|HFrEF drug therapy||Quality of evidence supporting recommendation|
|Chronic ambulatory HF||New-onset HF||HF hospitalization|
The recent SOLOIST-WHF trial showed that sotagliflozin (an SGLT1/2 inhibitor) could be safely prescribed before discharge or shortly after discharge in patients with diabetes who were stabilized after hospitalization for heart failure. Ongoing randomized controlled trials will further evaluate the efficacy and safety of initiating SGLT2 inhibitors in a spectrum of HF patients, including those without diabetes.
- 1.We recommend that in the absence of contraindications, patients with HFrEF be treated with combination therapy including 1 evidence-based medication from each of the following categories:
- a.ARNI (or ACEI/ARB);
- c.MRA; and
- d.SGLT2 inhibitor.
- (Strong Recommendation; Moderate-Quality Evidence).
- 2.We recommend preferentially use of 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 2; Strong Recommendation; High-Quality Evidence).Table 2Standard therapies and their initial and optimal dose targets for patients with HFrEF
Drug class Specific agent Start dose Target dose ARNI Sacubitril-valsartan 50-100 mg BID (dose rounded) 200 mg BID (dose rounded) ACEI Enalapril
1.25-2.5 mg BID
2.5-5 mg daily
2-4 mg daily
1.25-2.5 mg BID
1-2 mg daily
10 mg BID/20 mg BID (NYHA IV)
20-35 mg daily
4-8 mg daily
5 mg BID
4 mg daily
4-8 mg daily
40 mg BID
32 mg daily
160 mg BID
3.125 mg BID
1.25 mg daily
12.2-25 mg daily
25 mg BID/50 mg BID (> 85 kg)
10 mg daily
200 mg daily
12.5 mg daily
25 mg daily
25-50 mg daily
50 mg daily
SGLT2 inhibitor Dapagliflozin
10 mg daily
10 mg daily
100 mg daily
10 mg daily
10-25 mg daily
100-300 mg daily
Sinus node inhibitor Ivabradine 2.5-5 mg BID 7.5 mg BID sGC stimulator Vericiguat 2.5 mg daily 10 mg daily Vasodilator Hydralazine and isosorbide dinitrate 10-37.5 mg TID/10-20 mg TID 75-100 mg TID or QID/40 mg TID Cardiac glycosides Digoxin 0.0625-0.125 mg daily Not applicable: monitor for toxicityACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BID, twice per day; CR/XL, controlled release/extended release; HFrEF, heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; QID, 4 times per day; sGC, soluble guanylate cyclase; SGLT, sodium glucose transport; TID, 3 times per day.
- 3.We recommend that an ARNI be used in place of an ACEI or ARB, in patients with HFrEF, who remain symptomatic despite treatment with appropriate doses of GDMT to decrease CV death, HF hospitalizations, and symptoms (Strong Recommendation; High-Quality Evidence).
- 4.We recommend that patients admitted to hospital for acute decompensated HF with HFrEF should be switched to an ARNI, from an ACEI or ARB, when stabilized and before hospital discharge (Strong Recommendation; Moderate-Quality Evidence).
- 5.We suggest that patients admitted to hospital with a new diagnosis of HFrEF should be treated with ARNI as first-line therapy, as an alternative to either an ACEI or ARB (Weak Recommendation; Moderate-Quality Evidence).
ACEIs and ARBs
ACEI/ARB initiation and continuation during HF hospitalization
- Kane J.A.
- Kim J.K.
- Haidry S.A.
- Salciccioli L.
- Lazar J.
- Kane J.A.
- Kim J.K.
- Haidry S.A.
- Salciccioli L.
- Lazar J.
ACEIs/ARBs after acute myocardial infarction
- Dickstein K.
- Kjekshus J.
Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan.
- 6.We recommend an ACEI or ARB in those with ACEI intolerance, in patients with acute MI with HF or an LVEF < 40% post-MI to be used as soon as safely possible post-MI (Strong Recommendation; High-Quality Evidence).
- Hjalmarson A.
- Goldstein S.
- Fagerberg B.
- et al.
- Gattis W.A.
- O’Connor C.M.
- Gallup D.S.
- et al.
- 7.We recommend that β-blockers be initiated as soon as possible after the diagnosis of HF, including during the index hospitalization, provided that the patient is hemodynamically stable. Clinicians should not wait until hospital discharge to start β-blocker treatment in stabilized patients (Strong Recommendation; High-Quality Evidence).
- 8.We recommend patients with NYHA class IV symptoms be stabilized before initiation of β-blocker treatment (Strong Recommendation; High-Quality Evidence).
- 9.We recommend that β-blockers be initiated in all patients with an LVEF < 40% with previous MI (Strong Recommendation; Moderate-Quality Evidence).
MRA use in patients with HFrEF
- 10.We recommend MRA treatment for patients with acute MI and LVEF ≤ 40%, and HF symptoms or diabetes, to reduce mortality, CV mortality, and hospitalization for CV events (Strong Recommendation; High-Quality Evidence).
