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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.

Background: Discussions of medication costs between patients and clinicians are infrequent and often suboptimal. In the context of recently introduced drugs that are effective but expensive, patients with heart failure with reduced ejection fraction provide an ideal population to understand the perspectives of patients with chronic illness on medication cost and cost discussions., Methods: To explore patients' perspectives on discussing out-of-pocket medication costs with clinicians, 49 adults, aged 44 to 70 years, with heart failure with reduced ejection fraction were recruited from outpatient heart failure clinics. Descriptive qualitative analysis was performed on open-ended text data., Results: Participants who had prior medication-related cost discussions described their experience as generally positive, but about half of the participants had never had a cost discussion with their clinician. Most participants were open to cost discussions with clinicians and preferred that the clinician initiate discussions regarding medication cost. Importantly, these preferences held constant across reported levels of financial burden., Conclusions: These data suggest a substantial willingness on the part of patients with heart failure with reduced ejection fraction to incorporate cost discussions into their care and identify important aspects of these discussions for clinicians to consider when engaging in conversations where cost is relevant. Improving understanding about how to integrate patient preferences regarding cost discussions into clinical encounters is an important priority for advancing patient-centered care.

Importance: Sacubitril-valsartan use reduces mortality and hospitalizations compared with enalapril among patients with chronic heart failure with reduced ejection fraction (HFrEF); however, the cost-effectiveness of these treatments when initiated during hospitalization for HF is unknown., Objective: To estimate the cost-effectiveness of inpatient initiation of sacubitril-valsartan vs enalapril compared with no initiation or posthospitalization initiation of sacubitril-valsartan among stabilized patients with HFrEF., Design, Setting, and Participants: This economic evaluation included data on US patients with HFrEF who were eligible for sacubitril-valsartan treatment from December 8, 2009, to May 15, 2018., Main Outcomes and Measures: A 5-state Markov model with all-cause mortality, HF, and non-HF hospitalization probabilities was used. Quality of life was estimated using Euro-QoL EQ-5D scores. Hospitalization, long-term care, and medication costs for sacubitril-valsartan and enalapril were modeled with a discount rate of 3%. The base-case analysis included a lifetime horizon from a health care and societal perspective., Results: Modeled patients were a mean (SD) age of 63.8 (11.5) years. Inpatient treatment with sacubitril-valsartan ($5628 per year) was associated with 62 fewer HF-related admissions per 1000 patients compared with outpatient initiation or 116 fewer HF-related admissions compared with continuation of enalapril treatment. From a health care system perspective, initiation of sacubitril-valsartan during hospitalization saved $452 per year compared with continuing enalapril and $811 per year compared with initiation at 2 months after hospitalization and was associated with an incremental cost-effectiveness ratio of $21 532 per quality-adjusted life-year compared with continued enalapril treatment over a lifetime. From a societal perspective, inpatient initiation was estimated to save $460 per year per patient compared with no initiation of sacubitril-valsartan and $813 per year per patient compared with initiation after hospitalization. In a budget analysis, inpatient initiation of sacubitril-valsartan was estimated to save up to $449 per person for 1 year or $2550 per person over 5 years compared with continuation of enalapril., Conclusions and Relevance: The findings suggest that, for patients with HFrEF, initiation of sacubitril-valsartan during hospitalization may be associated with reduced hospitalizations, increased quality-adjusted life expectancy, and cost savings compared with no initiation or initiation after hospitalization.

An abundance of new data regarding the use of the novel drug compound sacubitril/valsartan in chronic heart failure (CHF) patients is published every year since the initial publication of the PARADIGM-HF study in 2014. This review summarises the most recent evidence (2019 and onwards) of sacubitril/valsartan in CHF patients as well as provides a critical appraisal of these data. New data are grouped in categories such as real-world data, randomised controlled trials, surrogate end-points, cost-effectiveness, use of sacubitril/valsartan as an anti-hypertensive treatment, effect on diuretic dosing and implementation of this novel compound in other populations. This review of recent literature identified important messages such as early initiation during index hospitalisation or immediately post-discharge, barriers against implementation of this novel treatment modality, analytical issues regarding measuring natriuretic peptides in patients under treatment and extrapolated use of sacubitril/valsartan in other than PARADIGM-HF populations. This update may serve as a very helpful evidence-based resource for practising clinicians, future research planning and health-related policy makers.

Aims of Study: Since January 2017, olmesartan-based treatment are no longer reimbursed by French national health insurance. Indeed, enteropathy cases, potentially lethal, were described in relation to this medication. Objectives were to study the impact of stopping the reimbursement of olmesartan for hypertensive patients., Patients and Method: A descriptive retrospective study was performed with data from two primary care facilities in French occidental Normandy. To evaluate the blood pressure control, different blood pressure measurements were considered during the year before (period 1) and the year after (period 2) potential stopping olmesartan. A medico-economic analysis was also realized., Results: From June 2015 to July 2017, 107 hypertensive patients treated by olmesartan were included. Among them, 47 patients (44%) had an antihypertensive monotherapy. olmesartan had been mainly switched by another sartan (75%, 80/107) including valsartan (59%, 47/80). Mean blood pressures during period 1 and period 2 were not statistically different. Moreover, 83% of patients were initially controlled with olmesartan and 81% after switching medication (P=0,86). The use of olmesartan generated an additional cost of 58% compared to the other drugs that replaced it during period 2., Conclusions: Stopping olmesartan reimbursement didn't seem to have a significant impact on blood pressure control of hypertensive patients while its cost is significant. In addition to potential serious side effects, olmesartan has not shown any improvement in cardiovascular morbi-mortality., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Objectives: This study assesses the cost-effectiveness of sacubitril/valsartan versus enalapril in patients with symptomatic heart failure with reduced ejection fraction (HFrEF). Methods: We used a previously developed Markov model calibrated with patient-level data from the PARADIGM-HF trial, adapted to the Portuguese setting. The model considers two health states (alive or dead) and uses regression analyzes to estimate hospitalizations and deaths over time. A panel of experts estimated resource consumption in the outpatient setting. To estimate resource consumption with hospitalizations, the National Health Service Diagnosis Related Groups database was used. Unit costs were based on national legislation, and on the Infomed database. The model considers a societal perspective, a time horizon of 30-years, and a 5% annual discount rate. Sensitivity analyses assessed the robustness of results. Results: Sacubitril/valsartan increases life expectancy by 0.5 life-years, corresponding to 0.4 incremental quality adjusted life-years (QALY) versus enalapril. The estimated incremental cost-effectiveness ratio (ICER) is 22,702€/QALY. Sensitivity analysis shows that results are robust, but sensitive to the parameter estimates of the cardiovascular survival curve. Conclusion: Sacubitril/valsartan is a cost-effective therapeutic option in the treatment of Portuguese patients with HFrEF and translate into significant health gains and increased life expectancy versus the current standard of care.

