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Role of nicorandil in myocardial infarction essay

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Published: October 31, 2021
Updated: October 31, 2021
University / College: Lancaster University
Language: English
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INTRODUCTION:Nicorandil’s simple chemical name is N-(2-Hydroxyethyl) –nicotinamide nitrate.

Clinical studies employing exercise tolerance test as the major end point show that nicorandil at doses 10 to 20 mg twice daily is as efficacious as other antianginal agents.(including diltiazem , nifedipine , isosorbide , mononitrate , isosobide dinitrate, propranolo, metprolol and atenolol ) in treating patients with chronic stable angina. Most of the studies which are controlled and comparative were of limited duration (3 months) which included anginal attacks patients less than five per week.Limited data’s are only available on the influence of nicorandil on myocardial infarction and mortality .When nicorandil is added to a beta-blocker or calcium channel blocker , increased antianginal efficacy is observed but not of momentous.Although no strictly comparative studies of different dosing frequencies were performed but some studies did investigate three times daily dosing with nicorandil and it did not appear to present any advantages over twice daily dosing.Some long term uncontrolled study reveals that nicorandil maintains its efficacy with no evidence of tolerance developing up to two years after commencement of therapy.The efficacy of nicorandil in thwarting coronary artery spasm in patients with vasospastic angina was compared to nifedipine in provocation testing using methylergometrine.

Results reveal that nicorandil is as best as of effect as nifedipine .The benefit of nicorandil in unstable angina is yet to be fully established .1Nicorandil relaxes the muscles in the walls of the veins and arteries which condense the workload of the heart and augment the supply of oxygen to the heart muscles.

It is used for the prevention of angina. It is usually used when angina can not be controlled by other drugs and is prescribed as an additional treatment.The common side effects are:

Headaches – this usually stop when the body fiddle with tablets.

It can also cause flushing.

Avoid driving or operating machineries when you have started to take nicorandil until you know that you are confident.

Nicorandil, a potent adenosine triphosphate –sensitive potassium –channel opener ameliorates lung allograft reperfusion injury.²Five thousand of heart patients are to be recruited to see whether a drug which relieves chest pain can also provide protection against coronary diseases. In a three year trial, the University of Glasgow will investigate whether nicorandil, used to treat angina, can also reduce deaths from heart diseases.³Nicorandil, an approved drug for the treatment of ischaemic heart disease, is said to have dual properties.

The intrinsic mechanism of drug (selective activation of^K+_ATPchannels at the sarcolemmal and mitochondrial level) allows coronary and peripheral vasodilatation with subsequent reduction of preload and afterload.Secondly, because of the role^K+_ATPchannels in ischaemic preconditioning, nicorandil has been attributed cardio protective effects .⁴The large scaled, randomized IONA( Impact of Nicorandil on Angina ) trial evaluated the efficacy of nicorandil on top of “conventional ‘antianginal drugs for the treatment of stable angina pectoris .

⁵The primary end-point (a composite cardiac death, myocardial infarction, unplanned hospital admission for chest pain) occurred considerably less in the nicorandil (13.1%) and in the placebo group (15.5%, P= 0.014). Only about 50% of patients were on ?-blockers and ‘unplanned hospital admission for chest pain ‘is a very weak end-point despite the randomized character of the trial.Despite of these limitations, nicorandil may be deemed as a safe additional drug to ?-Blockers for angina relief in patients with stable angina pectoris.

THE LITERATURE REVIEW METHODOLOGY:

A search of the literature was undertaken to determine the depth of knowledge available pertaining to the subject under examination. The following strategies were employed.

A search of data bases in pub med ,Medline , Cinahl , American Heart association journal ,Eur Heart Journal, the Second department of internal medicine , Hirosaki University school of Medicine , Hirosaki , Japan research papers , Am heart J from pub med to for the past five years with the words “ Nicorandil “ was made to determine the role of nicorandil in myocardial infarction .

A review of issues from the relevant journals such as pub med , AHA ( American Heart Association ) & Eur ( European ) Heart Journal.

Backward chaining from the articles obtained.

A search on relevant book and periodicals.

