Combination Use of Ivabradine with Sacubitril/Valsartan: A Review of Clinical Effectiveness and Guidelines [Internet]

Heart failure (HF) is a clinical syndrome that results from a structural or functional cardiac disorder that reduces the ability of the ventricle of the heart to fill with or eject blood. Heart failure is associated with a number of symptoms, including shortness of breath, difficulty breathing and fatigue, exercise intolerance, fluid retention, cough, and weight gain., Severity of HF can be described according to the New York Heart Association (NYHA) Classification system as follows: Class I, No symptoms; Class II, Symptoms with ordinary activity; Class III, Symptoms with less than ordinary activity; and Class IV, Symptoms at rest or with any minimal activity. Heart failure can be further categorized based on ejection fraction. Heart failure with preserved ejection fraction (HFpEF) is defined as left ventricular ejection fraction (LVEF) greater than or equal to 50%; HF with a mid-range ejection fraction (HFmEF) is defined as LVEF ranging from 41% to 49%, and HF with reduced ejection fraction (HFrEF) is defined as LVEF ≤ 40% according to Canadian guidelines.Approximately 600,000 Canadians have HF, and it is a leading cause of hospitalization in Canada. An estimated $2.8 billion dollars are spent each year on direct health care costs for HF in Canada. Morbidity and mortality rates in HF remain high despite the introduction of newer treatment options. An estimated 20% of those hospitalized for HF have a readmission within 30 days and the yearly mortality rate from HF exceeds 30%.Management of HF may relate to the individual’s NYHA classification and ejection fraction; but treatment generally involves the use of pharmacotherapies, which may include diuretics, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs). More recently, two newer pharmacotherapies, sacubitril/valsartan and ivabradine, became available for the management of HF in Canada. Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) and is the only drug in this class currently available in Canada. Neprilysin is an endopeptidase that breaks down endogenous vasoactive peptides, including natriuretic peptide, bradykinin, and adrenomedullin. Inhibition of neprilysin increases the levels of the vasoactive substances which helps to counter the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and other maladaptive processes in HF.Ivabradine is a heart rate lowering drug.. In HF patients, resting heart rate is an independent predictor of cardiovascular events. Ivabradine selectively inhibits the depolarizing If current in the sinus node, which regulates heart rates; thus, the pharmacological effect of ivabradine requires an individual to have sinus rhythm.Both ivabradine and sacubitril/valsartan are indicated in Canada for the treatment of stable chronic HFrEF in patients with NYHA Class II or III., However, in addition to this, the approved Canadian prescribing information specifies that ivabradine is only indicated in patients who are in sinus rhythm with a resting heart rate ≥77 beats per minute.Since ivabradine and sacubitril/valsartan have different mechanisms of action, this combination may be considered as a potential treatment option for those individuals who remain symptomatic despite optimized therapy with other alternatives. While both ivabradine and sacubitril/valsartan are indicated for heart failure NYHA class II or III severity, it is unclear if there is evidence from clinical trials or observational studies to support their use in combination from an effectiveness or safety perspective. As well, guidance from evidence-based practice guidelines could help to inform use of this combination in clinical practice. In 2017, CADTH reviewed ivabradine through the Common Drug Review process and noted in their recommendation that “patients who are eligible for treatment with ivabradine may also be eligible for treatment with sacubitril/valsartan” but the committee pointed out at the time of review that there was no evidence that evaluated the combination of sacubitril/valsartan and ivabradine or assessed the comparative safety and efficacy of the two treatments. The objective of this report is to provide a summary of the evidence of clinical effectiveness and clinical practice guidelines regarding the combination of ivabradine and sacubitril/valsartan for the treatment of heart failure.

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