Ranolazine for Microvascular (Small Vessel) Angina
Ranolazine is particularly effective for microvascular angina and should be added when first-line therapy (beta-blockers and/or calcium channel blockers) fails to control symptoms, though it provides symptom relief only without improving mortality or cardiovascular outcomes. 1, 2
Evidence for Microvascular Disease Specificity
Ranolazine demonstrates specific benefit in microvascular angina patients. A randomized controlled trial showed that ranolazine improved Seattle Angina Questionnaire scores, quality of life measures, and exercise test parameters in patients with documented microvascular dysfunction (coronary flow reserve <2.5) who remained symptomatic despite standard therapy 3. A subsequent real-world Canadian cohort confirmed these findings, with 73-81% of microvascular angina patients experiencing clinically significant improvements in physical limitation, treatment satisfaction, and disease perception scores 4.
The mechanism supporting this benefit relates to ranolazine's unique action through late sodium current inhibition, which prevents intracellular calcium overload without affecting heart rate or blood pressure—particularly advantageous in microvascular disease where hemodynamic alterations may worsen symptoms 1, 5.
Treatment Algorithm for Microvascular Angina
First-Line Therapy
- Beta-blockers remain the initial treatment for microvascular angina, targeting a resting heart rate of 55-60 bpm 2, 6
- Non-dihydropyridine calcium channel blockers (diltiazem or verapamil) should be substituted if beta-blockers are not tolerated 2
Adding Ranolazine (Second-Line)
- Add ranolazine when symptoms persist despite optimized first-line therapy with beta-blockers and/or calcium channel blockers 7, 2
- Start at 500 mg orally twice daily, escalating to 1000 mg twice daily based on symptom response 1, 5
- Ranolazine can be combined with beta-blockers, calcium channel blockers (amlodipine), or long-acting nitrates 1, 7
Alternative Second-Line Options
- Ivabradine may be superior to beta-blockers specifically for microvascular disease, improving coronary flow reserve more effectively despite similar heart rate reduction 2
- Trimetazidine can be considered as add-on therapy for refractory symptoms 2
Critical Contraindications and Dosing Adjustments
Absolute contraindications 5:
- Strong CYP3A inhibitors (ketoconazole, clarithromycin, nelfinavir)
- CYP3A inducers (rifampin, phenobarbital, St. John's wort)
- Liver cirrhosis
- Severe renal impairment (GFR <30 mL/min/1.73 m²) including hemodialysis patients 8
Dose limitation to 500 mg twice daily required with 5:
- Moderate CYP3A inhibitors (diltiazem, verapamil, erythromycin)
Monitor for QTc prolongation, though this appears clinically benign and ranolazine may actually have antiarrhythmic properties 1, 5, 9.
Important Clinical Caveats
Ranolazine does not improve cardiovascular outcomes. The MERLIN-TIMI 36 trial (N=6,560) demonstrated symptom relief but failed to reduce the composite endpoint of cardiovascular death, MI, or recurrent ischemia (HR 0.92,95% CI 0.83-1.02) 1. This is purely symptomatic therapy, not prognostic modification 7.
Common adverse effects include dizziness, nausea, headache, and constipation, occurring in >4% of patients 5, 9. These are generally mild and do not require discontinuation.
Drug interactions require attention: limit simvastatin to 20 mg daily and metformin to 1700 mg daily when using ranolazine 1000 mg twice daily 5. Digoxin and CYP2D6 substrates (tricyclic antidepressants) may require dose reduction 5.
Practical Implementation
For a patient with confirmed microvascular angina (normal coronary angiography, coronary flow reserve <2.5) who remains symptomatic on beta-blocker therapy, initiate ranolazine 500 mg twice daily 2, 3. Assess symptom response after 4-6 weeks using validated tools like the Seattle Angina Questionnaire 3, 4. If symptoms persist, increase to 1000 mg twice daily 5. Ranolazine's hemodynamic neutrality makes it particularly useful in patients with low blood pressure, bradycardia, or diabetes 1, 2.
Monitor renal function after initiation and periodically in patients with moderate renal impairment (CrCl <60 mL/min), discontinuing if acute renal failure develops 5.