Emergent nicorandil in acute myocardial infarction
Date First Published:
August 8, 2005
Last Updated:
August 9, 2005
Report by:
Richard Body, Clinical Research Fellow (Manchester Royal Infirmary)
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
OVID Embase 1980 - 2005 Week 29
The Cochrane Library 2005 Issue 2
Search Details:
Medline and Embase:
[exp Myocardial Infarction/ OR exp Coronary Thrombosis/ OR (heart adj attack OR AMI OR MI OR (myocard$ adj infarct$).mp. AND (exp Nicorandil/ OR nicorandil.mp. OR ikorel.mp.) limit to human and English language
Cochrane:
(Myocardial Infarction [MeSH] OR (myocard* NEAR infarct*)) AND (Nicorandil [MeSH] OR nicorandil)
[exp Myocardial Infarction/ OR exp Coronary Thrombosis/ OR (heart adj attack OR AMI OR MI OR (myocard$ 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)
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.
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):
| Study Title | Patient Group | Study type (level of evidence) | Outcomes | Key results | Study Weaknesses |
|---|---|---|---|---|---|
| Beneficial effects of nicorandil in acute myocardial infarction: a placebo-controlled, double-blind pilot safety study Sen S; Neuss H; Berg G; Nitsche K; Goddemeier T; Doring GA 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 | ||||
| Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction Ito H; Taniyama Y; Iwakura K; Nishikawa N; Masauyama T; Kuzuya T; Hori M; Higashino Y; Fujii K; Minamino T 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). | ||||
| Nicorandil affords cardioprotection in patients with acute myocardial infarction treated with primary percutaneous coronary angioplasty: Assessment with thallium-201/iodine-123 BMIPP dual SPECT Fukuzawa S; Ozawa S; Inagaki M; Shimada K; Sugiuka J; Tateno K; Ueda M 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. | ||||
| Intravenous nicorandil in conjunction with coronary reperfusion therapy is associated with better clinical and functional outcomes in patients with acute myocardial infarction Sugimoto K; Ito H; Iwakura K; Ikushima M; Kato A; Kimura R; Tanaka K; Masuyama T; Ogihara T; Kawano S; Fujii K 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). | ||||
| Cardioprotective effect of intravenous nicorandil in patients with successful reperfusion for acute myocardial infarction Koboyashi Y; Goto Y; Daikoku S; Itoh A; Miyazaki S; Ohshima S; Nonogi H; Haze K 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) | ||||
| Nicorandil improves cardiac function and clinical outcome in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: Role of inhibitory effect on reactive... Ono H; Osanai T; Ishizaka H; Hanada H; Kamada T; Onodera H; Fujita N; Sasaki S; Matsunaga T; Okumara K 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). | ||||
| Comparison between nicorandil and magnesium as an adjunct cardioprotective agent to percutaneous coronary intervention in acute anterior myocardial infarction Nameki M; Ishibashi I; Miyazaki Y; Sakai Y; Namikawa S; Kuriyama N; Komiyama N; Tsunoda K; Masuda Y; Komuro I 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). | ||||
| Nicorandil versus isosorbide dinitrate as adjunctive treatment to direct balloon angioplasty in acute myocardial infarction Ikeda N; Yasu T; Kubo N; Hashimoto S; Tsuruya Y; Fujii M; Kawakami M; Saito M 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). | ||||
| Intravenous nicorandil can reduce the occurrence of ventricular fibrillation and QT dispersion in patients with successful coronary angioplasty in acute mycoardial infarction Ueda H; Nakayama Y; Tsumura K; Yoshimaru K; Hayashi T; Yoshikawa J 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). |
Author Commentary:
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.
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.
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:
- 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
- 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
- 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
- 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
- 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
- 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...
- 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
- 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
- Pieper GM; Gross GJ. Anti-free-radical and neutrophil-modulating properties of the nitrovasodilator, nicorandil
- 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
- Ce M; Jennings RB; Reimer KA. Preconditioning with ischaemia: a delay of lethal cell injury in ischaemic myocardium
- The IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact of Nicorandil in Angina (IONA) randomised trial
- 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