The studies based on efficacy of nicorandil in ischaemic preconditioning in the human angioplasty model and impact of drug on left ventricular filling pressures in exercising patients with hypertrophic cardimyopathy were taken to prove the efficacy of nicorandil in the prevention and cure of myocardial infarction .Further the role of Nicorandil in improving cardiac function and clinical outcome in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention and role of inhibitory effect on reactive oxygen species formation were also taken to establish nicorandil is the best drug for controlling the MI diseases.

This study also taken into consideration the research work on the finding that how Nicorandil reduced coronary events in stable angina…

The reviewed literature will consider the strength of evidence using a critical analysis framework as shown below .The role of evidence based medicine within this field and how it can be used to inform clinical practice will be evaluated.

STRENGTH OF EVIDENCE:

1. EVIDENCE TYPE 1.The following Japanese researchers have made extensive research on use of nicorandil inMyocardial Infarction. Mr. Matsuo et al evaluates the efficacy of nicorandil in ischaemic preconditioning in the human angioplasty model while Mr. Izawa et al investigates the impact of drug on left ventricular filling pressures in exercising patients with hypertrophic cardiomyopathy.⁶^&7The efficacy of drug is revealed in both trials characterized by a heavy, ‘high –tech ‘methodology applied to small study cohort.

Matsue et al. have demonstrated by simple ST-segment analysis that nicorandil enhances pre-conditioning in the human PTCA model.5 ( percutaneous trnasluminal coronary angioplasty ) but the potential contribution of collateral blood flow was not satisfactorily assessed.In this present study , a homogenous group of 44 patients with isolated proximal LAD ( ( (Left anterior decending artery stenosis ) stenosis and normal left ventricular function , was randomized to intravenous nicorandil or saline prior to angioplasty.⁸Further to ST-segment analysis ,99mTc tetrofosmin SPECT acquisition was performed at the end of the PTCA as a surrogate for myocardial perfusion to the related myocardium.

A trend but no major flow increase to the ischemic bed was found together with a noteworthy attenuation of ST-segment elevation in the nicorandil group. This demonstrates that nicorandil seems to possess a cardio protective effect independent of myocardial (collateral) blood flow to the ischaemic bed.Mr. Izawa.et.al studied the effect of nicorandil on left ventricular end –diastolic pressure during exercise in patients with non-obstructive hypertrophic cardiomyopathy.⁹These researchers could previously distinguish a distinct behavior of left ventricular filling pressures during exercise in these patients depending upon the severity of the myocardial hypertrophy^.

¹⁰A continuous increase pressure was observed in patients with severe hypertrophy, while those with mild hypertrophy experienced a biphasic pattern with an initial increase following by a decrease prior to peak exercise. Both groups could further be distinguished by more severe Thallium -201 scintigraphy perfusion defects in case of severe hypertrophy. The biphasic pattern in the mild hypertrophy group was abolished by pre-treatment with propanolol, suggesting a ?-adrenergic medicated coronary vasodilatation induced by exercise. Vasodilatation may prevent myocardial ischaemia in a vascular bed that has grown in proportion to the hypertrophy, therefore preventing further rise in filling pressures.Without providing clear anatomic cut-off values to predict these haemodynamic alterations, the authors have now conducted a second trial. A total of 23 patients with non-obstructive hypertrophic cardio-myopathy were randomized to pre-treatment to nicorandil or propanolol prior to any knowledge of haemodynamic conditions induced by exercise.

Findings:Both above research studies revealed that nicorandil may act beneficial at the myocardial cellular level. The first research shows that a cardio protective effect during angioplasty independent of collateral flow to the ischaemic bed.Nicorandil is being prescribed to patients with an anticipated high interventional risk. Further nicorandil should more extensively be investigated during reperfusion strategies for acute myocardial infarction.3.2. EVIDENCE TYPE 2.Nicorandil improves cardiac function and clinical outcome in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: role of inhibitory effect on reactive oxygen species formation.

*The team examined the efficacy of nicorandil, a hybrid of K (ATP) channel opener and nicotinamide nitrate, on reactive oxygen species (ROS) formation and clinical outcomes after primary percutaneous coronary intervention (PCI) AMI.Methods: 58 patients with AMI were randomized into control (n=25) and nicorandil pretreatment groups (n=33) .In nicorandil group, nicorandil was administered just after admission.ROS formation was assessed and compared between two groups. Cardiac function and the incidence of reperfusion injury and cardiac events were also compared.Results:

Urinary 8-epi –PGF2alpha excretion was increased two fold at 60 to 90 minutes after PCI in the control group, where as it was unchanged in after PCI in the Nicorandil group.

