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.

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-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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Efficacy and cost-effectiveness of dabigatran etexilate versus warfarin in atrial fibrillation in different age subgroups.

This study aims to estimate the cost-effectiveness of dabigatran 150 mg twice daily versus warfarin for stroke and systemic embolism risk reduction in patients with nonvalvular atrial fibrillation initiating treatment before age 75 (<75), at or after age 75 (≥ 75), and the overall population (All) from a US Medicare payer perspective. Clinical event rates by age cohort with dabigatran or warfarin for safety-on-treatment and intent-to-treat populations were estimated from Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY). An economic model was adapted using these data to evaluate the impact of starting age on clinical and economic outcomes. Costs were obtained from Medicare payment schedules and utilities from publications. Model outputs included event rates, costs, quality-adjusted life-years, and incremental cost-effectiveness ratios. The RE-LY analysis shows that the <75 cohort has lower rates of all events than the ≥ 75 cohort; versus warfarin, dabigatran performed better in main efficacy and safety in all age cohorts with the exception of extracranial hemorrhage in the ≥ 75 cohort. The clinical event costs avoided per patient for dabigatran were $1,100, $135, and $713 for cohorts <75, ≥ 75, and All, respectively. Extrapolating over a lifetime horizon, the model found that dabigatran resulted in lower rates of stroke and intracranial hemorrhage and higher rates for extracranial hemorrhage versus warfarin for all age cohorts. Lifetime quality-adjusted life-years and costs were higher for dabigatran than warfarin, resulting in incremental cost-effectiveness ratios of $52,773, $65,946, and $56,131 for cohorts <75, ≥ 75, and All, respectively. In conclusion, dabigatran was cost-effective versus warfarin in US patients with atrial fibrillation regardless of age of treatment initiation.

Budgetary impact on a U.S. health plan adopting abiraterone acetate plus prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Abiraterone acetate, an androgen biosynthesis inhibitor, received FDA approval in 2011 for metastatic castration-resistant prostate cancer (mCRPC) patients who have received prior chemotherapy containing docetaxel. OBJECTIVE: To estimate the projected budgetary impact of adopting abiraterone for mCRPC patients from a U.S. health plan perspective. METHODS: A decision analytic model compared mCRPC treatment cost before and after abiraterone acetate adoption based on a hypothetical 1,000,000-member plan. Plan mCRPC prevalence was derived from prostate cancer incidence reported in U.S. epidemiology statistics and disease progression data from published trials. Market shares for comparator mCRPC treatments (prednisone alone; cabazitaxel + prednisone; mitoxantrone + prednisone; docetaxel retreatment + prednisone) were derived from market research simulation. Abiraterone + prednisone uptake (8% - scenario 1 to 55% - scenario 3) was based on assumptions for illustrative purposes. Treatment costs were computed using prescribing information, treatment duration from phase III trials, and drug costs considering common U.S. cost listing and reimbursement schemes. Prevalence and costs of managing treatment-related toxicities were estimated from literature, treatment guidelines, and expert clinical opinion. The model evaluated the perspectives of a commercial payer with no Medicare beneficiaries and a commercial payer with a subset of Medicare beneficiaries. Sensitivity analyses were conducted to assess changing input values. RESULTS: In each modeled scenario, 57 patients with prior docetaxel therapy received treatment for mCRPC. For the commercial perspective, the incremental per-member-per-month (PMPM) cost attributable to abiraterone ranged from $0.0019 in scenario 1 to $0.0133 in scenario 3. For the commercial/Medicare perspective, the incremental PMPM ranged from $0.0026 in scenario 1 to $0.0176 in scenario 3. The average incremental PMPM cost over 3 scenarios is $0.0112. When testing key sensitivity scenarios, the model indicated that abiraterone treatment duration and cabazitaxel market share were the main drivers of cost. CONCLUSIONS: The model results indicate that reimbursement for abiraterone may have a neutral impact on a U.S. health plan budget given the relatively small size of the eligible prostate cancer population and expected lower toxicity-related costs as compared with chemotherapy. The sensitivity analyses addressing the components of uncertainty in the model show that the budgetary impact of abiraterone is likely low.

Modeling hard clinical end-point data in economic analyses.

OBJECTIVE: The availability of hard clinical end-point data, such as that on cardiovascular (CV) events among patients with type 2 diabetes mellitus, is increasing, and as a result there is growing interest in using hard end-point data of this type in economic analyses. This study investigated published approaches for modeling hard end-points from clinical trials and evaluated their applicability in health economic models with different disease features. METHODS: A review of cost-effectiveness models of interventions in clinically significant therapeutic areas (CV diseases, cancer, and chronic lower respiratory diseases) was conducted in PubMed and Embase using a defined search strategy. Only studies integrating hard end-point data from randomized clinical trials were considered. For each study included, clinical input characteristics and modeling approach were summarized and evaluated. RESULTS: A total of 33 articles (23 CV, eight cancer, two respiratory) were accepted for detailed analysis. Decision trees, Markov models, discrete event simulations, and hybrids were used. Event rates were incorporated either as constant rates, time-dependent risks, or risk equations based on patient characteristics. Risks dependent on time and/or patient characteristics were used where major event rates were >1%/year in models with fewer health states (<7). Models of infrequent events or with numerous health states generally preferred constant event rates. LIMITATIONS: The detailed modeling information and terminology varied, sometimes requiring interpretation. CONCLUSIONS: Key considerations for cost-effectiveness models incorporating hard end-point data include the frequency and characteristics of the relevant clinical events and how the trial data is reported. When event risk is low, simplification of both the model structure and event rate modeling is recommended. When event risk is common, such as in high risk populations, more detailed modeling approaches, including individual simulations or explicitly time-dependent event rates, are more appropriate to accurately reflect the trial data.

