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Management of intolerances to angiotensin converting enzyme inhibitor, angiotensin II receptor blocker, or angiotensin receptor-neprilysin inhibitor in patients with heart failure with reduced ejection fraction*

Management of intolerances to angiotensin converting enzyme inhibitor, angiotensin II receptor blocker, or angiotensin receptor-neprilysin inhibitor in patients with heart failure with reduced ejection fraction*
Intolerance Agent Timing Monitoring Response
Symptomatic hypotension or severe asymptomatic hypotension (SBP <90 mmHg) ARNI, ACEI, or ARB
  • Anytime, particularly soon after initiation and uptitration; may improve with time
  • Check BP with each patient visit, particularly with changes in volume status, diuretic regimen, or drug doses.
  • If no congestion present, hold or reduce diuretic.
  • Check if other drugs with a hypotensive effect (eg, nitrates or calcium channel blockers) can be discontinued.
  • If other measures are insufficient:
    • Further evaluate and address cause of hypotension.
    • Reduce dose of ARNI, ACEI or ARB.
    • It is rarely necessary to stop ACEI, ARB, or ARNI; clinical deterioration may occur following discontinuation.**
AngioedemaΔ ACEI or ARNI
  • Most often starts during the first week to three months but can occur after years of therapy
  • Episodic (even with continued therapy) but frequency and severity tend to escalate
  • Inform patients of risk of angioedema, including risk of potentially life-threatening airway obstruction.
  • Ask about symptoms at patient visits, particularly during the first three months of therapy.
  • Stop ACEI or ARNI.
  • Supportive care for angioedema.
  • Replace ACEI or ARNI with ARB, but inform patient of risk of recurrent angioedema (up to 10%) that is ACEI-or ARNI-related in first few weeks following ACEI or ARNI discontinuation.
Persistent, nonproductive cough ACEI or ARNI
  • Usually begins within one to two weeks of initiation, but onset may be delayed by six months
  • Ask about cough at patient visits, particularly during the first six months of therapy.
  • Evaluate potential causes of cough (eg, worsening heart failure, lung disease).
  • If cough is impairing quality of life (eg, disturbing sleep) AND is related to ACEI or ARNI (recurs after ACEI or ARNI withdrawal and rechallenge), stop ACEI or ARNI and substitute with ARB.
Worsening renal function ACEI, ARB, or ARNI
  • Anytime, particularly in the setting of volume depletion or concomitant nephrotoxic drugs
  • Check baseline BUN, serum creatinine, and electrolytes.
  • Recheck labs approximately one to two weeks after initiation or uptitration.
  • During stable maintenance therapy, recheck labs every three to six months (sooner if patient has clinical or laboratory evidence of instability).
  • For worsening renal function and/or hyperkalemia, check labs frequently and serially until creatinine and potassium have decreased and stabilized.
  • Initial steps:
    • Avoid concomitant nephrotoxic drugs (eg, NSAIDs).
    • Evaluate and treat other potential causes of worsening renal function (eg, intrinsic kidney disease).
    • If no congestion is present, reduce or suspend diuretic therapy.
    • May need to hold or stop mineralocorticoid receptor antagonist.
  • If increase in serum creatinine by >50% above baseline OR serum creatinine 3.1 to 3.5 mg/dL (274 to 310 micromol/L) OR eGFR is 20 to 25 mL/minute/1.73 m2, decrease dose of ACEI or ARB or ARNI by one-half and recheck labs.◊
  • If serum creatinine >3.5 mg/dL (310 micromol/L) OR eGFR <20 mL/minute/1.73 m2, stop ACEI, ARB, or ARNI and recheck labs.◊
Hyperkalemia ACEI, ARB, or ARNI
  • Anytime, particularly in the setting of worsening renal function or concomitant use of agents that supplement or retain potassium
  • As above for worsening renal function.
  • Avoid K supplement (including K-containing salt substitute) and retaining drugs (eg, triamterene, NSAIDs).
  • If K is ≤5.5 mmol/L and no ECG changes, review drugs and diet for potential causes, including causes of worsening renal function, and recheck labs◊; ACEI, ARB, or ARNI dose may need to be reduced.
  • If K is >5.5 mmol/L, or 5 to 5.5 mmol/L with ECG changes, then temporarily stop ACEI, ARB, or ARNI, treat hyperkalemia, review drugs and diet for potential causes including causes of worsening renal function, and recheck labs.◊ When reintroduced, ACEI, ARB, or ARNI dose may need to be reduced.
  • Mineralocorticoid receptor antagonist may need to be reduced or held.
  • Refer to UpToDate clinical review of treatment and prevention of hyperkalemia for additional details on management.
SBP: systolic blood pressure; ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor blocker; ARNI: angiotensin receptor-neprilysin inhibitor; BP: blood pressure; BUN: blood urea nitrogen; HFrEF: heart failure with reduced ejection fraction (left ventricular ejection fraction <=40 percent); NSAIDs: nonsteroidal anti-inflammatory drugs; eGFR: estimated glomerular filtration rate; K: potassium; ECG: electrocardiogram.
* The three drugs discussed here should generally not be used concomitantly. An ARNI should not be used with an ACEI (wait at least 36 hours when switching to or from ACE inhibitor). Avoid use of an ARNI with an ARB. Avoid use of an ARB with an ACEI, as there is limited evidence of benefit from combined use of these drugs in this setting.
** The risk of hypotension is higher with an ARNI than with an ACEI (or an ARB). So if an ARNI is stopped due to hypotension, substitution with a low dose of an ACEI (or ARB) is a potential option. After discontinuing ARNI, wait at least 36 hours before starting an ACEI.
¶ In this setting, some patients with hyperkalemia or renal insufficiency with ARNI may tolerate low dose ACEI or ARB. If ACEI, ARB, and ARNI cannot be used for treatment of HFrEF due to hyperkalemia or renal insufficiency, we suggest treatment with a combination of hydralazine plus nitrate.
Δ The risk of angioedema is particularly high in Black patients.
◊ Serum creatinine, BUN, and serum potassium should be rechecked frequently (at least weekly) until levels have stabilized.
Adapted from: Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37:2129.
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