Health and Economic Evaluation of Sacubitril-Valsartan for Heart Failure Management.

Importance: The US Food and Drug Administration expanded labeling of sacubitril-valsartan from the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (EF) to all patients with HF, noting the greatest benefits in those with below-normal EF. However, the upper bound of below normal is not clearly defined, and value determinations across a broader EF range are unknown. Objective: To estimate the cost-effectiveness of sacubitril-valsartan vs renin-angiotensin system inhibitors (RASis) across various upper-level cutoffs of EF. Design, Setting, and Participants: This economic evaluation included participant-level data from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and the PARAGON-HF (Prospective Comparison of ARNi with ARB Global Outcomes in HF With Preserved Ejection Fraction) trials. PARADIGM-HF was conducted between 2009 and 2014, PARAGON-HF was conducted between 2014 and 2019, and this analysis was conducted between 2021 and 2023. Main Outcomes and Measures: A 5-state Markov model used risk reductions for all-cause mortality and HF hospitalization from PARADIGM-HF and PARAGON-HF. Quality-of-life differences were estimated from EuroQol-5D scores. Hospitalization and medication costs were obtained from published national sources; the wholesale acquisition cost of sacubitril-valsartan was $7092 per year. Risk estimates and treatment effects were generated in consecutive 5% EF increments up to 60% and applied to an EF distribution of US patients with HF from the Get With the Guidelines-Heart Failure registry. The base case included a lifetime horizon from a health care sector perspective. Incremental cost-effectiveness ratios (ICERs) were estimated at EFs of 60% or less (base case) and at various upper-level EF cutoffs. Results: Among 13 264 total patients whose data were analyzed, for those with EFs of 60% or less, sacubitril-valsartan was projected to add 0.53 quality-adjusted life-years (QALYs) at an incremental lifetime cost of $40 892 compared with RASi, yielding an ICER of $76 852 per QALY. In a probabilistic sensitivity analysis, 95% of the values of the ICER occurred between $71 516 and $82 970 per QALY. Among patients with chronic HF and an EF of 60% or less, treatment with sacubitril-valsartan vs RASis would be at least of economic intermediate value (ICER <$180 000 per QALY) at a sacubitril-valsartan cost of $10 242 or less per year, of high economic value (ICER <$60 000 per QALY) at a cost of $3673 or less per year, and cost-saving at a cost of $338 or less per year. The ICERs were $67 331 per QALY, $59 614 per QALY, and $56 786 per QALY at EFs of 55% or less, 50% or less, and 45% or less, respectively. Treatment with sacubitril-valsartan in only those with EFs of 45% or greater (up to ≤60%) yielded an ICER of $127 172 per QALY gained; treatment was more cost-effective in those at the lower end of this range (ICER of $100 388 per QALY gained for those with EFs of 45%-55%; ICER of $84 291 per QALY gained for those with EFs of 45%-50%). Conclusions and Relevance: Cost-effectiveness modeling provided an ICER for treatment with sacubitril-valsartan vs RASis consistent with high economic value for patients with reduced and mildly reduced EFs (≤50%) and at least intermediate value at the current undiscounted wholesale acquisition cost price at an EF of 60% or less. Treatment was more cost-effective at lower EF ranges. These findings may have implications for coverage decisions and value assessments in contemporary clinical practice guidelines.

Model parameters influencing the cost-effectiveness of sacubitril/valsartan in heart failure: evidence from a systematic literature review.

OBJECTIVES: To summarize cost-effectiveness (CE) evidence of sacubitril/valsartan for the treatment of heart failure (HF) patients with reduced ejection fraction (HFrEF). The impact of different modeling approaches and parameters on the CE results is also described. METHODS: We conducted a systematic literature review using multiple databases: Embase®; MEDLINE®; MEDLINE®-In Process; NIHR CRD database including DARE, NHS EED, and HTA databases; and the Cost Effectiveness Analysis registry. We also reviewed HTA countries' websites to identify CE reports of sacubitril/valsartan, published up to 25-July-2021. Articles published in English as full-texts, conference-abstracts, or HTA reports were included. RESULTS: We included 44 CE models [39 from 37 publications (22 full-texts; 15 conference-abstracts) and 5 HTAs; Europe, n = 20; North and South Americas, n = 14; Asia and Australia, n = 10]. Most models adopted a Markov structure with constant transition probabilities of events (n = 27) or a mix of Markov and regression-based models (n = 16), with variations in structural assumptions and chosen parameters. Study authors concluded sacubitril/valsartan to be a cost-effective therapy in 37/41 models in chronic HFrEF patients and 2/3 models in hospitalized patients stabilized after an acute decompensation for HF. CE models showing sacubitril/valsartan not to be a cost-effective treatment generally modeled a shorter time horizon. Effect of sacubitril/valsartan on cardiovascular and all-cause mortality, cost, duration of effect and time horizon was the main model drivers. CONCLUSIONS: Most evidence indicated sacubitril/valsartan is cost-effective in HFrEF. The use of a lifetime horizon is recommended in future models as HF is a chronic disease. Data on the CE of sacubitril/valsartan in the inpatient setting were limited and further research is warranted.

Cost Effectiveness of Inclisiran in Atherosclerotic Cardiovascular Patients with Elevated Low-Density Lipoprotein Cholesterol Despite Statin Use: A Threshold Analysis.

