Medical resource utilization of abiraterone acetate plus prednisone added to androgen deprivation therapy in metastatic castration-naive prostate cancer: Results from LATITUDE.

BACKGROUND: Abiraterone acetate plus prednisone (AA+P), when added to androgen deprivation therapy (ADT), demonstrated significant improvements in overall survival and disease progression over dual placebos added to ADT in the LATITUDE clinical trial (NCT01715285). The objective of this study was to assess event-driven medical resource utilization (MRU) of ADT plus AA+P (ADT+AA+P) versus ADT plus dual placebos (ADT+placebos) in LATITUDE. METHODS: Event-driven MRU data from LATITUDE while patients were on treatment were used for analyses. Types of MRU included overnight hospitalizations and length of stay (LOS), emergency room (ER) visits, radiotherapy, surgery, imaging, and specialist and general practitioner (GP) visits. Rates by treatment (per 100 person-years) and rate ratios comparing ADT+AA+P with ADT+placebos were estimated with zero-inflated Poisson regression. The difference in the average hospital LOS between arms was assessed with repeated measures regression analyses. Reasons for hospitalization were explored. Sensitivity analyses were conducted to assess the robustness of the results. RESULTS: A total of 1199 patients were enrolled in LATITUDE. Significantly lower rates of hospitalization (a 24% reduction), imaging (a 36% reduction), and radiotherapy (a 50% reduction) were observed with ADT+AA+P versus ADT+placebos. There was a nonsignificant trend of lower rates of specialist visits and surgery. The rates of ER and GP visits and the average LOS per hospitalization episode were similar across arms. The most common hospitalization reasons were genitourinary, musculoskeletal, and respiratory tract symptoms/disorders. The results remained consistent in a sensitivity analysis. CONCLUSIONS: Adding AA+P to ADT does not increase MRU and leads to lower rates of hospitalization, imaging, and radiotherapy. This likely reflects the more favorable clinical outcomes with ADT+AA+P therapy.

Axitinib, cabozantinib, or everolimus in the treatment of prior sunitinib-treated patients with metastatic renal cell carcinoma: results of matching-adjusted indirect comparison analyses.

BACKGROUND: In the absence of head-to-head trials comparing axitinib with cabozantinib or everolimus, the aim of this study was to conduct an indirect comparison of their relative efficacy in patients with metastatic renal cell carcinoma (mRCC), using data from the AXIS and METEOR trials. METHODS: Progression-free survival (PFS) and overall survival (OS) in prior sunitinib-treated patients with mRCC were compared by conducting matching-adjusted indirect comparison (MAIC) analyses, including base-case and sensitivity analyses. Individual patient-level data from prior sunitinib-treated patients who received axitinib in AXIS were weighted to match published baseline characteristics of prior sunitinib-treated patients who received either cabozantinib or everolimus in METEOR. RESULTS: There was no statistically significant difference in PFS (aHR [adjusted hazard ratio] = 1.15 [CI: 0.82-1.63]) and OS (aHR = 1.00 [CI: 0.69-1.46]) between axitinib versus cabozantinib in the base-case analysis. In the sensitivity analysis, PFS (aHR = 1.39 [CI: 1.00-1.92]) and OS (aHR = 1.35 [CI: 0.95-1.92]) were shorter for axitinib compared with cabozantinib; however, the OS difference was not statistically significant. Axitinib was associated with significantly longer PFS compared with everolimus in the base-case (aHR = 0.53 [CI: 0.36-0.80]) and sensitivity analyses (aHR = 0.63 [CI: 0.45-0.88]), respectively. Results suggested an OS benefit for axitinib versus everolimus in base-case analyses (aHR = 0.63 [CI: 0.42-0.96]); however, the difference in OS in the sensitivity analysis was not statistically significant (aHR = 0.84 [CI: 0.59-1.18]). CONCLUSIONS: MAIC analyses suggest PFS and OS for axitinib and cabozantinib are dependent on the Memorial Sloan Kettering Cancer Center definition used; in the base-case analysis, there was no significant difference in PFS and OS between axitinib and cabozantinib. In the sensitivity analysis, PFS in favour of cabozantinib was significant; however, the trend for prolonged OS with cabozantinib was not significant. For axitinib and everolimus, MAIC analyses indicate patients treated with axitinib may have an improved PFS and OS benefit when compared to everolimus. Disparities between the base-case and sensitivity analyses in this study underscore the importance of adjusting for the differences in baseline characteristics and that naïve indirect comparisons are not appropriate.

