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Three Part Question

In [acute myocardial infarction] does [nicorandil, given orally or intravenously, or standard therapy alone] lead to [fewer adverse cardiac events and lower mortality]?

Clinical Scenario

A fifty year-old man presents having experienced 2 hours of central crushing chest pain. He is diaphoretic and the ECG shows 4mm ST elevation in the anterior leads with reciprocal inferior ST depression. You prescribe aspirin, oxygen, clopidogrel, morphine, thrombolysis and buccal glyceryl trinitrate (GTN). Unfortunately his pain is not relieved. As you start to write "GTN; IV" on the drug kardex you wonder whether there is any evidence that nicorandil, a potassium channel opener with nitrate-like activity, will have a beneficial effect in this 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 (heart adj attack OR AMI OR MI OR (myocard$ adj infarct$).mp. AND (exp Nicorandil/ OR nicorandil.mp. OR ikorel.mp.) limit to human and English language
Cochrane:
(Myocardial Infarction [MeSH] OR (myocard* NEAR infarct*)) AND (Nicorandil [MeSH] OR nicorandil)

Search Outcome

Cochrane: 25 papers, seven of which were relevant.
Medline: 50 papers, nine of which were relevant.
Embase: 173 papers were identified, nine of which were relevant.
In total, nine relevant papers were identified. Eight trials investigated nicorandil in acute myocardial infarction (AMI) plus primary percutaneous coronary intervention (PCI). One trial investigated nicorandil in AMI treated medically.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Sen et al 1998 Germany	45 patients with AMI treated medically (20 thrombolysed), randomised to receive either nicorandil 10mg or placebo every 12 hours, starting as soon as possible after admission. Study duration: Until discharge from coronary care unit or referral for PCI	PRCT	Changes in mean arterial pressure (MAP) and heart rate (HR) during 1st 72 hours	Fell gradually in both groups; No significant differences between groups	Small numbers - underpowered to detect mortality difference No statistical analysis (probably due to small numbers) No standard treatment duration (patients recevied "at least one dose") Arrhythmias were reported but not recorded by ECG monitoring due to "technical difficulties"
			Action potential duration (assessed by corrected QT interval)	No change with treatment, no significant differences between groups
			Death	2 nicorandil v. 2 placebo
			All arrhythmias	1/23 (4%) nicorandil v. 6/22 (27%) placebo
			All adverse events	9/23 (39%) nicorandil v. 13/22 (59%) placebo
			Serious adverse events (recurrent transmural ischaemia, unstable angina and severe angina	2 nicorandil v. 1. placebo
Ito et al 1999 Japan	81 eligible patients (of 90) with first anterior MI, randomly allocated to receive either nicorandil (4mg IV bolus plus continuous infusion for 24 hours then 15mg bd orally for 28 days) or no nicorandil (control group). All patients had PTCA within 12 hours of symptom onset, followed by serial echocardiography and repeat angiography at (mean) 25 days.	PRCT	Infarct extension, post-infarction angina, coronary restenosis and coronary reocclusion	No significant differences (low incidences - study probably underpowered)	Not placebo-controlled (although angiographic analysis was blinded) No sample size calculation, probably underpowered.
			In-hospital VT or VF	2 (5%) nicorandil v. 8 (20%) control. RR 0.22 (95% CI 0.04-1.10, p=0.048)
			Early congestive heart failure (CHF), in-hospital	6 (15%) nicorandil v. 15 (37%) control. RR 0.31 (95% CI 0.10-0.90, p=0.027)
			"Late" CHF, in-hospital	1 (3%) nicorandil v. 5 (12%) control (95% CI 0.02-1.66, p=0.028)
			Death, in-hospital	0 nicorandil v. 4 (10%) control. P=0.043.
			No reflow on myocardial contrast echocardiography	Lower (superior) in nicorandil group (15% v. 33%, p<0.05).
Fukuzawa et al 2000 Japan	62 eligible (of 74) patients admitted to the Coronary Care Unit with a first MI, within 6 hours of symptom onset. Randomised to receive either nicorandil (IV bolus plus 24 hour infusion) or no nicorandil (controls). All patients underwent PTCA for reperfusion.	PRCT	Myocardial perfusion-metabolism mismatch (assessed by dual BMIPP and thallium SPECT)	No significance in BMIPP severity (metabolism); significantly lower thallium severity in the nicorandil group with preceding angina (p<0.05). Significantly lower thallium/BMIPP (perfusion/metabolism) severity ratio in nicorandil group with preceding angina (p<0.05). No difference with nicorandil if no preceding angina. Authors propose that this suggests cardioprotective effect of nicorandil	Randomisation procedure not described. No placebo control. Perfusion-metabolism mismatch is a laboratory-based outcome, which is only theoretically relevant in the clinical situation. Clinical follow-up data would be desirable.
			Left ventricular function (assessed by echocardiography)	Significant reduction in wall motion score in nicorandil group with preceding angina (p<0.05), suggesting greater preservation of LV function. No difference with nicorandil without preceding angina.
Sugimoto et al 2003 Japan	158 patients who had been admitted to CCU with AMI from 11/1997 - 04/1998 and received IV nicorandil and 114 controls admitted to CCU with AMI from 11/1995 - 04/1996 All patients underwent PCI. Nicorandil was given by IV bolus then infusion from the time of diagnosis to 24 hours, followed by 15mg od for a mean of 28 days.	Retrospective observational trial	LV function (assessed by echocardiography, wall motion score)	Total: No significant differences. Anterior MI's only: Superior in nicorandil group (p<0.03).	Study design subject to considerable bias. Retrospective, control group were treated two years earlier. Stent use significantly higher in nicorandil group (p<0.01). Follow-up of all patients assessed in July 2000
