Mapping EORTC QLQ-C30 and QLQ-MY20 to EQ-5D in patients with multiple myeloma.

BACKGROUND: In oncology, health-related quality of life (HRQoL) data are often collected using disease-specific patient questionnaires while generic, patient-level utility data required for health economic modeling are often not collected. METHODS: We developed a mapping algorithm for multiple myeloma that relates HRQoL scores from the European Organization for Research and Treatment of Cancer (EORTC) questionnaires QLQ-C30 and QLQ-MY20 to a utility value from the European QoL-5 Dimensions (EQ-5D) questionnaire. Data were obtained from 154 multiple myeloma patients who had participated in a multicenter cohort study in the UK or Germany. All three questionnaires were administered at a single time point. Scores from all 19 domains of the QLQ-C30 and QLQ-MY20 instruments were univariately tested against EQ-5D values and retained in a multivariate regression model if statistically significant. A 10-fold cross-validation model selection method was also used as an alternative testing means. Two models were developed: one based on QLQ-C30 plus QLQ-MY20 scores and one based on QLQ-C30 scores alone. Adjusted R-squared, correlation coefficients, and plots of observed versus predicted EQ-5D values were presented for both models. RESULTS: Mapping revealed that Global Health Status/QoL, Physical Functioning, Pain, and Insomnia were significant predictors of EQ-5D utility values. Similar results were observed when QLQ-MY20 scores were excluded from the model, except that Emotional Functioning and became a significant predictor and Insomnia was no longer a significant predictor. Adjusted R-squared values were of similar magnitude with or without inclusion of QLQ-MY20 scores (0.70 and 0.69, respectively), suggesting that the EORTC QLQ-MY20 adds little in terms of predicting utility values in multiple myeloma. CONCLUSIONS: This algorithm successfully mapped EORTC HRQoL data onto EQ-5D utility in patients with multiple myeloma. Current mapping will aid in the analysis of cost-effectiveness of novel therapies for this indication.

Effect of general symptom level, specific adverse events, treatment patterns, and patient characteristics on health-related quality of life in patients with multiple myeloma: results of a European, multicenter cohort study.

PURPOSE: Novel multiple myeloma (MM) therapies have increased patient longevity but are often associated with notable symptom burden. This study quantified the effect of general symptom level, specific symptoms, and treatment-related adverse events (AEs) on MM patients' health-related quality of life (HRQoL). METHODS: The European Organization for Research and Treatment of Cancer (EORTC) generic cancer questionnaire (Quality of Life Questionnaire Core 30) and MM-specific questionnaire (QLQ-MY20) were used in this study to assess patients' HRQoL. Data were collected on sociodemographics, disease and treatment history, and the presence/severity of MM-related symptoms or treatment-related AEs from patients with MM in UK and German centers. Multiple regression analyses were conducted. RESULTS: Of 154 patients (63 % male; mean age, 66.4 years; mean time since diagnosis, 3.7 years; 52 % currently on treatment; and 43 % with ≥ 1 prior MM therapy), 25, 32, 31, and 11 % were severely symptomatic, moderately symptomatic, mildly symptomatic, and asymptomatic, respectively. Fatigue (59 %), bone pain (51 %), sleepiness (36 %), hypoesthesia or paresthesia (33 %), and muscle cramps (31 %) were most commonly reported. Moderate and severe general symptom levels, bone symptoms, depression, and mental status changes were identified as strong determinants of HRQoL. CONCLUSIONS: Severity, type of disease symptoms, and treatment related AEs are important HRQoL determinants in patients with MM, allowing for targeted treatment.

Cost-Effectiveness Analysis of Empagliflozin for Treatment of Patients With Heart Failure With Reduced Ejection Fraction in the United States.

