What is the role of Ranexa (ranolazine) in managing chronic angina?

Ranolazine for Chronic Stable Angina

Ranolazine (Ranexa) is FDA-approved for treating chronic angina and should be used as add-on therapy when symptoms remain inadequately controlled on standard antianginal agents (beta-blockers, calcium channel blockers, or nitrates), or as initial therapy in select patients who cannot tolerate first-line agents due to bradycardia, hypotension, or specific comorbidities. 1

Indications and Place in Therapy

• Ranolazine is indicated for chronic angina pectoris and may be used with beta-blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. 1

• The European Society of Cardiology recommends ranolazine as add-on therapy in patients with inadequate control of chronic angina symptoms while on treatment with beta-blockers and/or calcium channel blockers (Class IIa, Level B recommendation). 2

• Ranolazine can be considered as part of initial treatment in properly selected patients, particularly those with bradycardia, hypotension, or diabetes. 2, 3

Dosing Algorithm

• Start ranolazine at 500 mg orally twice daily, then increase to 1000 mg twice daily as needed based on clinical symptoms. 1

• Maximum recommended dose is 1000 mg twice daily. 1

• Take with or without meals; swallow tablets whole—do not crush, break, or chew. 1

• Limit maximum dose to 500 mg twice daily in patients on moderate CYP3A inhibitors (diltiazem, verapamil, erythromycin). 1

Mechanism of Action and Unique Advantages

• Ranolazine works through concentration-dependent inhibition of the late sodium current (late INa), preventing intracellular calcium overload during ischemia. 2, 4

• Ranolazine exerts antianginal effects without significantly affecting heart rate or blood pressure, making it particularly useful in patients with bradycardia or hypotension where traditional antianginal agents would be problematic. 2, 4, 3

• This neutral hemodynamic profile distinguishes ranolazine from nitrates (which cause hypotension and reflex tachycardia) and beta-blockers/calcium channel blockers (which cause bradycardia and hypotension). 3

Special Populations Where Ranolazine Excels

• Patients with diabetes and chronic stable angina benefit from ranolazine as it reduces glycated hemoglobin (HbA1c) levels, though it is not considered a diabetes treatment. 2, 4, 3

• Patients with left ventricular hypertrophy might experience greater efficacy with ranolazine compared to other antianginal drugs. 2, 4, 3

• Ranolazine may be useful in cases of bradycardia and/or hypotension due to its neutral hemodynamic profile. 2, 4

Absolute Contraindications

• Ranolazine is contraindicated in patients with liver cirrhosis or hepatic impairment. 2, 1

• Contraindicated with strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, ritonavir). 1

• Contraindicated with CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine). 1

Critical Safety Considerations and Monitoring

• Ranolazine causes dose-related QT interval prolongation, though torsades de pointes has not been observed at therapeutic doses. 2, 3

• There is little clinical experience with high doses (>1000 mg twice daily), patients with congenital long QT syndrome, or those taking other QT-prolonging drugs—exercise caution in these scenarios. 1

• Use ranolazine with caution in patients taking digoxin, as ranolazine increases digoxin concentration. 2

• Acute renal failure has been observed in patients with severe renal impairment (CrCL <30 mL/min) while taking ranolazine. 1

• P-gp inhibitors (such as cyclosporine) may increase ranolazine exposure; titrate based on clinical response. 1

Important Limitation on Outcomes

• Ranolazine effectively reduces angina symptoms and improves exercise tolerance, but has NOT been shown to improve major cardiovascular outcomes, reduce mortality, or prevent cardiovascular death and myocardial infarction in patients with chronic stable angina. 2

• In patients with non-ST-elevation acute coronary syndrome, ranolazine provided symptom relief but did not significantly reduce the composite of cardiovascular death, myocardial infarction, or recurrent ischemia. 2

Common Pitfalls to Avoid

• Do not use ranolazine as monotherapy when standard first-line agents (beta-blockers, calcium channel blockers, nitrates) have not been tried, unless specific contraindications exist. 2

• Do not exceed 500 mg twice daily when co-administering moderate CYP3A inhibitors—this is a critical dose adjustment. 1

• Do not prescribe ranolazine expecting mortality or morbidity benefit—its role is purely symptomatic relief. 2

• Monitor for QT prolongation, especially when combining with other QT-prolonging medications. 2, 1