			Death at late follow-up (mean 3.1 years)	Significantly lower in nicorandil group (cardiac cause p<0.04, all-cause p<0.01).
			Cardiac events at late follow-up	Significantly less in nicorandil group (p<0.01).
			Re-infarction at late follow-up	Significantly less in nicorandil group (p<0.01).
			Multiple regression analysis to derive factors related to cardiac events	Nicorandil related (p<0.0011), odds ratio 0.27 (95% CI 0.12-0.58).
Kobayashi et al 1998 Japan	36 (of 70 initially included) patients admitted to CCU with AMI, randomised to receive either nicorandil (IV bolus/infusion, starting before reperfusion, for 3 hours) (n=19) or placebo (n=17). All patients had primary PCI (PTCA or intracoronary thrombolysis)	PRCT	Reperfusion phenomena	No significant differences	Almost 50% of patients excluded for varying reasons Small numbers No clinical outcome data. The outcomes are laboratory-based and only theoretically clinically relevant.
			Left ventricular ejection fraction	No significant differences between groups at baseline and 4 weeks
			Regional chord shortening (echocardiographic measure of wall motion)	Not significantly different at baseline; significant improvement in nicorandil but not placebo (p<0.01 for comparison)
			Hypocontractile ventricular perimeter (echocardiographic measure of wall motion)	No significant differences immediately after reperfusion; Significant improvement in nicorandil group but not placebo group at 4 weeks (p<0.05 for change in nicorandil group)
Ono et al 2003 Japan	58 patients wth AMI, randomised to receive either nicorandil (IV bolus then infusion, n=33) from admission (Emergency Room) to 24 hours or no nicorandil (control, n=25). All patients underwent primary PCI with stenting within 60 minutes of admission.	PRCT	Plasma BNP levels 7 and 14 days and 6 months post-PCI	All lower in nicorandil group (P<0.05)	Small numbers. Not blinded or placebo-controlled. No clinical outcome data at 6-month follow-up.
			TIMI frame count (validated angiographic index of coronary flow) immediately after PCI	Significantly smaller (superior) in nicorandil group (p<0.05)
			Reperfusion injury phenomena immediately after PCI	No significant differences between groups
			Total in-hospital cardiac events (CHF, arrhythmia, pericardial effusion or recurrent MI)	No significant differences when each outcome assessed individually. As a composite outcome, significantly fewer in nicorandil group (p=0.032).
			In-hospital death	0 in both groups
			Left ventricular function (LVEF and CIn)	LVEF: No significant difference immediately after PCI; Significantly greater at 6 months in nicorandil group (p<0.05); CIn: Significantly greater immediately after PCI and at 6 months in nicorandil group (p<0.05).
			Urinary 8-epi-PGF-2alpha excretion	Significant increases in control group following PCI (P<0.01); No change in excretion following PCI in nicorandil group (P<0.0001).
Nameki et al 2004 Japan	40 consecutive patients with first AMI who underwent primary PCI and had occluded LAD. Randomised to receive either (1) nicorandil (IV bolus, IC bolus then IV infusion for 24 hours), (2) magnesium sulphate (IV bolus then infusion for 24 hours) or (3) neither (control). All patients had repeat coronary angiography at 3 months.	PRCT	Reperfusion injury phenomena	Trend towards less in both treatment groups (not significant)	Method of randomisation not desribed. Small numbers. No clinical outcome data at follow-up. Exclusions not reported but randomisation occurred before fulfilment of inclusion criteria (LAD occlusion).
			Restenosis rates, TIMI frame count (measure of wall motion), ejection fraction	No significant differences between the groups.
			Change in regional wall motion	Significant improvement from baseline in nicorandil group but not other groups (p<0.05 v. control, not significant v. magnesium).
Ikeda et al 2004 Japan	60 eligible (of 209 consecutive) patients with AMI, randomly assigned to receive either nicorandil (n=30) or ISDN (n=30) by IV infusion (+ slow IC bolus at PCI) from immediately after diagnosis - 72 hours. All patients underwent primary PCI and had repeat coronary angiography at 3 weeks.	PRCT	Recovery of ST elevation imediately after reperfusion	Nicorandil 15/27 (55.5%) v. ISDN 5/26 (19.2%), p=0.006.	No clinical outcome data at follow-up. Relatively small numbers with no sample size calculations.
			Regional wall motion (left ventriculography)	Significantly greater in nicorandil group, both immediately (p=0.015) and at 3 weeks (p=0.046).
			Coronary flow measurements	Significantly higher in nicorandil group 40 minutes post-PCI (p<0.05 for all measurements).
Ueda et al 2004 Canada	83 eligible (of 150 consecutive) patients with AMI (symptom onset <12 hours) who underwent primary PTCA. Patients enrolled in the 1st 6 months were controls (n=37). Patients in the 2nd 8 months received nicorandil IV infusion from admission - 48 hours after PTCA (n=46).	Historical cohort study	QT interval	Maximum shorter in nicorandil group 48 hours after PTCA (P<0.05). No significant difference in minimum QT interval.	No randomisation or blinding. Historical cohort design subject to considerable bias. Of note, nicorandil group was enrolled after controls. Standards of care in general may have improved. Nicorandil group less likely to be on ACE inhibitors (P=0.029) - possibly because of less CHF in that group. Relatively small numbers - only three patients developed ventricular fibrillation No clinical outcome data. QT intervals calculated manually by same (blinded) observer. No assessment of intraobserver variability.
			QT dispersion	Significantly lower at 48 hours in nicorandil group (P<0.05); Nicorandil (but no other variables) independently associated with QT dispersion on multivariate analysis (r=0.342, P<0.05).
			Ventricular fibrillation within 48 hours of PTCA	Nicorandil 0 v. control 3 (P<0.05).

