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Three Part Question

In [patients with unstable angina] does [nicorandil or standard therapy alone] lead to [fewer adverse cardiovascular events and lower mortality]?

Clinical Scenario

A forty-five year-old man presents with classical ischaemic chest pain occurring with increasing frequency over the past 48 hours, with intermittent rest pain for 4 hours. ECG shows deep, downsloping lateral ST depression without left ventricular hypertrophy. You diagnose unstable angina and prescribe aspirin, clopidogrel, low-molecular weight heparin, beta-blockers, statins and buccal nitrates. His pain is refractory to nitrates. Knowing that nicorandil is a useful adjunct in the treatment of poorly-controlled stable angina, you wonder if there is any evidence for its benefit in the acute situation.

Search Strategy

OVID Medline 1966 - 2005 July Week 4
OVID Embase 1980 - 2005 Week 29
The Cochrane Library 2005 Issue 2
Medline and Embase:
[exp Myocardial Infarction/ OR exp Coronary Thrombosis/ OR exp Angina, Unstable/ OR (heart attack OR AMI OR MI OR unstable angina OR acute adj coronary adj syndrome OR ACS OR (myocard$ ADJ (infarct$ OR ischem$ OR ischaem$)).mp. AND (exp Nicorandil/ OR nicorandil.mp. OR ikorel.mp.) limit to human and English language
Cochrane:
(Myocardial Infarction [MeSH] OR (myocard* NEAR infarct*) OR Angina, Unstable [MeSH] OR acute coronary syndrome OR (myocard* NEAR ischem*) OR (myocard* NEAR ischaem*)) AND (Nicorandil [MeSH] OR nicorandil)

Search Outcome

Medline: 97 papers were identified, two of which were relevant.
Embase: 230 papers were identified, two of which were relevant.
Cochrane: 42 papers were identified, one of which was relevant.
In total, two relevant papers were identified.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Patel et al 1999 England	200 patients with unstable angina (UA) (12 excluded due to poor ECG trace), randomly allocated to receive nicorandil 20mg bd or placebo for at least 48 hours and up to 28 days. All patients had continuous ECG monitoring for a mean of 41 hours, and troponin testing to exclude myocardial infarction (MI).	PRCT	Transient myocardial ischaemia (painful or silent)	11 (12.4%) patients on nicorandil had 37 episodes of transient ischaemia v. 21 (21.2%) patients with 74 episodes on placebo (p=0.0028)	Despite the stated protocol, it is stated that all included patients "received at least one dose of study medication". No sample size calculation. Underpowered to detect a mortality difference.
			Chest pain	20 (16.5%) patients on nicorandil v. 38 (31.1%) on placebo (p=0.008)
			Any arrhythmia	6 (6.7%) nicorandil v. 17 (17.2%) placebo (p=0.04)
			Non-sustained ventricular tachycardia	3 runs in 3 patients nicorandil v. 31 runs in 10 patients placebo (p=0.087 patients; p<0.0001 runs)
			Supraventricular tachycardia	4 runs in 3 patients nicorandil v. 15 runs in 9 patients placebo (p=0.14 patients; p=0.017 runs)
			Clinical outcome	Nicorandil: No events; Placebo: No deaths, 2 non-fatal MI's
Kim et al 2005 Korea	103 eligible patients (200 initially included) with unstable angina who underwent elective percutaneous coronary interention (PCI) 12-48 hours after study drug administration. Randomised to receive either isosorbide dinitrate (ISDN) or nicorandil by intravenous infusion. Follow up at 6 months	PRCT	Myocardial infarction (MI) by 6 months	2 cases ISDN v. 1 case (2%) nicorandil.	Not blinded. Small numbers, no sample size calculation and probably underpowered. No intention to treat analysis; almost 50% of patients were ultimately excluded.
			PCI or CABG by 6 months	1 (17%) ISDN v. 4 (10%) nicorandil.
			Major adverse cardiac events by 6 months	9 (17%) ISDN v. 5 (12%) nicorandil (p=0.57).
			LVEF (by echocardiography)	No significant difference at baseline; Significantly higher in nicorandil group at 6 months (p=0.03).

Comment(s)

Nicorandil has a dual mode of action. Like nitrates, it acts as a nitric oxide donor, causing dilatation of systemic veins and large epicardial vessels. However, it is also a potassium channel agonist, causing dilatation of peripheral and coronary arterioles. By dilating these small coronary vessels, nicorandil may mimic the cardioprotective ischaemic preconditioning phenomenon that is seen in patients with chronic stable angina. By causing hyperpolarisation and shortening the action potential, nicorandil may have antiarrhythmic properties. It may also improve fibrinolytic capacity, potentially reducing the risk of coronary thrombus formation (Sakamoto et al, 2004), and may reduce leucocyte activation and migration in to the vessel wall (Yasu et al, 2002), which is increasingly recognised as central to the pathogenesis of acute coronary syndromes. All of these properties are potentially desirable in the emergency setting for patients with unstable angina. The large IONA trial (IONA Study Group, 2002) demonstrated significantly improved outcome in patients with stable angina who were prescribed nicorandil for a mean of 1.6 years. However, only two small trials have investigated the effects of nicorandil in a population with unstable angina. Although underpowered to detect a mortality benefit, the trial by Patel et al demonstrated significantly fewer episodes of ischaemia, chest pain and arrhythmias in the nicorandil group, and highlighted no safety concerns. The small trial by Kim et al had several important limitations, but demonstrated significantly improved left ventricular function following nicorandil infusion in place of nitrates, suggesting a cardioprotective effect. Further evidence from large trials is still required, but on the basis of the currently available data nicorandil should be strongly considered as an adjunct to management for eligible patients with unstable angina.

Editor Comment

Abbreviations: CABG: Coronary artery bypass graft LVEF: Left ventricular ejection fraction

Clinical Bottom Line

Nicorandil may lead to less ischaemic complications in unstable angina and should be considered for use in this patient group.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.

References

1. Patel DJ; Purcell HJ; Fox KM; on behalf of the CESAR 2 Investigation Cardioprotection by opening of the KATP channel in unstable angina: Is this a clinical manifestation of myocardial preconditioning? Results of a randomized study with nicorandil European Heart Journal 1999; 20: 51-57
2. The IONA Study Group Effect of nicorandil on coronary events in patients with stable angina: the Impact of Nicorandil in Angina (IONA) randomised trial The Lancet 2002; 359: 1269-1275
3. Kim JH; Jeong MH; Yun KH; Kim KH; Kand DK; Hong SN; Lim SY; Lee SH; Lee YS; Hong YJ; Park HW; Kim W; Ahn YK; Cho JG; Park JC; Kang JC Myocardial protective effects of nicorandil during percutaneous coronary intervention in patients with unstable angina Circulation Journal 2005; 69: 306-310
4. Yasu T; Ikeda N; Ischizuka N; Matsuda E; Kawakami M; Kuroki M; Imai N; Ueba H; Fukuda S; Schmid-Schonbein GW; Saito M Nicorandil and leucocyte activation [Abstr] Journal of Cardiovascular Pharmacology 2002; 40(5): 684-692
5. Sakamoto T; Kaikita K; Miyamoto S; Kojima S; Sugiyama S; Yoshimura M; Ogawa H Effects of nicorandil on endogenous fibrinolytic capacity in patients with coronary artery disease Circulation Journal 2004; 68(3): 232-235