Heart Failure in Older Adults: A Geriatrician Call for Action

Angiotensin Receptor Blockers

Although less studied than ACE inhibitors, angiotensin receptor blockers (ARBs) share similar benefits. Among patients with symptomatic HFrEF taking an ACE inhibitor, the addition of candesartan reduced the risk of CV death and HF hospitalization as demonstrated in the Candesartan in Heart Failure Assessment of Reduction Mortality and Morbidity (CHARM-added and CHARM-alternative trials).^12,13 The CHARM-added trial targeted patients with left ventricular ejection fraction (LVEF) ≤ 40% and NYHA class II to IV HF symptoms who were taking an ACE inhibitor. Adding candesartan reduced CV mortality by 37.9% and HF hospitalization by 42.3% compared with that of placebo.

The CHARM-alternative study found that use of candesartan in symptomatic HFrEF patients who do not tolerate ACE inhibitors,resulted in a 20% reduction in CV mortality as well as a 40% reduction in hospitalization for HF. Among patients with HF with preserved ejection fraction (HFpEF) and NYHA class II to IV symptoms, adding candesartan modestly reduced the rate of HF-related hospitalizations and had no effect on CV mortality in the CHARM-preserved study.¹⁴ The CHARM trials examined mostly white men, but 26% of patients were aged > 75 years. However, there was no subgroup analysis for patients aged > 75 years. The study excluded patients with serum creatinine > 2 mg/dL.

Other ARB trials included the following:

• The I-PRESERVE trial, which found that irbesartan did not improve outcomes of patients with HF with preserved ejection fraction (HFpEF).¹⁵ The study of mostly white patients did not include patients aged ≥ 80 years.
• A randomized trial of valsartan in HF improved symptoms and mortality in NYHA II to IV HF but showed no benefit when added to ACE inhibitors.¹⁶ The trial had no patients aged ≥ 75 years and excluded those with several common comorbidities.
• A randomized, double-blind trial studied the effects of high-dose vs low-dose losartan on clinical outcomes in 3,846 patients with HF and demonstrated that high-dose losartan (150 mg/d) reduces all-cause mortality and hospitalization for HF more effectively than does low-dose losartan (50 mg/d).¹⁷ The study, however, had several exclusion criteria, and no patients were aged ≥ 75 years.

Mineralocorticoid Receptor Antagonists

Major studies of aldosterone antagonists demonstrated extra benefit when added to ACE inhibitors/ARBs in patients with HFrEF and NYHA class II HF.^18,19

In the RALES study, spironolactone was found to reduce all-cause mortality by 30% and symptoms in NYHA III HF without a significant increase in the risk of serious hyperkalemia or renal failure.¹⁸ Most patients were white men aged < 80 years. This study demonstrated the importance of closely following serum potassium levels after initiating aldosterone antagonists in patients with subclinical renal disease because extensive structural damage within the kidney occurs before serum creatinine increases. Patients with advanced renal failure or those who cannot have close monitoring of serum potassium levels have an unfavorable risk–benefit ratio with aldosterone antagonists. Patients with cancer and liver failure were excluded from this trial.

In the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure study, (EMPHASIS-HF Study) eplerenone was found to reduce all-cause mortality and hospitalization for HFrEF.¹⁹ Similar to RALES, patients were mostly white males aged < 80 years, and patients with clinically significant, coexisting conditions were excluded.

The 2014 Treatment of Preserved Cardiac FunctionHeart Failure with an Aldosterone Antagonist Trial (TOPCAT) randomized 3,445 patients with well-controlled blood pressure to spironolactone or placebo.²⁰ Inclusion criteria were LVEF ≥ 45%, findings of HF, and either a HF hospitalization or elevated B-type natriuretic peptide level. There was no difference in the primary composite outcome of CV mortality, aborted cardiac arrest, or HF hospitalization over the 3.3-year follow-up period. The study found that among patients with HFpEF, spironolactone does not reduce the composite endpoint of CV mortality, aborted cardiac arrest, or HF hospitalizations compared with that of placebo.²⁰ In the trial, 29% of patients were aged > 75 years, and most were white men. There was no subgroup analysis for older patients.²⁰ In all 3 trials, patients with kidney injury (serum creatinine of ≥ 2.5 or estimated glomerular filtration rate of ≤ 30 mL/min) were excluded because of the risk of hyperkalemia.

An observational study after the RALES trial demonstrated a nearly 4-fold increase in admissions for hyperkalemia with a 6-fold increase in associated mortality in patients taking spirolactone.²¹ Therefore, it is important to closely follow serum potassium levels after initiating aldosterone antagonists in older patients with subclinical renal disease. Patients with advanced renal failure or those without close monitoring of serum potassium levels have an unfavorable risk–benefit ratio with aldosterone antagonists.