Recommendation 26: We recommend that most patients with HFrEF be treated with triple therapy including an ACEi (or an ARB in those that are ACEi intolerant), a beta-blocker and a mineralocorticoid receptor antagonist (MRA) unless specific contraindications exist (Strong Recommendation, Moderate Quality Evidence).

Values and preferences: Preference is given to the use of pharmacotherapy in the majority of patients with HFrEF across the spectrum of symptoms. There is limited clinical trial data to inform decision-making surrounding the use of MRA as part of guideline-directed medical therapy (GDMT) in those without symptoms of HF or high risk features.

Recommendation 27: We recommend preferentially using the specific drugs at target doses that have been proven to be beneficial in clinical trials as optimal medical therapy. If these doses cannot be achieved, the maximally tolerated dose is acceptable [Table 11] (Strong Recommendation, High Quality Evidence).

Practical tips:

• If a drug with proven mortality or morbidity benefits does not appear to be tolerated by the patient (e.g., low blood pressure, low heart rate or renal dysfunction), other concomitant drugs, including diuretics, with less proven benefit should be carefully reevaluated to determine whether their dose can be reduced or the drug discontinued.
• HFrEF guideline-directed medical therapy (GDMT) should be continued at their usual dose during acute intercurrent illness (e.g., pneumonia, exacerbation of COPD, other systemic infection, etc.), unless they are not tolerated (e.g., if significant reactive airways disease is present). GDMT should be restarted before discharge if temporarily withheld.
• In a life-threatening complication, GDMT may be discontinued abruptly, but generally, if there is concern about their use, the dose should be decreased by one-half, and the patient should be reassessed. If the dose is reduced, it should be up-titrated to the previous tolerated dose as soon as safely possible.
• If symptomatic hypotension persists with GDMT, consider separating the administration of the dose from the timing of other medications that could also lower blood pressure.

• ACEi intolerance describes a patient that is unable to tolerate ACEi therapy secondary to a bothersome cough (most commonly, 10-20%) or those experiencing angioedema with ACEi therapy (uncommon, < 1%). ARB therapy is a reasonable alternative in both of these cases, however caution should be used in those that develop angioedema while on ACEi therapy as there have been case reports of patients that subsequently develop angioedema with ARB therapy. There is no significant difference in rates of hypotension, hyperkalemia or renal dysfunction between these agents to warrant a substitution between agents.
• An increase in serum creatinine or eGFR of up to 30% is not unexpected when an ACE inhibitor or ARB is introduced; if the increase stabilizes at 30% or less, there is no immediate need to decrease the drug dose but closer long-term monitoring might be required.
• Blood pressure may fall when an ACE inhibitor or ARB is introduced, especially if introduced at a high dose or in combination with diuretic therapy. Check blood pressure supine and erect to detect whether hypotension is present, requiring slower up-titration.
• Cough occurs in 10-20% of patients on ACEi and does not require discontinuation of the agent unless it is bothersome to the patient.

• Objective improvement in cardiac function might not be apparent for 6-12 months after beta-blocker initiation.
• Patients in NYHA class I or II can be safely initiated and titrated with a beta-blocker by non-specialist physicians.
• Patients in NYHA class III or IV should have their beta-blocker therapy initiated by a specialist experienced in HF management and titrated in the setting of close follow-up, such as can be provided in a specialized clinic, if available.
• The starting dose of beta-blockers should be low and increased slowly (e.g., double the dose every two to four weeks). Transient fluid retention may occur with initiation or uptitration of beta-blockers and may require assessment of diuretic dosage (e.g., may consider deferring dosage reduction).
• If concomitant reactive airways disease is present, consider using more selective beta-1 blockade (e.g., bisoprolol).
• If AV block is present, consider decreasing other AV blocking drugs, such as digoxin or amiodarone (where appropriate). The type/severity of AV block and the patient’s history of arrhythmias will help guide the most appropriate treatment modifications.

• MRAs can increase serum potassium, especially during an acute dehydrating illness in which renal dysfunction can worsen, and close monitoring of serum creatinine and potassium is required. High risk groups include those with diabetes, pre-existing renal dysfunction, and older age.