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.

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.

Economic evaluation of azoles as primary prophylaxis for the prevention of invasive fungal infections in Spanish patients undergoing allogeneic haematopoietic stem cell transplant.

Patients undergoing allogeneic haematopoietic stem cell transplantation (alloHSCT) are at risk of developing invasive fungal infections (IFIs). Even with introduction of oral triazole antifungal agents (fluconazole, itraconazole, posaconazole and voriconazole) IFI-associated morbidity and mortality rates and economic burden remain high. Despite their proven efficacy, it is currently unknown which is the most cost-effective antifungal prophylaxis (AFP) agent. To determine the costs and outcomes associated with AFP, a decision-analytic model was used to simulate treatment in a hypothetical cohort of 1000 patients undergoing alloHSCT from the perspective of the Spanish National Health System. Generic itraconazole was the least costly AFP (€162) relative to fluconazole (€500), posaconazole oral suspension (€8628) or voriconazole (€6850). Compared with posaconazole, voriconazole was associated with the lowest number of breakthrough IFIs (36 vs 60); thus, the model predicted fewer deaths from breakthrough IFI for voriconazole (24) than posaconazole (33), and the lowest predicted costs associated with other licensed antifungal treatment and IFI treatment in a cohort of 1000. Voriconazole resulted in cost savings of €4707 per patient compared with posaconazole. Itraconazole demonstrated a high probability of being cost-effective. As primary AFP in alloHSCT patients 180 days posttransplant, voriconazole was more likely to be cost-effective than posaconazole regarding cost per additional IFI and additional death avoided.

Systematic review and mixed treatment comparison meta-analysis of randomized clinical trials of primary oral antifungal prophylaxis in allogeneic hematopoietic cell transplant recipients.

BACKGROUND: Antifungal prophylaxis is a promising strategy for reducing invasive fungal infections (IFIs) in allogeneic hematopoietic cell transplant (alloHCT) recipients, but the optimum prophylactic agent is unknown. We used mixed treatment comparison (MTC) meta-analysis to compare clinical trials examining the use of oral antifungals for prophylaxis in alloHCT recipients, with the goal of informing medical decision-making. METHODS: Randomized controlled trials (RCTs) of fluconazole, itraconazole, posaconazole, and voriconazole for primary antifungal prophylaxis were identified through a systematic literature review. Outcomes of interest (incidence of IFI/invasive aspergillosis/invasive candidiasis, all-cause mortality, and use of other antifungals) were extracted from eligible RCTs and incorporated into a Bayesian hierarchical random-effects MTC. RESULTS: Five eligible RCTs, randomizing 2147 patients in total, were included. Relative to fluconazole, prophylaxis with itraconazole (odds ratio [OR]: 0.52; interquartile range [IQR]: 0.35-0.76), posaconazole (OR: 0.56; IQR: 0.32-0.99), and voriconazole (OR: 0.46; IQR: 0.28-0.73) reduced incidence of overall proven/probable IFI. Posaconazole (OR: 0.31; IQR: 0.17-0.58) and voriconazole (OR: 0.33; IQR: 0.17-0.58) prophylaxis reduced proven/probable invasive aspergillosis more than itraconazole (OR: 0.68; IQR: 0.42-1.12). All-cause mortality was similar across all mould-active agents. CONCLUSION: As expected, mould-active azoles prevented IFIs, particularly invasive aspergillosis, more effectively than fluconazole in alloHCT recipients. The paucity of comparative efficacy data suggests that other factors such as long-term tolerability, availability of intravenous formulations, local IFI epidemiology, and drug costs may need to form the basis for selection among the mould-active azoles.

The social and organisational factors shaping acceptability of a self-management education and exercise intervention for people with hip or knee osteoarthritis in Greenland.

