|Year : 2020 | Volume
| Issue : 2 | Page : 44-51
Effect of nicorandil on short-term echocardiographic and acute angiographic outcomes in acute coronary syndrome patients undergoing percutaneous coronary intervention
Ashish Jha1, Manoj Kumar Rohit2
1 Department of Cardiology, Dr. RMLIMS, Lucknow, Uttar Pradesh, India
2 Department of Cardiology, PGIMER, Chandigarh, India
|Date of Submission||24-May-2020|
|Date of Decision||10-Jun-2020|
|Date of Acceptance||11-Jun-2020|
|Date of Web Publication||4-Aug-2020|
Dr. Ashish Jha
Department of Cardiology, Dr. RMLIMS, Vibhuti Khand, Gomati Nagar, Lucknow, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Context: Patients with acute coronary syndrome (ACS) often have the suboptimal results of percutaneous coronary intervention (PCI) despite adequate restoration of coronary patency.
Aims: This study evaluated the utility of starting nicorandil before PCI in patients with ACS, in terms of acute angiographic and short-term echocardiographic outcomes.
Settings and Design: It was a prospective, randomized, blinded, single-center trial; involving stable patients with recent ACS and no prior revascularization.
Subjects and Methods: Patients started on intravenous (IV) nicorandil infusion or placebo at least 2 h before PCI, continued till 48 h after PCI. Echocardiographic parameters (left ventricular ejection fraction [LVEF], Wall Motion Score Index (WMSI) score, and myocardial performance index (MPI)) were assessed at baseline and at 4 weeks post-PCI. Thrombolysis in myocardial infarction (TIMI) flow grade and corrected TIMI frame count were assessed before and after PCI. The primary endpoints were improvement in regional wall motion abnormality, MPI, LVEF, and corrected TIMI frame count. The secondary endpoints were the major adverse cardiovascular event (MACE) (cardiac death, angina, myocardial infarction [MI], or revascularization) within 30 days, no reflow, slow flow, and periprocedural MI.
Results: Fifty-five patients were recruited over 1 year, of which 13 patients were excluded. There were numerically lower but statistically nonsignificant improvement in slow flow and no reflow in nicorandil arm. Significant improvement in echocardiographic parameter of MPI was seen in nicorandil group at follow-up. There was no significant improvement in other echocardiographic parameters and MACE.
Conclusions: In patients with ACS and a single-vessel disease on undergoing PCI for recent ACS, the use of IV nicorandil was associated with a significant improvement in MPI at 1-month follow-up. There was no significant difference in the acute angiographic parameters, MACE, LVEF, or wall motion score index.
Keywords: Acute coronary syndrome, coronary artery disease, left ventricular ejection fraction, myocardial performance index, percutaneous coronary intervention
|How to cite this article:|
Jha A, Rohit MK. Effect of nicorandil on short-term echocardiographic and acute angiographic outcomes in acute coronary syndrome patients undergoing percutaneous coronary intervention. Heart India 2020;8:44-51
|How to cite this URL:|
Jha A, Rohit MK. Effect of nicorandil on short-term echocardiographic and acute angiographic outcomes in acute coronary syndrome patients undergoing percutaneous coronary intervention. Heart India [serial online] 2020 [cited 2020 Sep 19];8:44-51. Available from: http://www.heartindia.net/text.asp?2020/8/2/44/291355
| Introduction|| |
Patients with acute coronary syndromes (ACSs) who undergo revascularization procedures often have suboptimal functional results in spite of open epicardial arteries due to either structural (cell membrane disruption) or functional (reperfusion associated injury) reasons (the “no reflow” phenomenon).,,
Nicorandil, a hybrid molecule consisting of an ATP-sensitive potassium channel (K + ATP channel) opener and a nitric oxide donor, has approval as a treatment for angina pectoris. A large clinical trial, the impact of nicorandil on angina study, showed that nicorandil reduces the frequency of cardiovascular events in patients with stable effort angina compared with placebo.
