What are the indications, dosing, contraindications, and common adverse effects of ranolazine for chronic stable angina?

Ranolazine Uses in Chronic Stable Angina

Ranolazine is a second-line antianginal agent indicated for chronic stable angina when symptoms are inadequately controlled with beta-blockers and/or calcium channel blockers, or as initial therapy in patients who cannot tolerate first-line agents. 1

Primary Indication

• Ranolazine is FDA-approved for treatment of chronic angina pectoris, either as monotherapy or in combination with amlodipine, beta-blockers, or nitrates when angina is not adequately controlled with standard therapy. 2
• The drug provides symptomatic relief only and does not reduce cardiovascular death, myocardial infarction, or major adverse cardiovascular events. 3, 4

Clinical Positioning

First-Line Therapy Considerations

• Beta-blockers and/or calcium channel blockers remain the recommended initial therapy for most patients with chronic coronary syndrome. 1
• Ranolazine should be considered as add-on therapy when initial treatment with beta-blockers and/or calcium channel blockers fails to adequately control symptoms (Class IIa, Level B recommendation). 1

Alternative to Beta-Blockers

• Ranolazine can be used as a substitute for beta-blockers when beta-blockers cause unacceptable side effects, are ineffective, or are contraindicated. 1
• This is particularly useful in patients with bradycardia and/or hypotension, as ranolazine has a neutral hemodynamic profile with no significant effect on heart rate or blood pressure. 3, 2

Combination Therapy

• Ranolazine in combination with beta-blockers is effective for symptom relief when initial beta-blocker treatment is unsuccessful (Class IIa, Level A recommendation). 1
• The drug remains effective even in patients receiving maximally-tolerated doses of beta-blockers or calcium channel blockers. 5

Dosing

• Initial dose: 500 mg orally twice daily, which can be escalated to a maximum of 1000 mg twice daily based on clinical response. 3, 2
• Dose adjustments are required with moderate CYP3A inhibitors (limit to 500 mg twice daily). 2
• When used with metformin, limit metformin to 1700 mg daily with ranolazine 1000 mg twice daily. 2

Special Populations

Patients with Diabetes

• Ranolazine should be the preferred antianginal agent in patients with type 2 diabetes and chronic stable angina, as it significantly reduces HbA1c, fasting glucose, and postprandial glucose levels while improving angina symptoms. 3
• The American Diabetes Association notes ranolazine reduces glycated hemoglobin levels in diabetic patients, though it is not considered a diabetes treatment. 3

Patients with Microvascular Angina

• Ranolazine and trimetazidine are particularly effective for patients with microvascular angina. 1, 6

Patients with Left Ventricular Hypertrophy

• Patients with left ventricular hypertrophy may experience greater efficacy with ranolazine compared to other antianginal drugs. 3

Patients with Atrial Fibrillation

• Ranolazine can be added to beta-blockers in patients with both chronic stable angina and atrial fibrillation, as it suppresses supraventricular arrhythmias. 3

Contraindications

• Liver cirrhosis (absolute contraindication). 1, 3, 2
• Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir). 2
• CYP3A inducers (e.g., rifampin, phenobarbital, St. John's wort). 2

Precautions and Monitoring

Renal Impairment

• Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCl <60 mL/min). 2
• Plasma levels increase 50-97% as kidney function declines; discontinue if acute renal failure develops. 3, 2

Hepatic Impairment

• Plasma levels increase 50-60% in patients with moderate hepatic impairment. 3

QT Prolongation

• Ranolazine causes dose-related QT interval prolongation, though torsades de pointes has not been observed at therapeutic doses. 3, 2
• Use caution in patients with hepatic impairment or when co-administered with QT-prolonging drugs. 3

Drug Interactions

• Use caution with digoxin, as ranolazine increases digoxin concentration. 1, 2
• Limit simvastatin to 20 mg when used with ranolazine. 2
• Doses of other CYP3A substrates and OCT2 substrates may require adjustment. 2

Common Adverse Effects

• Most common adverse reactions (>4% and more common than placebo): dizziness, headache, constipation, and nausea. 2, 7, 8
• These adverse effects are generally mild and infrequent. 9

Mechanism of Action

• Ranolazine primarily inhibits the late sodium current (late INa), preventing intracellular calcium overload during ischemia. 3
• This reduces oxygen demand and left ventricular wall tension without significantly affecting heart rate, blood pressure, or myocardial perfusion. 3

Clinical Efficacy

• Ranolazine produces modest but statistically significant improvements in exercise duration, reduces frequency of angina episodes, and decreases nitroglycerin consumption. 7, 9, 5
• The drug effectively reduces angina symptoms and improves exercise tolerance but has not been shown to improve major cardiovascular outcomes or reduce mortality. 3, 4

Common Pitfalls to Avoid

• Do not confuse ranolazine with prognostic medications like aspirin or statins—ranolazine only treats symptoms and has no mortality benefit. 4
• Avoid combining ranolazine with strong CYP3A inhibitors or inducers. 2
• Do not use ranolazine in patients with liver cirrhosis. 1, 2
• Monitor for drug interactions, particularly with digoxin, statins, and metformin. 1, 2