Heart Failure Therapy: The Good, the Bad, and the Ugly

This article highlights the latest literature surrounding both new and old heart failure therapies.

The central problem in heart failure is not that patients are short of breath or retain fluid. The problem is that they die. —Dr. Arnold Katz1

Those words resonate in our current era of outcomes-focused heath care perhaps even more than when they were penned in 1993.

In the 1980s, the primary pharmacologic agents for heart failure with reduced ejection fraction (HFrEF) were digoxin and hydralazine-isosorbide dinitrate (H-ISDN). The field has come a long way since then, with the emergence of cornerstone therapies like beta-blockers and mineralocorticoid receptor antagonists (MRAs).

I previously summarized the recent guideline recommendations for 2 new HF therapies: the angiotensin receptor blocker-neprilysin inhibitor (ARNI) combination of sacubitril/valsartan (Entresto), and the funny current inhibitor ivabradine (Corlanor). Several recent post-hoc analyses further clarify the role of these new agents.

The Good

  • The reduction in HF-related hospitalization was seen within 30 days of randomization to ARNI over enalapril.2 Patients randomized to ARNI also had fewer emergency department visits and were less likely to require outpatient intensification of medical therapy.
  • Rates of hospital readmission for HF at 30 days were also lower in patients assigned to ARNI therapy versus enalapril.3
  • Among cardiovascular (CV) deaths, both sudden cardiac death and death due to worsening HF were reduced by treatment with ARNI versus enalapril.4 Of note, the reductions in rates of sudden death weren’t influenced by the presence of an implantable cardioverter defibrillator (ICD), which is noteworthy because the PARADIGM trial has been criticized for low use of ICD therapy.
  • The magnitude of benefit for patients on lower doses of ARNI therapy relative to those on lower doses of enalapril was similar to that of patients who remained on target doses of both drugs.5 In other words, even patients only able to tolerate lower doses of an angiotensin-converting enzyme inhibitor (ACEI) may still benefit from switching to a lower dose of ARNI therapy.
  • ARNI therapy is more expensive than enalapril when only considering direct costs. However, 2 recent papers reported acceptable cost effectiveness of ARNI therapy over enalapril (approximately $50,000/QALY).6,7

One important caveat is this entire data set is from a single large clinical trial where patients of African descent and those with severe HF weren’t well represented. However, the potential benefits of ARNI are hard to ignore. Of 2,736,000 HFrEF patients in the United States, 2,287,296 (84%) are projected to be candidates for ARNI therapy.8 Optimal implementation of ARNI therapy is empirically estimated to prevent 28,484 deaths per year in the United States alone.8

The Bad

H-ISDN and digoxin are still guideline-recommended medications today,9 which I find especially surprising in light of recent literature:

  • A new study of 4663 Medicare patients with HFrEF found that 1 in 5 were newly prescribed H-ISDN therapy at discharge.10 After 3 years of follow-up, poor medication adherence had led to H-ISDNs having no impact on mortality or hospitalization. These findings were consistent in both the black cohort and those intolerant to ACEI or angiotensin receptor blocker (ARB) therapy.

The Ugly

  • Contemporary data from a registry of more than 100,000 HF patients showed digoxin was still prescribed to 1 in 5 patients during the study period. Although this number decreased from 33.1% in 2005 to 10.7% in 2014, those with concomitant atrial fibrillation (AF) were more than twice as likely to receive this medication.11
  • Several recent meta-analyses found digoxin use to be associated with a roughly 20% increased risk of death in HF patients, including those with AF.12,13

The continued prescription of antiquated therapies is really striking when juxtaposed with the positive findings for ARNI therapy and ivabradine. According to these guidelines, ARNI therapy has the potential to supplant ACEIs as the preferred agent for neurohormonal modulation in HFrEF.9,14

Both the American and European guidelines provide a softer recommendation for ivabradine, which is appropriate because this agent doesn’t appear to reduce CV mortality.9,14 Ivabradine can, however, reduce HF-related hospitalization when added to standard medical therapy in those in normal sinus rhythm with HFrEF and a resting heart rate of ≥70 bpm. Given the relatively favorable adverse effect profile for this medication (bradycardia and visual disturbance were the main adverse effects seen in clinical trials), it’s possible ivabradine may establish a niche for use in patients with persistent symptoms despite maximally tolerated doses of neurohormonal antagonists. This is especially true for patients unable to reach target doses of beta-blockers (or completely intolerant of the class).