Nicorandil promotes the recovery of postischemic contractile dysfunction and reduces infarct size in animals.,,, Various mechanisms have been postulated for the beneficial effects of nicorandil, including reduction of preload and afterload, anti-free radical and neutrophil modulating properties,,, vasodilatation of small coronary arteries, and mimicking of ischemic preconditioning. Studies have shown that nicorandil improves the functional and clinical outcomes as compared with coronary reperfusion alone in patients presenting with acute myocardial infarction (AMI).,,
The aim of this study was to evaluate the effect of intravenous (IV) nicorandil on acute angiographic and short-term echocardiographic parameters in patients undergoing revascularization for ACSs. It also assessed the impact of nicorandil on the outcomes of revascularization and occurrence of adverse events over subsequent 4 weeks in patients undergoing revascularization for ACSs.
| Subjects and Methods|| |
The study protocol was approved by the Institutional Ethics Committee, and written informed consent was obtained from all patients before the study. The study was designed as an interventional, prospective, randomized, blinded, single center trial. The study was conducted at a government, tertiary care, teaching hospital in the northern part of India.
Patients were eligible for this study if they presented with a history of chest discomfort at rest within the previous 48 hours, or chest discomfort of recent (<4 weeks) onset proven to be of ischemic etiology. In addition, patients were required to have either presence of significant ST-T changes on ECG or elevated CK-MB or Troponins levels. Written informed consent was obtained from all the patients.
Patients were excluded if they had any of these: history of myocardial infarction (MI) >4 weeks back, prior coronary bypass surgery or percutaneous coronary intervention (PCI), cardiogenic shock, multivessel disease, recent stroke (<8 weeks), end-stage hepatic, renal or pulmonary disease, active malignancy, surgical emergency, or poor echo window.
All patients underwent a detailed clinical evaluation, baseline hematological tests, renal function tests, ECG, chest X-ray, and other investigations as indicated.
Randomization was done by the block randomization method with variable block design. Allocation concealment was done by sequentially numbered opaque envelopes. The treatment regimen and medications were masked for both patient and treating physicians.
After randomization patients were put either on IV nicorandil at a rate of 6 mg/h in a graded fashion (beginning at 3 mg/h and increasing to 6 mg/h) keeping systolic blood pressure above 90 mm Hg for a duration of 48 h or on placebo (normal saline) infusion at a similar rate. Infusion was started at least 2 h before the procedure. All patients underwent coronary angiography and revascularization percutaneous transluminal coronary angioplasty (with/without stenting) as per the standard American College of Cardiology/American Heart Association guidelines. Intracoronary injection of 2 mg bolus of either nicorandil or placebo was given to the patients during PCI in their respective groups. All patients received aspirin and clopidogrel in conventional doses. Glycoprotein (GP) IIB/IIIA inhibitors, heparin, or low-molecular-weight heparin (LMWH), angiotensin-converting enzyme (ACE)-inhibitors, and beta-blockers were used as per the discretion of the treating physician.
Serum concentrations of CK were measured 6 hourly from the recruitment till 48 h after the procedure. Left ventricular (LV) systolic function, (left ventricular ejection fraction [LVEF]), LV diastolic function (deceleration time, E/A), myocardial performance index (MPI), and regional wall motion abnormality (RWMA) were assessed by echocardiography before PCI and again 4 weeks after revascularization (as per the American Society of Echocardiography guidelines). The difference in ejection fraction and RWMA (wall motion score index) was compared and analyzed.
