Contemporary outpatient management of patients with worsening heart failure with reduced ejection fraction: Rationale and design of the CHART-HF study.

BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) and worsening HF events (WHFE) represent a distinct subset of patients with a substantial comorbidity burden, greater potential for intolerance to medical therapy, and high risk of subsequent death, hospitalization and excessive healthcare costs. Although multiple therapies have been shown to be efficacious and safe in this high-risk population, there are limited real-world data regarding factors that impact clinical decision-making when initiating or modifying therapy. Likewise, prior analyses of US clinical practice support major gaps in medical therapy for HFrEF and few medication changes during longitudinal follow-up, yet granular data on reasons why clinicians do not initiate or up-titrate guideline-directed medication are lacking. METHODS: We designed the CHART-HF study, an observational study of approximately 1,500 patients comparing patients with and without WHFE (WHFE defined as receipt of intravenous diuretics in the inpatient, outpatient, or emergency department setting) who had an index outpatient visit in the US between 2017 and 2019. Patient-level data on clinical characteristics, clinical outcomes, and therapy will be collected from 2 data sources: a single integrated health system, and a national panel of cardiologists. Furthermore, clinician-reported rationale for treatment decisions and the factors prioritized with selection and optimization of therapies in real-world practice will be obtained. To characterize elements of clinician decision-making not documented in the medical record, the panel of cardiologists will review records of patients seen under their care to explicitly note their primary reason for initiating, discontinuing, and titrating medications specific medications, as well as the reason for not making changes to each medication during the outpatient visit. CONCLUSIONS: Results from CHART-HF have the potential to detail real-world US practice patterns regarding care of patients with HFrEF with versus without a recent WHFE, to examine clinician-reported reasons for use and non-use of guideline-directed medical therapy, and to characterize the magnitude and nature of clinical inertia toward evidence-based medication changes for HFrEF.

Cost Effectiveness of Vericiguat for the Treatment of Chronic Heart Failure with Reduced Ejection Fraction Following a Worsening Heart Failure Event from a US Medicare Perspective.

OBJECTIVE: Given the high economic burden of disease among adult patients with chronic heart failure with reduced ejection fraction (HFrEF) following a worsening heart failure event in the US, this study aimed to estimate the cost effectiveness of vericiguat plus prior standard-of-care therapies (PSoCT) versus PSoCT alone from a US Medicare perspective. METHODS: A four-state Markov model (alive prior to heart failure hospitalization, alive during heart failure hospitalization, alive post-heart failure hospitalization, and death) was developed to predict clinical and economic outcomes, based on the results of the VICTORIA trial, in which patients with chronic HFrEF following a worsening heart failure were randomized to placebo or vericiguat, in addition to PSoCT, which consisted of ß-blockers, renin-angiotensin-aldosterone inhibitors, mineralocorticoid receptor antagonists, and the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan. Risks of heart failure hospitalization and cardiovascular mortality were based on multivariable regression models derived from VICTORIA data. Utilities were derived from VICTORIA EQ-5D data and the literature. Costs included drug acquisition, heart failure hospitalization, routine care, and terminal care. Primary outcomes included heart failure hospitalization, cardiovascular mortality, life-years, quality-adjusted life-years (QALYs), and incremental costs per QALY gained over a 30-year lifetime horizon, discounted at 3.0% annually. RESULTS: For the VICTORIA overall intent-to-treat population, compared with PSoCT, vericiguat plus PSoCT resulted in 19 fewer heart failure hospitalizations and 13 fewer cardiovascular deaths per 1000 patients, as well as 0.28 QALY gained per patient at an incremental cost of $23,322, leading to $82,448 per QALY gained. CONCLUSIONS: Based on the results of VICTORIA, patients treated with vericiguat had lower rates of heart failure hospitalization and cardiovascular death. The addition of vericiguat to PSoCT was estimated to increase QALYs and to be cost effective at a willingness-to-pay threshold of $100,000 per QALY gained.

Representativeness of the VICTORIA Trial Population in Clinical Practice: Analysis of the PINNACLE Registry.

