CCS is a growing clinical burden worldwide, particularly in the Gulf region. |
Current guideline recommendations for anti-anginal escalation have a limited evidence base. |
Nitrates are frequently used for the treatment of CCS but have their limitations. |
Nicorandil is a useful therapeutic option offering vasodilatory and cardioprotective effects. |
Nicorandil has a contemporary randomised evidence base and a favourable clinical profile. |
Digital Features
Introduction
Clinical Presentation
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Patients with suspected CAD and ‘stable’ anginal symptoms, and/or dyspnoea
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Patients with new onset heart failure or left ventricular dysfunction and suspected CAD
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Asymptomatic and symptomatic patients with stabilised symptoms < 1 year after acute coronary syndrome (ACS) or with recent revascularisation
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Patients with angina and suspected vasospastic or microvascular disease
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Asymptomatic patients in whom CAD is detected at screening
Epidemiology
High Burden of Cardiovascular Disease
Need For Gulf Region-Specific Data on CCS
Impact of Diabetes Mellitus (DM)
Management Challenges
Stratified Selection of Anti-anginal Drug Therapy
ESC recommendations | Treatment option | Class | Level |
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First line | β-blockers and/or calcium channel blockers to control heart rate and symptoms | I | A |
If symptoms not controlled on a β-blocker or a calcium channel blocker, the combination of a β-blocker and a dihydropyridine calcium channel blocker should be considered | IIa | C | |
Initial first-line treatment with a β-blocker and a dihydropyridine calcium channel blocker should be considered | IIa | B | |
Second line | Long-acting nitrates should be considered when initial therapy with a β-blocker and/or a non-dihydropyridine calcium channel blocker is contraindicated, poorly tolerated or inadequate in controlling symptoms | IIa | B |
Nicorandil, ranolazine, ivabradine or trimetazidine should be considered to reduced angina frequency and improve exercise tolerance in those who cannot tolerate, have contraindications to, or whose symptoms are not controlled by β-blockers, calcium channel blockers and long-acting nitrates | IIb | B | |
In selected patients, the combination of a β-blocker or a calcium channel blocker with second-line drugs (nicorandil, ranolazine, ivabradine and trimetazidine) may be considered for first-line treatment according to heart rate, blood pressure and tolerance | |||
Other | Short-acting nitrates are recommended for immediate relief of effort angina | I | B |
When long-acting nitrates are prescribed, a nitrate-free or low-nitrate interval should be considered to reduce tolerance | IIa | B | |
In patients with a low heart rate and blood pressure, ranolazine or trimetazidine may be considered as first-line to reduce angina frequency and improve exercise tolerance | IIb | C | |
In selected patients, the combination of a β-blocker or a calcium channel blocker with a second-line drug (nicorandil, ranolazine, ivabradine and trimetazidine) may be considered for first-line treatment according to heart rate, blood pressure and tolerance | IIb | B | |
Nitrates are not recommended in patients with hypertrophic obstructive cardiomyopathy or co-administration with phosphodiesterase inhibitors | III | B |
AHA recommendations | Treatment option | Class | Level |
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First line | β-blocker | I | B |
Long-acting non-dihydropyridine calcium channel blocker (e.g. verapamil or diltiazem) | IIa | B | |
Second line | Calcium channel blocker/long-acting nitrates when β-blockers contraindicated or unacceptable side effects | I | B |
Addition of calcium channel blocker/long-acting nitrates if β-blocker unsuccessful alone | I | B | |
Ranolazine can be used as a substitute if initial treatment with a β-blocker is ineffective, contraindicated or not tolerated | IIa | B | |
Addition of ranolazine if initial treatment with β-blocker unsuccessful | IIa | A | |
Other | Sublingual nitroglycerin for immediate relief of angina | I | B |
Lack of Improved Cardiovascular Outcomes with Anti-anginals
Should Long-Acting Nitrates be the First Choice Second-Line Agent?
