Effect of intravenous application of nicorandil on area of myocardial infarction in patients with STEMI during the perioperative stage of PCI

Abstract

OBJECTIVE:

The aim of the present study was to evaluate the effectiveness and safety of nicorandil in improving the area of myocardial infarction in patients with acute myocardial infarction (AMI).

METHODS:

One hundred and twenty patients with acute ST-segment elevation myocardial infarction (STEMI) admitted to our hospital between December 1, 2018 and December 31, 2019 were selected and randomly allocated to the experimental group (group A, n = 60) and the control group (group B, n = 60). In the experimental group, an infusion of nicorandil was given intravenously before the first balloon dilation or 1 minute before the stent placement, and with the completion of the infusion, nicorandil maintenance infusion was given. In the control group, only balloon dilation and stent placement were undertaken.

RESULTS:

The postoperative peak levels of myoglobin, creatine kinase isoform and hypersensitive troponin T were significantly lower in group A than in group B (p < 0.05). Moreover, the left ventricular ejection fraction (LVEF) on the 180th day post operation was substantially greater in group A than in group B (p < 0.01), and the area of myocardial infarction was significantly smaller in patients in group A than those in group B on the 180th day post operation (p < 0.01). In terms of the safety, there were no statistically significant differences in the incidence of slow flow/no reflow, malignant arrhythmias, and hypotension within 24 hours post operation between the two groups (p > 0.05), and no major adverse cardiovascular event (MACE) occurred in either group during the postoperative follow-up period of 180 days (p > 0.05).

CONCLUSION:

Intravenous administration of nicorandil in patients with STEMI during the perioperative percutaneous coronary intervention (PCI) period was effective in reducing the area of myocardial infarction and myocardial injury without increasing the incidence of malignant arrhythmias, hypotension, or composite cardiovascular events during the drug administration period.

Keywords

Percutaneous coronary intervention acute ST-segment elevation myocardial infarction nicorandil myocardial infarction area myocardial injury

1 Introduction

In recent decades, the economic development in China has made continuous progress, the income has increased, and the living standards have improved; however, the incidence of cardiovascular disease has also increased. Currently, the leading cause of death among people in China is cardiovascular disease, which accounts for 45.50%of all deaths in rural areas and 43.16%of all deaths in urban areas [1]. ST-segment elevation myocardial infarction (STEMI) is one of the most common and most critical cardiovascular diseases, and it can cause severe arrhythmia, heart failure, shock, and sudden death. The mortality rate in inpatients during the acute phase is approximately 4%after the intervention therapy within 90 minutes after hospitalization. Ischemic heart disease is one of the most common causes of death worldwide [2]. Unlike the situation in Europe and the United States, the incidence of acute myocardial infarction (AMI) in China has been on the rise in both urban and rural areas in the past 10 years [3].

Percutaneous coronary intervention (PCI) is one of the most common and important reperfusion strategies for patients with STEMI and one of the most effective ways to treat patients with STEMI [4, 5]. Direct PCI is superior to thrombolysis in STEMI patients with the onset time <120 min. Drug therapy combined with PCI may further reduce the myocardial injury in AMI [6, 7]. However, after the routine use of dual-anti-platelet therapy and anticoagulants, and timely implementation of PCI, the ischemic myocardium in some patients has not yet fully recovered with effective reperfusion, wh-ich makes it difficult to save the dying myocardium and leads to further injury and necrosis of cardiomyocytes, which is known as slow flow/no reflow [8, 9]. According to previous studies, there are several therapeutic strategies to improve the microcirculatory obstruction and reduce the area of myocardial infarction, including post-coronary ischemia adaptation, intravenous application of metoprolol, glycoprotein IIb/IIIa receptor inhibitors, remote post-ischemic conditioning, adenosine, and cryotherapy [10, 11]. However, there is still a lack of clinically effective therapies to reduce the microcirculatory obstruction with the goal of reducing the area of myocardial infarction.

Nicorandil is an adenosine triphosphate(ATP)-sensitive K⁺ channel opener and is currently used to treat coronary angina pectoris [12, 13]. The most recent studies on nicorandil focus on its application during PCI in patients with AMI. Nicorandil can improve the ischemia/reperfusion injury, protect the myocardial microcirculation, reduce the incidence of no reflow, prevent the ischemia/reperfusion arrhythmias, improve the left ventricular function, and reduce the incidence of long-term adverse cardiac events in these patients [14, 15]. However, there are fewer studies on whether nicorandil can reduce the area of myocardial infarction. Currently, nicorandil for injection can be given intravenously. The aim of the present study was to evaluate the efficacy and safety of nicorandil in improving the infarction area in patients with AMI by conducting a prospective, randomized, double-blind, parallel-controlled study to provide evidence-based support for the optimization of the PCI therapy.

