Impact of Lactate Dehydrogenase and Hemoglobin Levels on Clinical Outcomes in Patients With Paroxysmal Nocturnal Hemoglobinuria: Results From the National Korean PNH Registry.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder caused by uncontrolled terminal complement activation, which leads to intravascular hemolysis (IVH), thromboembolism (TE), renal failure, and premature mortality. METHODS: We performed a secondary analysis of data collected from patients enrolled in the Korean National PNH Registry to assess the relative importance of risk factors, specifically lactate dehydrogenase (LDH) and hemoglobin (Hb), in predicting the incidence of TE, impaired renal function, and death in complement inhibitor-naïve patients with PNH. RESULTS: Multivariate regression modeling indicated that LDH ≥ 1.5 × upper limit of normal (ULN), male sex, and pain were associated with increased risk of TE (P = 0.016, 0.045, and 0.033, respectively), hemoglobinuria and pain were associated with an increased risk of impaired renal function (P = 0.034 and 0.022, respectively), and TE was associated with an increased incidence of death (P < 0.001). Hb < 8 g/dL was not a predictor of TE, impaired renal function, or death in multivariate regression analyses. Standardized mortality ratio analysis indicated that LDH ≥ 1.5 × ULN (P < 0.001), Hb < 8 g/dL (P < 0.001), and Hb ≥ 8 g/dL (P = 0.004) were all risk factors for death; in contrast, patients with LDH < 1.5 × ULN had similar mortality to the general population. CONCLUSION: In complement inhibitor-naïve patients with PNH, LDH ≥ 1.5 × ULN was a significant predictor of TE, and TE was a significant predictor of death. Hb was not a significant predictor of TE, impaired renal function, or death. Therefore, controlling IVH will improve clinical outcomes for patients with PNH.

[Japanese patient preferences between ravulizumab and eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria].

Ravulizumab is the first long-acting complement inhibitor approved for paroxysmal nocturnal hemoglobinuria (PNH) treatment. We evaluated patient preference for ravulizumab or eculizumab among Japanese adults with PNH. The ALXN1210-PNH-301 (NCT02946463) and ALXN1210-PNH-302 (NCT03056040) studies included 23 Japanese adults who are enrolled in complement inhibitor treatment-naive and eculizumab (≥6 months) treatment. Patient preference was assessed using the PNH-specific patient preference questionnaire (PNH-PPQ©). Most patients preferred ravulizumab (19/23, 82.6%), none preferred eculizumab, and four (17.4%) reported no preference (χ2 test, p<0.005). The preference for ravulizumab was driven by its lower infusion frequency (every 8 weeks) compared with eculizumab (every 2 weeks). The included Japanese patients with PNH preferred ravulizumab because of its reduced infusion frequency, which increases activity planning ability, treatment convenience, and overall quality of life, as compared with eculizumab. These data provide useful insight into patient perspectives and may aid decision-making for PNH treatment.

Indirect and Direct Mapping of the Cancer-Specific EORTC QLQ-C30 onto EQ-5D-5L Utility Scores.

OBJECTIVE: The aim of this study was to develop a response mapping algorithm to predict EQ-5D-5L utilities from European Organisation for Research and Treatment Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scores and compare performance with direct mapping approaches to identify the best performing algorithm. METHODS: The Multi-Instrument Comparison dataset contains responses to both the EQ-5D-5L and QLQ-C30 questionnaires from 692 individuals with a broad range of cancers. Response mapping was conducted, fitting ordered logistic regressions to predict response levels for each of the five EQ-5D dimensions and utilities were predicted using the US and Japanese EQ-5D-5L value sets to test the algorithm performance. Various direct mapping models were fitted: ordinary least squares, tobit, two-part (TPM), adjusted limited dependent variable mixture and beta mixture models. Model assessment and recommendations regarding the best mapping algorithm was based on goodness-of-fit statistics, predictive ability (measures of error, distribution of predicted utilities) and in sample cross-validation. RESULTS: The response mapping model performed well in terms of predictive ability and measurement error using the US or Japanese value set, with mean absolute error ranging from 0.0708 to 0.0988, and comparably to the TPM, which was the best performing direct algorithm. CONCLUSION: The developed mapping algorithms enable the prediction of EQ-5D-5L utilities from QLQ-C30 scores when EQ-5D-5L data have not been directly collected in clinical trials. The response mapping model offers the possibility of predicting EQ-5D-5L utility values using any national value set and can be generalised to multiple countries and oncology settings.