Nicorandil
Long-acting nitrates | Nicorandil | Molsidomine | |
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Evidence for benefit in stable angina | Yes | Yes | |
Randomised evidence | Yes [105] | Yes | Yes [104] |
Comparison against placebo | Yes [105] | Yes | Yes [104] |
Benefit as add-on to first line therapy | Yes, although poor-quality evidence [37] | Yes | Yes |
Benefit in microvascular dysfunction | Yes, but limited evidence | No evidence | |
Concerns about tolerance and endothelial dysfunction | Yes | No | |
Cost for 28 days treatment [109] | Isosorbide mononitrate 25 mg modified-release capsules; NHS prescription price: £9 | Nicorandil (20 mg twice a day); NHS prescription price: £9 | Molsidomine tablets (2 mg); NHS prescription price: £9.00 |
Isosorbide mononitrate MR tablets (60 mg); Basic NHS price: £10.50 | Nicorandil (20 mg twice a day); Basic NHS price: £4.59 | ||
Isosorbide dinitrate (20 mg four times a day): £29.04 | Nicorandil (10 mg; 30 tablets): 30 Saudi Riyal | ||
Isosorbide dinitrate (10 mg; 30 tablets): 25 Saudi Riyal; (20 mg; 30 tablets): 45 Saudi Riyal | Nicorandil (20 mg; 30 tablets): 60 Saudi Riyal |
Pharmacology and Physiology
Pharmacokinetics and Dosage
Mechanism of action | Absorption | Peak dose | Half-life | Metabolism | Elimination | Prescribing considerations | Adverse effects |
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Nitric oxide donor | > 75% oral bioavailability | 30–60 min | 1–2 h | Extensive hepatic metabolism | Mainly renal | Twice-daily dosing | Hypotension Dizziness Headache Vasodilation and flushing |
Activates adenosine-sensitive potassium-channel (K+ATP) | Almost complete enteral absorption | Linear dose-to-plasma concentration | Mostly eliminated from plasma within 8 h | Predominantly denitration followed by subsequent nicotinamide metabolism | More than 60% of administered dose eliminated in urine 24 h after dosing | No specific dosing in the elderly or in patients with chronic renal or hepatic impairment | Weakness, nausea and vomiting, haemorrhage |
Avoids first-pass metabolism | Only 1% excreted unchanged in urine | Rarely skin, mucosal, gastro-intestinal and eye ulceration |
Clinical Efficacy
Author and date | Study size and treatment duration | Study design | Dosing and comparator | Outcome |
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Nicorandil vs. placebo | ||||
IONA study group 2002 [95] | n = 5126 Median 1.6 years ± 0.5 | Multicentre placebo-controlled RCT | 20 mg nicorandil twice daily vs. placebo | Significant improvement in reduction in major coronary events:15.5% vs. 13.1% (hazard ratio 0.83, 95% CI 0.72–0.91, p = 0.068) of primary composite endpoint (coronary heart disease death, non-fatal myocardial infarction, unplanned hospitalisation for angina) |
Comparison with long-acting nitrates | ||||
Döring et al. 1992 [83] | n = 129 4–6 weeks | Multicentre RCT Two double-blind studies: 1. Comparison with isosorbide mononitrate in crossover design 2. Nicorandil and isosorbide dinitrate administered to two parallel groups | 1. 20 mg nicorandil vs. 20 mg mononitrate twice daily 2. 10 mg three times a day for 2 weeks, then 20 mg three times a day for 4 weeks | Equally effective in treatment of stress-induced angina Prolonged bicycle exercise tolerance, reduced ST-segment depression and reduced weekly angina attack rates No significant difference between groups No development of tolerance to nitrates |
Falcone et al. 1993 [85] | n = 41 | Double-blind RCT | Nicorandil 10–20 mg twice daily | Significant increases in time to angina and maximum ST depression |
Ciampricotti et al. 2000 [82] | n = 194 Elderly patients ≥ 65 years with stable angina and positive exercise test (≥ 0.1 mV ST-segment depression) 4 weeks | Multicentre, double-blind, double-dummy controlled | 10 mg twice daily nicorandil ISMN | Significant postponement of onset of ischaemia compared with baseline No differences between nicorandil and ISMN |