This study aimed to explore the experiences and perspectives of people with osteoarthritis attending the "Osteoarthritis School" (OA School) in Nuuk, Greenland to generate insights and lessons that can inform the development of self-management education and exercise interventions for people with other lifestyle conditions in a Greenland context. We conducted a qualitative interpretive description (ID) study based on ten semi-structured interviews with people with hip or knee osteoarthritis. Interviews were audio-recorded, transcribed, and coded. Using ID, we identified three themes: 1) perceptions and experiences of how the OA School intervention was organised (time and place); 2) perspectives and experiences of the education and exercise components (social factors, motivation, and education); and 3) significant change stories (physical and mental improvements and increased knowledge of OA). Social and organisational factors, such as working out with peers and the time and place of the intervention, influenced the participants' acceptance of the OA School intervention. Knowledge from this study will help us gain insight into what to address when developing future self-management education and exercise interventions in the Greenlandic healthcare system.

Cost-per-responder analysis of patients with lenalidomide-refractory multiple myeloma receiving ciltacabtagene autoleucel in CARTITUDE-4.

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy approved for patients with relapsed/refractory multiple myeloma (RRMM). In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated improved efficacy vs. standard of care (SOC; daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with a ≥ complete response (≥CR) rate of 73.1% vs. 21.8%. Methods: A cost-per-responder model was developed to assess the value of cilta-cel and SOC (87% DPd and 13% PVd) based on the CARTITUDE-4 trial data from a US mixed payer perspective (76.7% commercial, 23.3% Medicare). The model was developed using progression-free survival (PFS), overall survival (OS), and ≥CR endpoints from CARTITUDE-4 over a period of 25.4 months. Inpatient stays, outpatient visits, drug acquisition, administration, and monitoring costs were included. The base-case model assumed an inpatient setting for each cilta-cel infusion; another scenario included 30% outpatient and 70% inpatient infusions. Costs of managing grade 3-4 adverse events (AEs) and grade 1-4 cytokine release syndrome and neurotoxicity were included. Subsequent therapy costs were incurred after disease progression; terminal care costs were considered upon death events. Outcomes included total cost per treated patient, total cost per complete responder, and cost per month in PFS between cilta-cel and SOC. Costs were adjusted to 2024 US dollars. Results: Total cost per treated patient, total cost per complete responder, and total cost per month in PFS were estimated at $704,641, $963,941, and $30,978 for cilta-cel, respectively, and $840,730, $3,856,559, and $42,520 for SOC over the 25.4-month period. Cost drivers included treatment acquisition costs before progression and subsequent treatment costs ($451,318 and $111,637 for cilta-cel; $529,795 and $265,167 for SOC). A scenario analysis in which 30% of patients received an outpatient infusion (assuming the same payer mix) showed a lower cost per complete responder for cilta-cel ($956,523) than those with an infusion in the inpatient setting exclusively. Discussion: This analysis estimated that cost per treated patient, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower than for DPd or PVd, highlighting the substantial clinical and economic benefit of cilta-cel for patients with RRMM.

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.

Incidence-based cost-of-illness model for metastatic breast cancer in the United States.

OBJECTIVES: This study aims to estimate the annual U.S. societal costs associated with treatment of metastatic breast cancer (MBC) patients using an incidence-based cost-of-illness (COI) framework. METHODS: An incidence-based COI model was constructed in which MBC patients were simulated from diagnosis through active treatment, palliative care, and death over 5 years. Key model parameters included: annual incidence of breast cancer in the metastatic stage, utilization of cancer therapies and other medical care resources, treatment-related adverse events, unit costs, work days missed by patient and caregiver, and wage rates. Overall survival was based on SEER data and costs were assigned to living patients monthly, according to their disease management phase. The outcomes measures were total discounted societal costs, cost/year, and cost/patient-year. RESULTS: The annual incidence of MBC in the United States in 2007 was estimated to be 49,674 patients (de novo and progressed from earlier stages). The total discounted cost to society attributable to MBC was $12.2 billion for the incident cohort, or $98,571 per patient-year. The 5-year direct medical cost of this incident cohort was $9.3 billion, or $75,415 per patient-year. Treatment-related costs (active treatment, toxicity management, and medical follow-up) contributed 44 percent of MBC expenditure, followed by palliative/best supportive care costs (31 percent). Lost productivity accounted for approximately 21 percent of the total cost ($2.6 billion over 5 years or $21,153 per patient-year). CONCLUSIONS: The societal burden of MBC in the United States is substantial. Earlier detection and effective treatment could lead to a significant decrease in costs while improving overall disease prognosis.

