The United States has an increasing number of patients with heart failure (HF) who experience significant disease burden as well as contribute to high economic healthcare costs and usage of healthcare resources. HF costs are currently estimated at $30.7 billion. If no improvements are made to current treatment outcomes, it is expected to grow to $69.8 billion by the year 2030. Hospital admissions account for the driving factor of direct medical costs. There has been increased focus on decreasing HF-related hospital readmission rates in the United States for the past decade; however, few interventions have positively affected hospital readmission rates. Some transitional care programs have been successful at positively affecting readmissions, though not all programs have demonstrated improvement of end points. These mixed program outcomes show the importance of evaluating HF-related transitional care program components for future directions. Newly approved treatments for HF with preserved ejection fraction may improve clinical outcomes for these patients. Pharmacists and physicians can help improve access to HF medications by assisting patients on how to navigate manufacturer assistance programs, submitting complete and well-supported prior authorization forms when needed, and encouraging the use of pharmacy price matching and price checkers.
Am J Manag Care. 2021;27(suppl 9):S191-S195. https://doi.org/10.37765/ajmc.2021.88673
The burden of heart failure (HF) in the United States is considerable. In 2012, total costs for HF were estimated to be $30.7 billion, with two-thirds attributed to direct medical costs.1 Without improvements to the cost of care by the year 2030, costs are predicted to reach $69.8 billion (127% increase). This equates to approximately $244 for each US adult.1 This projected increase is due to an aging population and epidemiologic factors such as obesity, hypertension, diabetes mellitus, and coronary artery disease.2 In addition to the overall rise in number of HF cases, the complexity of the disease appears to be increasing as more comorbidities generally lead to more clinical events and hospitalizations for both HF and other causes.3
Incidence of HF increases with age and is associated with poor mortality, as older adults diagnosed with HF have a 5-year mortality approaching 50%.4 In 2014, HF was the primary cause of 1.1 million emergency department (ED) visits, 1 million hospitalizations, and 84,000 deaths.4 HF was a comorbidity or contributing cause in an additional 4.1 million ED visits, 3.4 million hospitalizations, and 231,000 deaths and was associated with significantly higher costs compared with patients without HF as a listed comorbidity.4 In 2014, the estimated mean cost of HF hospitalizations was $11,552, with a total estimated cost of more than $11 billion.4 Although HF greatly affects older adults, the costs are also significant when treating HF comorbidities and HF exacerbations in younger populations, totaling $1 billion in inpatient costs, which may be rising.1
A 2020 systematic review across HF literature in the United States between 2014 and 2020 aimed to assess the quality of published evidence and provide a narrative synthesis of current data. The review found that the median cost for HF-specific hospitalizations was $13,418 (interquartile limit [IQL], $11,125-$15,667) per patient. Patients with comorbidities had a slightly higher cost at $14,015 (IQL, $11,769-$20,373).5 The 30-day post-discharge cost following a worsening HF admission was estimated at $6283 per patient. A patient readmitted over a 30-day period following an HF hospitalization showed an estimated cost of $15,732 per patient in the same hospital and $25,879 per patient at a different hospital. Average annual outpatient healthcare costs were estimated at $8487 for medical/surgical, $2178 for diagnostic costs, $550 for behavior costs, $2904 for pharmacy costs, and $973 for other costs. The median cost per ED visit was $1441 (IQL, $829-$1933). The annual estimated cost for patients with home healthcare was $2227 per patient per year. Based on median data, HF hospitalizations contributed to 65% of all medical HF costs over a 1-year treatment period post hospitalization.5
In addition to direct medical costs, it is important to evaluate the social care costs. Absenteeism, presenteeism, and informal care are all indirect costs from the physical and social limitations experienced by HF patients. These factors present a significant disease burden for patients and their families. The total loss of earnings attributed to HF morbidity and mortality is estimated at $12.4 billion for 2020 in the United States. One-third of patients also often need informal care of approximately 45 hours per week. The estimated annual cost of informal care is $836 per patient. This systematic review highlights the disease burden and high healthcare usage of patients with HF.5
In general, the overall costs associated with heart failure with reduced ejection fraction (HFrEF) is well known compared with patients diagnosed with heart failure with preserved ejection fraction (HFpEF). A study in Germany and Australia focused on assessing total costs in a young cohort of patients with HFpEF including medications, number of primary care and specialist visits, and hospitalizations. This analysis suggested that economic burden is typically lower than anticipated in the HFpEF population because the prevention and treatment of comorbidities early on can reduce costs.6
HF is a progressive condition with poor outcomes leading to at least 1 million hospitalizations every year, with more than half of those patients being readmitted and 30% dying within 1 year.7 A recent cohort suggests hospitalizations may be on the rise. A 2021 analysis evaluated hospital admissions between January 2010 and December 2017 and found the rate of overall hospitalizations, unique patient hospitalizations, and post-discharge HF readmissions declined between 2010 and 2014 but showed an increase between 2014 and 2017.8 As hospitalizations are a major contributor to increased healthcare usage and poorer clinical outcomes, this recent finding supports the continued need to evaluate which HF therapies and treatment strategies have demonstrated improved quality measures.
