What is the role of Ranolazine (ranolazine) in managing severe heart failure with reduced ejection fraction (EF)?

Ranolazine in Severe Heart Failure with Reduced Ejection Fraction

Ranolazine is not recommended for the management of severe heart failure with reduced ejection fraction (HFrEF) as it is not included in any major heart failure guidelines as a standard therapy for this condition.

Current Guideline-Directed Medical Therapy for HFrEF

The 2022 AHA/ACC/HFSA guidelines for heart failure management clearly outline the evidence-based therapies for HFrEF, which include:

1. First-line therapies (Class I recommendations):

   • SGLT2 inhibitors 1
   • ACE inhibitors, ARBs, or ARNIs 1
   • Evidence-based beta-blockers 1
   • Mineralocorticoid receptor antagonists (MRAs) 1
   • Diuretics for symptom relief 1, 2

2. Additional therapies for specific populations:

   • Ivabradine for patients with heart rate ≥70 bpm on maximum tolerated beta-blocker dose 1, 2
   • Hydralazine and isosorbide dinitrate for African American patients 2

Evidence Regarding Ranolazine in HFrEF

The FDA label for ranolazine specifically states: "Heart failure (NYHA Class I to IV) had no significant effect on ranolazine pharmacokinetics. Ranolazine Extended-Release Tablets had minimal effects on heart rate and blood pressure in patients with angina and heart failure NYHA Class I to IV" 3. However, this statement only addresses the pharmacokinetics and safety of ranolazine in heart failure patients, not its efficacy for treating heart failure.

Small studies have investigated ranolazine in heart failure:

• A small study showed that ranolazine preserved or improved LVEF in 70% of patients with heart failure when added to guideline-directed therapy, with an average increase of 11.3 units in LVEF 4. However, this was an open-label study with a small sample size.

• Another study found that ranolazine combined with amiodarone was effective for conversion of post-cardiac surgery atrial fibrillation in patients with HFrEF 5, but this addresses a specific arrhythmia scenario rather than chronic heart failure management.

• The RALI-DHF study investigated ranolazine in heart failure with preserved ejection fraction (HFpEF), not HFrEF, and showed only modest hemodynamic improvements without changes in relaxation parameters 6.

Mechanism and Potential Rationale

Ranolazine inhibits the late sodium current, potentially reducing calcium overload in cardiomyocytes and favoring glucose utilization over fatty acid oxidation 7. While these mechanisms could theoretically benefit the failing heart, the clinical evidence supporting ranolazine specifically for HFrEF is insufficient to warrant its inclusion in guidelines.

Clinical Recommendation

For patients with severe HFrEF, the following approach should be prioritized:

1. Optimize guideline-directed medical therapy (GDMT) with all four foundational medication classes:

   • SGLT2 inhibitor (empagliflozin or dapagliflozin)
   • ARNI (sacubitril/valsartan) or ACE inhibitor/ARB if ARNI is not tolerated
   • Evidence-based beta-blocker (carvedilol, metoprolol succinate, or bisoprolol)
   • MRA (spironolactone or eplerenone)

2. Consider device therapy for eligible patients:

   • ICD for primary prevention in patients with LVEF ≤35% despite optimal medical therapy 1, 2
   • CRT for patients with LVEF ≤35%, QRS ≥130 ms, and LBBB 2

3. Address specific comorbidities that may worsen heart failure

Conclusion

While ranolazine has theoretical benefits and some promising preliminary data in small studies, it is not currently recommended by any major guideline for the management of severe HFrEF. Clinicians should focus on optimizing the well-established guideline-directed medical therapies that have demonstrated mortality and morbidity benefits in large randomized controlled trials.