Modeling Clinical Outcomes in Prostate Cancer: Application and Validation of the Discrete Event Simulation Approach.

OBJECTIVES: Treatment landscape in prostate cancer has changed dramatically with the emergence of new medicines in the past few years. The traditional survival partition model (SPM) cannot accurately predict long-term clinical outcomes because it is limited by its ability to capture the key consequences associated with this changing treatment paradigm. The objective of this study was to introduce and validate a discrete-event simulation (DES) model for prostate cancer. METHODS: A DES model was developed to simulate overall survival (OS) and other clinical outcomes based on patient characteristics, treatment received, and disease progression history. We tested and validated this model with clinical trial data from the abiraterone acetate phase III trial (COU-AA-302). The model was constructed with interim data (55% death) and validated with the final data (96% death). Predicted OS values were also compared with those from the SPM. RESULTS: The DES model's predicted time to chemotherapy and OS are highly consistent with the final observed data. The model accurately predicts the OS hazard ratio from the final data cut (predicted: 0.74; 95% confidence interval [CI] 0.64-0.85 and final actual: 0.74; 95% CI 0.6-0.88). The log-rank test to compare the observed and predicted OS curves indicated no statistically significant difference between observed and predicted curves. However, the predictions from the SPM based on interim data deviated significantly from the final data. CONCLUSIONS: Our study showed that a DES model with properly developed risk equations presents considerable improvements to the more traditional SPM in flexibility and predictive accuracy of long-term outcomes.

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.

Uncertain about uncertainty in matching-adjusted indirect comparisons? A simulation study to compare methods for variance estimation.

In health technology assessment, matching-adjusted indirect comparison (MAIC) is the most common method for pairwise comparisons that control for imbalances in baseline characteristics across trials. One of the primary challenges in MAIC is the need to properly account for the additional uncertainty introduced by the matching process. Limited evidence and guidance are available on variance estimation in MAICs. Therefore, we conducted a comprehensive Monte Carlo simulation study to evaluate the performance of different statistical methods across 108 scenarios. Four general approaches for variance estimation were compared in both anchored and unanchored MAICs of binary and time-to-event outcomes: (1) conventional estimators (CE) using raw weights; (2) CE using weights rescaled to the effective sample size (ESS); (3) robust sandwich estimators; and (4) bootstrapping. Several variants of sandwich estimators and bootstrap methods were tested. Performance was quantified on the basis of empirical coverage probabilities for 95% confidence intervals and variability ratios. Variability was underestimated by CE + raw weights when population overlap was poor or moderate. Despite several theoretical limitations, CE + ESS weights accurately estimated uncertainty across most scenarios. Original implementations of sandwich estimators had a downward bias in MAICs with a small ESS, and finite sample adjustments led to marked improvements. Bootstrapping was unstable if population overlap was poor and the sample size was limited. All methods produced valid coverage probabilities and standard errors in cases of strong population overlap. Our findings indicate that the sample size, population overlap, and outcome type are important considerations for variance estimation in MAICs.

Efficacy of avalglucosidase alfa on forced vital capacity percent predicted in treatment-naïve patients with late-onset Pompe disease: A pooled analysis of clinical trials.