Zhu et al. 2007 [86] | n = 232 2 weeks | Double-dummy RCT | Nicorandil 5 mg three times a day vs. ISMN 20 mg twice daily | Nicorandil and ISMN significantly increased time to 1 mm ST segment depression, total exercise time and time to angina onset Both reduced number of anginal attacks Use of short-acting nitrates significantly reduced only with nicorandil |
Comparison with β-blockers | ||||
Hughes et al. 1990 [88] | n = 37 6 weeks | Double-dummy, placebo-controlled parallel RCT | Nicorandil 10–20 mg twice daily vs. atenolol 50–100 mg daily | Improvements in exercise time, time to angina and 1 mm ST depression compared to baseline No significant difference between treatment groups |
Di Somma et al. 1993 [87] | n = 20 6 weeks | Double-blind parallel RCT | 10–20 mg twice daily nicorandil vs. 100 mg metoprolol twice daily | Total exercise duration and time to ischaemia reduced Sublingual nitroglycerin use and angina attacks reduced Both nicorandil 10 mg and 20 mg twice daily exerted similar effects to that of metoprolol |
Meeter et al. 1992 [89] | n = 77 men 6 weeks | Double-blind parallel RCT | Nicorandil 10–20 mg twice daily Propranolol 40–80 mg three times a day | Number of anginal attacks decreased relative to baseline with nicorandil and propranolol (p < 0.002) Total exercise duration not influenced by either drug Delay in occurrence of ischaemia with both |
Raftery et al. 1993 [90] | n = 37 6 weeks | Double-blind parallel RCT | Nicorandil 10–20 mg twice daily or atenolol 50–100 mg once a day | Significant improvement with both to time to 1 mm ST segment depression, time to angina onset and time to peak exercise compared to baseline No significant difference between nicorandil or atenolol |
Comparison with calcium channel blockers | ||||
Ulvenstam et al. 1992 [94] | n = 58 8 weeks | Multicentre double-blind RCT | Nicorandil 10–20 mg twice daily vs. nifedipine 20 mg twice daily | Anginal attack rate decreased significantly compared with baseline Both treatments significantly increased exercise duration, time to angina onset and time to 1 mm ST depression No significant differences between treatment groups |
Guermonprez et al. 1993 [91] | n = 123 3 months | Double-blind parallel RCT | Nicorandil 20 mg twice a day vs. diltiazem 60 mg three times a day | Both reduced frequency of anginal attacks and use of nitroglycerin Significant improvements in maximum exercise capacity and work required to angina onset No significant difference between groups |
Swan Study Group (Chatterjee et al.) 1999 [93] | n = 121 8 weeks | Multicentre, double-blind, RCT | Nicorandil 10–20 mg twice daily vs. amlodipine 5–10 mg daily | Time to onset of ST-segment depression increased only with amlodipine Time to onset of angina and total exercise duration increased with both Both reduced magnitude of ST depression at maximal workload, weekly angina attacks and nitroglycerin use No differences between treatment groups |
Comparison with standard anti-anginal therapy | ||||
Jiang et al. 2016 [99] | n = 402 12 weeks | Multicentre, open-label, RCT | 12 weeks of nicorandil (5 mg three times daily) plus current standard anti-anginal therapy vs. current standard anti-anginal therapy | Significantly reduced number of myocardial ischaemic attacks with nicorandil compared to control (adjusted ratio 0.503; 95% CI 0.301–0.840; p = 0.0086) No significant differences in total myocardial ischaemic burden, maximum ST-depression, longest duration of ST-depression, 6-min walk test or heart rate variability 11.7% (n = 23) of nicorandil group and 6.3% (n = 13) of control group reported at least treatment adverse event |