When to start SGLT2 inhibitor treatment in patients with HFrEF
- 11.We recommend an SGLT2 inhibitor, such as dapagliflozin or empagliflozin, be used in patients with HFrEF, with or without concomitant type 2 diabetes, to improve symptoms and quality of life and to reduce the risk of HF hospitalization and/or CV mortality (Strong Recommendation; High-Quality Evidence).
- 12.We recommend an SGLT2 inhibitor, such as empagliflozin, canagliflozin, or dapagliflozin be used for treatment of patients with type 2 diabetes and atherosclerotic CV disease to reduce the risk of HF hospitalization and death (Strong Recommendation; High-Quality Evidence).
- 13.We recommend an SGLT2 inhibitor, such as dapagliflozin, be used in patients with type 2 diabetes who are older than 50 years with additional risk factors for atherosclerotic CV disease to reduce the risk of HF hospitalization (Strong Recommendation; High-Quality Evidence).
- 14.We recommend SGLT2 inhibitors such as canagliflozin or dapagliflozin be used in patients with albuminuric renal disease, with or without type 2 diabetes, to reduce the risk of HF hospitalization and progression of renal disease (Strong Recommendation; High-Quality Evidence).
Practical approach to SGLT2 inhibitors for treatment of cardiovascular disease.
Sinus Node Inhibition
- 15.We recommend that ivabradine be used for patients with HFrEF and symptoms despite treatment with GDMT, a resting heart rate ≥ 70 bpm, and sinus rhythm for the prevention of CV death and HF hospitalization (Strong Recommendation; High-Quality Evidence).
- 16.We recommend that vericiguat, an oral sGC stimulator, be considered in addition to optimal HF therapies for HFrEF patients with worsening symptoms and HHF in the past 6 months, to reduce the risk of subsequent HF hospitalization (Conditional Recommendation; Moderate-Quality Evidence).
- 17.We suggest digoxin be considered in patients with HFrEF and atrial fibrillation, with poor control of ventricular rate and/or persistent symptoms despite optimally tolerated β-blocker therapy, or when β-blockers are not tolerated, in the setting of chronic HF, new onset HF, or HF hospitalization (Weak Recommendation; Low-Quality Evidence).
- 18.We suggest digoxin be considered in patients with HFrEF in sinus rhythm who continue to have moderate to severe symptoms despite appropriate doses of GDMT to relieve symptoms and reduce hospitalizations (Weak Recommendation; Moderate-Quality Evidence).
Hydralazine and isosorbide dinitrate
- 19.We recommend that H-ISDN be considered for treatment of patients with HFrEF who are unable to tolerate an ACEI, ARB, or ARNI because of hyperkalemia, renal dysfunction, or other contraindications, in the following settings:
- i.Chronic HF (Strong Recommendation, Moderate-Quality Evidence);
- ii.New-onset HF (Weak Recommendation, Low-Quality Evidence); and
- iii.HF hospitalization (Weak Recommendation, Low-Quality Evidence).
- 20.We recommend that H-ISDN treatment be considered in addition to standard GDMT at appropriate doses for black patients with HFrEF and advanced symptoms (Strong Recommendation; Moderate-Quality Evidence).
Referral for ICD and CRT
When to refer for ICD/CRT in the current era of medical therapy for HFrEF
- 21.We recommend that after a diagnosis of HFrEF, standard medical therapy should be initiated and titrated to target or maximally tolerated doses with a repeat assessment of LVEF before referral for ICD or CRT (Strong Recommendation; Moderate-Quality Evidence).
- •For eligible patients, switching to ARNI therapy should be considered before referral for ICD or CRT.
- •Additional use of ivabradine, where otherwise indicated after β-blocker optimization, should be considered before referral for ICD implantation or CRT.
Areas of Uncertainty and Evolving Evidence
1 Should ARNIs be prescribed in the setting of HF after MI?
2 Should SGLT2 inhibitor treatment be initiated during an HHF episode in patients with HFrEF?
3 Do myosin activators (myotropes) have a role in managing patients with HFrEF?
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The disclosure information of the authors and reviewers is available from the CCS on their guidelines library at www.ccs.ca.
This statement was developed following a thorough consideration of medical literature and the best available evidence and clinical experience. It represents the consensus of a Canadian panel comprised of multidisciplinary experts on this topic with a mandate to formulate disease-specific recommendations. These recommendations are aimed to provide a reasonable and practical approach to care for specialists and allied health professionals obliged with the duty of bestowing optimal care to patients and families, and can be subject to change as scientific knowledge and technology advance and as practice patterns evolve. The statement is not intended to be a substitute for physicians using their individual judgement in managing clinical care in consultation with the patient, with appropriate regard to all the individual circumstances of the patient, diagnostic and treatment options available and available resources. Adherence to these recommendations will not necessarily produce successful outcomes in every case.