Cost-effectiveness of warfarin: trial versus "real-world" stroke prevention in atrial fibrillation.

BACKGROUND AND PURPOSE: Previous cost-effectiveness analyses analyzed warfarin for stroke prevention in randomized trial settings. Given the complexities of warfarin treatment, cost-effectiveness should be examined within a real-world setting. METHODS: Our model followed patients with atrial fibrillation at moderate to high risk of stroke through primary and recurrent ischemic stroke, hemorrhages--intracranial and extracranial, and the resulting disability. Four scenarios were examined: (1) all patients start on warfarin with perfect control, that is, international normalized ratio (INR) values always within range; (2) all patients start on warfarin with trial-like control, where INR can fall outside the recommended range; (3) all patients start on warfarin with real-world INR control; and (4) real-world prescription (and control) of warfarin, aspirin, or neither for warfarin-eligible patients. Reported warfarin discontinuation rates were used. Main outcomes were total number of events, quality adjusted life years, and costs in a US setting. RESULTS: The total number of primary and recurrent ischemic strokes in a 1,000-patient cohort (age 70 years, lifetime analysis) was 626, 832, 984, and 1,171 in scenarios 1 to 4, respectively. The corresponding mean quality adjusted life years per patient were 7.21, 6.92, 6.75, and 6.67 for scenarios 1 to 4, respectively. Costs per patient were $68,039, $77,764, $84,518, and $87,248 in scenarios 1 to 4, respectively. If "perfect" adherence to warfarin was assumed, except for discontinuations for clinical reasons, strokes would decrease to 503, 737, 909, and 1,120 in scenarios 1 to 4, respectively. CONCLUSIONS: Clinical and cost outcomes are strongly dependent on the quality of anticoagulation and rates of warfarin discontinuation. Clinicians should work to improve both. Policy makers should use real-world INR control and warfarin discontinuation rates when assessing cost-effectiveness.

Model-based simulation to explore the cost-effectiveness of following practice guidelines for triglyceride and low-density lipoprotein cholesterol control among patients with diabetes mellitus and mixed dyslipidemia.

BACKGROUND: The National Cholesterol Education Program Adult Treatment Panel III guidelines recommend maintaining lipid levels within particular targets to reduce the risk of coronary heart disease (CHD) events. OBJECTIVE: The objective of this simulation study was to evaluate the cost-effectiveness of following guideline-recommended care compared with current practice or usual care for patients with diabetes mellitus (DM) and mixed dyslipidemia (ie, high low-density lipoprotein cholesterol [LDL-C] and triglyceride [TG] levels). METHODS: A simulation model using a US health care payer perspective was designed to predict changes in lipid levels (LDL-C, TG, high-density lipoprotein cholesterol, and total cholesterol) and long-term CHD risk. Data about patients with DM and uncontrolled TG and/or LDL-C were taken from an electronic medical records database to develop the description of current care (eg, statin, fibrate, or no medication) and cholesterol levels. Patients with uncontrolled lipid levels who were not following guideline recommendations were assumed to be receiving combination treatment (ie, coadministration of statin and fibrate) or monotherapy for the uncontrolled lipids under guideline care. Results from a previous study were used to project incremental benefits of combination treatment compared with monotherapy. CHD events were predicted based on risk equations. A 20-year model of direct costs and quality-adjusted life-years (QALYs) was created. RESULTS: Among patients switched to guideline therapy, the model predicted 72% achieved 2 lipid targets and 44% achieved 3 lipid targets in 1 year. Over 20 years, in a modeled sample of 1000 patients, 176 myocardial infarction and angina events would be avoided by following guideline care. Total present value of costs for drug treatment and medical care for CHD events would be $33,626 per patient for guideline treatment versus $25,264 per patient for current care. The discounted QALY gain would be 0.18 per patient for an incremental cost per QALY of $50,315. CONCLUSIONS: The results of this model simulation suggest that for patients with DM and mixed dyslipidemia, following treatment guidelines rather than current practice (including combination therapy rather than monotherapy) would result in more patients achieving lipid targets, fewer CHD events, and more QALYs gained at a reasonable cost (less than $109,000) per QALY.

