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, ACE inhibitor, 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, ACE inhibitor, or ARB It is rarely necessary to stop ACE inhibitor, ARB, or ARNI; clinical deterioration may occur following discontinuation^¶
Angioedema^Δ	ACE inhibitor or ARNI	Most often starts during the first week to 3 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 3 months of therapy	Stop ACE inhibitor or ARNI Supportive care for angioedema Replace ACE inhibitor or ARNI with ARB, but inform patient of risk of recurrent angioedema (up to 10%) that is ACE inhibitor- or ARNI-related in first few weeks following ACE inhibitor or ARNI discontinuation
Persistent, nonproductive cough	ACE inhibitor or ARNI	Usually begins within 1 to 2 weeks of initiation, but onset may be delayed by 6 months	Ask about cough at patient visits, particularly during the first 6 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 ACE inhibitor or ARNI (recurs after ACE inhibitor or ARNI withdrawal and rechallenge), stop ACE inhibitor or ARNI and substitute with ARB
Worsening renal function	ACE inhibitor, 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 1 to 2 weeks after initiation or uptitration During stable maintenance therapy, recheck labs every 3 to 6 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/min per 1.73 m², decrease dose of ACE inhibitor or ARB or ARNI by one-half and recheck labs^◊. If serum creatinine >3.5 mg/dL (310 micromol/L) or eGFR <20 mL/min per 1.73 m², stop ACE inhibitor, ARB, or ARNI^§ and recheck labs^◊.
Hyperkalemia	ACE inhibitor, 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^◊; ACE inhibitor, 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, ACE inhibitor, 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; ARNI: angiotensin receptor-neprilysin inhibitor; ACE: angiotensin converting enzyme; ARB: angiotensin II receptor blocker; BP: blood pressure; BUN: blood urea nitrogen; NSAIDs: nonsteroidal antiinflammatory drugs; eGFR: estimated glomerular filtration rate; K: potassium; ECG: electrocardiogram; HFrEF: heart failure with reduced ejection fraction (left ventricular ejection fraction ≤40%).

* The 3 drugs discussed here should generally not be used concomitantly. An ARNI should not be used with an ACE inhibitor (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 ACE inhibitor, 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 ACE inhibitor (or an ARB). So if an ARNI is stopped due to hypotension, substitution with a low dose of an ACE inhibitor (or ARB) is a potential option. After discontinuing ARNI, wait at least 36 hours before starting an ACE inhibitor.

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.

§ In this setting, some patients with hyperkalemia or renal insufficiency with ARNI may tolerate low-dose ACE inhibitor or ARB. If ACE inhibitor, 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.

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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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*