Cost-effectiveness of new oral anticoagulants in the prevention of stroke in patients with atrial fibrillation.

Atrial fibrillation (AF) is a common arrhythmia and the leading cause of stroke, an event with high human and economic burden. Novel oral anticoagulants have been approved in many markets as alternatives to warfarin for stroke prevention in patients with AF - dabigatran etexilate, apixaban and rivaroxaban. Given the high burden of AF, and given that new treatments can more effectively prevent stroke than warfarin, but at higher drug cost, there has been a need for systematic evaluation of the costs and benefits of these new treatments. In this study, we summarize the findings of a systematic literature review on the cost-effectiveness of the new oral anticoagulants. We find that there is substantial heterogeneity between the studies and their numerical findings, despite using a common set of four trials for their clinical inputs. However, there is broad consensus among them that each of the novel oral anticoagulants is cost-effective versus warfarin or aspirin.

A comparative analysis of models used to evaluate the cost-effectiveness of dabigatran versus warfarin for the prevention of stroke in atrial fibrillation.

BACKGROUND: A number of models exploring the cost-effectiveness of dabigatran versus warfarin for stroke prevention in atrial fibrillation have been published. These studies found dabigatran was generally cost-effective, considering well-accepted willingness-to-pay thresholds, but estimates of the incremental cost-effectiveness ratios (ICERs) varied, even in the same setting. The objective of this study was to compare the findings of the published economic models and identify key model features accounting for differences. METHODS: All aspects of the economic evaluations were reviewed: model approach, inputs, and assumptions. A previously published model served as the reference model for comparisons of the selected studies in the US and UK settings. The reference model was adapted, wherever possible, using the inputs and key assumptions from each of the other published studies to determine if results could be reproduced in the reference model. Incremental total costs, incremental quality-adjusted life years (QALYs), and ICERs (cost per QALY) were compared between each study and the corresponding adapted reference model. The impact of each modified variable or assumption was tracked separately. RESULTS: The selected studies were in the US setting (2), the Canadian setting (1), and the UK setting (2). All models used the Randomized Evaluation of Long-Term Anticoagulation study (RE-LY) as the main source for clinical inputs, and all used a Markov modelling approach, except one that used discrete event simulation. The reference model had been published in the Canadian and UK settings. In the UK setting, the reference model reported an ICER of UK£4,831, whereas the other UK-based analysis reported an ICER of UK£23,082. When the reference model was modified to use the same population characteristics, cost inputs, and utility inputs, it reproduced the results of the other model (ICER UK£25,518) reasonably well. Key reasons for the different results between the two models were the assumptions on the event utility decrement and costs associated with intracranial haemorrhage, as well as the costs of warfarin monitoring and disability following events. In the US setting, the reference model produced an ICER similar to the ICER from one of the US models (US$15,115/QALY versus US$12,386/QALY, respectively) when modelling assumptions and input values were transferred into the reference model. Key differences in results could be explained by the population characteristics (age and baseline stroke risk), utility assigned to events and specific treatments, adjustment of stroke and intracranial haemorrhage risk over time, and treatment discontinuation and switching. The reference model was able to replicate the QALY results, but not the cost results, reported by the other US cost-effectiveness analysis. The parameters driving the QALY results were utility values by disability levels as well as utilities assigned to specific treatments, and event and background mortality rates. CONCLUSIONS: Despite differences in model designs and structures, it was mostly possible to replicate the results published by different authors and identify variables responsible for differences between ICERs using a reference model approach. This enables a better interpretation of published findings by focusing attention on the assumptions underlying the key model features accounting for differences.

Inclusion of compliance and persistence in economic models: past, present and future.

Economic models are developed to provide decision makers with information related to the real-world effectiveness of therapeutics, screening and diagnostic regimens. Although compliance with these regimens often has a significant impact on real-world clinical outcomes and costs, compliance and persistence have historically been addressed in a relatively superficial fashion in economic models. In this review, we present a discussion of the current state of economic modelling as it relates to the consideration of compliance and persistence. We discuss the challenges associated with the inclusion of compliance and persistence in economic models and provide an in-depth review of recent modelling literature that considers compliance or persistence, including a brief summary of previous reviews on this topic and a survey of published models from 2005 to 2012. We review the recent literature in detail, providing a therapeutic-area-specific discussion of the approaches and conclusions drawn from the inclusion of compliance or persistence in economic models. In virtually all publications, variation of model parameters related to compliance and persistence was shown to have a significant impact on predictions of economic outcomes. Growing recognition of the importance of compliance and persistence in the context of economic evaluations has led to an increasing number of economic models that consider these factors, as well as the use of more sophisticated modelling techniques such as individual simulations that provide an avenue for more rigorous consideration of compliance and persistence than is possible with more traditional methods. However, we note areas of continuing concern cited by previous reviews, including inconsistent definitions, documentation and tenuous assumptions required to estimate the effect of compliance and persistence. Finally, we discuss potential means to surmount these challenges via more focused efforts to collect compliance and persistence data.