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) were previously the mainstays of therapy due to their improved clinical outcomes until 2015, when a first-in-class therapy was introduced to the market.2 Sacubitril/valsartan contains a neprilysin inhibitor and ARB and is used in patients with New York Heart Association (NYHA) functional class II to IV symptoms.2 Sacubitril/valsartan trials have shown its ability to reduce risk of cardiovascular death and first HF hospitalizations among patients with HFrEF by 20% compared with traditional ACEI therapy with enalapril.2
To evaluate the real-world efficacy outside of a traditional trial setting, a 2019 study aimed to compare hospitalization and healthcare costs among stable patients with HFrEF treated with sacubitril/valsartan versus traditional ACEI or ARB therapy in clinical practice. This retrospective study was conducted using claims data from October 1, 2014 to September 30, 2016, from a large population representative database containing de-identified medical and pharmacy claims data and linked enrollment information for individuals enrolled in US commercial and Medicare Advantage health plans. This analysis found that the mean standard deviation (SD) number of post-index per-patient per-month (PPPM) hospitalizations was lower in the sacubitril/valsartan versus the ACEI/ARB cohort for HF hospitalizations (0.01 [0.06] vs 0.03 [0.10]; P = .003) and all-cause hospitalizations (0.05 [0.11] vs 0.11 [0.20]; P <.001). In addition to lower hospitalizations, the sacubitril/valsartan was also associated with lower hospital costs. Patients treated with ACEI/ARB versus sacubitril/valsartan had mean (SD) PPPM costs that were more than 4 times higher for HF hospitalization ($1122 [$7290] vs $248 [$1588]; P = .048) and more than 3 times higher for all-cause hospitalization ($2770 [$9189] vs ($810 [$2921]; P <.001).2
Patients who decline and develop a worsening HF event (WHFE), such as escalating HF signs or symptoms requiring intravenous diuretic therapy in the outpatient setting or hospitalization, have higher rates of recurrent HF hospitalizations and mortality.7 A 2020 study evaluated the healthcare resource usage and healthcare costs in patients with chronic HFrEF following a WHFE versus those with a chronic HFrEF who remain stable. The retrospective study used claims from IBM MarketScan Commercial and Medicare Supplemental databases from January 1, 2015 to December 31, 2018. An HFrEF index date was identified and evaluated patients 12 months before this date and continued to follow them 12 months after to identify WHFEs based on the presence of HF-related hospitalization and/or intravenous diuretic use. The study found that the adjusted mean total HF-related cost of care PPPM during the worsening assessment period was $383 ± $1064 for patients with stable chronic HFrEF and $3647 ± $7636 for patients with chronic HFrEF following a WHFE (P <.0001). The mean total all-cause cost of care PPPM was $2195 ± $4572 for patients with stable chronic HFrEF and $8657 ± $13,150 for patients with chronic HFrEF following a WHFE (P <.0001). Hospitalizations were the primary driver in all-cause costs for patients with chronic HFrEF following a WHFE, while the main driver in all-cause costs was outpatient visits for those patients with stable chronic HFrEF.7 This study highlights the need to improve outcomes of patient with chronic HFrEF following a WHFE.