Objectives: To evaluate the cost-effectiveness of olmesartan/amlodipine fixed-dose combination vs olmesartan and amlodipine free combination, amlodipine single drug, and valsartan/amlodipine fixed-dose combination in the treatment of hypertensive patients from payer perspective in China. Methods: A Markov model was constructed, which included five health states of hypertensive patients who are aged 35-84 years at baseline and free of cardiovascular disease. Clinical data were obtained from a network meta-analysis. Epidemiology data, adverse events (AEs), cost, and utility data were obtained from the literature. The cost associated with AEs was estimated based on the cost of same symptoms of hypertensive patients in an electric medical record database. The model projected quality-adjusted life years (QALYs) gained, total costs per patient in a 20-year time horizon, and incremental cost-effectiveness ratios. Probability sensitivity analyses (PSA) and one-way sensitivity analyses were conducted for the main parameters to test the robustness of the model. Results: Compared to olmesartan and amlodipine free combination, amlodipine, and valsartan/amlodipine fixed-dose combination, treatment with olmesartan/amlodipine fixed-dose combination led to fewer CVD events and deaths; resulted in an incremental cost of ¥-5,439 ($-791.36), ¥6,530 ($950.09), and ¥-1,019 ($-148.26) and gained additional QALYs of 0.052, 0.094, and 0.037 per patient, respectively. Compared with olmesartan and amlodipine free combination and valsartan/amlodipine fixed-dose combination, olmesartan/amlodipine fixed-dose combination was dominant. Compared with amlodipine alone, the incremental cost-effectiveness ratios were below the WHO recommended cost-effectiveness threshold, indicating the olmesartan/amlodipine fixed-dose combination was a cost-effective option for hypertensive patients in China. The 10-years' time horizon scenario analysis showed similar results to the 20-years' time horizon. Probabilistic sensitivity analysis and one-way sensitivity analyses showed the robustness of the model results. Conclusions: Olmesartan/amlodipine fixed-dose combination confers better health outcomes and costs less compared with olmesartan and amlodipine free combination and valsartan/amlodipine fixed-dose combination, and is cost-effective compared to amlodipine for hypertension treatment in China.

Importance: In 2015, the US Food and Drug Administration approved 2 new medications for treatment of heart failure with reduced ejection fraction, sacubitril/valsartan and ivabradine. However, few national data are available examining their contemporary use and associated costs., Objective: To evaluate national patterns of use of sacubitril/valsartan and ivabradine and associated therapeutic spending in Medicare Part D and Medicaid., Design, Setting, and Participants: In this US nationwide claims-based study, we analyzed data from the Medicare Part D Prescription Drug Event and Medicaid Utilization and Spending data sets to compare national patterns of use of sacubitril/valsartan and ivabradine between 2016 and 2017., Main Outcomes and Measures: Changes in total spending, per-beneficiary/claim spending, number of beneficiaries, and number of claims between 2016 and 2017 for sacubitril/valsartan and ivabradine., Results: The number of Medicare beneficiaries prescribed sacubitril/valsartan increased from 35 423 to 90 606 (156% increase from 2016 to 2017). Medicare beneficiaries prescribed ivabradine increased from 15 856 to 23 213 (46% increase). In 2017, Medicare Part D spent $227 million and $7.3 million on sacubitril/valsartan and ivabradine, respectively. This represented increases of 241% and 59% compared with 2016 spending, respectively. The annual Medicare per-beneficiary spending on sacubitril/valsartan and ivabradine was $2512 and $2400. Parallel trends in use patterns and spending were observed among Medicaid beneficiaries., Conclusions and Relevance: Although initial experiences suggested slow uptake after regulatory approval, these national data demonstrate an increase in use of sacubitril/valsartan and, to a lesser degree, ivabradine in the United States. Current annual per-beneficiary expenditures remain less than spending thresholds that have been reported to be cost-effective. Ongoing efforts are needed to promote high-value care while improving affordability and access to established and emerging heart failure therapies.

Background: To assess the cost-effectiveness of new treatments in Germany, the efficiency frontier (EF) method has been developed. We compared the cost-effectiveness analysis using international standards and the German methodology, using the heart failure drug sacubitril/valsartan as an example., Methods: A previously developed Markov model was adapted to include 4 treatment options: no treatment, enalapril, candesartan, and sacubitril/valsartan. The internationally used incremental cost-effectiveness ratio (ICER) was calculated, as well as cost-effectiveness acceptability curves. Additionally, EFs, net monetary benefits (NMBs), and price-acceptability curves were created according to German guidelines. All analyses were performed from the perspective of the German Statutory Health Insurance., Results: The base-case ICER for sacubitril/valsartan compared to enalapril is €19  300/quality-adjusted life-year. On the cost-effectiveness acceptability curve, sacubitril/valsartan is most likely to be cost-effective, out of all included comparators, from a hypothetical willingness-to-pay threshold of €18 250/quality-adjusted life-year onward. No EF could be constructed for the base case. Taking the uncertainty of the input parameters into account for the probabilistic sensitivity analysis, a NMB of around -€14 000 was calculated, depending on the outcome considered, with the NMB being zero at a daily price for sacubitril/valsartan ranging from €1.52 to €1.67., Conclusion: We calculated an ICER for Germany, comparable to previously published cost-effectiveness analyses for Europe, which widely concluded sacubitril/valsartan to be cost-effective. Using the German EF approach, a considerable discount needs to be applied before sacubitril/valsartan can be considered cost-effective., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Aims: The Heart Outcomes Prevention Evaluation-3 (HOPE-3) found that rosuvastatin alone or with candesartan and hydrochlorothiazide (HCT) (in a subgroup with hypertension) significantly lowered cardiovascular events compared with placebo in 12 705 individuals from 21 countries at intermediate risk and without cardiovascular disease. We assessed the costs implications of implementation in primary prevention in countries at different economic levels., Methods and Results: Hospitalizations, procedures, study and non-study medications were documented. We applied country-specific costs to the healthcare resources consumed for each patient. We calculated the average cost per patient in US dollars for the duration of the study (5.6 years). Sensitivity analyses were also performed with cheapest equivalent substitutes. The combination of rosuvastatin with candesartan/HCT reduced total costs and was a cost-saving strategy in United States, Canada, Europe, and Australia. In contrast, the treatments were more expensive in developing countries even when cheapest equivalent substitutes were used. After adjustment for gross domestic product (GDP), the costs of cheapest equivalent substitutes in proportion to the health care costs were higher in developing countries in comparison to developed countries., Conclusion: Rosuvastatin and candesartan/HCT in primary prevention is a cost-saving approach in developed countries, but not in developing countries as both drugs and their cheapest equivalent substitutes are relatively more expensive despite adjustment by GDP. Reductions in costs of these drugs in developing countries are essential to make statins and blood pressure lowering drugs affordable and ensure their use., Clinical Trial Registration: HOPE-3 ClinicalTrials.gov number, NCT00468923., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Purpose: Sacubitril/valsartan, the first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is a possible treatment option for chronic heart failure patients with reduced ejection fraction (HFrEF). The aim of this study was to estimate the cost-effectiveness of sacubitril/valsartan use in South Korea for treating patients with HFrEF compared with that of enalapril, an angiotensin-converting enzyme inhibitor, and with angiotensin receptor blockers (ARBs)., Methods: A Markov model was designed to estimate the lifetime cost-effectiveness of treatment for patients with HFrEF. Cohorts in the alive-state incurred a monthly risk of hospitalization because of deteriorated HF, adverse events (AEs), or death. Transition probabilities of sacubitril/valsartan and enalapril were estimated by using data from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. The effectiveness of ARBs (eg, reduction in mortality and hospitalization rates) was assumed to be identical to that of enalapril, according to the results of the meta-analysis. However, there was no comparative evidence for AEs. We therefore conducted a Bayesian network meta-analysis and adjusted the incidence rate of AEs for ARBs. The utility for estimating quality-adjusted life years (QALYs) was elicited by the survey of the general South Korean population by using EuroQol-5 dimensions. We calculated the medical costs, including medication, monitoring, hospitalization, AEs, and terminal care, from the health care sector perspective. Costs and effectiveness were discounted by 5%. One-way sensitivity analyses and a probabilistic sensitivity analysis were conducted to determine the model robustness., Findings: The total cost per patient for sacubitril/valsartan and enalapril was $25,832 and $18,295, respectively. Sacubitril/valsartan was associated with an ∼8- month longer life expectancy compared with enalapril and a QALY gain of 0.59. As a result, the incremental cost-effectiveness ratio for sacubitril/valsartan versus enalapril was $12,722 per QALY. The incremental cost-effectiveness ratio of sacubitril/valsartan versus ARB was $11,970 with an incurred cost of $18,741 for the ARB group. The main results and those of various sensitivity analyses were lower than a threshold of $20,000., Implications: From a health care sector perspective, sacubitril/valsartan is a cost-effective treatment for HFrEF compared with enalapril and ARBs. This finding could be helpful for cardiologists or decision makers in reaching cost-effective choices regarding the treatment selection process., (Copyright © 2019. Published by Elsevier Inc.)