MPI (Tei index) was calculated as IVCT + IVRT/LVET (IVCT = IsovVolumic contraction time, IVRT = IsoVolumic relaxation time, LVET = LV ejection time) [Figure 1].
|Figure 1: Calculation of myocardial performance index. MPI: Myocardial performance index, ICT: Isovolumic contraction time, IRT: Isovolumic relaxation time|
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Thrombolysis in myocardial infarction (TIMI) flow grade and TIMI frame count was independently assessed by two experienced angiographers. The corrected TIMI frame count was calculated by dividing the left anterior descending artery frame counts by 1.7. All observations were performed at baseline, at reperfusion (after wire crossing or balloon inflation), at no reflow or slow flow, and at the end of the procedure. No reflow was defined as a decrease of ≥1 TIMI trial flow grade after initial successful reperfusion of the culprit artery not due to abrupt vessel closure, spasm, dissection, or significant residual stenosis.
Occurrence of periprocedural complications, adverse effects of Nicorandil, and in-hospital complications was noted. Angiographic success was defined as achievement of minimum stenosis diameter reduction to <20%, in the presence of TIMI III flow. Periprocedural MI was defined as the elevation of CPK-MB ≥3 times the upper limit of normal.
The results are presented in frequencies, percentages, and mean ± standard deviation and percentages. The Chi-square test was used to compare the categorical variables between the groups. The unpaired t-test was used to compare the continuous variables between the groups. The Paired t-test was used to compare the mean change in continuous variables from baseline to 6 months. P < 0.05 was considered statistically significant. All the analysis was carried out by using IBM SPSS 21.0 version (Inc., Chicago, IL, USA).
The primary endpoints of the study was improvement in MPI, RWMA, LVEF, E/A, and corrected TIMI frame count post-PCI. The secondary endpoints were the incidence of significant CK-MB elevation, major adverse cardiovascular event (MACE) (cardiac death, angina, MI, or revascularization) within 30 days, frequency of no reflow and slow flow.
| Results|| |
A total of 55 patients were recruited over the study period of 1 year. These patients were randomized and were taken for the revascularization 2 h or more after start of the infusion.
Thirteen patients were excluded from the study after angiography as they were found to fulfil the exclusion criteria [Figure 2]. The baseline characteristics of the excluded patients were similar to the remaining patients. The most common reason for exclusion was the presence of multivessel coronary artery disease. Two patients with unstable angina had normal coronary angiogram and thus were excluded.
Baseline characteristics as well as risk factor profile of the two groups was similar except for a significantly higher number of smokers in Nicorandil arm (P = 0.028) [Table 1]. Majority of patients had presentation with ST elevation myocardial infarction (STEMI). Unstable angina/non-STEMI was present in only 17% of patients. There was no statistically significant difference between the two groups in the clinical presentation [Table 1].
The two groups were similar in terms of the medical treatment received [Table 2]. Transient hypotension was seen in 4/21 patients (19%) who required temporary stoppage of nicorandil infusion for 1–4 h. Headache was seen in 3/21 patients (14%).
Both the groups were similar in terms of echocardiographic and angiographic parameters at baseline [Table 3]. Left anterior descending artery was the most commonly involved vessel (74%). Lesion was high grade (Type B2/C) in 76%. Mean lesion length was 14.4 (7) mm and percentage luminal stenosis was 90.5%(8.6).
|Table 3: Baseline echocardiographic and angiographic parameters and procedural variables|
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There was a trend toward better angiographic outcomes in nicorandil group as compared to placebo group, but the difference was not statistically significant [Table 4]. Slow flow and no reflow were seen in six and three patients each in control arm and two patients each in Nicorandil arm, respectively. Periprocedural myocardial infarction as defined by elevation in CPK-MB by >3 times upper limit of normal was less frequent in Nicorandil group as compared to control group (1/21 vs. 4/21); but the difference was not statistically significant [Table 4].
Significant improvement in MPI was seen in Nicorandil group as compared to placebo group at 1-month follow-up [Table 5]. No significant difference was seen in LVEF and wall motion score between the two groups. One patient in each arm had recurrence of angina (exertional) at 1-month follow-up. Both were advised to undergo a check angiography followed by revascularization if necessary. The patient in the control group denied consent for the procedure and was continued on medical management. The patient in nicorandil group had a 70% focal in-stent restenosis, which was successfully treated with balloon angioplasty. There were no deaths or recurrence of ACS in any patient, over the follow-up period of 1 month. There was no statistically significant difference between the two groups in combined MACEs of cardiac death, angina, MI or revascularization within 30 days of revascularization.
| Discussion|| |
The results of the present randomized, single blinded, single center study showed that IV Nicorandil is more effective than placebo in improving LV function (as measured by MPI), in patients with ACS who are undergoing percutaneous coronary revascularization.