No impact of Asian ethnicity on EORTC QLQ-C30 scores: Group differences and differential item functioning in paroxysmal nocturnal hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening terminal-complement-mediated disease resulting in intravascular hemolysis and thrombosis with significant morbidity and premature mortality. There exists no disease-specific quality-of-life (QOL) measure for PNH. Its QOL effects resemble those of hematologic cancers, which supports the use of cancer-specific QOL measures in PNH clinical trials. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 has published norms for many European and North American countries, but not for Asian countries. We investigated differences by Asian ethnicity in scores and item function on the EORTC QLQ-C30. METHODS: This secondary analysis focused on two non-inferiority PNH trials (301 and 302) comparing eculizumab and ravulizumab (n = 441). Analysis of covariance examined the main effect of Asian ethnicity on baseline EORTC QLQ-C30 scores, after adjusting for propensity scores encompassing trial, demographic and clinical factors. Mixed modeling of longitudinal data compared subscale scores in Asian vs. non-Asian patients, after propensity adjustment. Differential item function (DIF) was examined using ordinal regression models at baseline and longitudinally, to predict item score from total score, ethnicity, and their interaction to test for uniform DIF (significant main effect for Asian) and non-uniform DIF (significant Asian-by-total-score interaction). RESULTS: Of the 15 baseline domains, Asian patients scored slightly better on role and emotional functioning and slightly worse on constipation and diarrhea (0.22 < Cohen's d < 0.36). In longitudinal models, Asians reported slightly higher appetite loss, diarrhea, and financial difficulties than non-Asians (R2 increment < 0.0005). There was negligible uniform and non-uniform DIF, i.e., R2 0 to 0.018, far below Zumbo's (1999) criterion of 0.13. On average there were larger differences from norms for Asians (mean = 0.05, sd = 0.44) than non-Asians (mean = -0.07, sd = 0.36), but the size and direction of the differences varied considerably by domain, age, and gender. CONCLUSION: When compared to norms, Asian patients showed no systematic biases. DIF results supported this finding. We conclude that Asian ethnicity does not impact interpretation of EORTC QLQ-C30 scores.

Norm-based comparison of the quality-of-life impact of ravulizumab and eculizumab in paroxysmal nocturnal hemoglobinuria.

AIMS: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening intravascular hematologic disorder with significant morbidity and premature mortality. Clinical trials (NCT02946463 and NCT03056040) comparing ravulizumab with eculizumab for PNH have supported the non-inferiority of the former and similar safety and tolerability. This secondary analysis compared PNH trial participants after 26 weeks on either treatment (n = 438) to a general-population sample (GenPop) (n = 15,386) and investigated response-shift effects. METHODS: Multivariate analysis of covariance (MANCOVA) investigated function and symptom scores on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 of people with PNH as compared to GenPop, after covariate adjustment. Risk-factor groups were created based on clinical indicators known to be associated with worse PNH outcomes, and separate MANCOVAs were computed for lower- and higher-risk-factor groups. Differential item functioning (DIF) analyses examined whether item response varied systematically (1) by treatment, (2) compared to GenPop, and (3) over time, the latter two suggesting and reflecting response-shift effects, respectively. DIF analyses examined 24 items from scales with at least two items. Recalibration response shift was operationalized as uniform DIF over time, reflecting the idea that, for a given group, the difficulty of endorsing an item changes over time, after adjusting for the total subscale score. Reprioritization response shift was operationalized as non-uniform DIF over time, i.e., the relative difficulty of endorsing an item over time changes across the total domain score. RESULTS: Across PNH risk-factor levels, people who had been on either treatment for 26 weeks reported better-than-expected functioning and lower symptom burden compared to GenPop. Ravulizumab generally showed larger effect sizes. Results were similar for lower and higher PNH risk factors, with slightly stronger effects in the former. DIF analyses revealed no treatment DIF, but did uncover group DIF (9 items with uniform DIF, and 11 with non-uniform) and DIF over time (7 items with uniform DIF, and 3 with non-uniform). CONCLUSIONS: This study revealed that people with PNH on ravulizumab or eculizumab for 26 weeks reported QOL levels better than those of the general population. Significant effects of DIF by group and DIF over time support recalibration and reprioritization response-shift effects. These findings suggest that the treatments enabled adaptive changes.

A US cost-minimization model comparing ravulizumab versus eculizumab for the treatment of atypical hemolytic uremic syndrome.