Background In the South African private sector context, generically similar products are grouped together and the reimbursement rate is set at the average price of the generically equivalent products. Very little evidence exists in low and middle-income countries with regards to the impact of this policy over time. Objectives To determine the impact of the introduction of generics and generic reference pricing on candesartan and rosuvastatin in the South African private health care sector in terms of medicine utilisation, medicine price and medicine expenditure. Setting South African private health sector. Method Medicine claims for candesartan and rosuvastatin was obtained from a Pharmacy Benefit Manager in South Africa. The claims covered a 48-month period from January 2012 to December 2015 and provided a pre- and post-reference price period for analysis. Medicine utilisation was measured as the number of Defined Daily Doses dispensed per 100,000 beneficiaries. Medicine price and expenditure was calculated as the average per Defined Daily Dose. Main outcome measure Medicine utilisation, price and expenditure. Results Candesartan experienced an average 7.0% year-on-year decline in utilisation and rosuvastatin a 5.0% increase. Medicine expenditure reduced by an additional 34.6% and 20.9% for candesartan and rosuvastatin respectively. The total savings was 54.8% for candesartan and 31.9% for rosuvastatin. Conclusion The introduction of generics and generic reference pricing did not have an impact on medicine utilisation, but reduced the price and expenditure of both candesartan and rosuvastatin.

Background "Financial toxicity" is a concern for patients, but little is known about how patients consider out-of-pocket cost in decisions. Sacubitril-valsartan provides a contemporary scenario to understand financial toxicity. It is guideline recommended for heart failure with reduced ejection fraction, yet out-of-pocket costs can be considerable. Methods and Results Structured interviews were conducted with 49 patients with heart failure with reduced ejection fraction at heart failure clinics and inpatient services. Patient opinions of the drug and its value were solicited after description of benefits using graphical displays. Descriptive quantitative analysis of closed-ended responses was conducted, and qualitative descriptive analysis of text data was performed. Of participants, 92% (45/49) said that they would definitely or probably switch to sacubitril-valsartan if their physician recommended it and out-of-pocket cost was $5 more per month than their current medication. Only 43% (21/49) would do so if out-of-pocket cost was $100 more per month ( P<0.001). At least 40% across all income categories would be unlikely to take sacubitril-valsartan at $100 more per month. Participants exhibited heterogeneous approaches to cost in decision making and varied on their use and interpretation of probabilistic information. Few (20%) participants stated physicians had initiated a conversation about cost in the past year. Conclusions Out-of-pocket cost variation reflective of contemporary cost sharing substantially influenced stated willingness to take sacubitril-valsartan, a guideline-recommended therapy with mortality benefit. These findings suggest a need for cost transparency to promote shared decision making. They also demonstrate the complexity of cost discussion and need to study how to incorporate out-of-pocket cost into clinical decisions.

Background: Heart failure affects over 1 million people in Germany and contributes to morbidity, mortality, and high healthcare costs. A recent large randomized controlled trial compared the novel compound sacubitril/valsartan (LCZ696) with the angiotensin-converting enzyme (ACE) inhibitor enalapril and found a 16% reduction in mortality hazard. In Germany, sacubitril/valsartan was launched at the beginning of 2016., Objective: The purpose of this study was to conduct a post hoc analysis of the cost effectiveness, budget impact, and disease burden reduction of sacubitril/valsartan compared with ACE inhibitors for patients with heart failure from the perspective of the German social health insurance (SHI), based on the results of this trial., Methods: A Markov (cohort) state transition model was constructed to simulate treatment over a remaining lifetime. Based on the Markov model, a dynamic population model was developed that projects the incidence, prevalence, mortality, and healthcare costs of heart failure in the SHI population from 2017 to 2060. The population model follows prevalent and incident cohorts over time. Each year a new cohort is added, while the existing cohorts age by 1 year or die. To test for sensitivity of results, a Monte Carlo simulation was run., Results: Based on the price negotiated between manufacturer and representatives of the SHI, the base-case incremental cost-effectiveness ratio (ICER) of sacubitril/valsartan versus ACE inhibitors is €23,401 per life-year gained (in 2018 Euros). At a price of zero, the cost-effectiveness ratio is already €9594 per life-year gained due to high background costs of heart failure. Annual budget impact and reduction of disease burden reach a maximum at 4-8 years after launch (€221 million and 2.9%, respectively, in the base case)., Conclusions: The ICER of sacubitril/valsartan is projected to be at or below the level of other accepted interventions for the treatment of asymptomatic to severe heart failure in Germany. Projected budget impact leads to an increase in SHI expenditures by < 0.04% per year.

Aims: The availability of novel drugs might affect the modern interplay between pharmacological and device therapy of heart failure with reduced ejection fraction (HFrEF). The aim of this study was to assess the cost-effectiveness of sacubitril/valsartan as compared with an implantable cardioverter-defibrillator (ICD) on top of optimal medical therapy in patients with HFrEF., Methods: Data from 2000 adults with demographic and clinical characteristics similar to those in the PARADIGM-HF were derived as inputs for a four-state Markov model simulated HFrEF. Probabilities of all-cause mortality, heart failure hospitalization and ICD-related complications along with quality of life data and costs, discounted at 3%, from an Italian healthcare payer perspective were projected over a 10-year time horizon. Sensitivity analyses on key inputs were performed., Results: According to the model, sacubitril/valsartan would lead to 5.85 life years saved, whilst reducing by more than 20% the risk of heart failure hospitalizations for 1000 patients with HFrEF over 10 years. Estimated incremental costs with sacubitril/valsartan were -&OV0556;13 302 associated with incremental 0.14 quality-adjusted life years gained, yielding an incremental cost-effectiveness ratio of -&OV0556;98 500 per quality-adjusted life year gained for the base-case consistent with a dominant, cost-saving and clinically superior treatment strategy. Sacubitril/valsartan was dominant in more than 80% of the scenarios explored with sensitivity analyses., Conclusion: The findings of this model suggest that in patients with HFrEF sacubitril/valsartan would be cost-effective by increasing survival at lower costs compared with an ICD. Sensitivity analyses confirmed the cost-effectiveness of sacubitril/valsartan that remained dominant across most of the ranges of the variables tested.

Background: Sacubitril-valsartan is a new medication that has recently been recommended as a replacement for enalapril in the treatment of patients with heart failure with reduced ejection fraction (HFrEF)., Objective: This study aimed to determine the cost effectiveness of sacubitril-valsartan compared with enalapril., Methods: An analytical decision model was developed to estimate the long-term costs and outcomes from a healthcare perspective. Clinical inputs were mostly derived from the PARADIGM-HF study. Enalapril-related costs, risk of non-cardiovascular death, and all-cause readmission rate were based on data from Thailand. The costs and outcomes were discounted at 3% annually. The incremental cost-effectiveness ratio (ICER) was calculated and presented for the year 2017. A series of sensitivity analyses were also performed., Results: For the base-case, the increased cost (144,146 vs. 16,048 Thai baht [THB]) of sacubitril-valsartan was associated with gains in both life-years (9.214 vs. 8.367 years) and quality-adjusted life-years (QALYs) (7.698 vs. 6.909) compared with enalapril, yielding an ICER of 162,276 THB/QALY ($US4857.11/QALY). This ICER is not considered to be cost effective at the willingness-to-pay (WTP) level of 160,000 THB/QALY. The risk of cardiovascular death and costs of both sacubitril-valsartan and hospitalization influenced the ICER. At a WTP of 160,000 THB/QALY, sacubitril-valsartan had a 48% probability of being a cost-effective treatment., Conclusions: At its current price in Thailand, sacubitril-valsartan may not represent good value for the nations's limited healthcare resources. The cost of sacubitril-valsartan needs to reduce by approximately 2% to yield an ICER below the threshold.

