Guideline-Directed Medical Therapy for Heart Failure: Hospice Considerations

Guideline Directed Medical Therapy (GDMT) for Heart Failure¹

Guideline-directed medical therapy (GDMT) for heart failure (specifically, for heart failure (HF) with reduced ejection fraction, or HFrEF) now includes four medication classes. These classes include evidence-based beta blockers, angiotensin receptor/neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose co-transporter 2 inhibitors (SGLT2i). The most recent guidelines recommend all four classes be initiated within four weeks of heart failure diagnosis, and then titrated as appropriate. This rapid sequence of medication initiation is relatively new GDMT and is now an integral element of care for these patients prior to hospice. For this reason, most patients with HF are already on most if not all these therapies when they are admitted to hospice. While the evidence-based beta blockers, angiotensin-converting enzyme (ACEi) inhibitors/angiotensin II receptor blockers (ARBs) and mineralocorticoid receptor antagonists have long been standard therapy for patients with heart failure in hospice, the addition of the angiotensin receptor neprilysin inhibitors (ARNI) and sodium glucose co-transporter 2 (SGLT2) classes may pose new questions for hospice providers regarding the roles of these medications in hospice care.

What Is Heart Failure

Heart failure (HF) is a complex clinical syndrome with symptoms and signs resulting from a structural or functional disorder that impairs the ability of the heart’s ventricles to fill with or eject blood.¹ The heart is unable to pump enough blood to meet the metabolic demands of the body, which leads to changes in the structure of the ventricles that then decreases the pumping ability of the heart. Patients progress to advanced heart failure when the heart’s pumping function is weakened so that it fails to meet the body’s demands, and a patient feels symptoms (like shortness of breath) even at rest.

Disease-specific criteria for patients admitted to hospice with a terminal diagnosis of heart failure include:

1. The patient is already optimally treated with diuretics and vasodilators or has a medical reason for not being on these drugs such as hypotension or renal disease.
2. The patient’s HF is classified as NYHA Class IV (the most severe classification), which means the patient has significant symptoms of HF, even at rest.²

Role(s) of New Medication Classes in Heart Failure

Angiotensin Receptor Neprilysin Inhibitors (ARNI)

In general, inhibition of the renin-angiotensin system is recommended to reduce morbidity and mortality for patients with HFrEF. For this reason, an ACE Inhibitor (ACEi, e.g., lisinopril, enalapril) or angiotensin receptor blocker (ARB, e.g. losartan, valsartan) has long been a mainstay of HF therapy.  The ANRIs, which combine the neprilysin inhibitor sacubitril with the angiotensin receptor blocker valsartan, inhibit both neprilysin and angiotensin II type-I receptors, and have been shown to improve morbidity and mortality in some patients with heart failure.

It’s important to note, however, that current research suggests the benefits of the ARNI may not be present in patients with end-stage heart failure. The PARADIGM-HF trial³, upon which the ARNI class was approved, reported that sacubitril/valsartan reduced the relative risk of cardiovascular mortality and heart failure hospitalizations by 20% compared with an ACE inhibitor alone in ambulatory patients with HFrEF. However, this trial essentially excluded patients with end-stage heart failure. In other words, this trial didn’t include patients similar to those admitted to hospice with heart failure as their terminal diagnosis.

The LIFE Trial⁴ was conducted to provide additional information about the tolerability, safety, and potential efficacy of sacubitril/valsartan in patients with more advanced heart failure who were underrepresented in the PARADIGM-HF trial. THE LIFE trial compared the use of sacubitril/valsartan and valsartan alone and found no differences between the treatment arms with respect to death from cardiovascular causes or hospitalization for heart failure, all-cause death, or the number who received a significant cardiac intervention (e.g., left ventricular assist device, heart transplant, inotropic therapy). Additionally, the LIFE trial revealed significant tolerability issues for patients with end-stage HF:

• 18% of the patients who met the enrollment criteria in the LIFE trial could not be randomized because they were unable to tolerate a 100 mg/day dose of sacubitril/valsartan during the run-in phase
• 30% of the randomized patients discontinued sacubitril/valsartan during the study
• Less than 35% of the patients were receiving the target dose of 400 mg/day of sacubitril/valsartan at the end of the study⁵

According to Douglas Mann, MD, FACC, the lead author of the LIFE study: “We assume that all heart failure patients are the same and therefore will respond the same to all therapies; however, the patient population with advanced heart failure is different from patients with less advanced heart failure because of the organ changes that occur in the heart and kidneys. These organ changes limit the ability of the failing heart to respond to conventional therapies to the same extent as occurs in patients with milder forms of heart failure.” ⁴

For this reason, it is clinically reasonable to consider switching a patient from an ARNI to valsartan only. However, it should be noted that there are specific dosing considerations to be made, since the salt form of valsartan in the ARNi is different than in generic valsartan.

• If switching from sacubitril/valsartan 49/51 mg twice daily to generic valsartan, valsartan would be dosed at 80 mg twice daily.
• If switching from sacubitril/valsartan 97/103 mg twice daily to generic valsartan, valsartan would be dosed 160 mg twice daily.⁶
• In addition, since the patient’s loop diuretic (e.g., furosemide) may have been decreased or stopped when starting sacubitril/valsartan, it may be necessary to augment this when deprescribing an ARNI in favor of generic valsartan.