2 Materials and methods

2.1 Study objects

Patients who were admitted to the Department of Cardiovascular Medicine at the our hospital between December 1, 2018 and December 31, 2019 and diagnosed with acute STEMI according to the third edition of the Global Definition of Myocardial Infarction jointly developed by the American College of Cardiology (ACC), American Heart Association (AHA), European Society of Cardiology (ESC) and World Heart Federation (WHF) in 2012 were selected for the present study. The study protocol was implemented with the approval of the General Hospital of the People’s Liberation Army and the Medical Ethics Committee of Yulin First People’s Hospital, and all the patients signed an informed consent form.

2.2 Diagnostic criteria of STEMI

The diagnostic criteria of STEMI [16]: The diagnostic criteria for AMI referred to the third edition of the Global Definition of Myocardial Infarction jointly developed by the ESC, ACCF, AHA, and WHF in 2012.

2.3 Method of determining the area of myocardial infarction

The area of myocardial infarction was determined by measuring the delayed-enhancement image enhancement area of MRI, which was analyzed by two experienced MRI cardiac diagnosticians and judged by Segment v1.9 post-processing software. The Segment v1.9 program was used to draw the endocardium and epicardium on a short-axis image to determine the size of the left ventricle (the papillary muscles were considered part of the left ventricular cavity). The range of the infarction was determined from the automatic analysis of the delayed enhancement images by the software program. The infarction range was expressed as a percentage (%) (area of the infarction/the size of the whole left ventricle).

2.4 Method of determining the area of myocardial edema

The area of myocardial edema was determined by measuring the area of enhancement of the T2-weighted flip-over sequence image of the cardiac MRI on the 7th day after PCI by two experienced MRI cardiac diagnosticians. The multidimensional short-axis scanning (11–13 layers) should cover as much of the left ventricle as possible. The borders of the epicardium and endocardium were delineated on each short-axis image by the Segment v1.9 program to determine the size of the left ventricle (excluding the suture between the papillary and papillary muscles). The edema range was expressed as a percentage (%) (area of the edema/the size of the whole left ventricle).

2.5 Inclusion and exclusion criteria

2.5.1 Inclusion criteria

No gender restriction

Patients aged 18–80 years

Patients with acute STEMI with the onset within 12 hours

Patients who had given consent to receive emergency PCI treatment

Patients with signed informed consent forms.

2.5.2 Exclusion criteria

Patients with systolic blood pressure < 80 mmHg

Patients with stenosis of the left main stem of the coronary artery

Patients complicated with aortic dissection

Patients with AMI within 6 months

Patients with revascularization surgery (PCI or Coronary artery bypass grafting (CABG)) within 6 months

Patients undergoing treatment with nicorandil

Patients with any known allergic reaction, hypersensitivity reaction, or contraindication to nicorandil or niacin

Patients with contraindication for cardiac magnetic resonance (CMR) and MRI

Patients currently participating or within three months of participation in other research projects

Female patients during pregnancy and lactation

Patients with the presence of other significant abnormal physical signs, laboratory tests, and clinical conditions who were unsuitable for participation in the present study based on the judgment of the clinician.

2.6 Research drugs

Generic name: Nicorandil for injection (Beijing Sihuan Kebao Pharmaceutical Co. Ltd., Production Lot No.: 2012S00559).

Chemical name: N-(2-Hydroxyethyl) nicotinamide nitrate.

Formulations and specifications: Freeze-dried powder, with each bottle containing 12 mg of nicorandil.

Storage conditions: Shaded, airtight, and kept below 10°.

2.7 Research design

The random number table method was used to randomly assign the enrolled patients diagnosed with acute STEMI to the experimental group (group A) and the control group (group B). An oral aspirin loading dose (300 mg) was routinely given to all patients once before undergoing the emergency PCI and thereafter maintained at 100 mg/qd, together with the oral loading dose of ticagrelor (180 mg) once and maintained at 90 mg/bid thereafter. In the experimental group, an infusion of nicorandil was given intravenously before the first balloon dilation or 1 minute before the stent placement, and with the completion of the infusion, nicorandil maintenance infusion was given immediately. In the control group, only balloon dilation and stent placement were undertaken. Moreover, the routine drug therapy regimens for all the patients were based on the latest STEMI diagnostic and treatment guidelines and changed according to the patient’s condition as appropriate.