BACKGROUND: Inclisiran is a novel, cholesterol-lowering therapy, with a long duration of effect, administered every 6 months (subcutaneously by a healthcare professional). In the ORION-10 trial in US patients with atherosclerotic cardiovascular disease (ASCVD) in addition to maximum tolerated statins, with or without ezetimibe, inclisiran demonstrated statistically significant reductions in low-density lipoprotein cholesterol (LDL-C) of up to 51%. This is the first peer-reviewed publication to investigate the price at which inclisiran is cost effective in the US. OBJECTIVE: The aim of this study was to determine the maximum price at which inclisiran is cost effective in addition to standard of care, in US patients with ASCVD, versus standard of care alone, at different willingness-to-pay thresholds. DESIGN, SETTING AND PARTICIPANTS: A lifetime Markov model from the US health system perspective, including 15 health states, was used to evaluate the cost effectiveness of inclisiran. The following states were separated by time from a previous cardiovascular event (0-1 years, 1-2 years, 2+ years ['stable']): initial, unstable angina, myocardial infarction, and stroke. Additional states included revascularization and death (cardiovascular or non-cardiovascular causes). Baseline risk of cardivoascular events were from US database sources or published literature. Reductions in LDL-C from inclisiran were from the ORION-10 trial. LDL-C reduction was used to adjust baseline risk of cardiovascular events, based on established relationships between 1 mmol/L reduction in LDL-C and decreases in cardiovascular events, from the Cholesterol Treatment Trialists studies. The population included adults with a history of ASCVD, and LDL-C ≥ 70 mg/dL, despite maximum tolerated doses of statin therapy. INTERVENTIONS: Inclisiran as an adjunct to standard of care, compared with standard of care alone. MAIN OUTCOMES AND MEASURES: The threshold price of inclisiran. RESULTS: Inclisiran as an adjunct to standard of care resulted in threshold annual inclisiran prices of $6383, $9973, and $13,563 at willingness-to-pay thresholds of $50,000, $100,000, and $150,000 per quality-adjusted life-year, respectively. Probabilistic sensitivity analysis showed that at a threshold of $100,000 per QALY, inclisiran had a 100% probability of being cost effective, with an annual price below $9000. At the publicly available price of $3250 per dose, inclisiran was found to have an incremental cost-effectiveness ratio just above the $50,000 per QALY threshold, of $51,686. CONCLUSIONS AND RELEVANCE: This study identified the price at which inclisiran is cost effective for the US health system, at generally accepted willingness-to-pay thresholds.

Mapping the Kansas City Cardiomyopathy Questionnaire (KCCQ) Onto EQ-5D-3L in Heart Failure Patients: Results for the Japanese and UK Value Sets.

Background. Health technology assessment bodies in several countries, including Japan and the United Kingdom, recommend mapping techniques to obtain utility scores in clinical trials that do not have a preference-based measure of health. This study sought to develop mapping algorithms to predict EQ-5D-3L scores from the Kansas City Cardiomyopathy Questionnaire (KCCQ) in patients with heart failure (HF). Methods. Data from the randomized, double-blind PARADIGM-HF trial were analyzed, and EQ-5D-3L scores were calculated using the Japanese and UK value sets. Several different model specifications were explored to best fit EQ-5D data collected at baseline with KCCQ scores, including ordinary least square regression, two-part, Tobit, and three-part models. Generalized estimating equations models were also fitted to analyze longitudinal EQ-5D data. To validate model predictions, the data set was split into a derivation (n = 4,465) from which the models were developed and a separate sample (n = 1,892) for validation. Results. There were only small differences between the different model classes tested. Model performance and predictive power was better for the item-level models than for the models including KCCQ domain scores. R 2 statistics for the item-level models ranged from 0.45 to 0.52. Mean absolute error in the validation sample was 0.10 for the models using the Japanese value set and 0.114 for the UK models. All models showed some underprediction of utility above 0.75 and overprediction of utility below 0.5, but performed well for population-level estimates. Conclusions. Using data from a large clinical trial in HF, we found that EQ-5D-3L scores can be estimated from responses to the KCCQ and can facilitate cost-utility analysis from existing HF trials where only the KCCQ was administered. Future validation in other HF populations is warranted.

Cost-effectiveness of denosumab versus zoledronic acid for preventing skeletal-related events in the Czech Republic.

AIMS: This study assessed the cost-effectiveness of the subcutaneous RANKL inhibitor, denosumab, vs the intravenous bisphosphonate, zoledronic acid, for the prevention of skeletal-related events (SREs) in patients with prostate cancer, breast cancer, and other solid tumors (OST) in the Czech Republic. MATERIALS AND METHODS: A lifetime Markov model was developed to compare the effects of denosumab and zoledronic acid on costs (including drug costs and administration, patient management, SREs, and adverse events), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios from a national payer perspective. Different discount rates, time horizons, SRE rates, distributions, and nature (asymptomatic vs all SREs), and the inclusion of treatment discontinuation were considered in scenario analyses. The robustness of the model was tested using deterministic and probabilistic sensitivity analyses. RESULTS: Across tumor types, denosumab was associated with fewer SREs, improved QALYs, and higher total costs over a lifetime. The incremental cost per QALY gained for denosumab vs zoledronic acid was 382,673 CZK for prostate cancer, 408,450 CZK for breast cancer, and 608,133 CZK for OST. Incremental costs per SRE avoided for the same tumor type were 54,007 CZK, 51,765 CZK, and 94,426 CZK, respectively. In scenario analyses, the results remained similar to baseline, when different discount rates and time horizons were considered. At a non-official willingness-to-pay threshold of 1.2 million CZK, the probabilities of denosumab being cost-effective vs zoledronic acid were 0.64, 0.67, and 0.49 for prostate cancer, breast cancer, and OST, respectively. LIMITATIONS: The SRE rates used were obtained from clinical trials; studies suggest rates may be higher in clinical practice. Additional evidence on real-world SRE rates could further improve the accuracy of the modeling. CONCLUSIONS: Compared with zoledronic acid, denosumab provides a cost-effective treatment option for the prevention of SREs in patients with prostate cancer, breast cancer, and OST in the Czech Republic.