Objective: Chronic heart failure with reduced ejection fraction (HF-REF) represents a major public health issue and is associated with considerable morbidity and mortality. We evaluated the cost-effectiveness of sacubitril/valsartan (formerly LCZ696) compared with an ACE inhibitor (ACEI) (enalapril) in the treatment of HF-REF from the perspective of healthcare providers in the UK, Denmark and Colombia., Methods: A cost-utility analysis was performed based on data from a multinational, Phase III randomised controlled trial. A decision-analytic model was developed based on a series of regression models, which extrapolated health-related quality of life, hospitalisation rates and survival over a lifetime horizon. The primary outcome was the incremental cost-effectiveness ratio (ICER)., Results: In the UK, the cost per quality-adjusted life-year (QALY) gained for sacubitril/valsartan (using cardiovascular mortality) was £17 100 (€20 400) versus enalapril. In Denmark, the ICER for sacubitril/valsartan was Kr 174 000 (€22 600). In Colombia, the ICER was COP$39.5 million (€11 200) per QALY gained. Deterministic sensitivity analysis showed that results were most sensitive to the extrapolation of mortality, duration of treatment effect and time horizon, but were robust to other structural changes, with most scenarios associated with ICERs below the willingness-to-pay threshold for all three country settings. Probabilistic sensitivity analysis suggested the probability that sacubitril/valsartan was cost-effective at conventional willingness-to-pay thresholds was 68%-94% in the UK, 84% in Denmark and 95% in Colombia., Conclusions: Our analysis suggests that, in all three countries, sacubitril/valsartan is likely to be cost-effective compared with an ACEI (the current standard of care) in patients with HF-REF., Competing Interests: Competing interests: CD and RH are permanent employees of Novartis AG. CD and RH oversaw the all stages of the economic evaluation and contributed to the design and reporting of the economic model. DRG Abacus received funding from Novartis AG to undertake the analysis and has supported EH, DT JJVM and FW through salary payments. York Health Economics Consortium received funding from Novartis AG to provide consulting input and has supported MT through salary payments. MRC and AB have received consulting fees from Novartis AG. JJVM’s employer, Glasgow University, has received consulting fees and research grant support from Novartis AG., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Since January 2017, olmesartan-based treatments are no longer reimbursed by French health insurance. Health authorities have recommended switch to one of the "many effective, better tolerated and reimbursed alternatives". The objective of this study was to evaluate the consequences on the prescription of antihypertensive drugs in France and to evaluate the blood pressure control of treated hypertensive patients after the switch from olmesartan to another Angiotensin receptor blocker (ARB)., Methods: To evaluate antihypertensive prescriptions, the French League Against Hypertension Survey (FLAHS) was conducted in 2007, 2012 and 2017 by self-questionnaire sent by mail to a representative panel of the population living in metropolitan France aged 35 years and over. Antihypertensive treatments were grouped by pharmacological class. To evaluate blood pressure control in hypertensive patients treated with olmesartan alone or in combination, 3 home blood pressure monitoring (HBPM) were performed. The first and the second were performed without modification of the dose of olmesartan. The third was performed 1 month after the switch to another ARB., Results: Antihypertensive prescriptions changed between 2007 and 2017. Beta-blockers decreased between 2007 and 2012 and then increased slightly. Between 2012 and 2017, ARB and diuretics decreased and ACE inhibitors (ACE-I) and calcium antagonist (CA) drugs increased. Blood pressure control was assessed in 82 hypertensive patients aged 63±11 years treated with olmesartan. The difference in SBP/DBP between the first 2 self-measurements was -0.96/-0.83mmHg. After therapy switch, the 3rd self-measurement showed an increase in SBP/DBP of 3.4/1.2mmHg. In the subgroup of olmesartan-treated controlled hypertensive patients, the switch to another ARB lead to uncontrolled hypertension for 20% of patients with a 12.1mmHg increase in SBP., Conclusion: With the halt of reimbursement of olmesartan, there was a decrease in the prescription of ARB in France. When olmersartan was replaced by another ARB, a worse blood pressure control was observed in treated hypertensive patients. The cessation of the reimbursement of olmesartan has had consequences on the treatment of hypertension in France., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Objective: Sacubitril/valsartan (SAC/VAL) has been shown to reduce mortality and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF) compared with enalapril but at a substantially higher cost. This study evaluates the cost-effectiveness of SAC/VAL versus enalapril in patients with HFrEF over a 5-year time horizon from the U.S. payer perspective., Methods: A cohort-based Markov model was developed to compare costs and quality-adjusted life years (QALYs) between SAC/VAL and enalapril in patients with HFrEF over a 5-year time horizon. Markov states included New York Heart Association (NYHA) class (II-IV) and death. Treatment discontinuation, HF-related hospitalizations, and NYHA class progression were modeled as transition states based on data from the PARADIGM trial. Other probabilities, costs, and utilities were obtained from published literature and public databases., Results: In the base case analysis, SAC/VAL cost more than enalapril ($81,943 vs $67,287) and was more effective (2.647 QALYs vs 2.546 QALYs), resulting in an incremental cost-effectiveness ratio of $143,891/QALY gained. At a willingness to pay (WTP) of $100,000/QALY, SAC/VAL was cost-effective up to a cost of $298/month. Results were most sensitive to SAC/VAL cost, SAC/VAL mortality benefit, and NYHA progression probability. SAC/VAL had a 10% and 52% probability of being cost-effective at WTP thresholds of $100,000/QALY and $150,000/QALY, respectively., Conclusions: SAC/VAL is associated with clinical benefit and may be cost-effective compared with the current standard of care over realistic treatment durations from the payer perspective. Results of this analysis can inform discussions on the value and position of SAC/VAL in the current market., (© 2018 Pharmacotherapy Publications, Inc.)

Fixed-dose combinations (FDC) have been developed to reduce the pill burden for hypertensive patients. Data on fixed-dose or free-dose (freeDC) ramipril/amlodipine (R/A) or candesartan/amlodipine (C/A) combination treatment initiation were assessed. 71 463 patients were prescribed R/A and 10 495 C/A. For both R/A and C/A, FDC patients were younger (both P < .001) and less comorbid. Prior MI (OR: 0.61 and 0.60), prior stroke (OR: 0.68 and 0.70) and CHD (OR: 0.68 and 0.64) were negatively associated with FDC use, whereas hyperlipidemia was positively associated (OR: 1.26 and 1.19). Use of antihypertensive comedication (OR: 0.78; OR: 0.55) and treatment discontinuation within 12 months (HR: 0.65 and 0.82) were less likely in FDC patients, who also showed superior adherence (mean MPR; both P < .001). Cost of the combination was higher for FDCs (both P < .001). FDCs improve persistence and adherence, although they are more commonly prescribed in patients with less cardiovascular disease., (©2018 Wiley Periodicals, Inc.)