In an effort to address the lack of studies demonstrating improvement in mortality in patients with HFpEF, a 2018 systematic review and meta-analysis aimed to review the clinical trials and identify treatment effects on mortality, HF hospitalization, functional status, and biomarkers in this patient population.9 The review included 25 randomized controlled trials between January 1996 and May 2016 and comprised data for 18,101 patients. It found that all-cause mortality was reduced with β-blocker therapy compared with placebo (RR, 0.78; 95% CI, 0.65-0.94; P = .008). No effect was demonstrated with ACEIs, aldosterone receptor blockers, mineralocorticoid receptor antagonists, or other drug classes when compared with placebo. No drug class demonstrated a reduction in HF hospitalizations when compared with placebo.9 This review reveals the difference of treatment efficacies among patients with HFrEF and HFpEF.
HF is the leading cause of hospitalizations among older adults, and Medicare beneficiaries with HF have the highest readmission rate of any condition.4 Approximately one-quarter of patients hospitalized with HF are readmitted within 30 days of discharge, and mortality rates of those patients within the first year after hospital discharge approach 30%.10 With a worldwide prevalence of 26 million patients with HF, there is a critical need for global attention, research, and quality improvement initiatives to improve the quality of care and clinical outcomes for the HF population.10 In response, the United States focused on efforts to reduce preventable readmissions. Hospital HF readmissions are a priority quality measure because reimbursement policies such as the Hospital Readmissions Reduction Program were implemented to incentivize hospitals to reduce readmission rates by decreasing Medicare reimbursement for hospitals with higher than predicted readmissions rates.11 Despite this increased focus on readmissions and resulting reimbursement incentive, a 2016 study that evaluated HF readmissions found no statistically significant change in 30-day mortality rates between 2009 (7.8%) and 2012 (7.6%; P = .71).11
To combat the lack of successful interventions, a 2018 observational qualitative study aimed to uncover the reason for poor HF readmission rates from the patient perspective. Understanding the patient and caregiver challenges to HF home management and perceived reasons for readmissions may provide insight to address these gaps in care. The study included patients with HF from 2 hospitals and included those hospitalized for HF at least twice within 30 days and those who had been recently discharged after their first HF admission. The patients participated in open-ended, semi-structured interviews. Two major themes were discovered, the home management as a struggle between adherence and adaptation, and hospital readmission as a rational choice in response to distressing symptoms. Discharge instructions were provided to patients, but they reported adapting, rather than adhering, to the recommendations. One reason for adapting included uncertainty regarding the recommendations for diet, fluid management, and physical activity and patients reported they would have benefited from more knowledge about the disease process and anticipatory guidance. Some patients reported comorbidities contributed an additional obstacle by difficulties consolidating their medications and different diet instructions provided by different providers. Socioeconomic factors also contributed as patients with limited resources made medication decisions based on what medications or food they were able to afford. Some patients also reported feelings of hopelessness from perceived lack of progress despite medication adherence. These cyclic feelings of despair affected their home management by decreased adherence, worsening symptoms, and intensification of negative emotions. Patients also reported frustration with their limitations and restrictions including dependence on others to perform activities of daily living, difficulty leaving their homes due to decreased physical capacity, or frequent urination caused by diuretics. The other main theme of readmission as a rationale choice was often a joint decision made between patients and their families. This was mainly due to difficulty in distinguishing symptoms that were truly life-threatening with those that could be safely managed at home. Readmission was regarded as the safest choice and not viewed as a negative action.12 This study helps to identify educational gaps and reveals the need for better care-coordination to truly impact hospital readmission rates and resulting clinical outcomes.
