What is the recommended treatment for chronic angina using Ranexa (ranolazine)?

Ranolazine (Ranexa) for Chronic Angina

Start ranolazine at 500 mg twice daily and increase to 1000 mg twice daily based on symptom response, using it as add-on therapy when angina remains inadequately controlled on beta-blockers and/or calcium channel blockers, or as initial treatment in selected patients who cannot tolerate standard antianginal agents due to bradycardia or hypotension. 1

Dosing and Administration

• Initial dose: 500 mg orally twice daily 1
• Titration: Increase to 1000 mg twice daily as needed based on clinical symptoms 1
• Maximum dose: 1000 mg twice daily 1
• Swallow tablets whole; do not crush, break, or chew 1
• Can be taken with or without food 1

Dose Modifications Required

• Moderate CYP3A inhibitors (diltiazem, verapamil, erythromycin): Limit maximum dose to 500 mg twice daily 1
• P-glycoprotein inhibitors (cyclosporine): Titrate based on clinical response due to increased ranolazine exposure 1

Clinical Indications and Place in Therapy

The European Society of Cardiology recommends ranolazine as Class IIa, Level B evidence for:

• Add-on therapy in patients with inadequate angina control despite beta-blockers and/or calcium channel blockers 2
• Initial treatment in properly selected patients 2

Ranolazine may be used in combination with: beta-blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers 1

Special Patient Populations Where Ranolazine Offers Advantages

Hemodynamically Compromised Patients

• Ranolazine exerts antianginal effects without significantly affecting heart rate or blood pressure, making it particularly valuable in patients with bradycardia or hypotension where traditional agents would be problematic 2, 3

Diabetic Patients

• Patients with diabetes and chronic stable angina may benefit from ranolazine as it reduces glycated hemoglobin (HbA1c) levels, though it is not indicated as diabetes treatment 2, 3

Left Ventricular Hypertrophy

• Patients with left ventricular hypertrophy might experience greater efficacy with ranolazine compared to other antianginal drugs 2, 3

Expected Clinical Benefits

Symptom Improvement

• Statistically significant increases in exercise duration and time to angina at both trough (12 hours) and peak (4 hours) plasma levels 1
• Reduces angina attack frequency (p=0.006 for 750 mg, p<0.001 for 1000 mg) 1
• Decreases nitroglycerin use (p=0.016 for 750 mg, p<0.001 for 1000 mg) 1

Important Limitation on Outcomes

Ranolazine does not improve major cardiovascular outcomes: It has not been shown to reduce cardiovascular death, myocardial infarction, or improve mortality in patients with chronic stable angina or non-ST-elevation acute coronary syndrome 2

Absolute Contraindications

• Strong CYP3A inhibitors (ketoconazole, itraconazole, clarithromycin, nefazodone, ritonavir, indinavir, nelfinavir) 1
• CYP3A inducers (rifampin, phenobarbital, phenytoin, carbamazepine, St. John's wort) 1
• Liver cirrhosis or hepatic impairment 1, 2

Critical Safety Considerations

QT Interval Prolongation

• Ranolazine causes dose-related QTc prolongation through IKr blockade 2, 1
• However, torsades de pointes has not been observed at therapeutic doses 2
• Avoid in patients with congenital long QT syndrome, family history of long QT, or known acquired QT prolongation 1

Renal Impairment

• Acute renal failure has been observed in patients with severe renal impairment (CrCL <30 mL/min) 1
• Monitor renal function if acute renal failure develops 1

Drug Interactions

• Digoxin: Use with caution as ranolazine increases digoxin concentrations; monitor digoxin levels 2
• Moderate CYP3A inhibitors: Dose reduction required as noted above 1

Common Adverse Effects

The most frequently reported adverse effects include:

• Dizziness 4
• Nausea 4
• Constipation 4
• Headache 4
• Asthenia (weakness) 5

Discontinuation rate due to adverse events is approximately 9.7% over 2 years of therapy 6

Mechanism of Action

Ranolazine works through concentration-dependent, voltage-dependent, and frequency-dependent inhibition of the late sodium current (late INa), which prevents intracellular calcium overload during ischemia 2, 3. This reduces oxygen demand and left ventricular wall tension without affecting myocardial perfusion 2.

Clinical Pearls

• No tolerance develops after 12 weeks of therapy 1
• No rebound angina observed following abrupt discontinuation 1
• Age ≥64 years predicts higher withdrawal rates, but ranolazine remains well tolerated in elderly patients 6
• Patients with history of congestive heart failure actually had lower withdrawal rates in long-term studies 6