What is Nicorandil?

Nicorandil: A Potassium Channel Activator with Nitrate Properties for Angina Treatment

Nicorandil is a potassium channel activator with a nitrate moiety that serves as a second-line antianginal agent for patients with persistent angina despite beta-blocker therapy or in those unable to tolerate first-line treatments. 1

Mechanism of Action

• Nicorandil has a dual mechanism of action: it activates ATP-sensitive potassium channels and has nitrate-like effects, making it a balanced coronary and peripheral vasodilator 2
• By opening potassium channels, nicorandil causes hyperpolarization of vascular smooth muscle cell membranes, leading to vasodilation 3
• The nitrate component contributes to venodilation, while the potassium channel activation primarily affects arterial vasodilation 4
• This combination reduces both preload and afterload without impairing myocardial contractility or atrioventricular conduction 2

Clinical Use in Angina

• Nicorandil is typically administered at a usual dose of 20 mg twice daily for the prevention of angina 5
• It can be considered as an alternative when beta-blockers cannot be tolerated (Class IIb, Level C recommendation by European Society of Cardiology) 1
• Nicorandil may be used as monotherapy or in combination with other antianginal drugs when symptoms persist despite first-line treatment 5
• It is particularly effective in vasospastic angina due to its strong spasmolytic activity 2

Efficacy

• Nicorandil has demonstrated antianginal efficacy comparable to beta-blockers (atenolol, propranolol) and calcium channel blockers (diltiazem) in comparative trials 2, 4
• In monotherapy, nicorandil controls symptoms in 69-80% of patients with stable chronic angina 2
• The IONA outcome study showed that nicorandil significantly reduced the composite primary endpoint of cardiovascular death, nonfatal myocardial infarction, or unplanned hospitalization for chest pain 5
• However, the benefits in the IONA trial were primarily driven by reduction in unplanned hospitalization for unstable angina rather than mortality benefits 5

Potential Cardioprotective Effects

• Nicorandil is thought to have cardioprotective properties beyond its antianginal effects 5
• Studies suggest it may protect the myocardium during ischemic events through its potassium channel activation mechanism 3
• A propensity-matched cohort of 5,115 Japanese patients with chronic stable angina showed beneficial effects when followed for 7 years 5

Side Effects and Precautions

• The main adverse effects include headache, reflux, tachycardia, facial flushing, and hypotension 5
• Headaches typically occur early in treatment and can be minimized by starting with a lower dose (5 mg twice daily) and gradually titrating upward 4
• Rarely, serious skin, mucosal, and eye ulceration have been reported 5
• The concomitant use of nicorandil with aspirin might increase the risk of gastrointestinal ulcers, perforations, and hemorrhage 5

Important Clinical Considerations

• Nicorandil should not be combined with nitrates due to lack of additional efficacy 1
• Combination with ivabradine or ranolazine is not recommended due to unknown safety profile 1
• Use in patients with heart failure should be approached with caution as safety remains uncertain 1
• Tolerance to the antianginal effect may develop with chronic dosing, but cross-tolerance with nitrates does not appear to be a problem 5

Place in Treatment Algorithm

• Beta-blockers remain the preferred first-line treatment for angina due to their proven mortality benefits 1
• If beta-blockers are contraindicated or poorly tolerated, alternative first-line options include ivabradine, nitrates, calcium channel blockers, or nicorandil 1
• Nicorandil has been downgraded to a Class IIb recommendation (may be considered) as add-on therapy for inadequate symptom control in the 2024 ESC guidelines 1
• For vasospastic angina specifically, nicorandil may be valuable in patients who do not respond to combination therapy with calcium antagonists and oral nitrates 5