Cost-effectiveness of linezolid versus vancomycin for hospitalised patients with complicated skin and soft-tissue infections in Germany.

This study used a decision analytic model approach to evaluate the cost-effectiveness of linezolid versus vancomycin in the empirical treatment of complicated skin and soft-tissue infection (cSSTI) due to suspected methicillin-resistant Staphylococcus aureus (MRSA) from the German hospital and health care system perspective. Clinical probabilities were obtained from trial data, resource utilisation and MRSA prevalence rates were obtained through German physician interviews, and costs from published sources were applied to resource units. Outcomes included total cost/patient and cure. The estimated first-line cure rate for linezolid-treated patients was 90.1% versus 85.5% for vancomycin; total cure rates after two lines of treatment were 98.4% and 98.1%, respectively. Average total cost/episode was 8,232 euro for linezolid versus 9,206 euro for vancomycin. The model outcomes were sensitive to changes in length of stay (LOS), isolation days, rate of confirmed MRSA and price of linezolid. Linezolid was expected to result in a shorter intravenous treatment duration and shorter LOS that offset its higher acquisition cost versus vancomycin in cSSTI in Germany.

Economic Evaluation of Nivolumab Plus Ipilimumab Combination as First-Line Treatment for Patients with Advanced Melanoma in Canada.

OBJECTIVE: Our objective was to evaluate the cost effectiveness of the combination of nivolumab and ipilimumab, referred to as "Regimen", as a first-line treatment for patients with advanced melanoma from the perspective of Canada's public healthcare system. METHODS: We developed a partitioned-survival model (progression-free survival, post-progression survival, and death) to determine the clinical and economic outcomes of immunotherapy for advanced melanoma over a 20-year time horizon. Regimen was compared with nivolumab, ipilimumab, and pembrolizumab. Two treatment durations for pembrolizumab were considered: (1) maximum of 24 months or until progression or (2) no maximum duration, until progression. The model used data from CheckMate-067 (28 months' follow-up) for treatments involving nivolumab and ipilimumab. The efficacy of pembrolizumab was estimated using indirect comparisons. A scenario looking at the cost of subsequent treatments following disease progression was examined. RESULTS: Regimen had better outcomes and was cost effective compared with all other immunotherapies at a threshold of $CAN100,000 per quality-adjusted life-year (QALY) gained. Compared with nivolumab and ipilimumab, the incremental cost-effectiveness ratios (ICERs) were $CAN47,119 and 66,750 per QALY, respectively. Compared with pembrolizumab with a treatment duration cap, the ICER was $CAN85,436. When assuming no duration cap, Regimen dominated pembrolizumab. With the inclusion of subsequent treatment costs following progression, Regimen's ICER improved compared with all other comparators. CONCLUSIONS: Despite the advent of effective new therapies for advanced melanoma, prognosis remains poor for some patients. Compared with other immunotherapies, Regimen offers marked benefit and may be a cost-effective treatment option.

How inducing covariation in simulated HDL-C, triglyceride, and total cholesterol data affects Framingham risk equation results.