Background: The efficacy of avalglucosidase alfa (AVA) versus alglucosidase alfa (ALG) on forced vital capacity percent predicted (FVCpp) in patients with late-onset Pompe disease (LOPD) has been assessed in the Phase 3 COMET trial (NCT02782741). Due to the rarity of LOPD and thus small sample size in COMET, additional data were analyzed to gain further insights into the efficacy of AVA versus ALG. Methods: Data from treatment-naive patients with LOPD were pooled from COMET and Phase 1/2 NEO1/NEO-EXT (NCT01898364/NCT02032524) trials for patients treated with AVA, and Phase 3 LOTS trial (NCT00158600) for patients treated with ALG. Regression analyses using mixed models with repeated measures consistent with those pre-specified in COMET were performed post-hoc. Analyses were adjusted for trials and differences in baseline characteristics. Four models were developed: Model 1 considered all trials; Model 2 included Phase 3 trials; Model 3 included Phase 3 trials and was adjusted for baseline ventilation use; Model 4 included COMET and NEO1/NEO-EXT (i.e., AVA trials only). Results: Overall, 100 randomized patients from COMET (AVA, n = 51, ALG, n = 49), 60 from LOTS (ALG arm only), and three patients from NEO1/NEO-EXT (who received open-label AVA only) were considered for analysis. Mean age at enrollment was similar across trials (45.3-50.3 years); however, patients from LOTS had a longer mean duration of disease versus COMET and NEO1/NEO-EXT trials (9.0 years and 0.5-2.2 years, respectively) and younger mean age at diagnosis (36.2 years and 44.7-48.6 years, respectively). Least squares mean (95% confidence interval) improvement from baseline in FVCpp at Week 49-52 for AVA versus ALG was 2.43 (-0.13; 4.99) for COMET (n = 98); 2.31 (0.06; 4.57) for Model 1 (n = 160); 2.43 (0.21; 4.65) for Model 2 (n = 157); 2.80 (0.54; 5.05) for Model 3 (n = 154); and 2.27 (-0.30; 4.45) for Model 4 (n = 101). Conclusions: Models 1 to 3, which had an increased sample size versus COMET, demonstrated a nominally significant effect on FVCpp favoring AVA versus ALG after 1 year of treatment, consistent with results from COMET.

Efficacy of Mobocertinib and Amivantamab in Patients With Advanced Non-Small Cell Lung Cancer With EGFR Exon 20 Insertions Previously Treated With Platinum-Based Chemotherapy: An Indirect Treatment Comparison.

INTRODUCTION: Exon 20 insertions (ex20ins) mutations of the EGFR gene account for 1% to 2% of all non-small-cell lung cancers (NSCLCs). Targeted therapies have been developed to treat this cancer type but have not been studied in head-to-head trials. Our objective was to use a matching-adjusted indirect comparison (MAIC) to assess the efficacy of mobocertinib and amivantamab in patients with NSCLC EGFR ex20ins mutations who were previously treated with platinum-based chemotherapy. MATERIALS AND METHODS: An unanchored MAIC was conducted to estimate the treatment effects of mobocertinib and amivantamab using individual-level data from the mobocertinib phase I/II single-arm trial (NCT02716116) and published data from the amivantamab single-arm CHRYSALIS trial (NCT02609776). Confirmed overall response rate (cORR), progression-free survival (PFS), overall survival (OS), and duration of response (DoR) were assessed. RESULTS: Both trials were comparable in terms of study population, study design, and outcome definitions and included 114 patients who received mobocertinib and 114 patients who received amivantamab. After MAIC weighting, all reported baseline characteristics were balanced between mobocertinib and amivantamab. The weighted odds ratio (OR) [95% confidence interval (CI)] comparing mobocertinib to amivantamab was 0.56 (0.30-1.04) for independent review committee (IRC)-assessed cORR and 0.98 (0.53-1.82) for investigator (INV)-assessed cORR. The weighted hazard ratio (HR) comparing mobocertinib to amivantamab was 0.74 (0.51-1.07) for IRC-assessed PFS, 0.92 (0.57-1.48) for OS, and 0.59 (0.30-1.18) for INV-assessed DoR. CONCLUSION: MAIC analysis showed that mobocertinib and amivantamab had similar efficacy in patients with NSCLC harboring EGFR ex20ins mutations whose disease progressed during or after platinum-based chemotherapy. These findings may benefit patients by supporting future treatment options.