The incidence of no-reflow phenomenon was lower in the nicorandil group than in the control group.

Left ventricular ejection fraction and cardiac index at six months were higher in the nicorandil group than in controls.

Plasma brain natriuretic peptide level at 6 months was lower in the nicorandil group.

Inhospital cardiac events and rehospitalization were lower in nicorandil group than in controls.

Findings :¹¹Nicorandil enhances the cardiac functions and clinical results in patient with acute Mmyocardial infarction. Suppression of reactive oxygen species formation may be involved in the mechanism.3.3.

EVIDENCE TYPE 3Nicorandil reduced coronary events in stable angina.5126 UK patients ( mean age 67 years ,76% men ) who had stable angina with a history of myocardial infection , coronary bypass surgery , a definite diagnosis ( by angiography ) of coronary heart diseases ( CHD ) , or a documented positive result on the exercise test .Patients with CHD or positive result on the exercise test were also required to have additional risk factors , including left ventricular ejection fraction? 45% , echocardiographical end –diastolic dimension >55 mm , type 1 or type 2 diabetes .Patients receiving treatment with a sulfonylurea were excluded .Patients were allocated to nicorandil, 20mg daily (n=2565). All patients received standard antianginal treatment.Findings :¹²In patients with stable angina and additional risk factors, nicorandil was more effective than placebo for reducing coronary events.

3.4. EVIDENCE TYPE 4Impact of a single intravenous administration of Nicorandil before reperfusion in patients with ST –Segment –Elevation Myocardial Infarction.¹³Background: Intravenous nicorandil has been reported to ameliorate early functional and clinical problems in patients with acute myocardial infarction.Methods and Results:This follow-up study to 5 years of a randomized , double-blinded trial conducted among 368 patients with first ST-segment –elevation myocardial infarction undergoing percutaneous coronary intervention ( PCI) .They were randomly assigned to receive 12 mg of nicorandil or a placebo intravenous just before reperfusion..

Analysis showed the incidence of cardiovascular death or rehospitalization for congestive heart failure after PCI as well as various aspects of epicardial flow and micro vascular function.Mean follow up was 2.4 years ( SD ,1.4) . A total of 12 ( 6.5%) patients receiving nicorandil and 30 (16.4%) receiving placebo had cardiovascular death or hospital admission for congestive heart failure ( hazard ratio ,0.

39 , 95% CI, 0.20 to 0.76; P= 0.0058 )Post procedural TIMI ( Thrombolysis in Myocardial Infarction )3 flow was obtained in 89.7% of the nicorandil group and in 81.4% of the Placebo (hazard ratio, 1.

99, 95% CI, 1.09 to 3.65; p=0.025). Corrected TIMI frame count was furthermore lower in the nicorandil group.

(21.0±9.1versus 25.

1±14.1; P=0.0009) ST –Segment resolution > 50% was observed in 79.5% and 61.

2% of the Nicorandil and Placebo groups, respectively (hazard ration, 2.45, 95% CI, 1.54 to 3.90; P=0.0002)Findings:¹⁴The addition of intravenous nicorandil to PCI leads to beneficial clinical outcomes and prevents cardiovascular events of long duration and death in patients with ST-segment –elevation of myocardial infarction.

3.5. EVIDENCE TYPE 5.EMERGENT NICORANDIL IN ACUTE MYOCARDIAL INFARCTIONQuestion: In acute Myocardial infarction, does nicorandil, given orally, intravenously or standard therapy alone lead to fewer adverse cardiac events and lower mortality?If a patient with consistent chest pain for the last two hours and treatment has been given on aspirin, oxygen, clopidogrel, morphine, thrombolysis and buccal glyceryl trinitrate (GTN) and despite of this patient is not recovered. Whether Nicorandil will have beneficial effect in this acute situation rather than GTN: IV.In total, nine papers were identified out 248 papers and eight trials investigated nicorandil in acute myocardial infarction (AMI) and PCI. One trial investigated nicorandil in AMI treated medically.