2.8 Indexes for detection

2.8.1 Observation of therapeutic effects

2.8.1.1. Area of myocardial infarction. The area of myocardial infarction on the 7th day and the 180th day after PCI was determined, and the range of myocardial infarction was calculated.

2.8.1.2. Area of myocardial edema. The area of myocardial edema on the 7th day after PCI was determined, and the range of myocardial infarction was calculated.

2.8.1.3. Cardiac enzymes and troponin. The levels of myoglobin (Mb), creatine kinase isoenzyme (CK-MB), and hypersensitive troponin T (cTnT-hs) were determined before PCI and at 6 h, 12 h, 18 h, and 24 h postoperatively. The peak values were taken from the highest at 6 h, 12 h, 18 h, and 24 h postoperatively.

2.8.1.4. The ST segment of ECG. The grouping of patients was blinded to the physician performing the ST segment measurement. The changes in ST 80 ms from the J-point backward for all 12 leads before and immediately after the reperfusion (0 min) together at 120 min after the reperfusion were calculated. The changes in the ST-segment for the anterior wall infarction were evaluated from the elevation of the ST-segment in leads V1–V6, I, and aVL, and depression of the ST-segment in leads II, III, and aVF. The changes in the ST-segment for the non-anterior infarction were evaluated by the ST-segment elevation in leads II, III, and aVF (including the possible changes in I, aVL, V5, and V6), and the ST-segment depression in leads V1–4. An ST-segment elevation recovery ≥50%was defined as “complete recovery,” while <50%was defined as “no recovery.”

2.8.1.5. Left ventricular ejection fraction (LVEF). The LVEF was determined by echocardiographic measurement on the 7th day after PCI.

2.8.1.6. TIMI blood flow grading. According to TIMI flow grading criteria, the epicardial coronary blood flow was divided into the following grades: Grade 0 was complete occlusion with no contrast passage and no perfusion of the distal myocardium; grade 1 referred to the slight flow of contrast and blood and failure of adequate demonstration of the distal arterial vascular bed; grade 2 meant that the contrast agent could pass slowly through the stenotic part of the lesion or the contrast agent was delayed distally in the stenotic part with the distal vascular segment being demonstrated, and there was perfusion in the distal part of the myocardium, namely the distal vascular bed was completely demonstrated for more than three cardiac cycles; and grade 3 meant rapid intravascular filling and emptying of the contrast medium and complete perfusion of all the distal myocardium, namely complete demonstration of the distal vascular bed within three cardiac cycles. A TIMI flow grade of 0–2 was defined as no reflow.

2.8.1.7. Cardiac rhythm and blood pressure during PCI and at 24 hours after PCI. The cardiac rhythm and blood pressure of the patients were recorded during and at 24 hours after the PCI procedure. Malignant arrhythmias were defined as the cardiac arrhythmias that could lead to hemodynamic disturbances within a short period of time, resulting in syncope or even sudden death, including ventricular fibrillation, ventricular tachycardia, and polymorphic premature ventricular beats. Hypotension was defined as blood pressure below 90/60 mmHg or a drop in the basal blood pressure of more than 30 mmHg [17].

2.8.2 Evaluation of the safety

The composite cardiovascular events during the study period included the following conditions:

All-cause death

Death from any cause.

Cardiovascular death

a)
Unanticipated sudden death: Death occurred suddenly (within one hour of the onset of symptoms) and was witnessed with a clear time of onset.

Fetal myocardial infarction in accordance with any of the following:
The death occurred after myocardial infarction with no evidence of other causes of death;

Patients who died suddenly during the treatment of a myocardial infarction that should be classified as death related to myocardial infarction;

An autopsy-confirmed recent myocardial infarction with no evidence of other causes of death was also classified as this group;

Sudden death in patients with evidence suggestive of myocardial infarction that did not meet the strict definition of myocardial infarction (e.g., with ECG suggestive of myocardial injury, abnormal myocardial markers that had not evolved, evidence suggestive of new abnormalities of the wall motion) was also classified as a myocardial infarction-related death.

