Recommendation 33: We recommend that an ARNI be used in place of an ACEi or ARB, in patients with HFrEF, that remain symptomatic despite treatment with appropriate doses of GDMT in order to decrease cardiovascular death, HF hospitalizations, and symptoms (Strong Recommendation, High Quality Evidence).

Values and preferences: This recommendation places high value on medications proven in large trials to reduce mortality, HF re-hospitalization, and symptoms. It also considers the health economic implications of new medications.

• Drug tolerability, side effects and laboratory monitoring with use of ARNIs is similar to that of ACEi or ARB noted above.
• The PARADIGM-HF trial excluded patients with a serum potassium > 5.2 mmol/l, an eGFR < 30 mL/min and symptomatic hypotension with a systolic blood pressure of < 100 mmHg.
• When switching between an ARNI and an ACEi, a washout period of at least 36 hours is required to decrease the risk of angioedema. No washout period is required for conversion between ARNIs and ARBs.
• ARNIs should not be used in anyone with a history of angioedema.
• Currently, there is only one ARNI, sacubitril-valsartan, available on the Canadian market. Initial dosing and rate of titration is dependent on pre-existing treatment and co-morbidities and should be individualized (Table 14). When selecting a dose or titration schedule consideration should be given to the likelihood of tolerability and ultimately successful titration to doses shown to improve important HF outcomes.