2016 ACLS Focused Update Takeaways - Pharmacological Therapy For Heart Failure
The information for the following review was obtained from the 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure. The material was reviewed and published in the September 2016 edition of Circulation.
The introduction of an angiotensin receptor–neprilysin inhibitor (ARNI) (valsartan/sacubitril) and a sinoatrial node modulator (ivabradine), when applied judiciously, complements established pharmacological and device-based therapies and represents a milestone in the evolution of care for patients with heart failure (HF).
ACC/AHA Recommendation System: Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015)
Recommendations for Renin-Angiotensin System Inhibition with an ACE Inhibitor or ARB or ARNI
The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors, or ARBs, or ARNI in conjunction with evidence-based beta blockers, and aldosterone antagonists in selected patients, is recommended for patients with chronic heart failure with reduced ejection fraction (HFrEF) to reduce morbidity and mortality.
Angiotensin-Converting Enzyme Inhibitors (ACEi) (Class I; Level A)
ACEi reduce morbidity and mortality in (HFrEF). Randomized controlled trials (RCTs) clearly establish the benefits of ACE inhibition in patients with mild, moderate, or severe symptoms of HF and in patients with or without coronary artery disease. ACEi need to be given cautiously in patients with hypotension, renal insufficiency, or elevated serum potassium. ACEi can produce a dry cough due to the increased level of bradykinin that can result. Elevated bradykinin can also cause vasodilation which may also help in the treatment of HF. Angioedema is a life-threatening side effect that may occur on some patients being treated with ACEi.
Angiotensin Receptor Blockers (ARB) (Class I; Level A)
Angiotensin receptor blockers (ARBs) were developed with the rationale that angiotensin II production continues in the presence of ACE inhibition, driven through alternative enzyme pathways. ARBs do not inhibit kininase and are associated with a much lower incidence of cough and angioedema than ACE inhibitors; but like ACE inhibitors, ARBs should be given with caution to patients with low systemic blood pressure, renal insufficiency, or elevated serum potassium.
Angiotensin Receptor-Neprilysin Inhibitors (ARNI) (Class 1; Level B-R)
In ARNI, an ARB is combined with an inhibitor of neprilysin, an enzyme that degrades natriuretic peptides, bradykinin, adrenomedullin, and other vasoactive peptides. In symptomatic patients with HFrEF tolerating an adequate dose of either ACE inhibitor or ARB, the ARNI reduced the composite endpoint of cardiovascular death or HF hospitalization significantly, by 20%. The use of ARNI is associated with the risk of hypotension and renal insufficiency and may lead to angioedema.
The use of ACE inhibitors is beneficial for patients with prior or current symptoms of chronic HFrEF to reduce morbidity and mortality. (Class 1; Level A)
ACE inhibitors have been shown in large RCTs to reduce morbidity and mortality in patients with HFrEF with mild, moderate, or severe symptoms of HF, with or without coronary artery disease. ACE inhibitors should be started at low doses and titrated upward to doses shown to reduce the risk of cardiovascular events in clinical trials. ACE inhibitors can produce angioedema and should be given with caution to patients with low systemic blood pressures, renal insufficiency, or elevated serum potassium (>5.0 mEq/L).
The use of ARBs to reduce morbidity and mortality is recommended in patients with prior or current symptoms of chronic HFrEF who are intolerant to ACE inhibitors because of cough or angioedema. (Class 1; Level A)
ARBs have been shown to reduce mortality and HF hospitalizations in patients with HFrEF in large RCTs. Long-term therapy with ARBs in patients with HFrEF produces hemodynamic, neurohormonal, and clinical effects consistent with those expected after interference with the renin-angiotensin system. Unlike ACE inhibitors, ARBs do not inhibit kininase and are associated with a much lower incidence of cough and angioedema, although kininase inhibition by ACE inhibitors may produce beneficial vasodilatory effects.
In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality. (Class 1; Level B-R)
In patients with mild-to-moderate HF—characterized by either 1.) mildly elevated natriuretic peptide levels, BNP [B-type natriuretic peptide] >150 pg/mL or NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥600 pg/mL; or 2.) BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL with a prior hospitalization in the preceding 12 months)—who were able to tolerate both a target dose of enalapril (10 mg twice daily) and then subsequently an ARNI (valsartan/sacubitril; 200 mg twice daily, with the ARB component equivalent to valsartan 160 mg), hospitalizations and mortality were significantly decreased with the valsartan/sacubitril compound compared with enalapril. HF effects and potential off-target effects may be complex with inhibition of the neprilysin enzyme, which has multiple biological targets. Use of an ARNI is associated with hypotension and a low-frequency incidence of angioedema.
ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor. (Class III (harm); Level B-R)
Oral neprilysin inhibitors, used in combination with ACE inhibitors, can lead to angioedema and concomitant use is contraindicated and should be avoided. ACE and neprilysin break down bradykinin, which directly or indirectly can cause angioedema. An ARNI should not be administered within 36 hours of switching from or to an ACE inhibitor.
ARNI should not be administered to patients with a history of angioedema. (Class III (harm); Level C-EO)
Omapatrilat, a neprilysin inhibitor (as well as an ACE inhibitor and aminopeptidase P inhibitor), was associated with a higher frequency of angioedema than that seen with enalapril in an RCT of patients with HFrEF. ARNI therapy should not be administered in patients with a history of angioedema because of the concern that it will increase the risk of a recurrence of angioedema.
- Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos G, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 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. Circulation. 2016;134:e282–e293. DOI: 10.1161/CIR.0000000000000435.