AIMS: Ravulizumab, engineered from eculizumab, provides sustained C5 inhibition in atypical hemolytic uremic syndrome (aHUS) while reducing dosing frequency (every 8 vs 2 weeks, respectively). Treatment choice often carries significant financial implications. This study compared the economic consequences of ravulizumab and eculizumab for treating aHUS. MATERIALS AND METHODS: A cost-minimization model compared direct medical costs for ravulizumab and eculizumab in treating aHUS, assuming equivalent efficacy and safety, and took a US payer perspective, a lifetime horizon, and a 3.0% cost discount rate. The base case modeled adult and pediatric treatment-naïve populations, with characteristics based on clinical trials, and treatment patterns (duration, discontinuation, re-initiation) derived from eculizumab studies with long-term follow-up. Treatment costs (2019 US$) were based on wholesale drug acquisition costs, Centers for Medicare & Medicaid fee schedules, and published disease management studies. Sensitivity analyses were conducted by adjusting relevant variables. RESULTS: Ravulizumab provided lifetime per-patient cost reductions (discounted) of 32.4% and 35.5% vs eculizumab in adult and pediatric base cases, respectively. Total costs for ravulizumab vs eculizumab were $12,148,748 and $17,979,007, respectively, for adults, and $11,587,832 and $17,959,814, respectively, for children. Pre-discontinuation treatment contributed the largest proportion of total costs for ravulizumab (94.8% and 88.0%) and eculizumab (94.8% and 87.8%) in adults and children, respectively. Across sensitivity analyses, ravulizumab provided cost reductions vs eculizumab. LIMITATIONS: The model included several typical assumptions. Base case patients with more severe stages of chronic kidney disease were assumed not to discontinue treatment, nor to experience an excess mortality risk in either treatment arm, which may not reflect real-world clinical observations. Additionally, rebates and discounts on medication acquisition or administration were not considered. CONCLUSIONS: In US patients with aHUS, ravulizumab provided cost reductions of 32.4-35.5% vs eculizumab, with a reduced dosing frequency for ravulizumab. The magnitude of reductions was consistent across sensitivity analyses.

Cost-utility analysis of life-long prophylaxis with recombinant factor VIIIFc vs recombinant factor VIII for the management of severe hemophilia A in Sweden.

AIMS: Prophylaxis with recombinant factor VIII (rFVIII) is the standard of care for severe hemophilia A in Sweden. The need for frequent injections with existing rFVIII products may, however, result in poor adherence to prophylaxis, leading to increased bleeding and long-term joint damage. Recombinant FVIIIFc (rFVIIIFc) is an extended half-life fusion protein which can offer prolonged protection and reduced dosing frequency. The objective of this study was to evaluate the cost-utility of prophylaxis with rFVIIIFc in severe hemophilia A from the perspective of the Swedish health system. METHODS: A Markov model was built to estimate lifetime costs and benefits of prophylaxis with rFVIIIFc vs rFVIII products. Clinical outcomes were represented by annualized bleeding rate (ABR) and quality of life via disutility applied to bleeding events and injection frequency. Costs included the cost of FVIII for routine prophylaxis and bleed resolution. The pooled comparator was costed by weighting the cost of individual products by their market share. RESULTS: In the base case, rFVIIIFc was dominant vs the pooled comparator. Savings of SEK 9.0 million per patient resulted from lower factor consumption for prophylaxis and bleed resolution. Fewer bleeds and reduced injection frequency yielded an estimated 0.59 quality-adjusted life years (QALYs). Results were sensitive to drug dosage and robust to variation in other parameters. Probabilistic sensitivity analysis suggested a greater than 85% probability of rFVIIIFc being cost-effective at a willingness-to-pay threshold of 500,000 SEK/QALY. LIMITATIONS: Due to unavailibilty of patient-level data, treatment benefit was based on a non-adjusted indirect comparison. Dosing and treatment outcomes were assumed to persist over the model duration in the absence of long-term outcome data. CONCLUSION: The results suggest that rFVIIIFc may be a cost-effective option for hemophilia A prophylaxis, generating greater quality of life and reduced costs for the Swedish payer compared to more frequently administered rFVIII alternatives.

Continuous prophylaxis with recombinant factor IX Fc fusion protein and conventional recombinant factor IX products: comparisons of efficacy and weekly factor consumption.

BACKGROUND: Continuous prophylaxis for patients with hemophilia B requires frequent injections that are burdensome and that may lead to suboptimal adherence and outcomes. Hence, therapies requiring less-frequent injections are needed. In the absence of head-to-head comparisons, this study compared the first extended-half-life-recombinant factor IX (rFIX) product-recombinant factor IX Fc fusion protein (rFIXFc)-with conventional rFIX products based on annualized bleed rates (ABRs) and factor consumption reported in studies of continuous prophylaxis. METHODS: This study compared ABRs and weekly factor consumption rates in clinical studies of continuous prophylaxis treatment with rFIXFc and conventional rFIX products (identified by systematic literature review) in previously-treated adolescents and adults with moderate-to-severe hemophilia B. Meta-analysis was used to pool ABRs reported for conventional rFIX products for comparison. Comparisons of weekly factor consumption were based on the mean, reported or estimated from the mean dose per injection. RESULTS: Five conventional rFIX studies (injections 1 to >3 times/week) met the criteria for comparison with once-weekly rFIXFc reported by the B-LONG study. The pooled mean ABR for conventional rFIX was slightly higher than but comparable to rFIXFc (difference=0.71; p = 0.210). Weekly factor consumption was significantly lower with rFIXFc than in conventional rFIX studies (difference in means = 42.8-74.5 IU/kg/week [93-161%], p < 0.001). CONCLUSION: Comparisons of clinical study results suggest weekly injections with rFIXFc result in similar bleeding rates and significantly lower weekly factor consumption compared with more-frequently-injected conventional rFIX products. The real-world effectiveness of rFIXFc may be higher based on results from a model of the impact of simulated differences in adherence.