OBJECTIVE: To assess the effect of inducing covariation among simulated high-density lipoprotein (HDL-C), triglyceride, and total cholesterol values on Framingham risk equation results. METHODS: National Health and Nutrition Examination Survey (NHANES) data were used to estimate means and standard deviations for HDL-C, triglyceride, and total cholesterol for all Type II diabetic patients (N = 293) and patients with metabolic syndrome (N = 2303). NHANES data were also used to estimate correlations between HDL-C, triglyceride, and total cholesterol. Data were simulated and bootstrapped for 1000 replications of the numbers of patients in NHANES. Four-year risks of coronary heart disease were estimated using the Framingham risk equation that includes a nonlinear Weibull function. The differences in means, with and without correlation, were compared to zero to determine whether not inducing correlation was associated with bias. The ratios of variances with and without correlation were compared to one to determine whether not inducing correlation was associated with a different level of precision. All simulation results were compared with bootstrapping results. RESULTS: Bootstrapping maintained the correlation in the original data. Inducing correlation leads to more precise estimates that are closer to the bootstrapped estimates for Framingham equations not including triglycerides. Using the Framingham equation for women with triglycerides, the correlated simulation data produce less precise estimates than the uncorrelated data; the uncorrelated data are more precise than the bootstrapped results. CONCLUSION: Not inducing correlation can affect results that combine multiple simulated parameters using nonlinear functions. Researchers engaged in modeling should consider the value of inducing correlation in their simulated data.

A comparison of costs and hospital length of stay associated with intravenous/oral linezolid or intravenous vancomycin treatment of complicated skin and soft-tissue infections caused by suspected or confirmed methicillin-resistant Staphylococcus aureus in elderly US patients.

OBJECTIVES: This study compared the costs and hospital length of stay (LOS) and duration of intravenous therapy associated with intravenous/oral linezolid or intravenous vancomycin treatment of complicated skin and soft-tissue infections (cSSTIs) caused by suspected or confirmed methicillin-resistant Staphylococcus aureus (MRSA) in elderly US patients. METHODS: Data were obtained from elderly (>or=65 years) US patients participating in a multinational randomized trial of hospitalized cSSTI patients treated with linezolid or vancomycin. Costs (hospital and total) from the provider perspective were estimated for intent-to-treat (ITT) patients (ie, all those receiving >or=1 dose) using national 2003 costs (ward, medication, intravenous administration). LOS for inpatient care, duration of intravenous linezolid and vancomycin therapy (ITT and MRSA groups), and cure rates were evaluated. RESULTS: Of 717 enrolled subjects, 163 (23%) were elderly (87 linezolid, 76 vancomycin), with no significant differences in demographic characteristics between the linezolid and vancomycin groups. Mean hospitalization and total costs were lower with linezolid compared with vancomycin (hospitalization: US $4510 vs US $6478, P<0.001; total: US $6009 vs US $7329, P=0.03). Linezolid was associated with a 3.5-day reduction in LOS and a 9.5-day reduction in the duration of intravenous therapy compared with vancomycin in the ITT group (both, P<0.001). Cure rates were comparable between linezolid and vancomycin in both the ITT group (88.7% vs 81.4%, respectively) and the MRSA group (80.0% vs 71.4%). In multivariate analyses of the ITT group, linezolid patients were 57% less likely than vancomycin patients to have a LOS >7 days (odds ratio = 0.43; 95% CI, 0.21-0.87). Chronic renal failure, malnutrition, and a diagnosis of infected ulcer predicted an LOS >7 days. CONCLUSIONS: In this analysis of data from elderly patients with cSSTI caused by suspected or confirmed MRSA, linezolid treatment was associated with reductions in the costs of care, LOS, and duration of intravenous treatment without affecting the clinical outcomes. Although the use of a subset of patients from a larger trial that did not focus on the elderly can be seen as a study limitation, the elderly represent an important population when evaluating health care resource use and costs.

Modeling Treatment Sequences in Pharmacoeconomic Models.