Death due to heart failure: Clinical, radiographic or autopsy evidence suggesting death due to heart failure without evidence of other causes such as ischemia, infection, or arrhythmias as a direct cause of death. Death caused by cardiogenic shock was included.

Death following invasive cardiovascular operations: Death occurring within 30 days after cardiovascular surgery, or 7 days after cardiac catheterization, radiofrequency ablation, angioplasty, atherectomy, stenting, or other invasive coronary or peripheral vascular intervention.

Presumed cardiovascular death: Suspected death from cardiovascular causes for which supportive clinical evidence existed, but other criteria were not met (e.g., the patient had typical chest pain of myocardial infarction, but no documentation of ECG or enzymology that met the criteria for myocardial infarction).

Death of unknown cause: No clear evidence of the existence of other diseases and death was regarded to be the result of a cardiovascular event.

Unplanned hospitalization for heart failure

An exacerbation of heart failure that required hospitalization and included at least one of the indications of exertional dyspnea, nocturnal dyspnea, sitting position, or signs of heart failure in radiation images.

Blood flow reconstruction

Stenosis shown by the coronary angiography > 75%, or no significant stenosis, but with a positive result suggested by the myocardial perfusion imaging.

2.9 Statistic analysis

SPSS 22.0 software was used for the data analysis. The independent samples t-test was used to perform the comparisons between groups in which the measurement data conformed to a normal distribution. The data were expressed as mean±standard deviation ( $\bar{x} \pm s$ ). Data that did not conform to a normal distribution and open-ended data were tested using the rank-sum test. The Chi-square test was used for enumeration data, and the data were expressed as examples (percentages) [n(%)]. P < 0.05 was considered statistically significant.

3 Results

3.1 Comparison of the baseline data

Of the 120 patients, 1 patient terminated the experiment due to cerebral hemorrhage on the first day after operation, and 119 patients (94 males and 25 females) were finally investigated, with 59 in group A and 60 in group B. There was no loss during the follow-up period in both groups. There were no statistically significant differences between the two groups in the clinical baseline data such as a history of hypertension, smoking, or diabetes; the administration rate of GPIIb/IIIa receptor antagonist; door-to-balloon(D2B) time; and time from onset to arrival at the hospital (p > 0.05 in all) (the details are provided in Table 1).

Table 1
Comparison of two groups of patients with basic information

Items/Grouping Nicorandil group (n = 59) Control group (n = 60) P

Age(year, $\bar{x} \pm s$ ) 54±9 55±8 0.449

Gender (n, %) 0.859

Male 47(79.7) 47(78.3)

Female 12(20.3) 13(21.7)

Hypertension (n, %) 25(42.4) 26(43.3) 0.916

Diabetes mellitus (n, %) 6(10.2) 5(8.3) 0.730

Smoking history (n, %) 40(67.8) 41(68.3) 0.950

Cardiac function (Killip grading) (n,%) 0.961

Grade1 55(93.2) 56(93.3)

Grade 2 2(3.4) 3(5)

Grade 3 2(3.4) 1(1.7)

Grade 4 0(0) 0(0)

GP IIb/III receptor antagonists (n, %) 7(11.9) 8(13.3) 0.809

Occluded coronary artery (n, %) 0.675

LAD 24(40.7) 26(43.3)

LCX 12(20.3) 15(25)

RCA 23(39.0) 19(31.7)

Number of affected vessels (n,%) 0.671

Single branch lesion 24(40.7) 26(43.3)

Dual branch lesion 19(32.2) 15(25.0)

Triple branch lesion 16(27.1) 19(31.7)

Duration from the onset to the hospital (h, $\bar{x} \pm s$ ) 4.97±2.33 4.69±2.48 0.535