Background: Sacubitril/valsartan reduces cardiovascular death and hospitalizations for heart failure (HF). However, decision-makers need to determine whether its benefits are worth the additional costs, given the low-cost generic status of traditional standard of care., Aims: To evaluate the cost-effectiveness of sacubitril/valsartan compared to enalapril in patients with HF and reduced ejection fraction, from the Singapore healthcare payer perspective., Methods: A Markov model was developed to project clinical and economic outcomes of sacubitril/valsartan vs enalapril for 66-year-old patients with HF over 10 years. Key health states included New York Heart Association classes I-IV and deaths; patients in each state incurred a monthly risk of hospitalization for HF and cardiovascular death. Sacubitril/valsartan benefits were modeled by applying the hazard ratios (HRs) in PARADIGM-HF trial to baseline probabilities. Primary model outcomes were total and incremental costs and quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) for sacubitril/valsartan relative to enalapril Results: Compared to enalapril, sacubitril/valsartan was associated with an ICER of SGD 74,592 (USD 55,198) per QALY gained. A major driver of cost-effectiveness was the cardiovascular mortality benefit of sacubitril/valsartan. The uncertainty of this treatment benefit in the Asian sub-group was tested in sensitivity analyses using a HR of 1 as an upper limit, where the ICERs ranged from SGD 41,019 (USD 30,354) to SGD 1,447,103 (USD 1,070,856) per QALY gained. Probabilistic sensitivity analyses showed the probability of sacubitril/valsartan being cost-effective was below 1%, 12%, and 71% at SGD 20,000, SGD 50,000, and SGD 100,000 per QALY gained, respectively., Conclusions: At the current daily price sacubitril/valsartan may not represent good value for limited healthcare dollars compared to enalapril in reducing cardiovascular morbidity and mortality in HF in the Singapore healthcare setting. This study highlights the cost-benefit trade-off that healthcare professionals and patients face when considering therapy.

Our aim was to summarize published secondary analyses of the PARADIGM-HF trial. In the original trial, published in September 2014, sacubitril/valsartan significantly reduced the primary composite outcome of cardiovascular death or heart failure hospitalization compared to enalapril. This summary provides a resource for clinicians to review subsequent analyses of the landmark trial evaluating the benefit of sacubitril/valsartan in various subgroups and providing information regarding optimal use of this new therapy in the broader heart failure population. A full list of publications of the existing PARDADIGM-HF post hoc analyses was obtained and summarized, grouped by focus (e.g., severity of illness, tolerability). Twenty-six publications and one abstract analyzing the PARADIGM-HF trial were reviewed, summarizing the most important results that compared the benefits of sacubitril/valsartan to enalapril, including pertinent subgroup information from each analysis. Key publications evaluated the treatment effect of sacubitril/valsartan based on heart failure severity (i.e., ejection fraction or heart failure risk scores), impact on alternate outcomes, influence of additional therapies, tolerability in patients with comorbidities (i.e., diabetes), long-term benefits, and cost-effectiveness. In addition, nine ongoing phase III and phase IV clinical trials with sacubitril/valsartan were briefly summarized to address potential future uses in more extensive heart failure settings. The benefit of sacubitril/valsartan over enalapril for the primary endpoint in the PARADIGM-HF trial is maintained throughout numerous secondary analyses. Though the subgroups analyzed are based on participants from a single clinical trial, clinicians can more confidently incorporate this novel therapy into practice with expanded knowledge of these existing analyses as well as ongoing prospective trials., (© 2017 Pharmacotherapy Publications, Inc.)

Background: The US Food and Drug Administration approved the use of sacubitril/valsartan in patients with heart failure with reduced ejection fraction in July 2015. We aimed to assess the adoption and prescription drug costs of sacubitril/valsartan in its first 18 months after Food and Drug Administration approval., Methods and Results: Using a large US insurance database, we identified privately insured and Medicare Advantage beneficiaries who filled a first prescription for sacubitril/valsartan between July 1, 2015, and December 31, 2016. We compared them to patients treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Outcomes included adoption, prescription drug costs, and 180-day adherence, defined as a proportion of days covered ≥80%. A total of 2244 patients initiated sacubitril/valsartan. Although the number of users increased over time, the proportion of heart failure with reduced ejection fraction patients taking sacubitril/valsartan remained low (<3%). Patients prescribed sacubitril/valsartan were younger, more often male, with less comorbidity than those taking an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. Although a majority of prescription costs were covered by the health plan (mean, $328.37; median, $362.44 per 30-day prescription), out-of-pocket costs were still high (mean, $71.16; median, $40.27). By comparison, median out-of-pocket costs were $2 to $3 for lisinopril, losartan, carvedilol, and spironolactone. Overall, 59.1% of patients were adherent to sacubitril/valsartan. Refill patterns suggested that nearly half of nonadherent patients discontinued sacubitril/valsartan within 180 days of starting., Conclusions: Adoption of sacubitril/valsartan after Food and Drug Administration approval has been slow and may be associated with the high cost., (© 2018 American Heart Association, Inc.)

A novel antihypertensive drug, LCZ696 (Entresto®), has recently been introduced, which combines the action of an antagonist of the renin-angiotensin-aldosterone system (RAAS), effectively decreasing the blood pressure, with an inhibition of neprilysin, which is responsible for metabolizing natriuretic peptides exerting antihypertensive and antifibrotic effects. In this MiniReview, we describe the pharmacokinetics and pharmacodynamics, efficacy and side effects of the combined angiotensin receptor antagonist and neprilysin inhibitor LCZ696. We summarize the effect of LCZ696 treatment of patients suffering from hypertension and heart failure (HF) and further highlight the role of this new drug as a treatment option in the future. In the earlier stages of the treatment of patients with heart failure, LCZ696 was superior in lowering the blood pressure compared to olmesartan, while the effect on blood pressure at long-term treatment was comparable for the two drugs. The numbers of adverse effects were comparable. LCZ696 was superior to enalapril in reducing mortality, hospitalizations and HF symptoms. Adverse effects were reduced with a slower up-titrating regimen of 6 weeks. The current results are promising and suggest that LCZ696 will be a new candidate for first-line treatment of HF. However, it needs to be explored whether LCZ696 is safe in pregnant women, what are the effects of long-term LCZ696 treatment on survival and whether the antifibrotic effects can be of major benefit in, for example HF with preserved ejection fraction., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Objectives: To describe the adaptation of a global health economic model to determine whether treatment with the angiotensin receptor neprilysin inhibitor LCZ696 is cost effective compared with the angiotensin-converting enzyme inhibitor enalapril in adult patients with chronic heart failure with reduced left ventricular ejection fraction in the Netherlands; and to explore the effect of performing the cost-effectiveness analyses according to the new pharmacoeconomic Dutch guidelines (updated during the submission process of LCZ696), which require a value-of-information analysis and the inclusion of indirect medical costs of life-years gained., Methods: We adapted a UK model to reflect the societal perspective in the Netherlands by including travel expenses, productivity loss, informal care costs, and indirect medical costs during the life-years gained and performed a preliminary value-of-information analysis., Results: The incremental cost-effectiveness ratio obtained was €17,600 per quality-adjusted life-year (QALY) gained. This was robust to changes in most structural assumptions and across different subgroups of patients. Probability sensitivity analysis results showed that the probability that LCZ696 is cost-effective at a €50,000 per QALY threshold is 99.8%, with a population expected value of perfect information of €297,128. On including indirect medical costs of life-years gained, the incremental cost-effectiveness ratio was €26,491 per QALY gained, and LCZ696 was 99.46% cost effective at €50,000 per QALY, with a population expected value of perfect information of €2,849,647., Conclusions: LCZ696 is cost effective compared with enalapril under the former and current Dutch guidelines. However, the (monetary) consequences of making a wrong decision were considerably different in both scenarios., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: Once the patent of a brand-name drug expires, generic drugs are commercialized, and substitution from brand-name to generics may occur. Generic drug equivalence is evaluated through comparative bioavailability studies. Few studies have assessed outcomes after generic drug commercialization at a population level. We evaluated the impact of 3 generic angiotensin II receptor blockers commercialization on adverse events: hospitalizations or emergency room consultations., Methods and Results: This is an interrupted time series analysis using the Quebec Integrated Chronic Disease Surveillance System. Rates of adverse events for losartan, valsartan, and candesartan users (N=136 177) aged ≥66 years were calculated monthly, 24 months before and 12 months after generics commercialization. Periods before and after generics commercialization were compared by negative binomial segmented regression models. Sensitivity analyses were also conducted. For all users, there was a monthly mean rate of 100 adverse events for 1000 angiotensin II receptor blocker users before and after generic commercialization. Among generic users of losartan, valsartan, and candesartan, there was an increase in rates of adverse events of 8.0% (difference of proportions versus brand-name, 7.5% [95% confidence interval, -0.9% to 15.9%]; P =0.0643), 11.7% (difference of proportions, 17.1% [95% confidence interval, 9.9%-24.3%]; P <0.0001), and 14.0% (difference of proportions, 16.6% [95% confidence interval, 7.9%-25.3%]; P <0.0001), respectively, the month of generic commercialization. The monthly trend of adverse events was affected for generic versus brand-name losartan users only (difference of proportions, 2.0% [0.7%-3.4%]; P =0.0033) ≤1 year after generics commercialization. Similar results were found in sensitivity analyses., Conclusions: Among generic users, immediate or delayed differences in adverse events rates were observed right after generic commercialization for 3 antihypertensive drugs. Rates of adverse events remained higher for generic users. Increases were more pronounced for generic candesartan, which is the studied product with the largest difference in comparative bioavailability. Risk and survival analysis studies controlling for several potential confounding factors are required to better characterize generic substitution., (© 2017 American Heart Association, Inc.)