BACKGROUND: In the VerICiguaT Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial, vericiguat reduced the risk of mortality due to cardiovascular problems and of hospitalization due to heart failure (HF) among patients with HF with reduced ejection fraction (HFrEF) and recent worsening HF events (WHFEs). The representativeness of the VICTORIA population of patients with WHFE in clinical practice is unknown. METHODS AND RESULTS: Patients with HF and ejection fraction <45% were identified in the Practice Innovation And Clinical Excellence (PINNACLE) registry and were stratified by the occurrence of WHFEs. Characteristics and outcomes of patients in the PINNACLE registry with and without WHFEs were compared to the VICTORIA population. Of the 14,180 PINNACLE patients identified with HFrEF, 26.5% had had a WHFE. The VICTORIA population was similar to PINNACLE patients with WHFEs in mean age (67.3 vs 66.7), ejection fraction (28.9% vs 28.3%), body mass index (26.8 vs 27.6), and comorbidity burden. The rate of hospitalization because of HF at 1 year was 29.6% in the placebo group of VICTORIA, compared to 35.8% in PINNACLE patients with WHFEs and 13.3% in patients without WHFEs. CONCLUSIONS: The PINNACLE patients with WHFEs meeting the VICTORIA definition resembled the VICTORIA population in characteristics and outcomes, suggesting that VICTORIA's population may be generalizable to patients with WHFEs in clinical practice.

Treatment patterns and clinical outcomes among patients <65 years with a worsening heart failure event.

AIMS: Data regarding patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF) following a worsening HF event (WHFE) are largely driven by findings from elderly patients. Younger patients are not well studied. The aim of this study was to evaluate treatment patterns and clinical outcomes in commercially insured chronic HFrEF patients <65 years old during 1-year periods before and after a WHFE. METHODS AND RESULTS: A retrospective claims analysis was performed using the IBM® MarketScan® Commercial Database on HFrEF patients aged <65 years during the year before and after a WHFE, defined as HF hospitalization or outpatient intravenous diuretic use. Treatment patterns, rehospitalizations, health care resource utilization, and costs were assessed. A total of 4460 HFrEF patients with WHFE were included. Guideline-recommended HF therapy was initially underutilized, increased pre-WHFE, and peaked 0-3 months post-WHFE. The proportions of patients using dual and triple therapy were 31.5% and 9.8% pre-WHFE, 41.5% and 17.4% 0-3 months post-WHFE, and 34.6% and 13.9% 10-12 months post-WHFE, respectively. Within 30 and 90 days after a WHFE, 12% and 23% of patients had HF-related and 16% and 30% had all-cause rehospitalizations, respectively. HF-related and all-cause hospitalizations and outpatient visits peaked 0-3 months post-WHFE, whereas emergency department visits peaked 0-3 months pre-WHFE. CONCLUSIONS: Use of HF medications increased pre-WHFE but decreased post-WHFE, despite recurrent hospitalizations. These findings suggest that age and insurance status may not totally explain the suboptimal treatment of HFrEF patients before and after a WHFE. Reasons for these trends need further study.

Budget Impact Analysis of Vericiguat for the Treatment of Chronic Heart Failure with Reduced Ejection Fraction Following a Worsening Event.

INTRODUCTION: In the USA, patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) following a worsening HF event (WHFE) have significantly increased healthcare resource use and medical costs. This analysis aimed to estimate the budget impact of vericiguat as an add-on therapy to guideline-directed medical therapy (GDMT) for the treatment of chronic HFrEF following a WHFE from a US commercial payer perspective. METHODS: A model was developed to estimate the budget impact of adding vericiguat to the formulary by comparing a current scenario (GDMT) and a new scenario (vericiguat plus GDMT) to a hypothetical 10-million-member commercial payer over a 3-year time horizon. Epidemiology data was obtained from literature. Treatment utilization rates of GDMT and clinical inputs (HF hospitalization and cardiovascular [CV] morality) were based on the VICTORIA trial in which patients with chronic HFrEF following a WHFE were randomized to GDMT plus placebo or GDMT plus vericiguat. Costs (2020 US$) included drug acquisition, hospitalization, routine care, and mortality. RESULTS: Approximately 20,510 prevalent cases in year 1 and 3109 annual incident cases in subsequent years were estimated to be eligible for treatment with vericiguat. At a utilization rate of 5%, 10%, and 15% for vericiguat over years 1-3, the per member per month (PMPM) budget impact was estimated to be $0.048, $0.064, and $0.086, respectively, associated with 44, 32, and 30 fewer HF hospitalizations and 7, 12, and 18 fewer CV deaths, respectively. Reduction in HF hospitalizations and CV deaths reduced the budget impact by 14% in total over 3 years. CONCLUSION: Adding vericiguat to commercial plan formulary was associated with limited budget impact, primarily driven by drug acquisition costs but partially offset by reduced cost of HF hospitalizations and CV deaths.