Following publication of the IONA trial ,nicorandil is being used as an anti-ischaemic agent .Nicorandil has a nitrate-like effect ,inducing venodilatation and dilation of large epicardial vessels. As a potassium channel agonist , it also augments myocardial micro vascular perfusion potentially emulating the so-called ischemic preconditioning effect that may limit infarct size among patients with chronic stable angina .( Ce et al,1986).Further , nicorandil has a favorable effect on the fibrinolytic system ( Sakamoto et al ,2004) and it has favorable anti-free radical and neutrophil-modulating characteristics that may limit the extent of reperfusion injury following AMI ( Pieper et al ,1992)Clinical Bottom Line :¹⁵Nicorandil should be strongly considered in the emergency setting for patients with acute myocardial infarction.CONCLUSION:All the above studies have confirmed that Nicorandil is one of the best drug for controlling the myocardial infarction.

Under evidence type -1, it is revealed that nicorandil may act beneficial at the myocardial cellular level. Nicorandil is being prescribed to patients with an anticipated high interventional risk. Further nicorandil should more extensively be investigated during reperfusion strategies for acute myocardial infarction.Under evidence type -2, it is divulged that Nicorandil enhances the cardiac functions and clinical results in patient with acute Myocardial infarctions. Suppression of reactive oxygen species formation may be involved in the mechanism.Under evidence type-3, it is disclosed that in patients with stable angina and additional risk factors, nicorandil was more effective than placebo for reducing coronary events.Under evidence type-4, it is exposed that the addition of intravenous nicorandil to PCI leads to beneficial clinical outcomes and prevents cardiovascular events of long duration and death in patients with ST-segment –elevation of myocardial infarctionUnder evidence type -5, it is recommended that Nicorandil should be strongly considered in the emergency setting for patients with acute myocardial infarction.

Nicorandil, being a potassium channel activator and beta –blockers do have some side effects also like headache, flushing, dizziness and indigestion, inability to exercise, claudication and impotence.In view of the many advantages as per the evidences illustrated above, nicorandil is being prescribed by the cardiologists nowadays in case of stable angina and myocardial infarction.However, it is suggested that nicorandil has to be cautiously prescribed for the patients with myocardial contraindications such as severe bradycardia, a pre-existing severe atrio-ventricular block or left ventricular failure.¹⁶ABBEREVIATIONS:IONA–Impact of Nicorandil on Angina .AHA– American Heart AssociationPTCA– percutaneous trnasluminal coronary angioplastyLAD: Left anterior decending artery stenosisROS :reactive oxygen speciesPCI;percutaneous coronary interventionTIMI: Thrombolysis in Myocardial InfarctionGTN: Glyceryl trinitrateAMI: Acute myocardial infarctionROS: Reactive oxygen speciesCHD: Coronary heart diseasesREFRENCES:

www.
experts.about.com/q/pharmacy-1407/Nicorandil.htm

2.Motohiro yamashita ,MD & others – supported by National institute of Health grant and a grant from Chugai Pharmaceutical Co Ltd – www.

jtcs.ctsnetjournals.org/cgi/content/abstract/112/5/13073Article Title – Health news in Brief. Newspaper Title – Sunday Mirror .

Publication date: May 10, 1988.Page No: 39.

4. Taira N. Nicorandil as a hybrid between nitrates and potassium channel activators. J Cardiol 1989, 63; 18-24

5.
The IONA Study group. Effect of nicorandil coronary events in patients with stable angina. The impact of nicorandil in Angina (IONA) randomized trial .Lancet 2002; 359:1269-75.

6.Matsuo H,Watanabe S, Segawa T et al .

Evidence of Pharmacological preconditioning during PTCA by intravenous pre-treatment with ATP –sensitive K+channel opener nicorandil . Eur Heart J 2003 : 2003:04 :1296-303.

Izawa H.Iwase M, Takeichi Y .et al .
Effect of nicorandil on left ventricular end-diastolic during exercise in patients with hypertrophic cardiomyopathy .Eur Heart J 2003;24:1340-8.

