Nicorandil - A review of its use in the management of stable angina pectoris, including high-risk patients

Nicorandil (Adancor(R), Angicor(R), Dancor(R), Nikoril(R) [Europe], Ikorel(R) [Europe and Oceania], Sigmart(R) [Japan, Korea and Taiwan]) is an adenosine triphosphate (ATP)-sensitive potassium (K-ATP) channel agonist with nitrate-like properties used in the management of stable angina pectoris. With well established monotherapeutic antianginal activity and a beneficial effect (when added to optimal antianginal therapy) on clinical outcomes in high-risk patients with stable angina, twice-daily oral nicorandil is a useful alternative or addition to other antianginal therapy. Pharmacological Properties The nitrate effect of nicorandil decreases cardiac preload by dilating venous capacitance vessels, and the K-ATP channel opening reduces cardiac afterload by producing a sustained dilating action on both arterial and coronary vasculature, including both coronary artery conductance and resistance vessels. Nicorandil also protects the heart against ischaemic damage by mimicking the cardioprotective effect conferred by single or multiple brief periods of ischaemia and reperfusion that often precede a prolonged episode of myocardial ischaemia. Although the exact mechanism by which nicorandil confers this cardioprotection is not fully understood, activation of mitochondrial K-ATP channels is thought to play a key role. In patients undergoing percutaneous transluminal coronary angioplasty, orally administered nicorandil reduced ST-segment elevation during ischaemia and QT dispersion after reperfusion, suggesting a cardioprotective effect. Additionally, nicorandil appears to improve myocardial energy metabolism in anginal patients during exertion. Oral nicorandil may also reduce the risk of coronary thrombus formation by improving fibrinolytic capacity, as it has been shown to reduce the activity of plasminogen activator inhibitor-1 in patients with coronary artery disease. Maximum plasma concentrations (C-max) of nicorandil are achieved 0.5-1 hour after oral administration, and the drug has an absolute bioavailability of approximate to75%. Plasma concentrations are dose proportional after oral doses of 5-40mg, and steady state is reached after 4 days of twice-daily administration. Steady-state C-max after twice-daily oral nicorandil 10 or 20mg was 124 and 246 mug/L, respectively. The drug is weakly bound to plasma proteins and has an apparent volume of distribution of approximate to1 L/kg after an oral 20mg dose. A single 10 or 20mg dose of nicorandil is almost entirely eliminated from the plasma within 8 hours, although a residual plasma concentration of 0.8-1.5 mug/L is detectable for a further 16 hours. The total body clearance is 51 L/h. Therapeutic Efficacy Nicorandil 10 or 20mg, administered orally twice daily, has well established antianginal efficacy that is similar to other nitrates (isosorbide di- and mononitrate), beta-adrenoceptor antagonists (metoprolol, propranolol and atenolol) and calcium channel antagonists (diltiazem, amlodipine and nifedipine). In the large, randomised, double-blind IONA (Impact Of Nicorandil on Angina) study in 5126 patients with stable angina and additional risk factors for a coronary event, nicorandil 10 or 20mg or placebo twice daily was added to optimal antianginal therapy and coronary heart disease (CHD) risk-modifying drugs. Nicorandil recipients had a significantly reduced incidence of CHD death, nonfatal myocardial infarction (MI) or unplanned admission for cardiac-related chest pain (the composite primary endpoint) [risk reduction 17%, p = 0.014 vs placebo]. The combined incidence of CHD death or nonfatal MI (secondary endpoint) was numerically less (but not statistically different) for nicorandil recipients than placebo recipients. However, nicorandil recipients had a significantly lower risk of experiencing a cardiovascular event (based on a composite of all cardiovascular events) or an acute coronary syndrome (CHD death, nonfatal MI or unstable angina). Tolerability Nicorandil was generally well tolerated in clinical trials (maximum treatment period 3 years). In a 1-year open-label study, the proportion of patients experiencing adverse events with nicorandil treatment was 36%, which was similar to the proportion of patients (30-35%) who experienced adverse effects with nicorandil or other antianginal agents in comparative studies. Adverse events were generally experienced at the start of nicorandil therapy and their incidence decreased during the treatment period. Headache (of mostly mild-to-moderate severity) was the most frequently reported drug-related adverse event with nicorandil treatment (up to 36% of patients). It was also the event that was most commonly responsible for patients discontinuing nicorandil therapy. A lower starting dosage appears to reduce the discontinuation rate and progressive dose titration is also recommended. Other adverse events included gastrointestinal events, dizziness, malaise and fatigue. Although age-specific adverse events were not monitored in the studies reviewed here, nicorandil appears to be well tolerated in elderly patients. There are reports of oral and anal ulceration being associated with nicorandil therapy.