As the number of interventions available in a therapeutic area increases, the relevant decision questions in health technology assessment (HTA) expand to compare treatment sequences instead of discrete treatments and identify optimal sequences or position for a particular treatment in a sequence. The objective of this work was to review approaches used to model treatment sequences and provide practical guidance on conceptualizing whether and how to model sequences in health economic models. Economic models including treatment sequencing assessed by the National Institute for Health and Care Excellence were reviewed, as these assessments generally provide both policy relevance and comprehensive model detail. We identified 40 treatment-sequence models in the following disease areas: oncology (13), autoimmune (7), cardiovascular (6), neurology/mental health (4), infectious disease (2), diabetes (2), and other (6). Modeling techniques included discrete event simulation (6), individual state-transition (3), decision tree (3) and, most commonly, cohort state-transition with tracking states (28). In most cases, treatment sequencing had been incorporated to reflect either clinical practice or clinical trial design. In other cases, it was used to assess where in a treatment sequence a new treatment should be placed, or to evaluate the addition of more efficacious treatment options to a current treatment sequence. Important considerations for determining how to best model sequences include the number of treatment options, patient heterogeneity, key outcomes, and event risk (time-varying or constant). The biggest challenge is the scarcity of clinical data, as clinical trials do not commonly evaluate different treatment sequences.

Indirect Treatment Comparisons of Ibrutinib Versus Physician's Choice and Idelalisib Plus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia.

PURPOSE: Treatment options for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL) are limited. Until recently, few effective treatment options existed, and even with the advent of new agents, studies evaluating comparative efficacy are scarce. In the Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE) Phase III study, ibrutinib, an oral, once-a-day, first-in-class covalent Bruton tyrosine kinase inhibitor, improved progression-free survival (PFS) and overall survival (OS) compared with ofatumumab (PFS hazard ratio [HR] = 0.106 and OS HR = 0.369 [adjusted for crossover] at a median of 16 months' follow-up). We sought to establish the relative efficacy of ibrutinib versus other treatment options for patients with R/R CLL using indirect comparison methods. METHODS: A systematic literature review was conducted to identify clinical trials sharing a common treatment arm with the RESONATE Phase III trial such that a network meta-analysis or indirect treatment comparisons (ITCs) could be conducted. Two trials were identified, each using the same comparator (ofatumumab) as the RESONATE study. Two pairwise ITCs were conducted using the Bucher method to establish the relative treatment efficacy of ibrutinib versus (1) idelalisib plus ofatumumab in the first study and (2) physician's choice, defined as a mix of therapies commonly used in R/R CLL, in the second study. Odds ratios for these ITCs were calculated for overall response rate (ORR) and HRs for PFS and OS. FINDINGS: A strong and consistent trend of superiority for ibrutinib was observed via these ITC models with idelalisib plus ofatumumab and physician's choice for ORR, PFS, and OS. Ibrutinib revealed prolonged PFS and OS versus comparators (PFS HR = 0.06; 95% CI, 0.04-0.11; and OS HR = 0.25; 95% CI, 0.12-0.54), physician's choice (PFS HR = 0.41; 95% CI, 0.25-0.66; and OS HR = 0.50; 95% CI, 0.23-1.08), and idelalisib plus ofatumumab. These findings were robust and continued to favor ibrutinib when adjusting (where appropriate) for underlying differences in patient population between the trials. Some trial differences were not accounted for in the models and thus some limitations remain; however, consistency of results supports the overall findings. IMPLICATIONS: In a randomized Phase III study, ibrutinib significantly improved ORR, PFS, and OS in patients with R/R CLL versus ofatumumab. In ITC models that used ofatumumab as the common comparator, ibrutinib appears to have higher ORR and longer PFS and OS versus both idelalisib plus ofatumumab and physician's choice. In the absence of head-to-head studies and taking into consideration inherent limitations of ITCs, these models provide useful estimates of comparative efficacy.

A taxonomy and economic consequences of nursing home falls.

