What is the role of Nikorandil (nicorandil) in the treatment of angina pectoris?

Nicorandil in the Treatment of Angina Pectoris

Nicorandil may be considered as a second-line antianginal agent in patients with persistent angina despite beta-blocker therapy or in those unable to tolerate beta-blockers, but its safety in heart failure remains uncertain. 1

Mechanism of Action and Pharmacology

• Nicorandil is a potassium channel activator with a nitrate moiety, providing a dual mechanism of action that combines arterial and venous vasodilation 2
• It causes sustained dilation of both arterial resistance and conductive vessels, increasing coronary blood flow without significant effects on heart rate, blood pressure, or cardiac contractility at clinical doses 3
• The coronary vasodilation mechanism appears to be associated with increases in cyclic GMP and hyperpolarization of smooth muscle membrane 3

Place in Therapy for Angina Pectoris

Current Guideline Recommendations:

• First-line therapy: Beta-blockers remain the preferred first-line treatment for angina due to their proven benefits in reducing heart failure hospitalization and mortality 1
• Alternative first-line options (when beta-blockers cannot be tolerated):
  • Ivabradine (Class IIa, Level A) 1
  • Oral or transcutaneous nitrates (Class IIa, Level A) 1
  • Amlodipine (Class IIa, Level A) 1
  • Nicorandil (Class IIb, Level C) - considered a potential alternative but with uncertain safety in heart failure 1

Second-line Therapy:

• Nicorandil may be considered when angina persists despite treatment with a beta-blocker (or alternative first-line agent) 1
• In the 2024 ESC guidelines for chronic coronary syndromes, nicorandil has been downgraded to a Class IIb recommendation (may be considered) as add-on therapy for inadequate symptom control 1

Efficacy

• Comparative studies have shown that nicorandil has similar efficacy to isosorbide dinitrate, beta-blockers (propranolol, atenolol), and calcium channel blockers (nifedipine, diltiazem) in treating stable angina 2, 4
• Efficacy is maintained for up to one year with no evidence of tolerance development 2, 4
• At recommended doses (10-40 mg daily), nicorandil controls symptoms in 69-80% of patients with stable chronic angina 4
• Preliminary evidence suggests potential efficacy in variant angina and unstable angina, including in patients refractory to conventional antianginal therapy 2

Dosing and Administration

• Usual dose: 10-20 mg twice daily 2
• For patients prone to headache, starting with a lower dose (5 mg twice daily) may improve tolerability 2
• The long duration of action allows for an effective twice-daily dosing regimen 4

Side Effects and Precautions

• Headache is the most common adverse event (occurring in approximately one-third of patients), typically mild to moderate in intensity and decreasing with continued treatment 2
• Approximately 5% of patients withdraw from treatment due to headache 2
• Unlike calcium channel blockers such as verapamil and diltiazem, nicorandil has no depressant effect on atrioventricular conduction 3

Important Contraindications and Combinations to Avoid

• Combination of nicorandil with nitrates is not recommended due to lack of additional efficacy 1
• Combination of nicorandil with ivabradine or ranolazine is not recommended due to unknown safety 1
• Use in patients with heart failure should be approached with caution as safety remains uncertain 1

Special Considerations

• Nicorandil may be particularly useful in patients with coronary vasospasm due to its strong spasmolytic activity 4
• Unlike some antianginal medications, nicorandil does not adversely affect lipid profiles or glucose levels 4
• In patients with left ventricular dysfunction, beta-blockers remain the preferred first-line therapy, with nicorandil considered only after other options with more established safety profiles 1

Treatment Algorithm for Angina

1. First-line: Beta-blockers (if tolerated and not contraindicated) 1
2. If beta-blockers contraindicated or not tolerated:
   • Ivabradine (if in sinus rhythm)
   • Nitrates
   • Amlodipine
   • Nicorandil (with caution in heart failure) 1
3. If symptoms persist on monotherapy: Add a second agent
   • Ivabradine, nitrates, or amlodipine (preferred)
   • Nicorandil (with caution in heart failure) 1
4. If symptoms persist on dual therapy: Consider coronary revascularization 1