Therapeutic advances in guideline‐directed medical therapy for heart failure: the idealistic versus the pragmatic truth for vulnerable patients

KEYWORDS:

• Heart failure
• HfrEF
• guided directed medical therapy
• Medicaid
• Medicare

We believe that the words of the British writer C.S. Lewis could not be farther from the truth when he said, ‘thirst was made for water; inquiry for truth’ when we begin to examine the increasing demand for heart failure (HF) medications, particularly among vulnerable patient populations such as those covered by Medicaid and Medicare.

In fact, when we are careful to examine the cost of the newly developed guideline‐directed medical therapy (GDMT) options now available for HF patients, it becomes clear that in fact the words that William F. Buckley, Jr. once uttered regarding ‘idealism is fine, but as it approaches reality, the costs become prohibitive’ are quite appropriate when referring to HF GDMT.

However, the cost of HF medications alone is not the only matter in question that we challenge the reader to examine. The complexity of treating one patient has increased for both the patient and the provider. Along with increasing costs, there are increasing number of medications recommended for a patient to take, increasing number of side effects and monitoring for each medication that is now required. Our purpose is to bring to light the changing landscape of HF treatment and begin the discussion for overcoming these obstacles.

Despite decades of stagnant research with regard to HF management, several blockbuster trials have recently revolutionized therapy and provided a new range of therapeutic options all acting on different disease pathways not only for reducing readmissions but most importantly improving outcomes [1].

We now recognize these new therapeutic options as the ‘four-pillar’ approach [2]. However, as we move forward with all this new armamentarium at our disposal with clear cut comprehensive pharmacological benefit; the first concern would undoubtedly have been as with any other trial if real-world attainment of target doses would ever occur. The next obvious concern that has been circulating across the board is not only in which sequence these drugs should be started but, more so, how these agents will be used alongside established therapies.

However, if we were to push the envelope somewhat further and be simply pragmatic, we should not be startled by an even greater barrier that hinders most current practices, particularly, when dealing with life-saving medications. What good are they, if not everyone can afford them?

In a recent systematic review addressing medical costs of HF in the USA between 2014 and 2020, the investigators included in their analysis 87 studies, 41 of which allowed comparison of cost estimates across studies. They found that the annual median total medical costs for HF care were estimated at $24,383 per patient, with HF-specific hospitalizations driving up costs and accounting for approximately $15,879 per patient [3].

If captivated by these numbers, let us face even more mind-boggling facts. HF has shown increasing prevalence in the USA, having an estimated 8.8% increase from 2013 to 2016 (6.2 million Americans) as compared with 2009 to 2012 (5.7 million Americans) [4]. The lifetime risk of developing HF is estimated to be 1 in 5 at 40 years of age [5]. Furthermore, not only the incidence of HF increases with age but most importantly, HF prevalence in the aging US population is projected to increase by 46% between 2012 and 2030 [6]. In the case of older adults diagnosed with HF, 5-year mortality approaches 50% [7,8]. Furthermore, while total direct medical costs of HF were in the vicinity of $30.7 billion in 2012, these are projected to increase by ≈127% and reach $69.7 billion by 2030 [6].

The staggering reality is that HF is a very expensive diagnosis, both for the patient and the healthcare system. As already stated, aside from the highest financial hurdle being hospital fees, HF costs are then mainly driven by medications (15.6% of direct costs) [1]. With increasing costs to both parties, special attention should be paid to our most vulnerable population, particularly the uninsured or underserved requiring Medicaid and Medicare assistance.

The main goal of prompt institution of appropriate GDMT is to prevent further cardiac remodeling that ultimately will result in gradual improvement in cardiac function and consequently improved prognosis. Therefore, current treatment guidelines for patients with systolic HF with reduced ejection fraction (LVEF ≤ 40%) as recommended by the American College of Cardiology (ACC) include medications listed in Table 1 [1].

Table 1. ACC medication recommendations based on indication.

Indication during HF treatment	Medication Class	Medication Names (Brand/Generic, if found more commonly as Brand name in practice)	Estimated Manufacturer’s AWP (30 day supply±) [9–19]
Symptomatic HFrEF (LVEF ≤ 40%)	ARNI ACEI ARB	ARNI: Entresto/Sacubitril + Valsartan ACEI: Lisinopril, Captopril, Enalapril, Ramipril ARB: Losartan, Valsartan, Candesartan	ARNI: $750 ACEI: $1-$5 ARB: $5-$10
	Beta-Blocker	Metoprolol Succinate Carvedilol Bisoprolol	$10
	Loop Diuretic	Furosemide Bumetanide Torsemide	$15-30
	SGLT2i	Jardiance/Empagliflozin Farxiga/Dapagliflozin	$650-$685
	Aldosterone Antagonist	Spironolactone Eplerenone	$40
Add if African American with persistent symptoms despite above medications (titrated to patient-specific goal)	Vasodilator	Hydralazine Isosorbide Dinitrate	Hydralazine: $10 Isosorbide Dinitrate: $40-$600 (depending on dose and frequency)
Add if resting HR ≥ 70 bpm in sinus rhythm on maximum tolerated beta-blocker dose	HCN Channel Blocker	Corlanor/Ivabradine	$624

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; AWP = Average Wholesale Price; HCN = Hyperpolarization-activated cyclic nucleotide-gated; HFrEF = heart failure with reduced ejection fraction; HR = heart rate; SGLT2i = sodium-glucose transport protein 2 inhibitor

±Lowest pricing available for highest dose of medication with anticipated dosing schedule (e.g. once daily vs twice daily) used to estimate cost

Aside from the reality of the data supporting their use [1,20,21], the pragmatic reality is that high cost of prescription drugs threatens healthcare budgets and limits funding available for other areas of public investment and population treatments. For HF patients, the monthly out-of-pocket cost of medications alone could potentially add up to thousands of dollars.