BACKGROUND: In the EMPEROR-Reduced trial (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction), empagliflozin plus standard of care reduced the composite of cardiovascular death or hospitalization for heart failure versus standard of care in adults with heart failure with reduced ejection fraction. This analysis investigated the cost-effectiveness of the 2 regimens from the perspective of US payors. METHODS AND RESULTS: A Markov cohort model was developed based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Score quartiles and death. Transition probabilities between health states, risk of cardiovascular/all-cause death, hospitalization for heart failure and adverse events, treatment discontinuation, and health utilities were estimated from trial data. Medicare and commercial payment rates were combined for treatment acquisition, acute event management, and disease management. An annual discount rate of 3% was used. Empagliflozin plus standard of care yielded 18% fewer hospitalizations for heart failure and 6% fewer deaths versus standard of care over a lifetime, providing cost-offsets while adding 0.19 life years and 0.19 quality-adjusted life years at an incremental cost of $16 815/patient. The incremental cost-effectiveness ratio was $87 725/quality-adjusted life years gained. Results were consistent across payors, subpopulations, and in deterministic sensitivity analyses. In probabilistic sensitivity analyses, empagliflozin plus standard of care was cost-effective in 3%, 62%, and 80% of iterations at thresholds of $50 000, $100 000, and $150 000/quality-adjusted life years. CONCLUSIONS: Empagliflozin plus standard of care may prevent hospitalizations for heart failure, extend life, and increase quality-adjusted life years for patients with heart failure with reduced ejection fraction at an acceptable cost for US payors.

Health state utilities associated with weight loss: preferences of people with type 2 diabetes and obesity in Japan.

AIMS: Health state utilities associated with weight change are needed for cost-utility analyses (CUAs) examining the value of treatments for type 2 diabetes and obesity. Previous studies have estimated the utility benefits associated with various amounts of weight reduction in the US and Europe, but preferences for weight change in Asian cultures may differ from these published values. The purpose of this study was to estimate utilities associated with reductions in body weight based on preferences of individuals with type 2 diabetes and obesity in Japan. METHODS: Health state vignettes represented type 2 diabetes with respondents' own current weight and weight reductions of 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, and 20%. Utilities were elicited in time trade-off interviews with a sample of respondents in Japan with type 2 diabetes and body mass index (BMI) ≥25 kg/m2 (the cutoff for obesity in Japan). RESULTS: Analyses were conducted with data from 138 respondents (84.8% male; mean age = 58.0 years; mean BMI = 29.4 kg/m2) from all eight regions of Japan. Utility gains gradually increased with rising percentage of weight reductions ranging from 2.5% to 15%. Weight reductions of 2.5% to 15% resulted in utility increases of 0.013 to 0.048. The health state representing a 20% weight reduction yielded a wide range of preferences (mean utility increase of 0.044). Equations are recommended for estimating utility change based on any percentage of weight reduction (up to 20%) in Japanese people with type 2 diabetes and obesity. LIMITATIONS: This study was conducted in a sample with limited representation of patients with BMI >35 kg/m2 (n = 13) and relatively few women (n = 21). CONCLUSION: Results may be used to provide inputs for CUAs examining the value of treatments that are associated with weight loss in patients with type 2 diabetes and obesity in Japan.

Applying the win ratio method in clinical trials of orphan drugs: an analysis of data from the COMET trial of avalglucosidase alfa in patients with late-onset Pompe disease.

BACKGROUND: Clinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context. METHODS: All possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant's response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses ("win ratio"), with ties excluded. RESULTS: In the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30-4.29, p = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13-3.62, p = 0.018). CONCLUSION: The win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains.

A European multinational cost-effectiveness analysis of empagliflozin in heart failure with reduced ejection fraction.

PURPOSE: This research examined the cost-effectiveness of adding empagliflozin to standard of care (SoC) compared with SoC alone for treatment of heart failure with reduced ejection fraction (HFrEF) from the perspective of healthcare payers in the United Kingdom (UK), Spain and France. METHODS: A lifetime Markov cohort model was developed to simulate patients' progression through health states based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Score. The model predicted risk of death, hospitalisation for worsening heart failure (HHF), treatment-related adverse events, and treatment discontinuation each monthly cycle. Clinical inputs and utilities were derived from EMPEROR-Reduced trial data, supplemented by published literature and national costing databases. Costs (2021 pound sterling/euro) and quality-adjusted life-years (QALYs) were discounted annually for the UK (3.5%), Spain (3.0%) and France (2.5%). RESULTS: In the UK, Spain and France, empagliflozin plus SoC yielded additional QALYs (0.19, 0.23 and 0.21) at higher cost (£1185, €1770 and €1183 per patient) than SoC alone, yielding incremental cost-effectiveness ratios of £6152/QALY, €7736/QALY and €5511/QALY, respectively. Reduced HHF incidence provided most cost offsets for empagliflozin plus SoC. Similar results were obtained for a range of subgroups and sensitivity analyses. Probabilistic sensitivity results indicated empagliflozin plus SoC remained cost-effective vs. SoC at willingness-to-pay thresholds of £20,000/QALY, €20,000/QALY and €30,000/QALY in 79.6%, 75.5% and 97.3% of model runs for the UK, Spain and France, respectively. CONCLUSIONS: Empagliflozin added to SoC leads to health benefits for patients with HFrEF and is a cost-effective treatment option for payers in multiple European countries (UK, Spain, France).