Poor adherence to antihypertensive treatment is the single most important factor of unsatisfactory blood pressure (BP) control. This review focuses on therapy-related factors affecting adherence and suggests how to improve it with a wise choice of treatment schedule. Complex drug treatment schemes, poor tolerability and drug substitutions are frequent causes of poor adherence which, in turn, causes insufficient BP control, greater incidence of cardiovascular events and, finally, higher global health costs. The effects of prescribing generic drugs and of drug substitutions on adherence is also discussed. In terms of adherence, generic drugs do not seem to be better than branded drugs, unless patients have to bear very high "out of pocket" expenses to buy original drugs, suggesting no advantages in switching drug with the mere goal of reducing the cost of therapy. An important role in improving adherence (and thus cardiovascular events and health expenditure) is also played by the availability of fixed-dose combinations; among antihypertensive drugs, angiotensin receptor blockers (ARBs) are those associated with higher levels of adherence and persistence. Among ARBs, olmesartan stands out for a wide choice of effective fixed-dose combinations.

Some industry observers wonder why the wunderkind hasn't done more wonderfully on the market. As a brand name drug, Entresto costs substantially more than the generic ACE inhibitors and ARBs. GoodRx reports the average cash price for uninsured patients for Entresto is $504 per month, compared with $44 for enalapril.

Sacubitril/valsartan combines a neprilysin inhibitor with an angiotensin receptor blocker. As an inhibitor of neprilysin, an enzyme that degrades biologically active natriuretic peptides, this first-in-class therapy increases levels of circulating natriuretic peptides, resulting in natriuretic, diuretic, and vasodilatory effects. In patients with chronic New York Heart Association class II-IV heart failure with reduced ejection fraction, the PARADIGM-HF trial demonstrated that sacubitril/valsartan significantly reduced the primary endpoint of cardiovascular mortality and heart failure hospitalization, compared with enalapril. The rate of all-cause mortality was also significantly reduced. Subsequently, the American College of Cardiology/American Heart Association/Heart Failure Society of America recently updated guideline recommendations for Stage C patients with heart failure with reduced ejection fraction to recommend angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril/valsartan in conjunction with other evidence-based therapies to reduce morbidity and mortality. Several analyses have suggested the cost-effectiveness of this new therapy. To ensure tolerability, initiating the lower dosage form of sacubitril/valsartan is warranted in patients with severe renal impairment, moderate hepatic impairment, and low blood pressure, and close monitoring is warranted in such patients. A 36-hour washout period is recommended when switching patients from an angiotensin-converting enzyme inhibitor to sacubitril/valsartan. Similarly, sacubitril/valsartan is contraindicated in patients receiving concomitant angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and those with a history of angioedema., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: In September 2014, the PARADIGM-HF trial showed the heart failure drug combination sacubitril/valsartan to be superior to enalapril for patients with a reduced ejection fraction., Objectives: To determine the incremental cost-effectiveness of sacubitril/valsartan compared with enalapril in the Netherlands using the clinical data from the PARADIGM-HF trial., Methods: To compare sacubitril/valsartan and enalapril in a cost-effectiveness study, a Markov model was developed using the effectiveness data from the PARADIGM-HF trial. A health care payer's perspective was applied in the economic evaluation. The developed model was used to evaluate the cost-effectiveness for sacubitril/valsartan at different per diem prices., Results: The base-case analysis showed that sacubitril/valsartan can be cost-effective at maximum daily costs of €5.50 and €14.14 considering willingness-to-pay thresholds of €20,000 and €50,000 per quality-adjusted life-year (QALY), respectively. Sensitivity analysis demonstrated the robustness of the model, identifying only the price of sacubitril/valsartan and the mortality within the sacubitril/valsartan group as significant drivers of the cost-effectiveness ratio. Sacubitril/valsartan was cost-effective at a willingness-to-pay threshold of €20,000 per QALY (€50,000 per QALY) in more than 80% of the replications with certainty at the price point of €3 (€10)., Conclusions: Sacubitril/valsartan can be considered a cost-effective treatment at a daily price of €5.25. Unless priced lower than enalapril (<€0.045 per day), sacubitril/valsartan is very unlikely to be cost-saving/dominant., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Biologically active natriuretic peptides (NPs) are an integral part of cardiac homeostasis as they help to maintain sodium and fluid balance. When homeostasis is perturbed by neurohormonal activation in heart failure, levels of NPs rise in response. Neprilysin (NEP) is a naturally occuring enzyme that breaks down NPs. Scientists have recently discovered a novel pharmacologic agent that combines a NEP inhibitor and an angiotensin receptor blocker. In a large clinical trial, this new drug was found to reduce hospitalization and mortality in systolic heart failure. The challenges of implementing this therapy include patient selection, cost, and risk of side effects including angioedema and Alzheimer's disease.

Background: Sacubitril-valsartan therapy reduces cardiovascular mortality compared with enalapril therapy in patients with heart failure with reduced ejection fraction., Objective: To evaluate the cost-effectiveness of sacubitril-valsartan versus angiotensin-converting enzyme inhibitor therapy in patients with chronic heart failure., Design: Markov decision model., Data Sources: Clinical trials, observational analyses, reimbursement data from the Centers for Medicare & Medicaid Services, drug pricing databases, and Centers for Disease Control and Prevention life tables., Target Population: Patients at an average age of 64 years, New York Heart Association (NYHA) class II to IV heart failure, and left ventricular ejection fraction of 0.40 or less., Time Horizon: Lifetime., Perspective: Societal., Intervention: Treatment with sacubitril-valsartan or lisinopril., Outcome Measures: Life-years, quality-adjusted life-years (QALYs), costs, heart failure hospitalizations, and incremental cost-effectiveness ratios., Results of Base-Case Analysis: The sacubitril-valsartan group experienced 0.08 fewer heart failure hospitalization, 0.69 additional life-year, 0.62 additional QALY, and $29 203 in incremental costs, equating to a cost per QALY gained of $47 053. The cost per QALY gained was $44 531 in patients with NYHA class II heart failure and $58 194 in those with class III or IV heart failure., Results of Sensitivity Analysis: Sacubitril-valsartan treatment was most sensitive to the duration of improved outcomes, with a cost per QALY gained of $120 623 if the duration was limited to the length of the trial (median, 27 months). No variations in other parameters caused the cost to exceed $100 000 per QALY gained., Limitation: The benefit of sacubitril-valsartan is based on a single clinical trial., Conclusion: Treatment with sacubitril-valsartan provides reasonable value in reducing cardiovascular mortality and morbidity in patients with NYHA class II to IV heart failure., Primary Funding Source: U.S. Department of Veterans Affairs and Institute for Clinical and Economic Review.