D2B (min, $\bar{x} \pm s$ ) 57.76±18.29 62.63±20.99 0.180

Items/Grouping	Nicorandil group (n = 59)	Control group (n = 60)	P
Age(year, $\bar{x} \pm s$ )	54±9	55±8	0.449
Gender (n, %)			0.859
Male	47(79.7)	47(78.3)
Female	12(20.3)	13(21.7)
Hypertension (n, %)	25(42.4)	26(43.3)	0.916
Diabetes mellitus (n, %)	6(10.2)	5(8.3)	0.730
Smoking history (n, %)	40(67.8)	41(68.3)	0.950
Cardiac function (Killip grading) (n,%)			0.961
Grade1	55(93.2)	56(93.3)
Grade 2	2(3.4)	3(5)
Grade 3	2(3.4)	1(1.7)
Grade 4	0(0)	0(0)
GP IIb/III receptor antagonists (n, %)	7(11.9)	8(13.3)	0.809
Occluded coronary artery (n, %)			0.675
LAD	24(40.7)	26(43.3)
LCX	12(20.3)	15(25)
RCA	23(39.0)	19(31.7)
Number of affected vessels (n,%)			0.671
Single branch lesion	24(40.7)	26(43.3)
Dual branch lesion	19(32.2)	15(25.0)
Triple branch lesion	16(27.1)	19(31.7)
Duration from the onset to the hospital (h, $\bar{x} \pm s$ )	4.97±2.33	4.69±2.48	0.535
D2B (min, $\bar{x} \pm s$ )	57.76±18.29	62.63±20.99	0.180

Note: LAD: the left anterior descending branch, LCX: the left circumflex artery, RCA: the right coronary artery, D2B: the time from the arrival of the hospital to the balloon dilation.

3.2 Comparison of the area of myocardial infarction on the 7th day after PCI between the two groups of patients

The absolute area of myocardial infarction on the 7th day post operation was smaller in group A than in group B, but the difference was not statistically significant (3.2±0.8 vs. 3.5±1.0, p > 0.05) (see Table 2 for details).

Table 2
Comparison of myocardial infarction area and myocardial edema area 7 days after PCI

Items/Grouping Group A (n = 59) Group A (n = 60) P

The absolute area of infarction on the 7th day post-operation (cm²) 3.2±0.8 3.5±1.0 0.136

The absolute area of edema on the 7th day post-operation (cm²) 4.1±1.2 4.4±1.0 0.089

The range of cardiac infarction on the 7th day post-operation (LV area%) 12.2±3.8 13.9±5.7 0.061

The range of edema on the 7th day post-operation (LV area%) 22.0±6.1 24.5±9.2 0.081

Items/Grouping	Group A (n = 59)	Group A (n = 60)	P
The absolute area of infarction on the 7th day post-operation (cm²)	3.2±0.8	3.5±1.0	0.136
The absolute area of edema on the 7th day post-operation (cm²)	4.1±1.2	4.4±1.0	0.089
The range of cardiac infarction on the 7th day post-operation (LV area%)	12.2±3.8	13.9±5.7	0.061
The range of edema on the 7th day post-operation (LV area%)	22.0±6.1	24.5±9.2	0.081

Note: PCI: percutaneous coronary intervention, LV: Left ventricle.

3.3 Comparison of the area of myocardial edema on the 7th day after PCI between the two groups of patients

The absolute area of myocardial edema on the 7th day post operation was smaller in group A than in group B, but the difference was not statistically significant (4.1±1.2 vs. 4.4±1.0, p > 0.05) (as shown in Table 2).

3.4 Comparison of cardiac enzymes and troponins between the two groups of patients

There were no statistically significant differences in the preoperative levels of Mb, CK-MB, and cTnT-hs between the two groups (p > 0.05 in all). The peak postoperative level of Mb was significantly lower in group A than in group B (311.48±235.31 vs. 503.71±564.18, p < 0.05). The peak postoperative level of CK-MB was significantly lower in group A than in group B (48.29 vs. 71.52, p < 0.01), and the peak postoperative level of cTnT-hs was significantly lower in group A than in group B (49.12 vs. 70.70, p < 0.01) (as shown in Table 3).

Table 3
Comparison of myocardial enzymes and troponin before and after PCI

Items/Grouping Group A (n = 59) Group B (n = 60) P

Pre-operative Mb (ng/ml) 348.22±221.80 392.15±299.77 0.379

Pre-operative CK-MB (ng/ml) 34.34±32.65 32.76±50.49 0.841

Pre-operative cTnT-hs (ng/L) 296.72±268.14 262.49±287.66 0.503

Post-operative Mb peak (ng/ml) 311.48±235.31 503.71±564.18 0.017

Post-operative CK-MB peak (ng/ml) 48.29 71.52 <0.01

Post-operative cTnT-hs peak ng/L 49.12 70.70 <0.01

Items/Grouping	Group A (n = 59)	Group B (n = 60)	P
Pre-operative Mb (ng/ml)	348.22±221.80	392.15±299.77	0.379
Pre-operative CK-MB (ng/ml)	34.34±32.65	32.76±50.49	0.841
Pre-operative cTnT-hs (ng/L)	296.72±268.14	262.49±287.66	0.503
Post-operative Mb peak (ng/ml)	311.48±235.31	503.71±564.18	0.017
Post-operative CK-MB peak (ng/ml)	48.29	71.52	<0.01
Post-operative cTnT-hs peak ng/L	49.12	70.70	<0.01

Note: PCI; percutaneous coronary intervention, Mb: myoglobin, CK-MB: creatine kinase isoenzyme, cTnT-hs: hypersensitive troponin T.