Regorafenib versus Cabozantinib as a Second-Line Treatment for Advanced Hepatocellular Carcinoma: An Anchored Matching-Adjusted Indirect Comparison of Efficacy and Safety.

Introduction: The tyrosine kinase inhibitors regorafenib and cabozantinib remain the mainstay in second-line treatment of advanced hepatocellular carcinoma (HCC). There is currently no clear evidence of superiority in efficacy or safety to guide choice between the two treatments. Methods: We conducted an anchored matching-adjusted indirect comparison using individual patient data from the RESORCE trial of regorafenib and published aggregate data from the CELESTIAL trial of cabozantinib. Second-line HCC patients with prior sorafenib exposure of ≥3 months were included in the analyses. Hazard ratios (HRs) and restricted mean survival time (RMST) were estimated to quantify differences in overall survival (OS) and progression-free survival (PFS). Safety outcomes compared were rates of grade 3 or 4 adverse events (AEs), occurring in >10% of patients, and discontinuation or dose reduction due to treatment-related AEs. Results: After matching adjustment for differences in baseline patient characteristics, regorafenib showed a favorable OS (HR, 0.80; 95% CI: 0.54, 1.20) and ∼3-month-longer RMST over cabozantinib (RMST difference, 2.76 months; 95% CI: -1.03, 6.54), although not statistically significant. For PFS, there was no numerical difference in HR (HR, 1.00; 95% CI: 0.68, 1.49) and no clinically meaningful difference based on RMST analyses (RMST difference, -0.59 months; 95% CI: -1.83, 0.65). Regorafenib showed a significantly lower incidence of discontinuation (risk difference, -9.2%; 95% CI: -17.7%, -0.6%) and dose reductions (-15.2%; 95% CI: -29.0%, -1.5%) due to treatment-related AEs (any grade). Regorafenib was also associated with a lower incidence (not statistically significant) of grade 3 or 4 diarrhea (risk difference, -7.1%; 95% CI: -14.7%, 0.4%) and fatigue (-6.3%; 95% CI: -14.6%, 2.0%). Conclusion: This indirect treatment comparison suggests, relative to cabozantinib, that regorafenib could be associated with favorable OS (not statistically significant), lower rates of dose reductions and discontinuation due to treatment-related AEs, and lower rates of severe diarrhea and fatigue.

Cost-Effectiveness of Lisocabtagene Maraleucel Versus Axicabtagene Ciloleucel and Tisagenlecleucel in the Third-Line or Later Treatment Setting for Relapsed or Refractory Large B-cell Lymphoma in the United States.

INTRODUCTION: The objective of this study was to evaluate the cost-effectiveness of lisocabtagene maraleucel (liso-cel) versus other available chimeric antigen receptor T-cell therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), in patients who had received at least two prior therapies from a United States (US) commercial third-party payer perspective. METHODS: To capture this heterogeneity in survival outcomes, we used mixture cure models to extrapolate progression-free survival (PFS) and overall survival (OS). Patient-level data from TRANSCEND NHL 001 for liso-cel and reconstructed patient-level data from ZUMA-1 for axi-cel, JULIET for tisa-cel, and SCHOLAR-1 for salvage chemotherapy, derived using the Guyot method, were used for OS and PFS. The model included adverse events associated with liso-cel, axi-cel, and tisa-cel. RESULTS: Liso-cel was less costly (incremental cost of - $74,980) and marginally more effective (0.002 incremental quality-adjusted life-years [QALY]) than axi-cel and had an incremental cost of $67,925 and 2.02 incremental QALYs over tisa-cel in the base case. Results remained consistent in sensitivity analyses, with the liso-cel OS cure fraction being the main driver of cost-effectiveness compared with both axi-cel and tisa-cel. CONCLUSION: This analysis estimated that liso-cel is cost-effective compared with tisa-cel and axi-cel from a commercial US payer perspective.