Additional avenues are being explored and implemented including care coordination and transition programs, such as those that facilitate the hospital-to-home transition and provide in-home aftercare.4 These referral programs have been associated with slightly lower (1%) relative 30-day risk adjustment readmission rates.11 A recent successful transitional program was implemented at the Phoenix VA Medical Center. The multidisciplinary program was implemented to encourage early post-discharge hospital follow-up in patients with HF and included new clinical slots, predischarge nurse visits that provided blood pressure cuff and scale, and cardiologist supervision. To determine success of the program, they compared a proportion of patients in both groups who were scheduled for and completed a cardiology appointment within 7 days after hospitalization. A Cox model evaluated effectiveness during the intervention period of 30-day composite outcomes including all-cause ED visits, all-cause hospitalizations, or death. Data for 261 patients were analyzed. The study found that after adjusting for significant clinical predictors (non-White ethnicity, left ventricular ejection fraction ≤40%, hemoglobin, systolic blood pressure, BNP [log]; P <.1 with outcome), the postintervention period was associated with a reduced hazard of the 30-day composite end point (HR, 0.59; 95% CI, 0.37-0.96; P = .04).13 They also found that the program was associated with a 3.3 times higher rate of referral for 7-day HF follow-up as well as observed a 41% lower risk of ED visits, rehospitalizations, or death during the intervention period.13
It is important to evaluate the individual measures of transitional care programs as not all programs have been deemed successful. A 2020 retrospective cohort study examined the association of individual HF-transitional care program components and their bundle with the primary outcomes of all-cause 30-day inpatient or observation stay readmission.14 It reviewed inpatient encounters for HF at 13 Kaiser Permanente Southern California hospitals between January 1, 2013 and October 31, 2018, who were followed up from discharge until 30 days, readmission, or death. The program included a home health visit or telehealth visit from a registered nurse within 2 days of hospital discharge, an HF care-manager call within 7 days, and a clinic visit with a physician or nurse practitioner within 7 days. They found the 30-day readmission rate to be 18.1%. Both the home health visit within 2 days of discharge (HR, 1.03; 95% CI, 0.96-1.10) and the 7-day HF case-manager call (HR, 1.08; 95% CI, 0.99-1.18) were not associated with a lower rate of admission when compared with no call or visit. However, the completion of a 7-day clinic visit was found to be associated with a lower readmission rate (HR, 0.88; 95% CI, 0.81-0.94) when compared with no clinic visit. There were no synergistic effects of all 3 components compared with a clinic visit alone (HR, 1.05; 95% CI, 0.87-1.28).14 This study demonstrates the need to continually evaluate what components make a successful transitional care program to improve overall quality of care and positively impact HF-related hospital readmissions for future endeavors.
Evaluating Place of Therapy for New Agents for Heart Failure and Patient Access
One recent major breakthrough in the treatment of HF is that the 2021 update to the 2017 Expert Consensus Decision Pathway ACC Guidelines now recommend therapy with an angiotensin receptor-neprilysin inhibitor (ARNI) even for patients who have not been previously treated with an ACEI/ARB.15 These recommendations are due to favorable study results in patients with newly diagnosed HF who were initially started on ARNI therapy experiencing a greater reduction in natriuretic peptide concentration, comparable safety data, and significant improvements in early clinical outcomes when compared with enalapril.15 Another inclusion to the recent ACC update was recognizing the approval of a sodium-glucose cotransporter-2 (SGLT2) inhibitor and adding the class to the armamentarium of medications available for the treatment of patients with HFrEF. Dapagliflozin has demonstrated a reduction in cardiovascular death and HF hospitalization in patients with and without type 2 diabetes. Empagliflozin also demonstrated a reduction in HF hospitalization/cardiovascular death in patients with HFrEF with and without diabetes. In recognition of these advances, the guidelines recognize a beneficial class effect in patients with HFrEF. The updated treatment algorithm recommends SGLT2 inhibitors as add-on therapy for patients already on an ARNI/ACEI/ARB, an evidence-based β-blocker, and as-needed diuretic agents for patients meeting estimated glomerular filtration rate criteria with NYHA class ll to IV.15
In addition to the change in treatment recommendations are suggestions for managing costs and access to HF medications. Medications are the second most important cost for patients with HF after hospital costs, accounting for 15.6% of direct costs.15 The guidelines recommend a variety of cost containment measures to support patients with this significant financial burden. Prescribers should be aware of patient insurance and potential limitations when determining the most appropriate medication therapies. Using generic medications whenever possible is one strategy for reducing costs. Common generic HF drugs include digoxin, β-blockers, ACE inhibitors, and ARBs. Patients may be incentivized to “shop around” for the best priced generic medications; however, this could have negative health implications when a single pharmacy is not overseeing a patient’s medications to be able to account for potential drug–drug and drug–disease interactions. Pharmacists, social workers, and physicians should work together to identify co-pay assistance programs, encourage pharmacy price matching, and using online price checkers to encourage patients to use a single pharmacy and identify which pharmacy offers the best pricing for patients’ medications.15