3.5 Comparison of the changes in ECG immediately after the operation and at the 120th minute after PCI between the two groups of patients

There was no statistically significant difference between the ST-segment recovery rate immediately after the operation and the ST-segment recovery rate at the 120th minute after the operation between the two groups (p > 0.05 in both) (as shown in Table 4).

Table 4
Comparison of ST segment fallback of ECG immediately, 120 min and left ventricular ejection fraction after PCI

Items/Grouping Group A (n = 59) Group B (n = 60) P

Recovery of the ST segment immediate after operation (n, %) 46(78.0) 43(71.7) 0.429

Recovery of the ST segment at 120 minutes after operation (n, %) 55(93.2) 51(85.0) 0.151

LVEF (%) 55.2±4.8 53.4±7.7 0.114

Items/Grouping	Group A (n = 59)	Group B (n = 60)	P
Recovery of the ST segment immediate after operation (n, %)	46(78.0)	43(71.7)	0.429
Recovery of the ST segment at 120 minutes after operation (n, %)	55(93.2)	51(85.0)	0.151
LVEF (%)	55.2±4.8	53.4±7.7	0.114

Note: LVEF: left ventricular ejection fraction.

3.6 Comparison of LVEF on the 7th day post operation between the two groups of patients

The LVEF (%) was greater in group A than in group B on the 7th day post operation, but the difference was not statistically significant (55.2±4.8 vs. 53.4±7.7, p > 0.05) (see Table 4 for details).

3.7 Comparison of the incidence of slow flow/no reflow between the two groups post operation

There was no statistically significant difference in the incidence of slow flow/no reflow between the two groups post operation (p > 0.05) (as shown in Table 5).

Table 5
Comparison of TIMI blood flow in infarct-related artery after PCI

Items/Grouping A B P

Malignant cardiac, 0 2(3.33) 0.496

Hypotension, n (%) 3(5.08) 3(5.00) >

TIMI grading before PCI, n

Grade 0 28(47.5) 36(60) 0.170

Grade 1 12(20.3) 9(15) 0.445

Grade 2 4(6.8) 6(10) 0.743

Grade 3 15(25.4) 9(15) 0.157

TIMI grading after PCI, n

Grade 0 0 0 –

Grade 1 0 0 –

Grade 2 4(6.8) 4(6.7) >

Grade 3 55(93.2) 56(93.3) >

No reflow, n(%) 4(6.8) 4(6.7) >

Items/Grouping	A	B	P
Malignant cardiac,	0	2(3.33)	0.496
Hypotension, n (%)	3(5.08)	3(5.00)	>
TIMI grading before PCI, n
Grade 0	28(47.5)	36(60)	0.170
Grade 1	12(20.3)	9(15)	0.445
Grade 2	4(6.8)	6(10)	0.743
Grade 3	15(25.4)	9(15)	0.157
TIMI grading after PCI, n
Grade 0	0	0	–
Grade 1	0	0	–
Grade 2	4(6.8)	4(6.7)	>
Grade 3	55(93.2)	56(93.3)	>
No reflow, n(%)	4(6.8)	4(6.7)	>

Note: PCI: percutaneous coronary intervention, TIMI: Thrombolysis in Myocardial Infarction.

3.8 Safety evaluation

The difference in the incidence of malignant arrhythmias and hypotension during the operation and within 24 hours post operation between the two groups was not statistically significant (p > 0.05) (as shown in Table 5).

3.9 Comparison of the occurrence of composite cardiovascular events during the study period between the two groups

No MACE occurred in both groups during the follow-up period of 180 days post operation (as shown in Table 6).