Indirect comparison of mobocertinib and real-world therapies for pre-treated non-small cell lung cancer with EGFR exon 20 insertion mutations.

OBJECTIVES: Mobocertinib, a novel oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is available for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) mutations after platinum chemotherapy. We performed an indirect comparison of clinical trial data and real-world data (RWD) to determine the relative efficacy of mobocertinib vs. other treatments for these patients. MATERIALS AND METHODS: Data on the efficacy of mobocertinib from a phase I/II trial (NCT02716116) were compared to RWD from a retrospective study in 12 German centers using inverse probability of treatment weighting to adjust for age, sex, Eastern Cooperative Oncology Group score, smoking status, presence of brain metastasis, time from advanced diagnosis, and histology. Tumor response assessment was based on RECIST v1.1. RESULTS: The analysis included 114 patients in the mobocertinib group and 43 in the RWD group. The confirmed overall response rate (cORR) according to investigator assessment was 0% for standard treatments and 35.1% (95% confidence interval [CI], 26.4-44.6) for mobocertinib (p < 0.0001). Compared to standard regimens in the weighted population, mobocertinib prolonged overall survival (OS, median [95% CI] = 9.8 [4.3-13.7] vs. 20.2 [14.9-25.3] months; hazard ratio [HR] = 0.42 [0.25-0.69], p = 0.0035), progression-free survival (PFS, median [95% CI] = 2.6 [1.5-5.7] vs. 7.3 [5.6-8.8] months; HR = 0.28 [0.18-0.44], p < 0.0001), and time to treatment discontinuation (median [95% CI] = 2.1 [1.2-3.1] vs. 7.4 [6.4-8.5] months; HR = 0.34 [0.18-0.65], p = 0.0004). CONCLUSION: Mobocertinib was associated with an improved cORR and prolonged PFS and OS compared to standard treatments for patients with EGFR ex20ins-positive NSCLC previously treated with platinum-based chemotherapy.

Cost-effectiveness of prasugrel versus clopidogrel in patients with acute coronary syndromes and planned percutaneous coronary intervention: results from the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with Prasugrel-Thrombolysis in Myocardial Infarction TRITON-TIMI 38.

BACKGROUND: In patients with acute coronary syndromes and planned percutaneous coronary intervention, the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) demonstrated that treatment with prasugrel versus clopidogrel was associated with reduced rates of cardiovascular death, MI, or stroke and an increased risk of major bleeding. We evaluated the cost-effectiveness of prasugrel versus clopidogrel from the perspective of the US healthcare system by using data from TRITON-TIMI 38. METHODS AND RESULTS: Detailed resource use data were prospectively collected for all patients recruited from 8 countries (United States, Australia, Canada, Germany, Italy, Spain, United Kingdom, and France; n=3373 prasugrel, n=3332 clopidogrel). Hospitalization costs were estimated on the basis of diagnosis-related group and in-hospital complications. Cardiovascular medication costs were estimated by using net wholesale prices (clopidogrel=$4.62/d; prasugrel=$5.45/d). Life expectancy was estimated from in-trial cardiovascular and bleeding events with the use of statistical models of long-term survival from a similar population from the Saskatchewan Health Database. Over a median follow-up of 14.7 months, average total costs (including study drug) were $221 per patient lower with prasugrel (95% confidence interval, -759 to 299), largely because of a lower rate of rehospitalization involving percutaneous coronary intervention. Prasugrel was associated with life expectancy gains of 0.102 years (95% confidence interval, 0.030 to 0.180), primarily because of the decreased rate of nonfatal MI. Thus, compared with clopidogrel, prasugrel was an economically dominant treatment strategy. If a hypothetical generic cost for clopidogrel of $1/d is used, the incremental net cost with prasugrel was $996 per patient, yielding an incremental cost-effectiveness ratio of $9727 per life-year gained. CONCLUSIONS: Among acute coronary syndrome patients with planned percutaneous coronary intervention, treatment with prasugrel versus clopidogrel for up to 15 months is an economically attractive treatment strategy. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov. Unique identifier: NCT00097591.