There are four published randomized controlled trials (RCTs) in literature which have evaluated the role of Nicorandil in patients undergoing PCI. The study population and the dose and route of administration were different in different studies [Table 6]. Three of these studies were done on the patients presenting with ACS,, and one in chronic CAD patients.
|Table 6: Comparison of trials in which nicorandil was used with percutaneous coronary intervention|
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The mean age of patients in the present study is much less as compared to the other trials. This may be due to the difference in the population characteristics from other studies. This finding is in consonance with previous studies which have shown that Indians are more prone for premature CAD and tend to present nearly a decade earlier than the Western population.
In the study by Ishii et al., Nicorandil was used as a single IV bolus upstream and compared against placebo in PCI for AMI. Improvement in angiographic outcomes (corrected TIMI frame counts), resolution of ST segment elevation, maximum CK-MB levels, all-cause mortality, hospitalization for CHF, and cardiovascular death was shown. In the study by Ikeda et al., Nicorandil was used intravenously with PCI for patients with AMI as an IV infusion 6 mg/h for 72 h and was shown to decrease infarct size, decrease incidence of no-reflow, improve Doppler indices of coronary flow, and to improve regional and global LV function as measured by ventriculography. In the study by Ono et al., Nicorandil was administered to AMI patients as an IV bolus followed by infusion for 24 h and was shown to decrease the incidence of “no reflow” and production of free radicals in acute stage and improvement of LV functions on follow-up. The study by Isono et al. recruited patients with stable CAD undergoing PCI. The patients received an IV infusion of Nicorandil for 24 h, followed by a prolonged oral therapy. Patients in the Nicorandil group were shown to have a lesser elevation of myocardial enzymes and a better regional wall motion, as compared to the control group.
In the present study, the study population comprised patients who had a recent ACS and had no history suggestive of CAD in the past. These patients were started on IV infusion of Nicorandil at least 2 h before the procedure and the infusion was continued for 48 h. The rationale for starting infusion early was that it will give the drug some time to act on the coronary circulation and to produce ischemic preconditioning before the procedure actually starts. In this point, IV administration has an advantage over intracoronary administration as the entire coronary arteriolar bed can be dilated instead of restricting the benefit to the affected coronary vasculature. Thus, it may block the progression of microvascular damage and inhibit reperfusion injury, after reestablishment of coronary flow; resulting in better myocardial performance. The rationale for prolonged administration was that majority of slow flow or no reflow phenomenon occurs within 48 h of PCI and a continuous infusion of Nicorandil might reduce the occurrence of these events.
There was a trend toward lower incidence of slow flow and no reflow in patients in Nicorandil arm, but the difference was not statistically significant. Angiographic success rate was similar in two groups.
Although there was no significant difference in the two groups in the measures of LV function such as LVEF, wall motion score, E/A ratio and tissue Doppler velocities; a significant improvement was seen in MPI in Nicorandil group as compared to the control group. Thus, overall myocardial function as reflected by MPI also improved. MPI has been validated as a simple, reproducible, load independent measure of overall myocardial function. Thus, nicorandil was associated with significantly better ventricular function than placebo.
The most likely explanation for the beneficial effects of IV nicorandil appears to be pharmacological prevention of slow flow and resultant improvement in myocardial perfusion, myocardial salvage, and overall myocardial function. A second possibility is that nicorandil may have an effect on ischemic preconditioning. Nicorandil has been shown to prevents reperfusion injury and protect the heart against ischemic injury., In a recent study, mitochondrial K-ATP channels were further shown to be related to preconditioning as the end factor of many signal transduction systems, so that nicorandil might exert salutary effects through their activation.