Lifetime economic burden of prostate cancer.

BACKGROUND: Prostate cancer (PCa) is the most common cancer affecting men in the United States. The initial treatment and subsequent monitoring of PCa patients places a large burden on U.S. health care systems. The objectives of this study were to estimate the total and disease-related per-patient lifetime costs using a phase-based model of cancer care for PCa patients enrolled in Medicare. METHODS: A model was developed to estimate life-time costs for patients diagnosed with PCa. Patients ≥ 65 years old and diagnosed with PCa between calendar years 1991-2002 were selected from the SEER database. Using SEER, we estimated survival times for PCa patients from diagnosis until death. The period of time patients contributed to treatment phases was determined using an algorithm designed to model the natural history of PCa. Costs were obtained from the US SEER-Medicare database and estimated during specific phases of care. Cost estimates were then combined with survival data to yield total and PCa-related life-time costs. RESULTS: Overall, the model estimated life-time costs of $110,520 (95% CI 110,324-110,739) per patient. PCa-related costs made up approximately 31% of total costs ($34,432). CONCLUSIONS: Prostate cancer places a significant burden on U.S. health-care systems with average life-time PCa-related costs in excess of $30,000.

Modeling long-term health outcomes of patients with cystic fibrosis homozygous for F508del-CFTR treated with lumacaftor/ivacaftor.

BACKGROUND: Lumacaftor/ivacaftor combination therapy is efficacious and generally safe for patients with cystic fibrosis (CF) homozygous for the F508del-CF transmembrane conductance regulator (CFTR) mutation. However, long-term survival benefits of lumacaftor/ivacaftor (LUM/IVA) cannot yet be quantified. Simulation models can provide predictions about long-term health outcomes. In this study, we aimed to project long-term health outcomes of LUM/IVA plus standard care (SC) in patients with CF homozygous for F508del-CFTR. METHODS: This modeling study was an individual patient simulation in US patients aged ⩾6 years with CF, homozygous for F508del-CFTR. The primary outcome was projected survival among (a) a cohort of patients who ever initiated LUM/IVA, accounting for treatment discontinuations, and (b) a cohort of patients who remain on continuous LUM/IVA. Patient characteristics and model parameters were derived from clinical trials: VX14-809-109, VX13-809-011B, TRAFFIC/TRANSPORT, and PROGRESS; published literature; and the US CF Foundation Patient Registry. RESULTS: Lumacaftor/ivacaftor + SC is expected to increase median survival by 6.1 years versus SC alone, accounting for treatment discontinuations. The incremental median predicted survival versus SC assuming initiation of LUM/IVA at ages 6, 12, 18, and 25 years was 17.7, 12.6, 8.0, and 3.8 years, respectively. Assuming lifetime treatment with LUM/IVA, incremental median survival was predicted to be 7.8 years longer in the LUM/IVA + SC cohort. Initiating LUM/IVA at ages 6, 12, 18, and 25 years and assuming lifetime treatment resulted in incremental median predicted survival of 23.4, 18.2, 11.0, and 4.8 years, respectively. CONCLUSIONS: Lumacaftor/ivacaftor is projected to increase survival for patients with CF. Initiation at an early age and treatment persistence result in further increments in projected survival.

Additivity of nebivolol/valsartan single-pill combinations versus other single-pill combinations for hypertension.

The single-pill combination (SPC) comprising nebivolol (5 mg), a vasodilatory ß1 -selective antagonist/ß3 -agonist, and valsartan (80 mg), a renin-angiotensin-aldosterone system inhibitor, is the only Food and Drug Administration-approved ß-blocker/renin-angiotensin-aldosterone system inhibitor SPC for hypertension. Additive effects of four nebivolol/valsartan SPC doses (5 mg/80 mg, 5/160 mg, 10/160 mg, 10/320 mg nebivolol/valsartan) were compared with five Food and Drug Administration-approved non-ß-blocker/renin-angiotensin-aldosterone system inhibitor SPCs (aliskiren/hydrochlorothiazide, aliskiren/amlodipine, valsartan/amlodipine, aliskiren/valsartan, and telmisartan/amlodipine). Additivity is the ratio of placebo-adjusted SPC blood pressure (BP) reduction to the placebo-adjusted monotherapy component BP reduction sums. A weighted average of comparator scores was calculated and compared vs nebivolol/valsartan. Additivity ratio scores for nebivolol/valsartan SPCs (diastolic BP range: 0.735-0.866; systolic BP range: 0.717-0.822) were similar to the comparator weighted average (diastolic BP: 0.837; systolic BP: 0.825). Among the nebivolol/valsartan SPCs, 5/80 mg had the greatest additivity (diastolic BP: 0.866; systolic BP: 0.822). BP reduction contributions with monotherapy were similar for nebivolol/valsartan 5/80 mg SPC. Additivity scores for nebivolol/valsartan and select non-ß-blocker/renin-angiotensin-aldosterone system inhibitor SPCs were comparable.