Cost of health care among patients with chronic and episodic migraine in Canada and the USA: results from the International Burden of Migraine Study (IBMS).

OBJECTIVE: To evaluate and compare healthcare resource use and related costs in chronic migraine and episodic migraine in the USA and Canada. BACKGROUND: Migraine is a common neurological disorder that produces substantial disability for sufferers around the world. Several studies have quantified overall costs associated with migraine in general, with recent estimates ranging from $581 to $7089 per year. Although prior studies have characterized the clinical and humanistic burden of chronic migraine relative to episodic migraine, to the best of our knowledge only 1 previous study has compared chronic migraine and episodic migraine healthcare costs. The purpose of this study was to quantify and compare the direct medical costs of chronic migraine and episodic migraine using medical resource use data collected as part of the International Burden of Migraine Study. METHODS: Cross-sectional data were collected from respondents in 10 countries via a Web-based survey. Respondents were classified as chronic migraine (≥15 headache days/month) or episodic migraine (<15 headache days/month). Data collection included socio-demographic and clinical characteristics and medical resource use for headache (clinician and emergency department visits and hospitalizations over the preceding 3 months and medications over the preceding 4 weeks). Unit cost data were collected outside of the Web-based survey using publicly available sources and then applied to resource use profiles. Cost estimates are presented in 2010 US and Canadian dollars. RESULTS: In this manuscript, the analysis included data from respondents with migraine in the USA (N=1204) and Canada (N=681). The most common medical services utilized by all respondents included headache-specific medication, healthcare provider visits, emergency department visits, and diagnostic testing. In the USA, approximately one-quarter (26.2%) of chronic migraine participants vs 13.9% of episodic migraine participants reported visiting a primary care physician in the preceding 3 months (P<.001). In Canada, one-half (48.2%) of chronic migraine participants had a primary care physician visit, compared with 12.3% of episodic migraine subjects (P< .0001). Total mean headache-related costs for participants with chronic migraine in the USA were $1036 (±$1334) over 3 months compared to $383 (±807, P< .001) for persons with episodic migraine. In Canada, total mean headache-related costs among chronic migraine subjects were $471 (±1022) compared to $172 (±920, P< .001) for episodic migraine subjects. CONCLUSIONS: Chronic migraine was associated with higher medical resource use and total costs compared to episodic migraine. Therapies that reduce headache frequency could become important approaches for containing or reducing headache-related medical costs.

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 and economic implications of new treatment strategies for Parkinson's disease: an individual patient simulation study.

Background: Simulation modeling facilitates the estimation of long-term health and economic outcomes to inform healthcare decision-making. Objective: To develop a framework to simulate progression of Parkinson's disease (PD), capturing motor and non-motor symptoms, clinical outcomes, and associated costs over a lifetime. Methods: A patient-level simulation was implemented accounting for individual variability and interrelated changes in common disease progression scales. Predictive equations were developed to model progression for newly diagnosed patients and were combined with additional sources to inform long-term progression. Analyses compared a hypothetical disease-modifying therapy (DMT) with a standard of care to explore the drivers of cost-effectiveness. Results: The equations captured the dependence between the various measures, leveraging prior values and rates of change to obtain realistic predictions. The simulation was built upon several interrelated equations, validated by comparison with observed values for the Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) and UPDRS subscales over time. In a case study, disease progression rates, patient utilities, and direct non-medical costs were drivers of cost-effectiveness. Conclusions: The developed equations supported the simulation of early PD. This model can support conducting simulations to inform internal decision-making, trial design, and strategic planning early in the development of new DMTs entering clinical trials.

Front-line daratumumab-VTd versus standard-of-care in ASCT-eligible multiple myeloma: matching-adjusted indirect comparison.

