What is the recommended dosage and treatment approach for ranolazine in patients with chronic angina?

Ranolazine for Chronic Angina: Dosing and Treatment Approach

Start ranolazine at 500 mg orally 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, calcium channel blockers, or nitrates. 1

Indications and Patient Selection

• Ranolazine is indicated for chronic stable angina as monotherapy or combination therapy when symptoms are not adequately controlled with standard antianginal agents (beta-blockers, calcium channel blockers, nitrates). 1

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

• Ranolazine is particularly useful in specific clinical scenarios:

  • Patients with bradycardia or hypotension who cannot tolerate rate-lowering or blood pressure-lowering agents 2, 3
  • Diabetic patients with chronic stable angina (ranolazine reduces HbA1c levels) 2, 3
  • Patients with left ventricular hypertrophy (may experience greater efficacy) 2

Dosing Regimen

• Initial dose: 500 mg orally twice daily 4, 1

• Maximum dose: 1000 mg orally twice daily, titrated based on clinical symptom response 4, 1

• The dose escalation should occur after assessing symptom control at the initial dose. 1

Mechanism and Hemodynamic Profile

• Ranolazine inhibits the late sodium current (late INa), preventing intracellular calcium overload during ischemia without significantly affecting heart rate or blood pressure. 4, 2

• This hemodynamically neutral profile distinguishes ranolazine from traditional antianginal agents, making it advantageous when rate or blood pressure reduction is undesirable. 4, 2

Expected Clinical Benefits

• Ranolazine reduces angina frequency and nitroglycerin use:

  • In the CARISA trial, ranolazine 1000 mg twice daily reduced angina attacks from 3.3 to 2.1 per week (p<0.001) 1
  • Nitroglycerin use decreased from 3.1 to 1.8 doses per week (p<0.001) 1

• Exercise tolerance improves modestly with statistically significant increases in exercise duration and time to angina at both trough and peak plasma levels. 1

• Important limitation: Ranolazine provides symptom relief but does not reduce major cardiovascular events (cardiovascular death, myocardial infarction) or improve mortality. 4, 2

Contraindications

• Absolute contraindications: 1
  • Liver cirrhosis or hepatic impairment
  • Concurrent use with strong CYP3A inhibitors (ketoconazole, clarithromycin, nelfinavir)
  • Concurrent use with CYP3A inducers (rifampin, phenobarbital, St. John's wort)

Dose Adjustments for Drug Interactions

• With moderate CYP3A inhibitors (diltiazem, verapamil, erythromycin): Limit ranolazine to 500 mg twice daily 1

• With P-glycoprotein inhibitors (cyclosporine): Titrate ranolazine based on clinical response 1

• Ranolazine affects other medications:

  • Limit simvastatin to 20 mg daily when used with ranolazine 1
  • Limit metformin to 1700 mg daily when used with ranolazine 1000 mg twice daily 1
  • Digoxin levels increase 40-60%; monitor and adjust digoxin dose 1, 5

Safety Considerations

• QTc prolongation occurs in a dose-related manner, but torsades de pointes has not been observed at therapeutic doses. 4, 2, 1

• Common adverse effects (>4%): dizziness, headache, constipation, nausea 1

• Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCl <60 mL/min); discontinue if acute renal failure develops. 1

• Ranolazine exposure increases up to 2-fold with advancing renal impairment. 5

Clinical Pitfalls to Avoid

• Do not use ranolazine for acute coronary syndrome—the MERLIN-TIMI 36 trial showed no benefit on outcome measures in 6,560 patients with non-ST-elevation ACS. 4, 1

• Gender effects are important: Women show considerably smaller improvements in angina frequency and exercise tolerance compared to men (approximately 33% of the male response in CARISA). 1

• Tolerance does not develop after 12 weeks of therapy, and rebound angina has not been observed following abrupt discontinuation. 1

• Do not expect mortality or major cardiovascular event reduction—ranolazine is purely for symptom management. 2