Despite the recent findings regarding the use of angiotensin receptor-neprilysin inhibitors (ARNI) and sodium glucose cotransporter 2 inhibitors (SGLT2 i) in reducing acute HF exacerbations requiring hospitalization and overall improvement in cardiovascular outcomes [20,22]; these two medications are particularly expensive when trying to offer our best ‘four-pillar’ GDMT approach to all our HF patients. The latter is quite troublesome for both the uninsured and underserved patient populations.

Two decades ago, we saw that being uninsured carried a host of adverse health consequences, including more advanced stages of disease when seeing a physician, avoidable deaths, and not receiving lifesaving treatments for conditions, including HF. To address this issue, the Affordable Care Act (ACA) was signed into law on 23 March 2010. Right after that, the overall uninsured rates in the USA dropped from 46.5 million in 2010 to 26.7 million in 2016 and by 2018, the total rate was 8.5% [21].

Data with regard to HF medication (angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and ARNI) use at discharge, at least for Hispanics, exploded by 146% after ACA expansion compared with before (after ACA: odds ratio [OR], 2.46; 95% CI, 1.10–5.51; before ACA: OR, 0.40; 95% CI, 0.13–1.23; P < .01) [21]. However, these significant improvements were not seen among other racial and ethnic groups regarding GDMT [22].

In terms of Medicare, Fendrick et al. examined Medicare Part D out-of-pocket costs for patients with HFrEF in 2018 and showed that the mean out-of-pocket costs per year were $1,166 with one-third of patients entering the deductible phase [23]. Since this study was conducted in 2018, data adjustments for costs that would have otherwise not included SGLT2i’s are lacking. It should be also pointed out that less than 0.5% of these HF patients were using an ARNI or Ivabradine [23]. In fact, costs were mainly attributed to other chronic comorbidities commonly seen in this elderly population such as diabetes mellitus [23].

High cost of prescription drugs have been attributed to several factors such as (a) the inherent monopoly directly created by the clinical need with no other alternate substitution, a practice not currently regulated; (b) seriousness of the clinical entity treated, making it not a luxury item but a clear necessity to either improve quality of life or to prolong life; (c) high cost of development has surely been cited as a constant undeniable barrier that needs to be improved as a number of trials have been mandated in order to meet regulatory guidelines and secure ultimate approval; and probably the most damaging of them all is (d) lobbying power of pharmaceutical companies to secure their products, which has been the main hindrance in providing much-needed legislative reform to make changes that will ultimately benefit patients [24].

Additional barriers and challenges imposed by Medicaid and/or Medicare include (a) Inability to use drug manufacturer coupons; (b) requirement to complete Prior Authorization paperwork for certain medications (includes other restrictions such as trialing and failing a different medication prior to approval); and (c) coverage gap or ‘donut hole’ in which patients are responsible for a certain percentage of medication costs.

Certainly, there is an urgent need to identify who, or which entity is responsible for treatment failures and which barriers limit the ability of our patients from getting recommended GDMT that will not only improve their well-being but most importantly be ultimately responsible of better clinical outcomes.

As providers, we need to take the lead in this proposed transformation and partner with Health Care Institutions and Insurance companies so we can always provide the best recommended GDMT to our patients, regardless of their source of income. Medications proven effective in clinical trials should not be limited to a certain few but to those that need them. The success of clinical medicine that has finally revolutionized the management of HF with life-saving treatments has to become affordable to all. Second-best alternatives do not seem to be neither reasonable nor acceptable.

There is a need for transparency in all arrangements that are being made between pharmacy-benefit managers and drug manufacturers, so that benefits could be passed directly to patients. Furthermore, we could also save by limiting or eliminating direct patient advertisement of these medications, the need and efficacy of these therapies should be solely in health providers’ hands.

In summary, as our current options of GDMT for managing HF have proven to slow disease progression, improve quality of life, and significantly reduce need for hospital readmissions, it is time for all of us to come together in this initiative of making these therapies available to all patients in need. These life-saving therapies cannot be limited to some and be negated to a large majority, mainly insured by Medicaid and Medicare. If we do this right, these treatments should in principle reduce the same big-ticket items that drive HF costs off the charts, namely listed hospital admissions. Therefore, it is in our best interest as health care providers to solve this issue and lessen the economic burden that HF exerts on hospital systems. It is time, to make changes and avoid what Albert Einstein warned us against, ‘We cannot solve our problems with the same thinking we used when we created them.’ The time is now.

Key take home points

• Increasing complexity for treatment of patients with HF

• Newer treatments now supported by guideline recommendations are expensive and certain patient population will suffer as a result (i.e. underserved, uninsured)

• Focus should be on ensuring access to these life-saving medications

• Increasing affordability and transparency of costs should be a priority

Declaration of funding

No funding was received for the production of this manuscript.

Declaration of any financial/other conflicts of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.