Aim: To compare daratumumab plus standard-of-care (SoC; bortezomib/thalidomide/dexamethasone [VTd]) and VTd alone with other SoC for transplant-eligible newly diagnosed multiple myeloma. Patients & methods: We conducted an unanchored matching-adjusted indirect comparison of progression-free and overall survival (PFS/OS) with D-VTd/VTd versus bortezomib/lenalidomide/dexamethasone (VRd), bortezomib/cyclophosphamide/dexamethasone (VCd) and bortezomib/dexamethasone (Vd). Results: After matching adjustment, significant improvements in PFS were estimated for D-VTd versus VRd (hazard ratio [HR]: 0.47 [95% CI: 0.33-0.69]), VCd (HR: 0.35 [95% CI: 0.21-0.58]) and Vd (HR: 0.42 [95% CI: 0.28-0.63]). OS was significantly longer with D-VTd versus VRd (HR: 0.31 [95% CI: 0.16-0.57]), VCd (HR: 0.35 [95% CI: 0.14-0.86]) and Vd (HR: 0.38 [95% CI: 0.18-0.77]). No significant PFS/OS differences were seen for VTd versus other SoC. Conclusion: This analysis supports front-line daratumumab for transplant-eligible newly diagnosed multiple myeloma.

Evaluation of the consequences associated with diffuse vascular disease history in patients diagnosed with peripheral arterial disease: estimates from Saskatchewan health data.

BACKGROUND: Peripheral arterial disease (PAD) is caused by narrowing of the arteries in the lower extremities. Limited data exist concerning the impact of diffuse vascular disease (DVD) on prognosis and costs. Thus, the objective of this study is to estimate the impact of DVD on morbidity, mortality and costs. METHODS: PAD was identified between 1985 and 1995 and classified by extent of DVD at diagnosis: none (PAD only, reference group), prior myocardial infarction (MI), prior stroke, prior MI and stroke (MI + stroke), prior transient ischemic attack (TIA). Deaths and hospitalizations were identified through December 2000. Hospitalization costs were estimated from the Ontario Case Cost Project, reported in 2002 $CAD. Proportional hazards analyses measured the impact of vascular involvement on mortality while controlling for risk factors (e.g., age, cardiovascular history). RESULTS: Overall, 16,439 patients with PAD were included; 14.8% had a prior MI, 10.2% a prior stroke, 2.6% prior MI + stroke, 6.4% prior TIA, two-thirds had PAD only. Median survival was shorter for patients with prior MI (9.3 yrs), TIA (6.3), stroke (4.7), and MI+stroke (4.1) versus the reference group (9.9, p < 0.05, all comparisons). Analyses revealed that the death risk was 60% higher in patients with prior stroke and 84% higher for MI + stroke. Atherothrombotic and bleeding event-related costs were $712, $337, $268, and $170 higher per patient/year of follow-up in patients with a history of MI+stroke, MI, stroke, and TIA, respectively. CONCLUSION: Patients diagnosed with PAD with DVD have higher risk of poor outcomes and increased costs.

Economic evaluation of atorvastatin for prevention of recurrent stroke based on the SPARCL trial.

OBJECTIVES: This study evaluated the economic implications of results obtained by the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. METHODS: To enable long-term projection of the trial results, a discrete event simulation of the course of clinical care after a recent stroke or transient ischemic attack (TIA) was developed. It generates pairs of identical patients; both receive usual care, one receives atorvastatin in addition. Their clinical course is simulated based on their risk of stroke, cardiovascular events, and case fatality rates taken from SPARCL, life expectancy from Saskatchewan Health data, and utility weights from literature. Costs, from a US health-care payer perspective in 2005 US dollars, were estimated for a within-trial 5-year period; survival and quality-adjusted life-years (QALYs) were extrapolated over a patient's lifetime; all discounted at 3%/year. RESULTS: The prevention of stroke, coronary, and other cardiovascular events expected with atorvastatin translates to mean gains of 0.155 life-years gained and 0.172 QALYs per patient over their lifetime. Reducing associated medical costs ($8405 vs. $11,237) but increasing drug costs ($13,984 vs. $8752) results in net $2400/patient, or $13,916/QALY gained. Probabilistic sensitivity analysis indicates no simulations yield ratios above $50,000/QALY. CONCLUSION: Prescribing atorvastatin for patients with prior stroke or TIA is expected to provide health benefits at an acceptable cost in the United States.