The objective of the present study was to systematically review the clinical and economic outcomes of olmesartan as monotherapy or in combination with other antihypertensive agents in the treatment of hypertension. A literature search was performed using PubMed and the Cochrane library until December 2015, with no limit on publication date. Eligible studies were selected using predetermined inclusion and exclusion criteria, limiting articles to those published in the English language. Background information of the study, participants' characteristics and study outcomes were collected. Meta-analysis of data was not performed. Fifty-five studies were included, of which fifty investigated the clinical efficacy of olmesartan and five the cost-effectiveness of olmesartan. In general results from clinical trials evaluating the efficacy of olmesartan as monotherapy and as combination therapy demonstrated that olmesartan provided better antihypertensive blood pressure-lowering efficacy and was generally well tolerated compared with other antihypertensive agents. Results from economic evaluations indicated that olmesartan may be more cost-effective than other ARBs such as losartan, valsartan, irbesartan and candesartan, having the potential of decreasing the overall medical costs of care for patients with hypertension. Evidence from the present systematic review confirms the antihypertensive efficacy and good safety profile of olmesartan both as monotherapy and as combination therapy. Olmesartan was also found to be cost-effective compared with other ARBs, though this area has yet relatively poor evidence and needs to further be explored., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Importance: The angiotensin receptor neprilysin inhibitor sacubitril/valsartan was associated with a reduction in cardiovascular mortality, all-cause mortality, and hospitalizations compared with enalapril. Sacubitril/valsartan has been approved for use in heart failure (HF) with reduced ejection fraction in the United States and cost has been suggested as 1 factor that will influence the use of this agent., Objective: To estimate the cost-effectiveness of sacubitril/valsartan vs enalapril in the United States., Design, Setting, and Participants: Data from US adults (mean [SD] age, 63.8 [11.5] years) with HF with reduced ejection fraction and characteristics similar to those in the PARADIGM-HF trial were used as inputs for a 2-state Markov model simulated HF. Risks of all-cause mortality and hospitalization from HF or other reasons were estimated with a 30-year time horizon. Quality of life was based on trial EQ-5D scores. Hospital costs combined Medicare and private insurance reimbursement rates; medication costs included the wholesale acquisition cost for sacubitril/valsartan and enalapril. A discount rate of 3% was used. Sensitivity analyses were performed on key inputs including: hospital costs, mortality benefit, hazard ratio for hospitalization reduction, drug costs, and quality-of-life estimates., Main Outcomes and Measures: Hospitalizations, quality-adjusted life-years (QALYs), costs, and incremental costs per QALY gained., Results: The 2-state Markov model of US adult patients (mean age, 63.8 years) calculated that there would be 220 fewer hospital admissions per 1000 patients with HF treated with sacubitril/valsartan vs enalapril over 30 years. The incremental costs and QALYs gained with sacubitril/valsartan treatment were estimated at $35 512 and 0.78, respectively, compared with enalapril, equating to an incremental cost-effectiveness ratio (ICER) of $45 017 per QALY for the base-case. Sensitivity analyses demonstrated ICERs ranging from $35 357 to $75 301 per QALY., Conclusions and Relevance: For eligible patients with HF with reduced ejection fraction, the Markov model calculated that sacubitril/valsartan would increase life expectancy at an ICER consistent with other high-value accepted cardiovascular interventions. Sensitivity analyses demonstrated sacubitril/valsartan would remain cost-effective vs enalapril.

Objectives: The objective of this study was to determine the cost-effectiveness and cost per quality-adjusted life year (QALY) gained of sacubitril-valsartan relative to enalapril for treatment of heart failure with reduced ejection fraction (HFrEF)., Background: Compared with enalapril, combination angiotensin receptor-neprilysin inhibition (ARNI), as is found in sacubitril-valsartan, reduces cardiovascular death and heart failure hospitalization rates in patients with HFrEF., Methods: Using a Markov model, costs, effects, and cost-effectiveness were estimated for sacubitril-valsartan and enalapril therapies for the treatment of HFrEF. Patients were 60 years of age at model entry and were modeled over a lifetime (40 years) from a third-party payer perspective. Clinical probabilities were derived predominantly from PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). All costs and effects were discounted at a 3% rate annually and are presented in 2015 U.S. dollars., Results: In the base case, sacubitril-valsartan, compared with enalapril, was more costly ($60,391 vs. $21,758) and more effective (6.49 vs. 5.74 QALYs) over a lifetime. The cost-effectiveness of sacubitril-valsartan was highly dependent on duration of treatment, ranging from $249,411 per QALY at 3 years to $50,959 per QALY gained over a lifetime., Conclusions: Sacubitril-valsartan may be a cost-effective treatment option depending on the willingness-to-pay threshold. Future investigations should incorporate real-world evidence with sacubitril-valsartan to further inform decision making., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension., (© 2016 American Heart Association, Inc.)

Background: Reducing patient cost-sharing and engaging patients in disease management activities have been shown to increase uptake of evidence-based care., Objective: To evaluate the effect of employer purchase of a disease-specific plan with reduced cost-sharing and disease management (the Diabetes Health Plan/DHP) on medication adherence among eligible employees and dependents., Design: Employer-level "intent to treat" cohort study, including data from eligible employees and their dependents with diabetes, regardless of whether they were enrolled in the DHP., Setting: Employers that contracted with a large national health plan administrator in 2009, 2010, and/or 2011., Participants: Ten employers that purchased the DHP and 191 employers that did not (controls). Inverse probability weighting (IPW) estimation was used to adjust for inter-group differences., Intervention: The DHP includes free or low-cost medications and physician visits. Enrollment strategies and specific benefit designs are determined by the employer and vary in practice. DHP participants are notified up front that they must engage in their own health care (e.g., receiving diabetes-related screening) in order to remain enrolled., Main Outcome Measure: Mean employee adherence to metformin, statins, and ACE/ARBs at the employer level at one year post-DHP implementation, as measured by the proportion of days covered (PDC)., Results: Baseline adherence to the three medications was similar across DHP and control employers, ranging from 64 to 69 %. In the first year after DHP implementation, predicted employer-level adherence for metformin (+4.9 percentage points, p = 0.017), statins (+4.8, p = 0.019), and ACE/ARBs (+4.4, p = 0.02) was higher with DHP purchase., Limitations: Non-randomized, observational study., Conclusions: The Diabetes Health Plan, an innovative health plan that combines reduced cost-sharing and disease management with an up-front requirement of enrollee participation in his or her own health care, is associated with a modest improvement in medication adherence at 12 months.

High blood pressure is a very common problem in the adult and elderly population, both in developed and developing countries. A relatively large number of drug classes are available to treat this condition and prevent its complications, which are not only more frequent in the aforementioned patients but also those affected by metabolic syndrome and/or Type 2 diabetes. Irbesartan is an angiotensin-receptor blocker class drug with good antihypertensive efficacy and specific pharmacological characteristics, whose efficacy has been more deeply evaluated in metabolically complex hypertensive patients. In this review, the authors will analyze its effectiveness in preventing or delaying organ damage in hypertensive patients, with a closer look at the economic implications of treating hypertension with irbesartan in the context of available antihypertensive drugs.