Table 6
Comparison of the incidence of MACE in both groups

Events/Grouping Group A (n = 59) Group B (n = 60) P

All-cause death, n (%) 0 0 –

Cardiovascular death, n (%) 0 0 –

Unplanned hospitalization for heart failure, n (%) 0 0 –

Blood reconstruction, n (%) 0 0 –

Total MACE, n (%) 0 0 –

Events/Grouping	Group A (n = 59)	Group B (n = 60)	P
All-cause death, n (%)	0	0	–
Cardiovascular death, n (%)	0	0	–
Unplanned hospitalization for heart failure, n (%)	0	0	–
Blood reconstruction, n (%)	0	0	–
Total MACE, n (%)	0	0	–

Note: MACE: major adverse cardiovascular events.

3.10 Comparison of LVEF on the 180th day post operation between the two groups

LVEF was significantly greater in group A than in group B on the 180th day post operation (58.1±6.2 vs. 54.1±6.9, p < 0.01) (see Table 7 for details).

Table 7
Comparison of left ventricular ejection fraction and myocardial infarction area180 days after PCI

Items/Grouping Group A (n = 59) Group B (n = 60) P

Absolute area of infarction on the 180th day postoperation (cm²⁾ 2.7±1.0 3.3±1.0 <0.01^*

Range of cardiac infarction on the 180th day postoperation (LV area%) 10.5±4.8 13.5±5.3 <0.01^*

LVEF (%) 58.1±6.2 54.1±6.9 <0.01^*

Items/Grouping	Group A (n = 59)	Group B (n = 60)	P
Absolute area of infarction on the 180th day postoperation (cm²⁾	2.7±1.0	3.3±1.0	<0.01^*
Range of cardiac infarction on the 180th day postoperation (LV area%)	10.5±4.8	13.5±5.3	<0.01^*
LVEF (%)	58.1±6.2	54.1±6.9	<0.01^*

Note: LVEF: left ventricular ejection fraction; PCI: percutaneous coronary intervention; LV: left ventricle.

3.11 Comparison of the area of myocardial infarction on the 180th day after PCI between the two groups

The absolute area of myocardial infarction on the 180th day post operation was significantly smaller in group A than in group B (2.7±1.0 vs. 3.3±1.0, p < 0.01) (as shown in Table 7).

4 Discussion

In the present study, it was observed that the absolute area of infarction on the 180th day after PCI was significantly smaller in the nicorandil group than in the control group (2.7±1.0 vs. 3.3±1.0, p < 0.01), and that the peak levels of Mb, CK-MB, and cTnT-hs in the nicorandil group than those in the control group (311.48±235.31 vs. 503.71±564.18, p < 0.05; 48.29 vs. 71.52, p < 0.01; 49.12 vs. 70.70, p < 0.01). These results indicated that nicorandil played a role in protecting cardiomyocytes during the perioperative period in patients with AMI. A study conducted by Qi et al. found that the intracoronary application of nicorandil during the perioperative period of PCI could reduce the incidence of slow flow/no reflow [26]. In the present study, four cases in group A (n = 59) and four cases in group B (n = 60) had slow flow/no reflow, but the difference in the incidence of slow flow/no reflow between the two groups was not statistically significant (p > 0.05). These results did not indicate that nicorandil could reduce the incidence of slow flow/no reflow, which might be due to the different skills of the operators.

In addition, there were four patients with slow flow/no reflow after PCI in each of the two groups, but the difference in the incidence was not statistically significant (p > 0.05). The LVEF on the 180th day post operation was significantly lower in group A than in group B (58.1±6.2 vs. 54.1±6.9, p < 0.01), indicating that nicorandil could improve the left ventricular function in patients. Wang et al. suggested that nicorandil could mitigate the myocardial injury by inhibiting the Mst1 gene [31], which could explain the reduction in the area of myocardial infarction due to nicorandil.

Moreover, the present study observed that the peak levels of Mb, CK-MB and cTnT-hs were lower in the nicorandil group than in the control group, suggesting that there was less myocardial necrosis in the nicorandil group, which was considered to be correlated with the myocardial protective effect of nicorandil. In the present study, 119 patients were followed for 180 days and no MACE events were found, and it was believed that the effect of nicorandil on the prognosis was unclear. Further clinical studies are needed to confirm the effect of nicorandil on the prognosis.

It was found that the differences in the rate of the ST-segment recovery in the ECG between the two groups immediately after the operation and at the 120th minute post operation were not statistically significant, and therefore we could not rule out the possibility that the differences were due to the small sample size. Moreover, nicorandil was administered intravenously in the present study, while in the study conducted by Feng et al., there was intracoronary application of nicorandil, and therefore the different routes of the application might affect the efficacy and safety.