Survival Analysis in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab.

INTRODUCTION: Complex underlying risk functions associated with immuno-oncology treatments have led to exploration of different methods (parametric survival, spline, landmark, and cure-fraction models) to estimate long-term survival outcomes. The objective of this study was to examine differences in estimated short- and long-term survival in previously treated metastatic Merkel cell carcinoma (mMCC) patients receiving avelumab, when using alternative extrapolation approaches. METHODS: Efficacy data from the phase 2 JAVELIN Merkel 200 trial (part A) with at least 12 months of follow-up were analyzed. Standard parametric survival analyses and analyses of overall survival (OS) as a function of surrogate outcomes comprised of response (landmark analyses) and progression-free survival plus post-progression survival (PFS + PPS) were used to project OS. Overall survival throughout lifetime was projected and compared with the observed OS data with at least 24 months of follow-up. RESULTS: Estimated OS from all three approaches provided a good fit to the observed OS curve from at least 12 months of follow-up. However, performance compared with OS data from at least 24 months showed that the landmark approach followed by PFS + PPS provided a better fit to the data as compared to standard parametric analysis. Mean life expectancy estimated with avelumab was 2.48 years with best-fitting parametric function (a log-normal distribution), 3.15 years with the landmark approach, and 3.54 years with PFS + PPS. CONCLUSION: Although standard parametric survival analysis may provide a good fit to short-term survival, it appears to underestimate the long-term survival benefits associated with avelumab in mMCC. Extrapolations based on surrogate outcomes of response or progression predict OS outcomes from longer follow-up better and appear to provide more clinically plausible projections. FUNDING: EMD Serono Inc, Rockland, MA, a business of Merck KGaA, Darmstadt, Germany.

Comparative efficacy of brigatinib versus ceritinib and alectinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small cell lung cancer.

OBJECTIVE: Brigatinib, ceritinib, and alectinib are approved to treat crizotinib-refractory anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC), but no trial has compared them head-to-head. A matching-adjusted indirect comparison (MAIC) was conducted to estimate the relative efficacy of these agents in the crizotinib-refractory setting. METHODS: MAIC is a propensity score-type method that adjusts for differences in baseline characteristics between trials to estimate relative efficacy. Analyses were based on patient-level data from the ALTA trial for brigatinib and published summary-level trial data from ASCEND-1 and ASCEND-2 for ceritinib and NP28761 and NP28673 for alectinib. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared. RESULTS: After matching, all key baseline characteristics were balanced between trials. Compared with ceritinib, brigatinib was associated with longer PFS (ASCEND-1: median 15.7 vs 6.9 months, hazard ratio (HR) [95% confidence interval] = 0.38 [0.26-0.57]; ASCEND-2: median = 18.3 vs 7.2 months, HR = 0.33 [0.20-0.56]) and OS (ASCEND-1: not available; ASCEND-2: median 27.6 vs 14.9 months, HR = 0.33 [0.17-0.63]). Versus alectinib, brigatinib was associated with longer PFS (NP28761: median = 17.6 vs 8.2 months, HR = 0.56 [0.36-0.86]; NP28673: median = 17.6 vs 8.9 months, HR = 0.61 [0.40-0.93]); results for OS were inconclusive (NP28761: median = 27.6 vs 22.7 months, HR = 0.70 [0.42-1.16]; NP28673: median = 27.6 vs 26.0 months, HR = 0.66 [0.39-1.09]). ORR was similar. CONCLUSION: In crizotinib-refractory ALK + NSCLC patients, relative efficacy estimates suggest brigatinib may have prolonged PFS and OS vs ceritinib and prolonged PFS vs alectinib.