES=0.60). Liver glycogen oxida-tion was not significantly different between conditions, but absolute and rela-tive contributions weremoderatelyattenuated for LGF (19.3�9.4 g�h�1,6.8�3.1%) compared with HGF (30.5�17.7 g�h�1, 10.1�4.0%, ES=0.79& 0.98). Total fat oxidation was suppressed in HGF compared with all otherCHO conditions (ES>0.90,P=0.024–0.17). In conclusion, there was no lin-ear dose response for CHO ingestion, with 90 g�h�1of glucose-fructose beingoptimal in terms of TT performance and fuel selectio

Differential humanistic and economic burden of mild, moderate and severe haemophilia in european adults: a regression analysis of the CHESS II study.

From Europe PMC via Jisc Publications RouterHistory: ppub 2022-04-01, epub 2022-04-04Publication status: PublishedFunder: Sanofi; Grant(s): SanofiBackgroundThe lifelong nature of haemophilia makes patient-centred and societal assessments of its impact important to clinical and policy decisions. Quantifying the humanistic and economic burden by severity is key to assessing the impact on healthcare systems. We analysed the annual direct medical (excluding factor replacement therapy costs) and non-medical costs as well as societal costs and health-related quality of life (HRQoL) of mild, moderate and severe disease among adults with haemophilia A or B without inhibitors in Europe. Participants in the CHESS II study reported their HRQoL, non-medical costs, and work impairment; physicians provided costs and consultation history from the medical chart. Descriptive statistics summarized patient characteristics, costs, and HRQoL scores. Regression models estimated differences in outcomes for moderate and severe versus mild disease, adjusting for age, body mass index, country, comorbidities, weight-adjusted factor consumption and education.ResultsThe analytic sample included 707 patients with a mean age of 38 years; the majority of patients had haemophilia A (81%), and 47% had severe disease, followed by moderate (37%) and mild disease (16%). Patients with severe or moderate disease had on average higher direct costs, €3105 and €2469 respectively, versus mild disease. Societal costs were higher for patients with severe and moderate disease by €11,115 and €2825, respectively (all P ConclusionSeverity of haemophilia is predictive of increasing economic and humanistic burden. The burden of moderate disease, as measured by direct costs and HRQoL, did not appear to be substantially different than that observed among patients with severe haemophilia

Health-related quality of life, direct medical and societal costs among children with moderate or severe haemophilia in Europe: multivariable models of the CHESS-PAEDs study.

From Europe PMC via Jisc Publications RouterHistory: ppub 2022-04-01, epub 2022-04-04Publication status: PublishedFunder: SanofiBackgroundHaemophilia bears substantial humanistic and economic burden on children and their caregivers. Characterising the differential impact of severe versus moderate paediatric haemophilia is important for clinical and health policy decisions. We analysed health-related quality of life (HRQoL), annual direct medical (excluding factor treatment costs), non-medical and societal costs among children and adolescents with moderate and severe haemophilia A or B without inhibitors from the European CHESS-PAEDs study. Information was reported by physicians and caregivers; patients aged ≥ 8 years self-reported their HRQoL. Descriptive statistics summarised demographic and clinical characteristics, costs, and HRQoL scores (EQ-5D-Y). Regression models estimated differences in HRQoL and costs for moderate versus severe haemophilia adjusting for age, body mass index z-score, country, number of comorbidities, and weight-adjusted annual clotting factor consumption.ResultsThe analytic sample comprised 794 patients with a mean age of 10.5 years; most had haemophilia A (79%) and 58% had severe haemophilia. Mean predicted direct medical costs in moderate patients were two-thirds of the predicted costs for severe disease (€3065 vs. €2047; p ConclusionChildren with haemophilia and their caregivers displayed a significant economic and humanistic burden. While severe patients showed the highest direct medical and societal costs, and worse HRQoL, the burden of moderate haemophilia on its own was substantial and far from negligible

Disturbance alters ecosystem engineering by a canopy-forming alga

Canopy-forming fucoid algae have an important role as ecosystem engineers on rocky intertidal shores, where they increase the abundance of species otherwise limited by exposure during low tide. The facilitative relationship between Ascophyllum nodosum and associated organisms was explored using a frond breakage experiment (100%, 50%, 25%, 0% intact-frond treatments) in southern England, to assess the consequences of disturbance. Understorey substratum temperature was on average 3°C higher in 0% and 25% intact-frond treatments than in plots with 50% and 100% intact fronds. Light (as PAR during low tide) doubled in 0% intact-frond treatments in comparison to other treatments (which had similar light levels). Mobile invertebrate species richness declined by on average 1 species per m2 in the treatments with only 25% and 0% intact fronds, and the abundance of Littorina obtusata declined by 2.4-4.2 individuals per m2 in the treatments with 25 and 0% intact fronds. Sessile taxa, including Osmundea pinnatifida and encrusting coralline algae, declined by half on average in the 0% intact-frond treatment. These results suggest that the ability of Ascophyllum to mediate environmental conditions to the understorey is the mechanism responsible for species distributed in the understorey (autogenic ecosystem engineering). The results of this study imply that a pulse disturbance resulting in a 50% breakage of Ascophyllum fronds significantly increases temperature and decreases the abundance of mobile invertebrates usually associated with Ascophyllum. Sessile taxa associated with Ascophyllum can, however, withstand disturbances down to 25% intact Ascophyllum fronds.</p

Real-world evidence on Kovaltry (81-8973) in children with moderate or severe hemophilia A in Europe: a nested cohort analysis