Health economic modeling of the potential cost saving effects of Neurally Adjusted Ventilator Assist.

OBJECTIVES: Asynchrony between patient and ventilator breaths is associated with increased duration of mechanical ventilation (MV). Neurally Adjusted Ventilatory Assist (NAVA) controls MV through an esophageal reading of diaphragm electrical activity via a nasogastric tube mounted with electrode rings. NAVA has been shown to decrease asynchrony in comparison to pressure support ventilation (PSV). The objective of this study was to conduct a health economic evaluation of NAVA compared with PSV. METHODS: We developed a model based on an indirect link between improved synchrony with NAVA versus PSV and fewer days spent on MV in synchronous patients. Unit costs for MV were obtained from the Swedish intensive care unit register, and used in the model along with NAVA-specific costs. The importance of each parameter (proportion of asynchronous patients, costs, and average MV duration) for the overall results was evaluated through sensitivity analyses. RESULTS: Base case results showed that 21% of patients ventilated with NAVA were asynchronous versus 52% of patients receiving PSV. This equals an absolute difference of 31% and an average of 1.7 days less on MV and a total cost saving of US$7886 (including NAVA catheter costs). A breakeven analysis suggested that NAVA was cost effective compared with PSV given an absolute difference in the proportion of asynchronous patients greater than 2.5% (49.5% versus 52% asynchronous patients with NAVA and PSV, respectively). The base case results were stable to changes in parameters, such as difference in asynchrony, duration of ventilation and daily intensive care unit costs. CONCLUSION: This study showed economically favorable results for NAVA versus PSV. Our results show that only a minor decrease in the proportion of asynchronous patients with NAVA is needed for investments to pay off and generate savings. Future studies need to confirm this result by directly relating improved synchrony to the number of days on MV.

Atomoxetine's effect on societal costs in Sweden.

OBJECTIVE: To compare societal costs between patients treated with atomoxetine and placebo in Sweden. METHOD: Ninety-nine pediatric ADHD patients were randomized to a 10-week double-blind treatment with atomoxetine (n = 49) or placebo (n = 50). All parents received four sessions of psycho-education. Parents filled out a resource utilization questionnaire covering the 10 weeks prior to treatment and the 10-week on-treatment period. Published unit costs/prices were used to calculate costs. RESULTS: Mean on-treatment costs in the atomoxetine group (SEK [Swedish Krona] 4,558) were significantly lower compared with placebo (SEK 7,684) after adjusting for baseline costs and site (p = .007). All 99 patients entered an open atomoxetine extension phase. Both groups had numerical reductions in direct and indirect costs while on atomoxetine treatment during the extension phase. The atomoxetine medication costs were offset by the reductions in direct nonmedical and indirect costs. CONCLUSIONS: These data provide preliminary evidence that atomoxetine together with parental psycho education reduces nonmedication costs associated with ADHD in Sweden.

Long-term psychosocial and health economy consequences of ADHD, autism, and reading-writing disorder: a prospective service evaluation project.

OBJECTIVE: The study aims to evaluate psychosocial, societal, and family cost consequences of a psychoeducational intervention program. METHODS: Sixty boys with ADHD, Asperger syndrome/high-functioning autism (AS/HFA), and reading and writing disorder (RD/WD) were allocated to participate in a service evaluation project. Every other boy in each diagnostic group was randomly allocated to receive either (a) a special education program (clinical index group) or (b) follow-up without the special education program (clinical comparison group). Nine years after initial assessments the stability of the psychosocial and economic resource consequences over time was studied. RESULTS: ADHD, AS/HFA, and RD/WD all had severe impact on family life quality. The societal costs were high, but no significant differences in resource use or in total costs were found between the clinical index and the comparison groups. CONCLUSIONS: The results underscore the very long-term need for support including individually tailored reevaluations and carefully monitored intervention programs adapted to family needs and severity of child disorder.