8. Matsuba T, Minatoguchi S, Matsuo H.Three minutes, but not one minute ischemia and nicorandil have a preconditioning effect in patients with coronary artery disease. J Am Coll Cariol 2000:35:345-51

9.Takeichi Y , Yokota M, Iwase M et al . Biphasic chnges in left ventricular end-diastolic pressure during dynamic exercise in patients with monobstructive hypertrophic cardio-myopathy , J Am Coll Cardiol 2001;38:335-4310.

De Bryne B.Hersbach F.Pijls N et al . Abnormal epicardial coronary resistance in patients with diffuse atherosclerosis but ‘normal’ coronary angiography .circulation 2001:104:2401-6*By Ono H and others, the Second department of internal medicine, Hirosaki University school of Medicine, Hirosaki , Japan – Am Heart J 2004 Oct ,148 ( 4) : E15.11.http://www.

ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15459610&query_hl=2&itool=pubmed_docsum12.http://ebm.

bmjjournals.com/cgi/content/full/7/6/169

13.Hideki Ishi , MD & Others from Department of Cardiology, Nagoya University Graduate of School of Medicine.

14http://circ.ahajournals.

org/cgi/content/abstract/112/9/1284?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=nicorandil&searchid=1140239595750_3024&FIRSTINDEX=0&search_url=http%3A%2F%2Fwww.ahajournals.org%2Fcgi%2Fsearc15.REPORT BY – RICHARD BODY – CLINICAL RESEARCH FELLOWINSTITUTION ; MANCHESTER ROYAL INFIRMARY.16.

Gibbons RJ, Abrams J, Chatterjee K et al ACC/AHA 2002 guideline update for management of patients with chronic stable angina. Available : www.acc.org/clinical/guidelines/stable/stable.pdf17.

Pieper GM;Gross GJ Anti –free-radical and neutrophil –modulating properties of the nitro vasodilator , nicorandil Cardiovascular Drugs and Threapy.1992 : 6 (3) : 225-232.18.Ce M; Jennings RB; Reimer KA Preconditions with ischaemia : a delay of lethal cell injury in ischaemic myocardium Circulation 1986;74;1124-1136.19.

Sakamoto T; Kakita 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;232-235.20.

Koboyashi Y;Goto Y; Daikoku S; Itoh A ; Miyazaki S ; Ohshima S ; Nonogi H ; Haze K . Cardio protective effect of intravenous nicorandil in patients with successful reperfusion for acute myocardial infarction, Japanese Circulation Journal 1998;62.183-189.

21.The IONA Study Group effect of nicorandil on coronary events in patients with stable angina :The impact of nicorandil in Angina ( IONA ) randomized trial The Lancet 2002;359;1269-1275.22.Ito H; Taniyama Y; Iwakura K; Nishikawa N; Masauyama T; Kuzuya T; Hori M;Higashino Y; Fuji K;Minamino T; Intravenous nicorandil can preserve micro vascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction .Journal of the American College of Cardiology .1999;33(3);654-660.23.

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 ,19985(4):208-220.24.Ono H; Osanai T; Ishizaka H; Hanada H ; Kamada T; Onodera H ; Fujita N ; Sasaki S ; Matsunga 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.e15.25.Fukuzawa S ; Ozawa S; Inagaki M; Shimada K; Sugiuka J ; Tateno K; Ueda M.

Nicorandil affords cardio protection 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;447-453,26.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;181-185.27.

Sujimoto K ; Ito H ; Iwakura K; Ikushima M; Kato A ; Kimura R; Tanaka k ; Massuyama 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;295-300.28.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 cardio protective agent to percutanous coronary intervention in acute anterior myocardial infarction .

Circulation Journal. 2004.68;192-197.29.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 myocardial infarction .

Canadian Journal of Cardiology 2004;20(6);625-628.ADDENDUM:In case ,if you want use the following table , you may use it as an additional source for evidence no 5.

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study weaknesses
Kobayashi et al1998Japan	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 reasonsSmall numbersNo 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)
Sen et al1998Germany	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 differenceNo 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 al1999Japan	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 al2000Japan	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.
Ono et al2003Japan	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).
Sugimoto et al2003Japan	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 – 04/1996All 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).
Ikeda et al2004Japan	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 al2004Canada	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 fibrillationNo 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).
Nameki et al2004Japan	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).

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