The effect of lomitapide on cardiovascular outcome measures in homozygous familial hypercholesterolemia: A modelling analysis.

Background Patients with homozygous familial hypercholesterolemia are at high risk of cardiovascular disease due to high low-density lipoprotein (LDL)-cholesterol levels. Cardiovascular disease outcome studies are impossible to conduct, due to the rarity of homozygous familial hypercholesterolemia. We modelled the potential efficacy of lomitapide, a microsomal transfer protein inhibitor, on major adverse cardiovascular events (MACEs) and survival. Design We calculated the effect on cardiovascular outcomes of a 38% plasma LDL-cholesterol reduction induced by lomitapide. Methods Age-dependent hazards and treatment-dependent hazard ratios for mortality and time to first MACE were calculated from an observational study of 149 South African homozygous familial hypercholesterolemia patients. Cardiovascular-related mortality hazards were derived by adjusting for general population non-cardiovascular-related mortality. For every mmol/L LDL-cholesterol reduction, a relative risk reductions of 23% (mortality) and 15% (major adverse cardiovascular events) were observed. Results For the most robust model, baseline median survival with current treatments (LDL-cholesterol 8.7 mmol/L) was 48 years. In the survival benefit analysis, starting lomitapide at age 18 years and reducing LDL-cholesterol by 3.3 mmol/L from baseline would increase life expectancy by 11.2 years and delay the time to first MACE by 5.7 years. Analysis suggested lifetime lomitapide treatment could increase median life expectancy by 11.7 years and time to first MACE by 6.7 years. Conclusion Our modelling analyses show that additional LDL-cholesterol lowering by lomitapide may increase life expectancy in patients with homozygous familial hypercholesterolemia. Further clinical studies are warranted to determine the cardiovascular morbidity and mortality benefits of lomitapide.

Cost-effectiveness of eplerenone compared with placebo in patients with myocardial infarction complicated by left ventricular dysfunction and heart failure.

BACKGROUND: In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), aldosterone blockade with eplerenone decreased mortality in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. The present study was performed to evaluate the cost-effectiveness of eplerenone compared with placebo in these patients. METHODS AND RESULTS: A total of 6632 patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction were randomized to eplerenone or placebo and followed up for a mean of 16 months. The coprimary end points were all-cause mortality and the composite of cardiovascular mortality/cardiovascular hospitalization. The evaluation of resource use included hospitalizations, outpatient services, and medications. Eplerenone was priced at the average wholesale price, 3.60 dollars per day. Survival beyond the trial period was estimated from data from the Framingham Heart Study, the Saskatchewan Health database, and the Worcester Heart Attack Registry. The incremental cost-effectiveness of eplerenone in cost per life-year and quality-adjusted life-year gained compared with placebo was estimated. The number of life-years gained with eplerenone was 0.1014 based on Framingham (95% CI, 0.0306 to 0.1740), 0.0636 with Saskatchewan (95% CI, 0.0229 to 0.1038), and 0.1337 with Worcester (95% CI, 0.0438 to 0.2252) data. Cost was 1391 dollars higher over the trial period in the eplerenone arm (95% CI, 656 to 2165) because of drug cost. The incremental cost-effectiveness ratio was 13,718 dollars per life-year gained with Framingham (96.7% under 50,000 dollars per life-year gained), 21,876 dollars with Saskatchewan, and 10,402 dollars with Worcester. CONCLUSIONS: Eplerenone compared with placebo in the treatment of heart failure after acute myocardial infarction is effective in reducing mortality and is cost-effective in increasing years of life by commonly used criteria.

Deriving health utility values from a randomized, double-blind, placebo-controlled trial of siltuximab in subjects with multicentric Castleman's disease.

