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5. Areas of Uncertainty and Evolving Evidence

The CCS HF Guidelines Panel identified a number of unresolved questions relevant for the management of patients with HFrEF. For the purposes of this guideline update, systematic evidence reviews were limited in scope to the therapies and settings discussed herein. However, on the basis of emerging evidence, some additional considerations are worth noting, and further research will likely inform future guidelines.

1. Should ARNIs be prescribed in the setting of HF after MI?

The Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI (PARADISE-MI; NCT02924727) trial has completed enrollment and will compare sacubitril-valsartan with ramipril treatment early after high-risk MI (12 hours to 7 days) with respect to the composite end point of CV death, HHF, or urgent outpatient HF visit.

2. Should SGLT2 inhibitor treatment be initiated during an HHF episode in patients with HFrEF?

In the recently published Sotagliflozin on Clinical Outcomes in Hemodynamically Stable Patients With Type 2 Diabetes POST Worsening Heart Failure (SOLOIST-WHF) trial,[83] sotagliflozin (a combined sodium glucose transport 1/SGLT2 inhibitor) was compared with placebo in 1222 patients with diabetes who were admitted to hospital with worsening HF. The medication was prescribed before discharge or shortly after discharge when hemodynamic stability was achieved. Sotagliflozin significantly reduced the risk of achieving the primary end point of CV death, HHF, or urgent visit for HF (51.0 vs 76.3 events per 100 patient-years; HR, 0.67 [95% CI 0.52-0.85]). Ongoing trials will further evaluate the efficacy and safety of initiating SGLT2 inhibitors in a spectrum of hospitalized HF patients, regardless of diabetes status (Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure –Thrombolysis in Myocardial Infarction 68 [DAPA ACT HF-TIMI 68; NCT04363697] and A Multicentre, Randomised, Double-blind, 90-day Superiority Trial to Evaluate the Effect on Clinical Benefit, Safety and Tolerability of Once Daily Oral Empagliflozin 10 mg Compared to Placebo, Initiated in Patients Hospitalised for Acute Heart Failure [de Novo or Decompensated Chronic HF] Who Have Been Stabilised [EMPULSE; NCT04157751]) trial.

3. Do myosin activators (myotropes) have a role in managing patients with HFrEF?

Omecamtiv mecarbil (OM) is a myosin activator that enhances systolic function in patients with HFrEF by augmenting actin-myosin interaction in the sarcomere.[84] In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF), OM was compared with placebo in 8256 patients with HFrEF and worsening symptoms (either currently hospitalized or hospitalized within the past year).[72] Dosing was adjusted according to study drug level, and the primary end point was a composite of HHF or urgent HF visit or CV death. Compared with placebo, OM reduced incidence of the primary outcome over 22 months of follow-up (37.0% vs 39.1%; HR, 0.92 [95% CI 0.85-0.99]). It is unclear whether there are important subgroups of patients (such as those with severely depressed LVEF) that might derive greater benefit from OM. Because of the relatively modest effect of this drug compared with placebo in a high risk HF population, and uncertainty around whether OM will receive regulatory approval in Canada, no recommendations have been made at this time.

References

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73. Ezekowitz JA, O’Connor CM, Troughton RW, et al. N-terminal proB-type natriuretic peptide and clinical outcomes: vericiguat heart failure with reduced ejection fraction study. JACC Heart Fail 2020;8:931-9.

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75. Hood WB Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ. Digitalis for treatment of heart failure in patients in sinus rhythm. Cochrane Database Syst Rev 2014;4:CD002901.

76. Malik A, Masson R, Singh S, et al. Digoxin discontinuation and outcomes in patients with heart failure with reduced ejection fraction. J Am Coll Cardiol 2019;74:617-27.

77. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-52.

78. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-10.

79. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049-57.

80. Tardif JC, O’Meara E, Komajda M, et al. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy. Eur Heart J 2011;32:2507-15.

81. Januzzi JL Jr, Prescott MF, Butler J, et al. Association of change in N-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA 2019;322:1-11.

82. Wang Y, Zhou R, Lu C, et al. Effects of the angiotensin-receptor neprilysin inhibitor on cardiac reverse remodeling: meta-analysis. J Am Heart Assoc 2019;8:e012272.

83. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;284:117-28.

84. Teerlink JR, Clarke CP, Saikali KG, et al. Dose-dependent augmentation of cardiac systolic function with selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study. Lancet 2011;378:667-75.

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