BACKGROUND: Falls are a primary cause of injury and disability in the nursing home environment and can be costly to treat. We propose a taxonomy of nursing home falls that accounts for both the severity of fall consequences and the duration of the treatment episode. No other systematic approach of this kind has been previously described. METHODS: We defined a 9-level taxonomy of fall types and outcomes. Components of each fall category include resource use during the acute, convalescent, and long-term phases of treatment. Three variants of each category describe typical, best-case and worst-case fall episodes. Treatment costs were estimated for each fall category by applying unit costs from national databases and published sources to projected medical resource utilisation. Long-term costs reflect adjustment in Medicare per diem reimbursement rates associated with change in patient status subsequent to the fall. RESULTS: The most common and least costly fall category was category 1 -- non-injurious, which accounted for 30% of falls and a 1-year cost of US dollars 319 per event (range US dollars 71-550). The least common and most costly was fall category 9 -- multiple injuries, which accounted for 1% of falls and a 1-year cost of US dollars 22,368 (range US dollars 9,969-64,382). CONCLUSIONS: The falls taxonomy represents a unique approach to estimating the cost of nursing home falls and offers a tool for evaluating the cost-effectiveness of fall prevention strategies. A validation study should be performed to confirm the magnitude of fall frequency and cost estimates.

Cost-effectiveness of DTG + ABC/3TC versus EFV/TDF/FTC for first-line treatment of HIV-1 in the United States.

OBJECTIVE: Data from the SINGLE trial demonstrated that 88% of treatment-naïve HIV-1 patients treated with dolutegravir and abacavir/lamivudine (DTG + ABC/3TC) achieved viral suppression at 48 weeks compared with 81% of patients treated with efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC). It is unclear how this difference in short-term efficacy impacts long-term cost-effectiveness of these regimens. This study sought to evaluate long-term cost-effectiveness of DTG + ABC/3TC vs EFV/TDF/FTC from a US payer perspective. METHODS: This study is an individual discrete-event simulation which tracked the disease status and treatment pathway of HIV-1 patients. The model simulated treatment over a lifetime horizon by tracking change in patients' CD4 count, clinical events occurrence (opportunistic infections, cancer, and cardiovascular events), treatment switch, and death. The model included up to four lines of treatment. Baseline patient characteristics, efficacy, and safety of DTG + ABC/3TC and EFV/TDF/FTC were informed by data from the SINGLE trial. The efficacy of subsequent treatment lines, clinical event risks, mortality, cost, and utility inputs were based on literature and expert opinion. Outcomes were lifetime discounted medical costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). RESULTS: Compared with EFV/TDF/FTC, DTG + ABC/3TC increased lifetime costs by $19,153 and per person survival by 0.12 QALYs, resulting in an ICER of $158,890/QALY. ICERs comparing DTG + ABC/3TC to EFV/TDF/FTC remained above the traditional, US willingness-to-pay threshold of $50,000/QALY gained in all scenarios, and above $100,000 or $150,000/QALY gained in most scenarios. LIMITATIONS: Due to data limitations, the treatment patterns, CD4 count during viral rebound and treatment switch, viral rebound after trial end, and long-term adverse event-related treatment discontinuation were based on assumptions, presented to and approved by clinical experts. CONCLUSIONS: Compared with EFV/TDF/FTC, DTG + ABC/3TC resulted in higher cost and only slightly increased QALYs over a lifetime, with an ICER that exceeded the standard cost-effectiveness threshold. This indicates that the incremental benefit in effectiveness associated with DTG + ABC/3TC may not be worth the incremental increase in costs.

Cost-effectiveness of DTG+ABC/3TC versus EFV/TDF/FTC for first-line treatment of HIV-1 in the United States.