SGLT2 Inhibitors⁷

The SGLT2 inhibitors (SGLT2i) have traditionally been used for the management of diabetes. However, several clinical studies have also shown that SGLT2i prevent HF hospitalizations compared with placebo. These medications (currently, empagliflozin, dapagliflozin, and sotagliflozin) have now been added to the four-drug GDMT regimen for heart failure regardless of whether the patient has a comorbidity of diabetes. The exact mechanism that provides benefit in HF is not currently known.

In the DAPA-HF⁸ and EMPEROR-Reduced⁹ trials, SGLT2i compared with placebo reduced the composite of cardiovascular death or HF hospitalization by approximately 25%. The benefit in reduction of HF hospitalization was greater (30%) in both trials.

While there were initial concerns about the increased risk of hypoglycemia and urinary tract infections with SGLT2i, a significant increase in these adverse events has not been reported across several trials.^7,10,11 Similarly, while there is an increased risk of genital mycotic infections with SGLT2i,¹² this is generally not a reason to discontinue therapy, unless infections are recurrent. A recent meta-analysis revealed a greater risk of diabetic ketoacidosis (DKA) with SGLT2i, but the baseline risk of DKA was low across trials.^7,13 However, this may be more of a concern in hospice patients experiencing variable food and fluid intake. Additionally, SGLT2i can lead to volume depletion and hypotension which can increase the risk of falls particularly for frail hospice patients. Furthermore, hospice patients may have reduced oral fluid intake, which may exacerbate the effects of volume depletion, hypotension and other adverse effects. This may require dose adjustment of other diuretic medications and may be a concern in patients with significant renal impairment.

Deprescribing GDMT for Heart Failure

In the context of effective symptom management, decreasing pill burden, simplifying the patient’s medication regimen, and minimizing adverse effects are all important components of the hospice patient’s plan of care and often lead to deprescribing of medications. While current evidence suggests patients with end-stage HF do not benefit from the use of ARNI (and can be switched to valsartan only), deprescribing decisions for the other three types of medications (evidence-based beta blockers, MRAs, and SGLT2i) are generally based more on assessment of current or potential adverse effects weighed against ongoing benefit to the patient at end of life (particularly those with a short prognosis). SGLT2i have not been studied in hospice patients, so their ongoing utility for symptom management at end of life is not known. While SGLT2i can be deprescribed without tapering the dose, gradual dose reduction should be attempted when deprescribing beta blockers, MRAs, and ACEi/ARB due to potential for adverse effects of abrupt discontinuation.

For additional information on Advanced Heart Failure:

Enclara Pharmacia resources via client portal

• An Overview of Medication Management of Advanced Heart Failure. Webinar, 2023.
• Cardiac Resources Toolkit. Collection of resources and links related to cardiac disease.

Palliative Care Network of Wisconsin (PCNOW)

• Reisfield GM, Wilson GR. Fast Fact #144: Palliative Care Issues in Heart Failure. 2019 Feb 11.
• Swetz KM, Matlock DD, Ferris H, Hunt S. Fast Fact #205: Mechanical Circulatory Support in Advanced Heart Failure.. 2019 Feb 28.
• Ciuksza MS, Hebert R, Sokos G. Fast Fact #283: Use of Home Inotropes in Patients Near the End-of-Life. 2019 Mar 19.
• Jozwiak R, Marks S. Fast Fact #353: Subcutaneous Diuretics for End-of-Life Management of Heart Failure. 2019 Mar 19.
• Jozwiak R, Stellmacher P, Zehm A. Fast Fact #410: Preparing for a Destination Therapy Ventricular Assist Device: The Palliative Care Planning Conversation. 2020 Nov 20.

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REFERENCES

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2. Centers for Medicare & Medicaid Services. Local Coverage Determination (LCD): Hospice – Determining Terminal Status (L33393) cms.gov. 2019 Nov 14. Available from: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?LCDId=33393
3. McMurray JJV, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371(11):993-1004.
4. American College of Cardiology. LIFE: Sacubitril/valsartan not superior to valsartan in advanced HFrEF. acc.org: Latest in Cardiology. 2021 May 17. Available at: https://www.acc.org/Latest-in-Cardiology/Articles/2021/05/12/19/40/Mon-8am-LIFE-acc-2021
5. Mann DL, Givertz MM, Vader JM, et al. Effect of treatment with sacubitril/valsartan in patients with advanced heart failure and reduced ejection fraction: A randomized clinical trial. JAMA Cardiol.2022;7(1):17–25.
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10. Mascolo A, Di Napoli R, Balzano N, et al. Safety profile of sodium glucose co-transporter 2 (SGLT2) inhibitors: a brief summary. Front Cardiovasc Med. 2022;9:1010693.
11. Toyama T, Neuen BL, Jun M, et al. Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta-analysis. Diabetes Obes Metab. 2019;21:1237–1250.
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13. Nuffield Department of Population Health Renal Studies Group, SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022;400:1788–1801.