The ACC 2021 update also addresses medication access to new HF therapies. Newer therapies for HFrEF are costly and often entail higher monthly co-payments and more steps may be involved in the process of obtaining them. For example, prior authorizations may be required that could be perceived as a potential barrier of initiating a therapy the prescriber feels most appropriate for a patient. Providing all the necessary information that supports the use of the requested medication in the selected patient and including clinical evidence and relevant patient-specific factors will reduce the risk of multiple correspondences with the payer that will delay medication initiation. Patient assistance programs are also available for newer agents. Pharmacists can help patients navigate through the usage management process and manufacturer assistance programs to help improve access to these therapies. If a patient has no income to provide as a requirement for assistance programs, many agencies accept a signed letter from the clinician indicating the patient has no known income, though this option is often not clearly apparent on manufacturer websites or materials.15
In February 2021, the FDA approved sacubitril/valsartan for a new indication to treat patients with HFpEF. This marks the first approved therapy for this population. Previous therapy had been aimed at symptom management and treatment of comorbidities. This approval comes from the FDA’s Cardiovascular and Renal Drugs Advisory Committee after reviewing results from the PARAGON-HF trial where sacubitril/valsartan fell just short of meeting the primary end point. The committee found it was worthy of some indication based on trial results.16 It is still to be determined what impact this will have on clinical practice as this is not part of the current guidelines; however, this approval does have promise if additional studies demonstrate improvement in quality measures and similar cost-effectiveness as demonstrated in patients with HFrEF.
Additionally, in January 2021, the FDA approved vericiguat, a first-in-class soluble guanylate cyclase stimulator, for HFrEF. A phase 3 trial included 5050 patients with NYHA class ll, lll, or IV with an ejection fraction of less than 45%. Patients were assigned to placebo or vericiguat treatment groups and followed for the primary outcome of composite death from cardiovascular causes or first hospitalization for HF. For the median follow-up period of 10.8 months, death from cardiovascular causes or first hospitalization for HF occurred in 897 patients (35.5%) in the vericiguat group versus 972 patients (38.5%) in the placebo group (HR, 0.90; 95% CI, 0.82-0.98; P = .02).17 This emerging treatment will add an additional pathway to consider when evaluating treatment options for patients. The growing number of target and therapy lists may add complication to HF treatment management for both patients and care teams. It is important for healthcare decision makers to continue to make guideline-directed medical therapy the foundation of HF care, and the therapy with the highest expected benefit, based on large randomized trials, shall be prioritized for HFrEF.15 This includes ARNIs, evidence-based β-blockers, aldosterone antagonists, and SGLT2 inhibitors for all populations. Additional first-line therapies may also be considered such as hydralazine/isosorbide dinitrate for self-identified African Americans and ivabradine as a second-line medication for select populations where an individual has a resting heart rate greater than or equal to 70 beats per minute in sinus rhythm despite maximally tolerated β-blocker therapy.15
HF contributes a significant disease and economic burden to the United States. Its prevalence is on the rise with the growing aging population. These patients often have multiple comorbidities that contribute to treatment complexity and create obstacles in patient home health management. Even with a focus on readmissions and implementation of programs to incentivize hospitals to meet 30-day readmission benchmarks, hospitals are still challenged at developing solutions to effectively target hospital readmissions and improve clinical outcomes. Some transitional care programs have shown to be successful, while others have not, which demonstrate the continued need to identify the most impactful components of programs for program replication. In 2015 the introduction ofsacubitril/valsartan changed the current landscape of disease treatment and has shown favorable disease and economic outcomes. However, more novel therapies are needed in order to continue to impact the treatment landscape of HF and change the current trajectory of HF prevalence and growth trends in the United States and globally.
Author affiliation: Jeenal Patel, PharmD, BCGP, is the associate director of Formulary Design and Strategy, Oscar Health, New York, NY.
Funding source: This activity is supported by an educational grant from Merck Sharp & Dohme Corp.
Author disclosure: Dr Patel has no relevant financial relationships with commercial interests to disclose.
Author information: Concept and design; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; provision of study materials; and final approval of manuscript.