Comment(s)

There has been growing interest in the utility of nicorandil as an anti-ischaemic agent following the publication of the IONA trial. This randomised placebo-controlled trial of 5126 patients demonstrated a significant reduction in coronary events among patients with stable angina treated with nicorandil (IONA Study Group, 2002). Nicorandil has a nitrate-like effect, inducing venodilatation and dilatation of large epicardial vessels. However, it also has many theoretical advantages over nitrates. As a potassium channel agonist, it also improves myocardial microvascular perfusion, potentially emulating the so-called ischaemic preconditioning effect that may limit infarct size among patients with chronic stable angina (Ce et al, 1986). In addition, nicorandil has a favourable effect on the fibrinolytic system (Sakamoto et al, 2004) and has favourable anti-free radical and neutrophil-modulating characteristics that may limit the extent of reperfusion injury following AMI (Pieper et al, 1992). There have been no large randomised controlled trials in this area. However, evidence from several small studies strongly suggests that nicorandil may have cardioprotective properties in AMI that help to preserve myocardial function. By demonstrating inhibition of urinary 8-epi-PGF-2alpha excretion with nicorandil, the study by Ono et al adds weight to the hypothesis that nicorandil scavenges free radicals, adding to the theoretical basis for its use in AMI. Although robust clinical outcome data from large randomised controlled trials are still necessary, strong consideration should be given to instigating emergent nicorandil therapy in patients with AMI.