PURPOSE: To estimate health utility values, explore predictors of utility values, and estimate the quality-adjusted life years (Q.A.L.Y.s) gained by treatment in multicentric Castleman's disease (M.C.D.). METHODS: The SF-36 was administered to 79 patients enrolled in a randomized, double-blind, placebo-controlled, multi-national study to determine the safety and efficacy of siltuximab plus best supportive care (B.S.C.) compared with B.S.C., in subjects with symptomatic M.C.D. Utility (SF-6D) scores were derived from the SF-36. Sensitivity analyses using utilities obtained by mapping the SF-36 to the EQ-5D were also conducted. Repeated measures, mixed effects models were conducted to estimate effects of treatment, responder status and ≥ Grade 3 adverse events (A.E.s) on changes in utility values over time, controlling for baseline utility value. Additionally, differential Q.A.L.Y. gain was assessed in the trial using multiple regression. RESULTS: Patients on siltuximab and those who experienced a complete or partial response had higher mean utility values over time than those on placebo or those with stable disease. After an initial response to treatment, the mean utility remained relatively stable for patients on siltuximab and those who experienced a complete or partial response during the period when most patients were on study. A significantly different Q.A.L.Y. gain was found for patients on siltuximab (versus placebo) as calculated by SF-6D (0.070 Q.A.L.Y.s, p < .05) scores at 6 months (EQ-5D 0.096 Q.A.L.Y.s, p < 0.05). CONCLUSIONS: Siltuximab demonstrated improved, durable health utility gains in this rare disease over B.S.C. The main SF-6D results were supported by EQ-5D sensitivity analysis. These findings are limited by the small study sample size and substantial missing data caused predominantly by crossover. A longitudinal, multisite international observational study capturing clinical, safety and health-related quality of life (H.R.Q.L.) endpoints are needed to confirm these findings.

Rational choice of cholinesterase inhibitor for the treatment of Alzheimer's disease in Canada: a comparative economic analysis.

BACKGROUND: Cholinesterase inhibitors, such as galantamine, donepezil and rivastigmine are approved for symptomatic treatment of Alzheimer's Disease (AD) in Canada. In making choices amongst these drugs, one should consider their clinical merits and their economic implications. METHODS: Each drug's short-term efficacy was estimated based on independent Cochrane reviews of the clinical trials. Long-term clinical and economic outcomes were estimated using the Assessment of Health Economics in Alzheimer's Disease (AHEAD) model. RESULTS: While all treatments reduced the need for full-time care, only galantamine and donepezil 10 mg reduced the overall management costs of AD patients. The somewhat greater cognitive effect provided over six months by galantamine leads to the longest estimated delay before full-time care is required and, consequently to lower overall costs, with savings estimated at between 323 dollars and 4,246 dollars. CONCLUSION: Although there is uncertainty in estimated results, the best information currently available suggests that the first choice for treatment of AD should be galantamine. These results should be interpreted with caution, however, as results are not based on direct comparisons among the drugs and the differences emerging from meta-analyses of the trials are relatively small.

Modelling survival in hepatocellular carcinoma.

OBJECTIVES: To identify the pattern of the risk of death over long-term in unresectable hepatocellular carcinoma by determining the appropriate distribution to extrapolate overall survival and to assess the role of the Weibull distribution as the standard survival model in oncology. RESEARCH DESIGN AND METHODS: To select the appropriate distribution, three types of data sources have been analysed. Patient level data from two randomized controlled trials and published Kaplan-Meier curves from a systematic literature review provided short term follow-up data. They were supplemented with patient level data, with long-term follow-up from the Cancer Institute New South Wales, Australia. Published Kaplan-Meier curves were read in and a time-to-event dataset was created. Distributions were fitted to the data from the different sources separately. Their fit was assessed visually and compared using statistical criteria based on log-likelihood, the Akaike information criterion (AIC), and the Bayesian information criterion (BIC). RESULTS: Based on both published and patient-level, and both short- and long-term follow-up data, the Weibull distribution, used very often in cost-effectiveness models in oncology, does not seem to offer a good fit in hepatocellular carcinoma among the different survival models. The best fitting distribution appears to be the lognormal, with loglogistic as the second-best fitting function. Results were consistent between the different sources of data. CONCLUSIONS: In unresectable hepatocellular carcinoma, the Weibull model, which is often treated at the gold standard, does not appear to be appropriate based on different sources of data (two clinical trials, a retrospective database and published Kaplan-Meier curves). Lognormal distribution seems to be the most appropriate distribution for extrapolating overall survival.