What is the recommended use of Ranolazine (ranolazine) in adult patients with a history of cardiovascular disease, hypertension, hyperlipidemia, or diabetes, and impaired renal function for the treatment of chronic angina?

Ranolazine Use in Chronic Angina

Ranolazine is indicated for chronic angina as monotherapy or add-on therapy when symptoms are inadequately controlled with standard antianginal agents (beta-blockers, calcium channel blockers, or nitrates), but it is absolutely contraindicated in patients with severe renal impairment (GFR <30 mL/min/1.73 m²) and in those with hepatic impairment or liver cirrhosis. 1, 2, 3

Primary Indications and Patient Selection

FDA-Approved Use

• Ranolazine is FDA-approved for treatment of chronic angina pectoris and may be used in combination with beta-blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers 1

Guideline-Recommended Patient Populations

• Add-on therapy: 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
• Initial treatment: Can be considered as part of initial treatment in properly selected patients 2

Special Populations Where Ranolazine May Be Particularly Beneficial

Diabetes Mellitus

Ranolazine should be the preferred antianginal agent in patients with type 2 diabetes and chronic stable angina. 4

• Ranolazine significantly reduces glycated hemoglobin (HbA1c) levels, fasting glucose, and 2-hour postprandial glucose levels while simultaneously reducing angina pain and increasing exercise tolerance 4, 2
• This dual benefit makes it particularly advantageous over other antianginal agents in diabetic patients 4
• The American Diabetes Association notes these glycemic benefits, though ranolazine is not considered a primary diabetes treatment 2

Bradycardia and/or Hypotension

• Ranolazine has a neutral hemodynamic profile, exerting antianginal effects without significantly affecting heart rate or blood pressure 2, 5
• This makes it particularly useful when other antianginal agents (beta-blockers, calcium channel blockers) would worsen these conditions 4, 2

Left Ventricular Hypertrophy

• Patients with left ventricular hypertrophy might experience greater efficacy with ranolazine compared to other antianginal drugs 2, 5

Hypertension

• Beta-blockers and dihydropyridine calcium channel blockers remain preferred in hypertension, but ranolazine can be added without concern for excessive blood pressure lowering 4

Atrial Fibrillation

• Ranolazine has been shown to suppress supraventricular arrhythmias and atrial fibrillation, making it particularly useful when added to beta-blockers in patients with both chronic stable angina and atrial fibrillation 4

Absolute Contraindications

Severe Renal Impairment

Do NOT prescribe ranolazine when GFR is <30 mL/min/1.73 m². 2, 3

• Ranolazine undergoes extensive hepatic metabolism but is primarily excreted by the kidney 4, 3
• Plasma levels increase 50-97% as kidney function declines 3
• Risk of acute renal failure exists in patients with severe renal impairment 3
• QT prolongation becomes more pronounced with drug accumulation in renal impairment 3

Hepatic Impairment

Ranolazine is contraindicated in patients with hepatic impairment or liver cirrhosis. 4, 2, 5

• Plasma levels increase up to 50-60% in patients with moderate hepatic impairment 4

Dosing Recommendations

Standard Dosing

• Initial dose: 500 mg orally twice daily 2
• Maximum dose: 1000 mg twice daily, escalated as needed 2

Moderate Renal Impairment (CrCl 30-60 mL/min)

• Limit dose to 500 mg twice daily due to increased risk of adverse effects 3

Important Drug Interactions and Precautions

Digoxin

• Use ranolazine with caution in patients taking digoxin, as ranolazine increases digoxin concentration 2, 5

CYP3A Inhibitors

• Exercise caution when co-administered with strong CYP3A inhibitors 2

QT Prolongation

• Ranolazine causes dose-related QT interval prolongation 2
• However, torsades de pointes has not been observed at therapeutic doses 2
• The QT prolongation does not appear to have clinical consequences, and several studies suggest ranolazine may have antiarrhythmic effects 2

Clinical Efficacy and Limitations

Symptom Relief

• Ranolazine effectively reduces angina symptoms and improves exercise tolerance 2
• Reduces angina attacks and nitroglycerin use by approximately 1 per week compared to placebo 2
• Exercise duration increases are modest but statistically significant 2

Cardiovascular Outcomes

Critical limitation: Ranolazine does NOT improve major cardiovascular outcomes or reduce mortality in patients with chronic stable angina. 2

• Has not been shown to reduce major cardiovascular events, including cardiovascular death and myocardial infarction, in patients with non-ST-segment elevation acute coronary syndrome 2
• Does not improve outcomes regardless of ventricular function 2

Alternative Agents in Renal Impairment

When ranolazine is contraindicated due to renal impairment (GFR <30 mL/min/1.73 m²):

• Calcium channel blockers and nitrates are preferred options, as they have no renal contraindications 3
• Beta-selective blockers (bisoprolol) or ivabradine can be used for heart rate control without renal dose adjustment concerns 3
• Trimetazidine should also be avoided when GFR is <30 mL/min/1.73 m² 4

Mechanism of Action

• Ranolazine works primarily through concentration-dependent, voltage-dependent, and frequency-dependent inhibition of the late sodium current (late INa) 2, 5
• This prevents intracellular calcium overload during ischemia, leading to reduced oxygen demand and left ventricular wall tension 2
• Also promotes glucose oxidation and improves anaerobic metabolism under ischemic conditions 2