Address correspondence to: email@example.com
Medical writing and editorial support provided by: Jenna Wood, PharmD
1. Benjamin E, Muntner P, Alonso A, et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2019 update: a report from the American Heart Association. Circulation. 2019;139(10):e56-e528. doi: 10.1161/CIR.0000000000000659
2. Albert N, Swindle J, Buysman E, Chang C. Lower hospitalization and healthcare costs with sacubitril/valsartan versus angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker in a retrospective analysis of patients with heart failure. J Am Heart Assoc. 2019;8(9):e011089. doi: 10.1161/JAHA.118.011089
3. von Lueder TG, Agewall S. The burden of heart failure in the general population: a clearer and more concerning picture. J Thorac Dis. 2018;10(suppl 17):S1934-S1937. doi: 10.21037/jtd.2018.04.153
4. Jackson S, Tong X, King RJ, Loustalot F, Hong Y, Ritchey MD. National burden of heart failure events in the United States, 2006 to 2014. Circulation. 2018; 11:e004873. doi: 10.1161/CIRCHEARTFAILURE.117.004873
5. Urbich, M, Globe, G, Pantiri K, et al. A systematic review of medical costs associated with heart failure in the USA (2014–2020). Pharmacoeconomics. 2020;38(11):1219-1236. doi: 10.1007/s40273-020-00952-0
6. Hashemi D, Dettmann L, Trippel TD, et al. Economic impact of heart failure with preserved ejection fraction: insights from the ALDO-DHF trial. ESC Heart Fail. 2020;7(3):786-793. doi: 10.1002/ehf2.12606
7. Butler J, Djatche LM, Sawhney B, et al. Clinical and economic burden of chronic heart failure and reduced ejection fraction following a worsening heart failure event. Adv Ther. 2020;37(9):4015-4032. doi: 10.1007/s12325-020-01456-1
8. Agarwal MA, Fonarow GC, Ziaeian B. National trends in heart failure hospitalizations and readmissions from 2010 to 2017. JAMA Cardiol. Published online February 10, 2021;e207472. doi: 10.1001/jamacardio.2020.7472
9. Zheng SL, Chan FT, Nabeebaccus AA, et al. Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Heart. 2018;104(5):407-415. doi: 10.1136/heartjnl-2017-311652
10. Smith SC Jr, Fonarow GC, Zhao D. Measuring and improving the quality of heart failure care globally. JAMA Netw Open. 2020;3(1):e1918642. doi: 10.1001/jamanetworkopen.2019.18642
11. Bergethon KE, Ju C, DeVore AD, et al. Trends in 30-day readmission rates for patients hospitalized with heart failure: findings from the Get With the Guidelines-Heart Failure Registry. Circ Heart Fail. 2016;9(6):10.1161/CIRCHEARTFAILURE.115.002594 e002594. doi: 10.1161/CIRCHEARTFAILURE.115.002594
12. Sevilla-Cazes J, Ahmad FS, Bowles KH, et al. Heart failure home management challenges and reasons for readmission: a qualitative study to understand the patient’s perspective. J Gen Intern Med. 2018;33(10):1700-1707. doi: 10.1007/s11606-018-4542-3
13. Dev S, Fawcett J, Ahmad S, Wu WC, Schwenke D. Implementation of early follow-up care after heart failure hospitalization. Am J Manag Care. 2021;27(2):e42-e47. doi: 10.37765/ajmc.2021.88588
14. Baecker A, Meyers M, Koyama S, et al. Evaluation of a transitional care program after hospitalization for heart failure in an integrated health care system. JAMA Netw Open. 2020;3(12):e2027410. doi: 10.1001/jamanetworkopen.2020.27410
15. Maddox TM, Januzzi JL Jr, Allen LA, et al; Writing Committee. 2021 Update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021;77(6):772-810. doi: 10.1016/j.jacc.2020.11.022
16. Caffrey M. Entresto wins first FDA nod in hard-to-treat type heart failure. Am J Manag Care. February 16, 2021. Accessed March 7, 2021. ajmc.com/view/entresto-wins-first-fda-nod-in-hard-to-treat-type-of-heart-failure
17. Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med. 2020;382(20):1883-1893. doi: 10.1056/NEJMoa1915928