From Springer Nature via Jisc Publications RouterHistory: received 2020-09-11, accepted 2021-01-05, registration 2021-01-05, online 2021-01-15, pub-electronic 2021-01-15, collection 2021-12Publication status: PublishedFunder: Bayer; doi: http://dx.doi.org/10.13039/100004326Abstract: Background: Untreated hemophilia A patients may experience recurrent bleeding events leading to debilitating joint damages. While RCT and pharmacokinetic data support the value of Kovaltry [an unmodified full-length recombinant factor VIII (FVIII) product], real world evidence in children is lacking. This report describes a descriptive and multivariate analysis of the effectiveness of Kovaltry in children with hemophilia A in the real-world setting, using data from medical chart abstraction and cross-sectional surveys of physicians, patients, and caregivers. Results: Male patients aged < 18 years with moderate or severe hemophilia A, residing in five European countries and treated with FVIII were studied. The co-primary endpoints were the annualized bleeding rate (ABR) and the annual FVIII utilization rate. Twenty nine patients treated with Kovaltry were included, of whom 93% had severe disease and 75% were on continuous prophylactic treatment. The mean ABR was 2.66 ± 2.06, with rates decreasing with age. The children received on average 2.45 infusions per week, consistent across age groups (median 3; range 1–3). There were no reports of inhibitor development or adverse events in the study (AEs), and all patients were satisfied or very satisfied with the treatment. An exploratory multivariate analysis suggests no significant difference in ABR or units utilized between Kovaltry and some extended half life products in children with severe hemophilia A, though characteristics of these patient cohorts were markedly different. Conclusion: This analysis demonstrates the effectiveness and safety of Kovaltry in a pan-European pediatric population with severe hemophilia A

Association of factor expression levels with annual bleeding rate in people with haemophilia B

From Wiley via Jisc Publications RouterHistory: received 2022-01-13, rev-recd 2022-07-29, accepted 2022-08-08, pub-electronic 2022-11-04Article version: VoRPublication status: PublishedIntroduction: Gene therapy clinical trials measure steady‐state clotting factor expression levels (FELs) to evaluate the modulation of the bleeding phenotype, aiming to offer consistent protection against breakthrough bleeding events. The link between FELs and bleeding risk in people with haemophilia B (PwHB) is not well understood. Aim: We evaluated the association between FEL and ABR in PwHB. Methods: This cross‐sectional study extended the CHESS burden of illness studies in Europe and the United States. Recruitment of additional adult males with haemophilia B supplemented the existing CHESS sample size of PwHB and FELs. PwHB receiving prophylaxis were excluded, as fluctuating FELs may have confounded the analysis. Demographic and clinical characteristics were reported descriptively. Any recorded baseline FEL was reported by the haemophilia‐treating physicians according to the medical records. Generalised linear models with log link explored the association between changes in FEL and ABR. Results: The study included 407 PwHB and no inhibitors receiving on‐demand treatment. Mean age was 36.7 years; 56% from the EU, 44% from the United States. Mean baseline FEL was 9.95 IU/dl (SD, 10.47); mean ABR was 2.4 bleeds/year (SD, 2.64). After adjusting for covariates, the model showed that for every 1% increase in FEL the average ABR decreased by .08 (p < .001). Predicted number of bleeding events according to FEL showed a significant non‐linear relationship between FEL and ABR (p < .05). Conclusion: This analysis showed a significant relationship between FEL and ABR, where increases in FEL were associated with decreases in ABR among men with HB in Europe and the US

Humanistic burden of problem joints for children and adults with haemophilia

From Wiley via Jisc Publications RouterHistory: received 2022-05-10, rev-recd 2022-11-25, accepted 2022-12-14, pub-electronic 2022-12-27Article version: VoRPublication status: PublishedFunder: BioMarin and uniQureFunder: Sanofi, BioMarin and TakedaFunder: Bayer, Roche, Swedish Orphan Biovitrum AB (Sobi), Novo Nordisk and SHIREIntroduction: The “problem joint” (PJ) concept was developed to address patient‐centric needs for a more holistic assessment of joint morbidity for people with haemophilia (PwH). Aim: To quantify the humanistic burden of PJs in PwH to further support validation of the PJ outcome measure. Methods: Multivariable regression models evaluated the relationship between PJs and health‐related quality of life (HRQoL, EQ‐5D‐5L) and overall work productivity loss (WPL) using data from the ‘Cost of HaEmophilia: a Socioeconomic Survey’ population studies (adults: CHESS II, CHESS US+; children/adolescents: CHESS‐Paeds). Covariates included were haemophilia severity, age, comorbidities and education. Results: The CHESS II sample included 292 and 134 PwH for HRQoL and WPL analyses, mean age 38.6 years (39% ≥1 PJ, 61% none). CHESS US+ included 345 and 239 PwH for HRQoL and WPL, mean age 35 years (43% ≥1 PJ, 57% none). CHESS‐Paeds included 198 PwH aged 4–17 (HRQoL only), mean age 11.5 years (19% ≥1 PJ, 81% none). In CHESS II and CHESS US+, presence of PJs was associated with worse HRQoL (Both p < .001). Few CHESS‐Paeds participants had PJs, with no significant correlation with HRQoL. In CHESS II, upper body PJs were significantly correlated to WPL (p < .05). In CHESS US+, having ≥1 PJ or upper and lower body PJs were significantly correlated to WPL (vs. none; both p < .05). Conclusion: This study has shown a meaningful burden of PJs on PwH, which should be considered in clinical and health policy assessments of joint health