INTRODUCTION: Data from the SINGLE trial demonstrated that 88% of treatment-naive HIV-1 patients treated with dolutegravir and abacavir/lamivudine (DTG+ABC/3TC) achieved viral suppression at 48 weeks compared with 81% of patients treated with efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC). It is unclear how this difference in short-term efficacy impacts long-term cost-effectiveness of these regimens. This study sought to evaluate the long-term cost-effectiveness of DTG+ABC/3TC versus EFV/TDF/FTC from a US payer perspective. MATERIALS AND METHODS: An individual discrete-event simulation model tracked the disease status and treatment pathway of HIV-1 patients. The model simulated treatment over a lifetime horizon by tracking change in patients' CD4 count, occurrence of clinical events (opportunistic infections, cancer and cardiovascular events), treatment switch and death. The model included up to four lines of treatment. Baseline patient characteristics, efficacy and safety of DTG+ABC/3TC and EFV/TDF/FTC were informed by data from the SINGLE trial. The efficacy of subsequent lines of treatment, clinical event risks, mortality, cost and utility inputs were based on literature and expert opinion. Outcomes were lifetime medical costs, quality-adjusted life-years (QALYs) (both discounted at 3% per annum) and the incremental cost-effectiveness ratio (ICER). RESULTS: Compared with EFV/TDF/FTC, DTG+ABC/3TC increased lifetime costs by $58,188 and per-person survival by 0.12 QALYs, resulting in an ICER of $482,717/QALY. In sensitivity analyses testing conservative assumptions about EFV/TDF/FTC's efficacy beyond the trial period, ICERs comparing DTG+ABC/3TC to EFV/TDF/FTC remained high (lowest reported ICER of $365,662/QALY). In a scenario in which the price of EFV/TDF/FTC was reduced by 10% to reflect the potential for price reduction as EFV goes off patent, DTG+ABC/3TC's ICER compared to EFV/TDF/FTC was $600,916/QALY. When DTG+ABC/3TC's price was reduced by 10%, the resulting ICER comparing DTG+ABC/3TC to EFV/TDF/FTC was $302,171/QALY. CONCLUSIONS: Compared with EFV/TDF/FTC, DTG+ABC/3TC resulted in substantially higher cost, slightly better QALY over lifetime, and ICERs far exceeding standard cost-effectiveness thresholds, indicating that the incremental benefit in efficacy associated with DTG+ABC/3TC may not be worth the incremental increase in costs.

Comparison of the cost-effectiveness of new oral anticoagulants for the prevention of stroke and systemic embolism in atrial fibrillation in a UK setting.

PURPOSE: Three new oral anticoagulants (NOACs) have recently become available in the United Kingdom as an alternative to warfarin in the prevention of stroke and systemic embolism in atrial fibrillation. This study examines the relative cost-effectiveness of dabigatran (BID dosing of 150 mg or 110 mg based on patient age), rivaroxaban, and apixaban from a UK payer perspective. METHODS: A previously published model that follows up patients through treatment of atrial fibrillation during a lifetime was adapted to allow comparison of the 3 NOACs and warfarin. Acute thromboembolic and bleeding events, as well as long-term consequences of stroke, intracranial hemorrhage, and acute myocardial infarction, were tracked. Relative efficacy was calculated from a formal indirect treatment comparison using data from the 3 key trials (Randomized Evaluation of Long-Term Anticoagulation Therapy, Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation, and Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) of the NOACs. Data from the rivaroxaban trial were adjusted for the difference in international normalized ratio control among warfarin patients versus the other 2 trials. Model outputs included total costs, event rates, and quality-adjusted life-years. FINDINGS: Among the patients taking NOACs, those taking dabigatran had the highest total QALYs (7.68 QALYs), followed by apixaban (7.63 QALYs) and rivaroxaban (7.47 QALYs). Patients taking dabigatran had the lowest total lifetime costs (£23,342), followed by apixaban (£24,014) and rivaroxaban (£25,220). The differences between dabigatran and apixaban were modest but consistent in sensitivity analyses, with the directionality only changing at the limits of the CIs for the relative risks of ischemic stroke or intracranial hemorrhage or when assuming that both treatment discontinuation and post-event disability rates differ by drug. IMPLICATIONS: Dabigatran was found to be economically dominant over rivaroxaban and apixaban in the UK setting. These economic findings are based on relative clinical efficacy from an indirect treatment comparison and would benefit from any data of direct comparisons of the NOACs in the future.