Pharmacists are charged with a duty to ensure our HFrEF patients are prescribed (and actually taking) contemporary, guideline-directed, mortality-reducing drug therapies. Additionally, pharmacists are well poised to assist with reducing the use of antiquated therapies, which can either be ineffective (eg, H-ISDN) or potentially harmful (eg, digoxin).

As such, I propose the following to all pharmacists caring for HFrEF patients:

  • Attempt to minimize H-ISDN use. Based on the aforementioned real-world data, this therapy is of little benefit (even in black patients) due to very low rates of adherence over time.
  • Consider all HFrEF patients currently taking an ACEI or ARB as candidates for ARNI therapy. Offer counselling to patients about the risks and benefits of switching, and engage providers about how to do so safely (eg, ensure at least a 36-hour washout between agents). Pharmacists should also anticipate prior authorization for this therapy and be prepared to assist prescribers with ensuring a smooth process for the patient to obtain the medication.
  • Evaluate those currently not taking either an ACEI or ARB for ARNI therapy. Assess for possible contraindications (eg, hypotension, hyperkalemia, severe renal impairment), and refer patients to their provider if none exist. Always start at the lowest dose of ARNI therapy in these patients and monitor closely for emergence of angioedema. This is especially true for black patients, who carry a higher risk for angioedema and weren’t well represented in the PARADIGM trial.
  • Digoxin has long been recommended for patients with persistent symptoms despite therapy with an ACEI, beta-blocker, and MRA.2 In line with the recent data outlined above, I’d argue digoxin no longer has a place for this type of HFrEF patient. Rather, ivabradine may be considered in this scenario, provided the patient has a resting heart rate of ≥70 bpm and is also in normal sinus rhythm.


  • Katz AM. Chairman’s introduction. Clin Cardiol. 1993;16(Suppl2):1-4.
  • Packer M, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131(1):54-61.
  • Desai AS, et al. Influence of sacubitril/valsartan (LCZ696) on 30-day readmission After heart failure hospitalization. J Am Coll Cardiol. 2016;68(3):241-248.
  • Desai AS, et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J. 2015;36:1990-1997.
  • Vardeny O, et al. Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial. Eur J Heart Fail. 2016 Jun 10.
  • Gaziano TA, et al. Cost-effectiveness analysis of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction. JAMA Cardiol. 2016 Jun 22.
  • King JB, et al. Cost-effectiveness of sacubitril-valsartan combination therapy compared with enalapril for the treatment of heart failure with reduced ejection fraction. JCHF. 2016;4(5):392-402.
  • Fonarow GC, et al. Potential mortality reduction with optimal implementation of angiotensin receptor neprilysin inhibitor therapy in heart failure. JAMA Cardiol. 2016. Jun 22.
  • 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail. 20 May 2016.
  • Khazanie P, et al. Clinical effectiveness of hydralazine-isosorbide dinitrate therapy in patients with heart failure and reduced ejection fraction: findings from the get with the guidelines-heart failure registry. Circ Heart Fail. 2016 Feb;9(2):e002444.
  • Patel N, et al. Temporal trends of digoxin use in patients hospitalized with heart failure: analysis from the American Heart Association get with the Guidelines-Heart Failure Registry. JCHF. 2016 May;4(5):348-356.
  • Vamos M, et al. Digoxin-associated mortality: a systematic review and meta-analysis of the literature. Eur Heart J. 2015;36(28):1831-1838.
  • Ouyang AJ, et al. Meta-analysis of digoxin use and risk of mortality in patients with atrial fibrillation. Am J Cardiol. 2015;115(7):901-906.
  • 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. JACC. 2016.