New Heart Failure Guidelines: What Pharmacists Need to Know

It was a busy weekend in the world of heart failure (HF), as both the American College of Cardiology/American Heart Association (ACC/AHA) and the European Society of Cardiology (ESC) published updated guidelines on May 20, 2016.

The ACC/AHA guidelines is a focused update on 2 new drug therapies for patients with HF and a reduced ejection fraction,¹ while the ESC guideline is a much more comprehensive overview of the management of both acute and chronic HF.²

1. Entresto Receives Class I Recommendation Over ACE Inhibitors and ARBs^1,2

The combination of sacubitril/valsartan (Entresto), an angiotensin-receptor/neprilysin inhibitor

(ARNI), has demonstrated superior reductions in both mortality and HF-related hospitalization compared with the angiotensin-converting enzyme (ACE) inhibitor enalapril. These data are quite striking, as ACE inhibitors have been the cornerstone of drug therapy for HF for over 2 decades.

In light of these positive data, the ACC/AHA guidelines recommend the use of Entresto in patients with chronic symptomatic HF with a reduced ejection fraction (NYHA class II or III) who tolerate an ACE inhibitor or an angiotensin receptor blocker (ARB) in order to further reduce morbidity and mortality (Class I, level of evidence B).

The ESC guidelines provide a softer endorsement for ARNI therapy, recommending it should only be used in patients who remain symptomatic despite optimal treatment with either an ACE inhibitor or ARB in combination with a beta-blocker and a mineralocorticoid receptor antagonist (eg, spironolactone) (Class I, level of evidence B).

While the mortality and morbidity reductions with ANRI therapy are impressive, the drug does have potential limitations:

• Rates of symptomatic hypotension are higher than with ACE inhibitor monotherapy. Patients need close blood pressure monitoring when starting or titrating ARNI therapy.
• The number of patients of African descent was very small in the pivotal clinical trial. Therefore, the benefits in this group of patients are not known.
• Long-term safety data are lacking, and there are theoretical toxicities associated with long-term inhibition of neprilysin. For instance, neprilysin affects the degradation of beta-amyloid peptide in the brain, which could theoretically accelerate amyloid deposition (eg, Alzheimer's disease). However, a recent, small, 14-day study with healthy subjects showed elevation of the beta-amyloid protein in the soluble rather than the aggregable form, which, if confirmed over longer time periods in patients with HF, may indicate the cerebral safety of Entresto.
• Entresto cannot be combined with an ACE inhibitor, and a 36-hour washout period is required between these 2 therapies to minimize the potential for life-threatening angioedema. This represents a huge opportunity for pharmacists to intervene and help prevent a potentially catastrophic medication error.
• All patients in the clinical trials were able to tolerate high doses of ACE inhibitor therapy so caution and close monitoring is needed when starting Entresto in patients who have not previously been on either an ACE inhibitor or an ARB.
• Patients with severe HF (eg, NYHA class 4) were not well-represented in the clinical trial with Entresto, so its use in these patients cannot be endorsed at this time.
• The cost of this medication is significantly higher than generic ACE inhibitor therapy. Therefore, pharmacists should make sure that patients who are prescribed this therapy are able to afford the medication. Novartis offers several patient assistance programs that can be accessed through its website.

Even with these limitations in mind, I believe Entresto represents the future of HF drug therapy. I would personally recommend this therapy as the preferred vasodilator therapy for patients with either class II or class III symptoms, especially in those already taking ACE inhibitor or ARB therapy.

Pharmacists can play a key role in both identifying patients who may be good candidates for Entresto, as well as monitoring patients for hypotension and angioedema during the transition phase. Pharmacists can also help to ensure that patients never take an ACE inhibitor concomitantly with Entresto, and should always question when a patient already taking one of these therapies is prescribed the other.

2. Corlanor Given Class IIa Recommendation for Use with Beta-Blocker^1,2

Ivabradine (Corlanor) inhibits the funny current in the sinoatrial node, which slows heart rate without affecting blood pressure or cardiac function (eg, inotropy). This distinguishes ivabradine from other HR drug therapies like beta-blockers, which possess negative inotropic agents, can lower blood pressure, and exacerbate HF symptoms.

Ivabradine was studied against placebo in a large, randomized trial of patients with a resting heart rate >70 bpm despite optimal treatment with an ACE inhibitor or ARB, a beta-blocker, and a mineralocorticoid receptor antagonist. While the addition of ivabradine did not further reduce mortality, it did reduce the number of HF-related hospitalizations.

Therefore, the ACC/AHA guidelines recommend that ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HF with a reduced ejection fraction (≤35%) who are receiving maximal HF medication therapy, including a beta-blocker at maximum tolerated dose, and are in sinus rhythm with a heart rate of ³70 bpm at rest (Class IIa, level of evidence B).

The ESC guidelines provide similar recommendations for those on maximally tolerated beta-blocker therapy (Class IIa, level of evidence B), but also include a provision for patients who cannot tolerate any beta-blocker therapy (Class IIa, level of evidence C). It’s also worth noting that the European Medicines Agency approved ivabradine for use in Europe in patients with HF and a reduced ejection fraction who are in sinus rhythm with a resting heart rate ≥75 bpm, based on data that this subgroup had better outcomes than those with a heart rate >70 bpm.

Ivabradine is generally well-tolerated, with bradycardia being the most common potential serious side effect. Patients may also report visual disturbances and should be counseled that this is a normal side effect of the drug. Like sacubitril/valsartan, ivabradine is relatively expensive and can be cost-prohibitive in patients with high co-payments or in those without prescription drug insurance.

While sacubitril/valsartan is likely to shift the landscape of HF therapy away from ACE inhibitors toward ARNI, I see ivabradine as more of a boutique therapy. Provided that patients can afford the medication, I believe it represents a reasonable therapy for those who cannot tolerate higher doses of beta-blockers.

This could be especially true for patients who aren’t able to tolerate any beta-blocker therapy, as these patients are likely at high risk of residual disease burden (eg, repeated hospitalizations). It’s important to note that patients with low baseline heart rate or those with atrial fibrillation are not appropriate candidates for ivabradine therapy.

Conclusion

This is an exciting time for HF drug therapy, as it has been many years since any new medications have been able to further advance the field. The addition of 2 new agents—Entresto and Corlanor—can help lower the risks of death and hospitalization due to HF.

Pharmacists practicing in all patient care settings should know when these therapies should be used and how to appropriately monitor patients who take these important medications.

References

• 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 Foundation/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2016 (epub ahead of print)
• 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal. 20 May 2016 (epub ahead of print) doi:10.1093/eurheartj/ehw128.