Ranolazine for Chronic Angina Management
Direct Recommendation
Ranolazine should be considered as add-on therapy when beta-blockers and/or calcium channel blockers fail to adequately control angina symptoms, or as part of initial treatment in patients with contraindications to first-line agents, particularly those with diabetes, bradycardia, hypotension, or microvascular angina. 1
Role in Treatment Algorithm
When to Add Ranolazine
Add ranolazine when initial monotherapy with beta-blockers or calcium channel blockers fails to control symptoms (Class IIa, Level B recommendation). 1
If combination therapy with beta-blocker plus dihydropyridine calcium channel blocker remains inadequate, ranolazine represents the next logical step before considering more invasive interventions. 1
Ranolazine can be used as part of initial treatment in properly selected patients who have contraindications or intolerance to beta-blockers and/or calcium channel blockers. 1
Optimal Patient Populations
Ranolazine offers particular advantages in specific clinical scenarios:
Diabetic patients with chronic stable angina should be preferentially considered for ranolazine, as it reduces HbA1c, fasting glucose, and 2-hour postprandial glucose levels while simultaneously improving angina symptoms. 2
Patients with bradycardia or hypotension benefit from ranolazine's neutral hemodynamic profile—it does not significantly affect heart rate or blood pressure. 2, 3
Patients with left ventricular hypertrophy may experience greater efficacy with ranolazine compared to other antianginal agents. 2
Microvascular angina responds well to ranolazine therapy. 1
Patients with concurrent atrial fibrillation can benefit from ranolazine added to beta-blockers, as it suppresses supraventricular arrhythmias. 2
Dosing and Administration
Initial dose: 500 mg orally twice daily, which can be escalated as needed to a maximum of 1000 mg twice daily. 2, 3
The drug can be combined with amlodipine, beta-blockers, or nitrates when angina is not adequately controlled with standard therapy. 2, 3
Tolerance does not develop after 12 weeks of therapy, and rebound angina has not been observed following abrupt discontinuation. 3
Expected Clinical Benefits
Symptomatic improvement without prognostic benefit:
Ranolazine produces statistically significant increases in exercise duration (24-34 seconds at trough, 26-34 seconds at peak) and time to angina (26-38 seconds). 3
Reduces angina frequency by approximately 0.8-1.2 attacks per week compared to placebo. 3
Decreases nitroglycerin use by approximately 0.9-1.3 doses per week. 3
Critical limitation: Ranolazine does NOT reduce major cardiovascular events, cardiovascular death, or myocardial infarction—it provides symptom relief only. 2, 3, 4
Mechanism of Action
Ranolazine inhibits the late sodium current (late INa), preventing intracellular calcium overload during ischemia, which reduces oxygen demand and left ventricular wall tension. 2
It exerts antianginal effects without significantly affecting heart rate, blood pressure, or myocardial perfusion. 2
The drug also promotes glucose oxidation and improves anaerobic metabolism under ischemic conditions. 2
Critical Contraindications and Precautions
Absolute Contraindications
Hepatic impairment or liver cirrhosis—ranolazine is absolutely contraindicated in these patients. 1, 2, 5, 6
Severe renal impairment (GFR <30 mL/min/1.73 m²)—ranolazine should NOT be prescribed, including patients on hemodialysis. 5, 6
Renal Dosing Adjustments
Moderate renal impairment (CrCl 30-60 mL/min): Limit dose to 500 mg twice daily due to 50-97% increase in plasma levels as kidney function declines. 2, 5
Ranolazine undergoes extensive hepatic metabolism but is primarily excreted by the kidney, leading to drug accumulation and increased risk of QT prolongation in renal impairment. 5, 6
Drug Interactions
Avoid combination with strong CYP3A4 inhibitors (increases ranolazine levels). 1
Use caution with digoxin—ranolazine increases digoxin concentration; monitor digoxin levels. 2
Do not combine with non-dihydropyridine calcium channel blockers (verapamil, diltiazem) if also using ivabradine. 1
QT Prolongation
Ranolazine causes dose-related QT interval prolongation (mean increase 2.4 ms), though torsades de pointes has not been observed at therapeutic doses. 2, 7
QT prolongation becomes more pronounced with drug accumulation in renal impairment. 5
Common Pitfalls to Avoid
Do not use ranolazine for acute angina relief—it will not abort an acute angina episode; only sublingual nitroglycerin or nitroglycerin spray should be used for immediate relief. 3, 8
Do not expect mortality or MACE reduction—ranolazine is purely for symptom control, not prognostic benefit. 2, 3
Do not prescribe in patients with GFR <30 mL/min/1.73 m²—this includes hemodialysis patients, where excessive drug accumulation poses serious risks. 5, 6
Gender considerations: Effects on angina frequency and exercise tolerance are considerably smaller in women than in men (approximately 33% of male benefit in exercise tolerance). 3
Alternative Antianginal Options in Renal Impairment
When ranolazine is contraindicated due to severe renal impairment:
Beta-blockers (particularly beta-selective agents like bisoprolol) can be used without renal dose adjustment concerns. 5
Calcium channel blockers have no renal contraindications. 5, 6
Nitrates can be used safely in patients with chronic kidney disease. 5, 6
Ivabradine can be used for heart rate control without renal dose adjustment concerns. 5
Safety Profile
Common adverse effects include dizziness, nausea, asthenia (weakness), constipation, and headache. 4
Long-term data from the ROLE program (mean follow-up 2.82 years) showed 76.7% of patients remained on therapy at 2 years, with only 9.7% discontinuing due to adverse events. 7
Annual mortality in high-risk patients was 2.8-3.0%, lower than predicted by Duke Treadmill Score (>5%), suggesting symptomatic improvements are not offset by increased mortality. 7
No increased incidence of death or arrhythmia with long-term use. 4, 7