Editor Comment

Abbreviations: IV: Intravenous; IC: Intracoronary; CCU: Coronary Care Unit; AMI: Acute myocardial infarction; LVEF: Left ventricular ejection fraction; CIn: Cardiac index; PCI: Percutaneous coronary intervention; PGF: prostaglandin F; ISDN: Isosorbide dinitrate; LAD: Left anterior descending artery; CI: Confidence intervals; CHF: Congestive heart failure.

Clinical Bottom Line

Nicorandil should be strongly considered in the emergency setting for patients with acute myocardial infarction.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.

References

1. Sen S; Neuss H; Berg G; Nitsche K; Goddemeier T; Doring GA Beneficial effects of nicorandil in acute myocardial infarction: a placebo-controlled, double-blind pilot safety study British Journal of Cardiology 1998; 5(4): 208-220
2. Ito H; Taniyama Y; Iwakura K; Nishikawa N; Masauyama T; Kuzuya T; Hori M; Higashino Y; Fujii K; Minamino T Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction Journal of the American College of Cardiology 1999; 33(3): 654-660
3. Fukuzawa S; Ozawa S; Inagaki M; Shimada K; Sugiuka J; Tateno K; Ueda M Nicorandil affords cardioprotection in patients with acute myocardial infarction treated with primary percutaneous coronary angioplasty: Assessment with thallium-201/iodine-123 BMIPP dual SPECT Journal of Nuclear Cardiology 2000; 7: 447-453
4. Sugimoto K; Ito H; Iwakura K; Ikushima M; Kato A; Kimura R; Tanaka K; Masuyama T; Ogihara T; Kawano S; Fujii K Intravenous nicorandil in conjunction with coronary reperfusion therapy is associated with better clinical and functional outcomes in patients with acute myocardial infarction Circulation Journal 2003; 67: 295-300
5. Koboyashi Y; Goto Y; Daikoku S; Itoh A; Miyazaki S; Ohshima S; Nonogi H; Haze K Cardioprotective effect of intravenous nicorandil in patients with successful reperfusion for acute myocardial infarction Japanese Circulation Journal 1998; 62: 183-189
6. Ono H; Osanai T; Ishizaka H; Hanada H; Kamada T; Onodera H; Fujita N; Sasaki S; Matsunaga T; Okumara K Nicorandil improves cardiac function and clinical outcome in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: Role of inhibitory effect on reactive... American Heart Journal 2004; 148: e15
7. Nameki M; Ishibashi I; Miyazaki Y; Sakai Y; Namikawa S; Kuriyama N; Komiyama N; Tsunoda K; Masuda Y; Komuro I Comparison between nicorandil and magnesium as an adjunct cardioprotective agent to percutaneous coronary intervention in acute anterior myocardial infarction Circulation Journal 2004; 68: 192-197
8. Ikeda N; Yasu T; Kubo N; Hashimoto S; Tsuruya Y; Fujii M; Kawakami M; Saito M Nicorandil versus isosorbide dinitrate as adjunctive treatment to direct balloon angioplasty in acute myocardial infarction Heart 2004; 90: 181-185
9. Pieper GM; Gross GJ Anti-free-radical and neutrophil-modulating properties of the nitrovasodilator, nicorandil Cardiovascular Drugs and Therapy 1992; 6(3): 225-232
10. 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: 232-235
11. Ce M; Jennings RB; Reimer KA Preconditioning with ischaemia: a delay of lethal cell injury in ischaemic myocardium Circulation 1986; 74: 1124-1136
12. 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
13. Ueda H; Nakayama Y; Tsumura K; Yoshimaru K; Hayashi T; Yoshikawa J Intravenous nicorandil can reduce the occurrence of ventricular fibrillation and QT dispersion in patients with successful coronary angioplasty in acute mycoardial infarction Canadian Journal of Cardiology 2004; 20(6): 625-628