Quality outcomes, healthcare resource utilization and costs in Medicare patients with chronic heart failure with reduced ejection fraction with and without a worsening event.

AIMS: The study compared quality outcomes, resource utilization, and costs in Medicare beneficiaries with chronic heart failure with reduced ejection fraction (HFrEF) with and without a worsening heart failure event (WHFE). METHODS: This retrospective observational study evaluated claims data for two cohorts of Medicare beneficiaries with chronic HFrEF who were enrolled in Medicare fee-for-service (FFS) or Medicare advantage (MA) plans. The index date was the first claim of HFrEF between October 2015 and September 2017. Patients with WHFE were identified if they had IV diuretic use or hospitalization for HF during 12 months after index date; with remaining patients classified as non-WHFE. During follow-up, starting from the 13th month after HFrEF index date to end of follow-up, generalized linear models were used to adjust for patient characteristics to compare mean per patient per year (PPPY) quality outcomes, resource utilization, and costs between HFrEF patients with and without WHFE. RESULTS: Of the 1,182,509 FFS and 28,645 MA patients with HFrEF, 34.2% and 32.5% developed WHFE, respectively. Compared to patients without WHFE, patients with WHFE had higher rates of all-cause 30-day readmissions (FFS: 42% vs. 31%; MA: 41% vs. 31%), hospitalizations (FFS: 2.27 vs. 1.36; MA: 1.47 vs. 0.78 PPPY) and ED visits (FFS: 1.82 vs. 1.25; MA: 1.43 vs. 0.96 PPPY); all comparisons p < .05. Mortality rates in FFS patients were higher among patients with WHFE (34.3%) compared to those without (23.4%). All-cause total PPPY costs were higher for patients with WHFE compared to those without by $20,825 in FFS and $15,974 in MA. Similar trends were observed for HF-related outcomes. CONCLUSION: Medicare patients with chronic HFrEF experiencing a WHFE had worse quality outcomes as well as higher resource utilization and costs compared to those without WHFE, thus, suggesting the need for better treatments and interventions to manage these patients.

Clinical and Economic Burden of Chronic Heart Failure and Reduced Ejection Fraction Following a Worsening Heart Failure Event.

INTRODUCTION: A worsening heart failure event (WHFE) is defined as progressively escalating heart failure signs/symptoms requiring intravenous diuretic treatment or hospitalization. No studies have compared the burden of chronic heart failure with reduced ejection fraction (HFrEF) following a WHFE versus stable disease to inform healthcare decision makers. METHODS: A retrospective study using the IBM® MarketScan® Commercial Database included patients younger than 65 years of age with HFrEF (one inpatient or two outpatient claims of systolic HF or one outpatient claim of systolic HF plus one outpatient claim of any HF). The first claim for HFrEF during 2016 was the index date. Patients were followed for the first 12 months after the index date (the worsening assessment period) to identify a WHFE, and for an additional 12 months or until the end of continuous enrollment (the post-worsening assessment period). Mean per patient per month (PPPM) health care resource use (HCRU) and costs were compared between patients following a WHFE and stable patients during the two periods using generalized linear models adjusting for patient characteristics. RESULTS: Of 16,646 patients with chronic HFrEF, 26.8% developed a WHFE. Adjusted all-cause hospitalizations (0.16 vs. 0.02 PPPM, P < 0.0001), outpatient visits (3.54 vs. 2.73 PPPM, P < 0.0001), and emergency department visits (0.25 vs. 0.06 PPPM, P < 0.0001) were higher in patients following a WHFE than stable patients during the worsening assessment period. Similar differences in HCRU were observed between the two cohorts during the post-worsening assessment period. Mean total adjusted cost of care PPPM was $8657 in patients with HFrEF following a WHFE versus $2195 in stable patients during the worsening assessment period, and $6809 versus $2849, respectively, during the post-worsening assessment period. CONCLUSION: HCRU and costs were significantly greater in patients with chronic HFrEF following a WHFE compared to those who remained stable, suggesting an unmet need to improve clinical and economic outcomes among these patients.

Cost-Effectiveness of Aspirin Adherence for Secondary Prevention of Cardiovascular Events.