There was no difference seen in MACE between the two groups. The most likely reason was that the sample size was too small, and the duration of follow-up was short to detect any difference in hard clinical end points such as death, MI, recurrence of ACS, or revascularization.
One of the factors responsible for the lesser benefit seen in the present study as compared to previous studies could be that a higher fraction of patients received the standard drug therapy in the present study. In this study, ACE inhibitors, beta blocker, and LMWH was received by >80% patients [Table 3]. All the patients, in addition, were on standard doses of aspirin, clopidogrel, and on high dose atorvastatin. GP IIb/IIIa antagonist was administered to 47% of the patients, which was much higher than the previous trials.
In the study by Ikeda et al., GP IIb/IIIa antagonists were not used at all and stents were used in only 66% of patients. Ishii et al. reported 83% stent use and did not report the use of GP IIb/IIIa antagonists. In the present study, stents were used in all the procedures. The higher use of the standard medical therapies could have been one of the reasons for the attenuation of benefit seen with nicorandil in the present study as compared to the previous studies.
There are a few limitations of this study. The sample size was small, though it was comparable to three out of the four RCTs published so far. Another limitation was short duration of follow-up (1 month). A longer follow-up could have been better, as studies have shown that recovery of stunned or hibernating myocardium may continue for several months after the revascularization. Another limitation is that in majority of patient the delay in procedure from the ACS was more than 3 days. The results of occluded artery trial showed that patient in Ac STEMI there was no benefit seen in patients who were intervened between the days 3–28 of the MI. In view of this knowledge, the ideal candidates for the present study would have been those who were intervened early after the onset of ACS (i.e., <3 days).
| Conclusions|| |
Use of Nicorandil as an adjunct to PCI was associated with a significant improvement in LV function as measured by MPI, in patients with ACS and a single vessel disease on coronary angiography, who underwent revascularization for a recent ACS. There was a trend toward improvement in corrected TIMI Frame count and reduction in frequency of slow flow and no reflow in patients who received nicorandil, but it did not reach the statistical significance. There was no significant difference between nicorandil and placebo in the MACE, wall motion index, LVEF, tissue Doppler velocities, and angiographic success rate.
There is a need for further studies, recruiting a higher number of patients and to assess the role of nicorandil as an adjunct to PCI in patients undergoing early revascularization.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
All procedures followed were in accordance with the ethical standards of institutional ethics committee and with the Helsinki Declaration of 1964 and later versions. Informed consent was obtained from all patients participating in the study.
| References|| |
Schofer J, Montz R, Mathey DG. Scintigraphic evidence of the “no reflow” phenomenon in human beings after coronary thrombolysis. J Am Coll Cardiol 1985;5:593-8.
Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K, et al
. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 1992;85:1699-705.
Ragosta M, Camarano G, Kaul S, Powers ER, Sarembock IJ, Gimple LW. Microvascular integrity indicates myocellular viability in patients with recent myocardial infarction. New insights using myocardial contrast echocardiography. Circulation 1994;89:2562-9.
IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: The impact of nicorandil in Angina (IONA) randomised trial. Lancet 2002;359:1269-75.
Auchampach JA, Cavero I, Gross GJ. Nicorandil attenuates myocardial dysfunction associated with transient ischemia by opening ATP-dependent potassium channels. J Cardiovasc Pharmacol 1992;20:765-71.
Mizumura T, Nithipatikom K, Gross GJ. Effects of nicorandil and glyceryl trinitrate on infarct size, adenosine release, and neutrophil infiltration in the dog. Cardiovasc Res 1995;29:482-9.
Klein HH, Pich S, Lindert-Heimberg S, Schade-Brittinger C, Maisch B, Nebendahl K. Comparative study on the effects of intracoronary nicorandil and nitroglycerin in ischaemic, reperfused porcine hearts. Eur Heart J 1995;16:603-9.
