What is the preferred treatment for a patient with stable angina pectoris, comparing nitroglycerin (glyceryl trinitrate) and ranolazine?

Nitroglycerin vs Ranolazine for Stable Angina

Nitroglycerin should be prescribed to all patients with stable angina for immediate symptom relief and situational prophylaxis, while ranolazine is reserved as add-on therapy when symptoms remain inadequately controlled despite optimal doses of first-line agents (beta-blockers, calcium channel blockers, or long-acting nitrates). 1, 2

Nitroglycerin: First-Line for Acute Relief

Short-acting nitroglycerin is mandatory for all stable angina patients regardless of other therapies, serving two critical functions 1:

• Immediate relief of acute anginal episodes
• Prophylactic use before activities known to trigger angina

This represents a Class I, Level B recommendation from the European Society of Cardiology—meaning nitroglycerin is essential, not optional 1.

Ranolazine: Second-Line Add-On Therapy

When to Use Ranolazine

Ranolazine should only be added when angina persists despite optimized first-line therapy (beta-blockers, calcium channel blockers, or long-acting nitrates at maximum tolerated doses) 1, 2. The European Society of Cardiology gives this a Class IIa, Level B recommendation 2, 3.

Clinical Efficacy

Ranolazine provides modest symptomatic benefit in properly selected patients 4, 5:

• In the CARISA trial, ranolazine 750-1000 mg twice daily increased exercise duration by 24-34 seconds versus placebo when added to standard therapy 4
• Angina frequency decreased from 3.3 to 2.1-2.5 attacks per week 4
• Nitroglycerin use decreased from 3.1 to 1.8-2.1 doses per week 4

Critical limitation: Ranolazine does not reduce mortality, myocardial infarction, or need for revascularization 1, 2, 3. The RIVER-PCI and MERLIN trials definitively showed no improvement in hard cardiovascular outcomes 1.

Unique Advantages of Ranolazine

Ranolazine has a neutral hemodynamic profile—it does not lower heart rate or blood pressure 1, 2, 6. This makes it particularly valuable in three specific scenarios:

• Patients with bradycardia who cannot tolerate beta-blockers 1, 2
• Patients with hypotension limiting use of other antianginals 1, 2
• Patients with diabetes and angina, as ranolazine reduces HbA1c levels 1, 2

Ranolazine may also be more effective in patients with left ventricular hypertrophy due to its effects on sodium and calcium homeostasis 1, 6.

Absolute Contraindications

Ranolazine is absolutely contraindicated in hepatic impairment or liver cirrhosis 1, 2, 3. This is critical because ranolazine causes dose-dependent QTc prolongation, and hepatic dysfunction leads to drug accumulation with increased arrhythmia risk 1, 2.

Important Drug Interactions

• Ranolazine increases digoxin concentrations—use with extreme caution if co-administered 1, 2, 3
• Avoid strong CYP3A inhibitors (ketoconazole, clarithromycin, ritonavir) which increase ranolazine levels 2, 3

Dosing

Start ranolazine at 500 mg twice daily, escalating to 1000 mg twice daily as needed and tolerated 2, 4. The 1000 mg dose showed no additional exercise benefit over 750 mg in CARISA, but did reduce angina frequency further 4.

Practical Algorithm

Step 1: Prescribe short-acting nitroglycerin to ALL stable angina patients 1

Step 2: Optimize a beta-blocker to maximum tolerated dose (or calcium channel blocker if beta-blocker contraindicated) 1

Step 3: If angina persists, add or switch to a second first-line agent (calcium channel blocker or long-acting nitrate) 1

Step 4: Only if angina remains inadequately controlled on optimized first-line therapy, consider adding ranolazine 1, 2

Step 5: Before adding ranolazine, verify:

• No hepatic impairment or cirrhosis 1, 2
• Check baseline QTc interval 1
• Review for digoxin use and CYP3A inhibitors 1, 2

Common Pitfalls

Do not use ranolazine as monotherapy or first-line treatment—it is approved only as add-on therapy 4, 7. The evidence supports its use exclusively in patients who remain symptomatic despite standard antianginal medications 8, 5.

Do not expect prognostic benefit from ranolazine—it improves symptoms but does not prevent death or myocardial infarction 1, 2, 3. This distinguishes it from beta-blockers, which do improve outcomes post-MI 1.

Ranolazine failed to show benefit in microvascular angina despite theoretical advantages—a larger trial showed no superiority over placebo for angina frequency or ischemia reduction 1, 3.

The most common adverse effects are dizziness, nausea, constipation, and headache 7, 5, 9. Despite QTc prolongation, torsades de pointes has not been observed at therapeutic doses 2, 6.