BACKGROUND: Suboptimal adherence to aspirin therapy for secondary prevention of cardiovascular (CV) events is an important public health problem. Prior studies have demonstrated non-adherent patients are at higher risk of experiencing CV events. OBJECTIVES: This study aimed to estimate the clinical and economic outcomes of aspirin non-adherence in patients with a prior primary CV event. METHODS: We developed a Markov model to estimate the cost-effectiveness of aspirin adherence from a generic US managed care payer perspective over a 5-year time horizon. Costs, utilities and rates of aspirin adherence, CV events and adverse events were gathered from published literature to populate the model. Outcomes were quality-adjusted life years (QALYs), costs (US$) and incremental cost-effectiveness ratios (ICERs). We applied the model separately to a population without type II diabetes as a comorbidity (non-diabetic model) and a population with type II diabetes (type II diabetes model). A one-way sensitivity analysis was performed to assess the model uncertainty. RESULTS: The base case showed adherent patients lived 0.25 and 0.36 QALYs longer than non-adherent patients in the non-diabetic model and type II diabetes model, respectively. Adherence to aspirin had an ICER of US$25/QALY in the non-diabetic population, while it saved US$297 per patient over a 5-year period in the type II diabetes population. One-way sensitivity analysis showed the models were most sensitive to rates of non-fatal events in non-adherent patients. CONCLUSION: This study suggests aspirin adherence may improve QALYs for patients with a prior primary CV event. Further, it may decrease costs in patients with type II diabetes. While additional research is needed to validate these results, payers may wish to increase strategies to promote adherence in order to improve population health. TRIAL REGISTRATION: Not applicable.

Evaluating Oncology Value-Based Frameworks in the U.S. Marketplace and Challenges in Real-World Application: A Multiple Myeloma Test Case.

BACKGROUND: With the continuous rise in costs for oncology drugs, the American Society of Clinical Oncology (ASCO), the Institute for Clinical and Economic Review (ICER), the Memorial Sloan Kettering Cancer Center's Drug Abacus (DrugAbacus), and the National Comprehensive Cancer Network (NCCN) have developed value-based frameworks (VBFs) to assist stakeholders in formulary and treatment decision-making processes. Since emerging VBFs have the potential to affect available treatment options for patients, it is important to understand the differences associated with these VBFs within various therapeutic areas. OBJECTIVES: To (a) compare VBFs across 3 therapeutic options for relapsed or refractory multiple myeloma (RRMM) and (b) identify challenges and limitations associated with real-world decision making using VBFs in the U.S. marketplace. METHODS: The values of regimens carfilzomib (CFZ), elotuzumab (ELO), and ixazomib (IX) were generated using the ASCO, NCCN, ICER, and DrugAbacus VBFs. These regimens, used for second- or third-line treatment of RRMM, shared a common comparator in clinical trials: lenalidomide + dexamethasone (LEN + DEX). ASCO's 2016 VBF, which incorporated clinical benefit, toxicity, and bonus points, was used to generate a net health benefit score, along with the drug wholesale acquisition cost, for each regimen compared with LEN + DEX. Results of the 2016 NCCN Evidence Blocks for multiple myeloma and the ICER 2016 report of treatment options for RRMM were extracted to generate the value of CFZ, ELO, and IX. No output was generated from DrugAbacus because of the lack of regimens included in the test case. Shortcomings associated with running the test case in RRMM for each VBF were also identified. RESULTS: Among the 3 therapeutic agents, CFZ, in combination with LEN + DEX, was the most valued. ASCO and ICER VBFs suggested that CFZ + LEN + DEX may be the most valued, followed by ELO + LEN + DEX and IX + LEN + DEX. NCCN suggested that LEN + DEX may be the most valued followed by CFZ + LEN + DEX, IX + LEN + DEX, and ELO + LEN + DEX. A number of shortcomings were noted across each VBF, such as complexities of drug evidence evaluation with the ASCO VBF, the inability to adjust the ICER and NCCN VBFs to specific populations, and subjectivity associated with the NCCN VBF and DrugAbacus. CONCLUSIONS: Although the test case provided some consensus on treatment decisions, there is much nuance and limitations with the VBFs available for RRMM. Clearer objectivity and better adaptability to specific treatment decisions are warranted. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. All authors contributed to study concept and design, as well data collection and interpretation. Djatche and Goble wrote and revised the manuscript, along with Chun and Varga. Portions of this work have previously been presented at the AMCP Managed Care and Specialty Pharmacy Annual Meeting 2017 in Denver, Colorado, March 27-30, 2017, and at the ISPOR 22nd Annual International Meeting in Boston, Massachusetts, May 20-24, 2017.