This retrospective claims database analysis compared two strategies of hypertension treatment in outpatient, emergency, and inpatient departments: a fixed-dose combination (FDC) of amlodipine/valsartan vs free combinations of angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) (ARB+CCB group). After a mean follow-up of 15.2 months, the FDC group had significantly lower total healthcare costs (US $1844 vs US $2158; P<.001) and hospitalization rates (14.57% vs 18.43%; P<.001), a higher proportion of days covered (80.35% vs 72.57%; P<.001), and better persistence (266 vs 225 days; P<.001) compared with the ARB+CCB group. The FDC group also had a better major adverse cardiovascular event (MACE)-free survival (hazard ratio, 0.83; 95% confidence interval, 0.73-0.94; P=.003) and decreased rates of heart failure (2.12% vs 3.26%; P<.001), malignant dysrhythmia (0.18% vs 0.42%; P=.021), and percutaneous coronary intervention (0.76% vs 1.26%; P=.015). Compared with free combinations of ARB+CCB, an FDC of amlodipine/valsartan improved MACE-free survival and medication compliance and decreased total healthcare costs and hospitalization rates in hypertensive patients., (© 2014 Wiley Periodicals, Inc.)

Purpose: National reimbursement policies in Denmark were changed in November 2010 favouring a shift in angiotensin-II receptor blocker (ARB) treatment to generic losartan for heart failure (HF) patients. We examined how changes in reimbursement policies affected the fraction of HF patients up-titrated to optimal or suboptimal ARB dosage., Methods: A historical cohort study was performed including HF patients with at least one prescription of ARB in the months of May-Jul 2010 (baseline). Patients were considered up-titrated at doses 100, 16 or 160 mg for losartan, valsartan and candesartan, respectively. Individual-level linkage of nationwide registries of hospitalization and drug dispensing in Denmark was used to describe patterns of ARB prescriptions and estimate dosage before and after November 2010. Logistic regression models were used to assess the probability for being up-titrated in the period., Results: Of 6036 individuals included (mean age 73.5 [standard deviation 11.2] years; 51% males), 3346 (55.4%) used losartan, 541 (9.0%) valsartan and 2149 (35.6%) candesartan at inclusion, respectively. 2887 (47.8%) were up-titrated at baseline (May-Jul 2010), followed by 2878 (48.2%) in the three months before the policy change (Aug-Oct 2010), and 2492 (43.7%) in the first months after the policy change (Feb-Apr 2011). Odds ratios for being up-titrated according to time period were 1.02 [0.95-1.09] in Aug-Oct 2010 (before policy change) and 0.84 [0.78-0.90] in Feb-Apr 2011 (after policy change), compared with May-Jul 2010 (reference)., Conclusion: Probability of being up-titrated in ARB treatment was reduced 20% following changes in drug reimbursement policies., (Copyright © 2014 John Wiley & Sons, Ltd.)

We assessed the cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for intermittent claudication due to peripheral arterial disease (PAD) in adults whose symptoms continue despite a period of conventional management. A Markov decision model was developed to assess the lifetime costs and benefits of each vasoactive drug compared to no vasoactive drug and with each other. Regression analysis was undertaken to model the relationship between maximum walking distance and utility. Resource use data were sourced from the literature and sensitivity analyses were undertaken. Naftidrofuryl oxalate is more effective and less costly than cilostazol and pentoxifylline and has an estimated cost per quality-adjusted life year gained of around £6070 compared to no vasoactive drug. The analysis uses effectiveness evidence from a network meta-analysis. In contrast to previous guidelines recommending cilostazol, the analysis suggests that naftidrofuryl oxalate is the only vasoactive drug for PAD which is likely to be cost-effective.

Objectives: Since treatment regimen type can influence adherence and other outcomes, this study examined adherence, cardiovascular events, and economic outcomes in patients with hypertension treated with fixed-dose combination (FDC) amlodipine/olmesartan (AML/OM), FDC AML/benazepril (AML/BEN), and loose-dose combination AML plus angiotensin II receptor blockers (LDC AML/ARBs)., Methods: Commercial health plan enrollees aged at least 18 years with index claim(s) for AML/OM, AML/BEN, or LDC AML/ARB were identified. Absence of study drug 6 months pre index, and continuous enrollment for at least 12 months post index were required. Descriptive analyses were executed to make comparisons between treatments, as well as multivariate models adjusting for baseline demographic and clinical characteristics, including propensity for assignment to study drug., Results: Descriptive results suggested mean follow-up adherence was higher in the AML/OM cohort [proportion of days covered (PDC) = 0.63] compared with the AML/BEN (PDC = 0.55; p < 0.001) and LDC AML/ARB cohorts (PDC = 0.34; p < 0.001). The proportion of individuals with an incident follow-up cardiovascular event composite was lower in the AML/OM cohort versus the AML/BEN and LDC AML/ARB cohorts (5.94% versus 7.85% and 16.89% respectively). Adjusted Cox models suggested that patients initiated on LDC AML/ARB (hazard ratio 1.35; p < 0.001), but not on AML/BEN, were at greater risk of a follow-up cardiovascular event (composite) compared with AML/OM. Adjusted generalized linear models suggested that mean follow-up per-member-per-month overall costs were higher in the AML/BEN (cost ratio = 1.169; p < 0.001; unadjusted mean cost US$780) and LDC AML/ARB cohorts (cost ratio = 1.286; p < 0.001; unadjusted mean cost US $1394) compared with the AML/OM cohort (unadjusted mean cost US $740)., Conclusion: The results suggested that treatment with FDC AML/OM was associated with greater likelihood of adherence and lower overall costs than with FDC AML/BEN and LDC AML/ARB, and lower risk of cardiovascular event composite versus LDC AML/ARB.

Background: Hypertension represents a major health problem, affecting more than one billion adults worldwide. Irbesartan, an angiotensin II receptor blocker, is considered to be a highly effective treatment in the management of hypertension. The purpose of this review is to evaluate the efficacy, safety and tolerability profile, and cost-effectiveness of treatment with irbesartan in hypertension., Methods: A review of the literature was conducted using the electronic PubMed and Cochrane Library databases and the Health Economic Evaluations Database of search terms relating to irbesartan efficacy, tolerability, and cost-effectiveness, and the results were utilized., Results: Findings from the present analysis show that irbesartan either as monotherapy or in combination with other antihypertensive agents can achieve significant reductions in blood pressure, both systolic and diastolic, compared with alternative treatment options. Irbesartan was also found to have a renoprotective effect independent of its blood pressure-lowering in patients with type 2 diabetes and nephropathy. Furthermore, irbesartan demonstrated an excellent safety and tolerability profile, with either lower or equal adverse events compared with placebo and other alternative treatments. In terms of economic analyses, compared with other antihypertensive therapy alternatives, irbesartan was found to be a preferred option, that is less costly and more effective., Conclusion: The evidence indicates that treating patients with hypertension alone or with type 2 diabetes and nephropathy using irbesartan can control hypertension, prolong life, and reduce costs in relation to existing alternatives.

We enrolled 196 patients with hypertension who were already being treated with free-drug combinations of angiotensin-II receptor blocker (ARB) and amlodipine. The free-drug combinations of ARB and amlodipine were replaced with the same dose of the fixed-dose combinations. The average home blood pressure (BP) in all patients receiving fixed-dose combinations was significantly lower than those receiving free-drug combinations (131 ± 10/75 ± 8 vs. 136 ± 11/77 ± 9 mm Hg, P < .01) accompanied with increasing drug adherence. After lowering BP by fixed-dose combinations, the costs for medications decreased by 31% over the 3 months.