Galiè N, Guarnieri C, Ussia GP, Zimarino M, Traini AM, Parlangeli R, et al
. Limitation of myocardial infarct size by nicorandil after sustained ischemia in pigs. J Cardiovasc Pharmacol 1995;26:477-84.
Gross G, Pieper G, Farber NE, Warltier D, Hardman H. Effects of nicorandil on coronary circulation and myocardial ischemia. Am J Cardiol 1989;63:11J-17J.
Pieper GM, Gross GJ. Anti-free-radical and neutrophil-modulating properties of the nitrovasodilator, nicorandil. Cardiovasc Drugs Ther 1992;6:225-32.
Yasu T, Ikeda N, Ishizuka N, Matsuda E, Kawakami M, Kuroki M, et al
. Nicorandil and leukocyte activation. J Cardiovasc Pharmacol 2002;40:684-92.
Kitakaze M, Minamino T, Node K, Komamura K, Shinozaki Y, Chujo M, et al
. Role of activation of ectosolic 5'-nucleotidase in the cardioprotection mediated by opening of K+c channels. Am J Physiol 1996;270:H1744-56.
Ito H, Taniyama Y, Iwakura K, Nishikawa N, Masuyama T, Kuzuya T, et al
. Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction. J Am Coll Cardiol 1999;33:654-60.
Sakata Y, Kodama K, Komamura K, Lim YJ, Ishikura F, Hirayama A, et al
. Salutary effect of adjunctive intracoronary nicorandil administration on restoration of myocardial blood flow and functional improvement in patients with acute myocardial infarction. Am Heart J 1997;133:616-21.
Kobayashi Y, Goto Y, Daikoku S, Itoh A, Miyazaki S, Ohshima S, et al
. Cardioprotective effect of intravenous nicorandil in patients with successful reperfusion for acute myocardial infarction. Jpn Circ J 1998;62:183-9.
Ikeda N, Yasu T, Kubo N, Hashimoto S, Tsuruya Y, Fujii M, et al
. Nicorandil versus isosorbide dinitrate as adjunctive treatment to direct balloon angioplasty in acute myocardial infarction. Heart 2004;90:181-5.
Ishii H, Ichimiya S, Kanashiro M, Amano T, Imai K, Murohara T, et al
. Impact of a single intravenous administration of nicorandil before reperfusion in patients with ST-segment-elevation myocardial infarction. Circulation 2005;112:1284-8.
Ono H, Osanai T, Ishizaka H, Hanada H, Kamada T, Onodera H, et al
. 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. Am Heart J 2004;148:E15.
Isono T, Kamihata H, Sutani Y, Motohiro M, Yamamoto S, Kyoui S, et al
. Nicorandil suppressed myocardial injury after percutaneous coronary intervention. Int J Cardiol 2008;123:123-8.
Bhatnagar D, Anand IS, Durrington PN, Patel DJ, Wander GS, Mackness MI, et al
. Coronary risk factors in people from the Indian subcontinent living in west London and their siblings in India. Lancet 1995;345:405-9.
Matsubara T, Minatoguchi S, Matsuo H, Hayakawa K, Segawa T, Matsuno Y, et al
. Three minute, but not one minute, ischemia and nicorandil have a preconditioning effect in patients with coronary artery disease. J Am Coll Cardiol 2000;35:345-51.
Liu Y, Sato T, O'Rourke B, Marban E. Mitochondrial ATP-dependent potassium channels: Novel effectors of cardioprotection? Circulation 1998;97:2463-9.
Sato T, Sasaki N, O'Rourke B, Marbán E. Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATP-dependent potassium channels. J Am Coll Cardiol 2000;35:514-8.
Bax JJ, Visser FC, Poldermans D, Elhendy A, Cornel JH, Boersma E, et al
. Time course of functional recovery of stunned and hibernating segments after surgical revascularization. Circulation 2001;104:I314-8.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]