In the present study, no malignant arrhythmias occurred in the nicorandil group, and the difference in the incidence of hypotension between the two groups was not statistically significant, indicating that the intravenous application of nicorandil was safe in patients with STEMI undergoing PCI. However, the sample size of the present study was small, and therefore a multicenter study with a large sample is needed to observe the safety definitively.

The limitations of the present study are as follows: 1. Small sample size and poor experimental representation; 2. the present study was a single-center study with samples composed of local patients in Yulin, and the results might be influenced by the geographical factors; 3. the myocardial microcirculation-related parameters such as the microvascular obstruction and cTFC were not observed in the present study.

In summary, it was suggested in the present study that nicorandil might protect the cardiomyocytes during the perioperative period of PCI and reduce the myocardial injury during PCI in patients with AMI without increasing the incidence of malignant arrhythmias, hypotension, and composite cardiovascular events after 180 days of follow-up. the perioperative intravenous application of nicorandil could be a promising new treatment option in PCI.

References

Hu Shengshou , Gao Runlin , Liu Lisheng , Zhu Manlu , Wang Wen , Wang Yongjun , et al. Summary of the 2018 Report on Cardiovascular Diseases in China. Chinese Circulation Journal. 2019;34(03):209–220.

Neumann

, Sousa-Uva

, Ahlsson

, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Kardiologia Polska. 2018;76(12):1585–1664.

Wu Si Jing , Fu Ming Jie , Liu Wei , et al. 2018 ESC/EACTS Guidelines for Myocardial Reconstruction Explained. Chinese Circulation Journal. 2018;33(z1):6–9.

RA K. Does reperfusion injury exist in humans. J Am Coll Cardiol. 1993;21:537–545.

Feng

, Liu

, Wang

, et al. Effects of Early Intracoronary Administration of Nicorandil During Percutaneous Coronary Intervention in Patients With Acute Myocardial Infarction. Heart, Lung and Circulation. 2019;28(6):858–865.

Taniyama

, Ito

, Iwakura

, et al. Beneficial effect of intracoronary verapamil on microvascular and myocardial salvage in patients with acute myocardial infarction. J Am Coll Cardiol. 1997;30(5):1193–1199.

Sakata

, Kodama

, Komamura

, 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(6):616–621.

Wang

, Shen

, Mao

, et al. Shock Index on Admission Is Associated with Coronary Slow/No Reflow in Patients with Acute Myocardial Infarction Undergoing Emergent Percutaneous Coronary Intervention. 2019,20(03):1450–1460.

Muller

, Trana

, Eeckhout

. Myocardial no-reflow treatment. Current Vascular Pharmacology. 2013;11(2):278–285.

10.

Thiele

, Wohrle

, Hambrecht

, et al. Intracoronary versus intravenous bolus abciximab during primary percutaneous coronary intervention in patients with acute ST-elevation myocardial infarction: a randomized trial. Lancet (London, England).. 2012;379(9819):923–931.

11.

Kumar

, O’Connor

. Coronary no-reflow in the modern era: a review of advances in diagnostic techniques and contemporary management. 2019;17(8):605–623.

12.

Taira

. Nicorandil as a hybrid between nitrates and potassium channel activators. The American Journal of Cardiology. 1989;63(21):18–24.

13.

Liu

, Sato

, O’Rourke

, et al. Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection?. Circulation. 1998;97(24):2463–2469.

14.

Wei

S-J

, Luan

F-Y

, He

D-y

, et al. Intracoronary administration of nicorandil-induced cardiac arrest during primary percutaneous coronary intervention. Medicine. 2019;15(04):520–526.

15.

Zhao

X-T

, Zhang

C-F

, Liu

Q-J

. Meta-analysis of Nicorandil effectiveness on myocardial protection after percutaneous coronary intervention. BMC Cardiovascular Disorders. 2019;12(04):560–569.

16.

Ma Yuliang . 2012 Global Definition of Myocardial Infarction Explained. Chinese Journal of Cardiovascular Disease. 2015;3(3):11.

17.

Chen

, Fu

, Li

, et al. Intracoronary administration of anisodamine and nicorandil in individuals undergoing primary percutaneous coronary intervention for acute inferior myocardial infarction: A randomized factorial trial. Experimental and Therapeutic Medicine. 2015;10(3):1059–1065.

18.

Celik

, Balta

, Ozturk

, et al. Predictors of No-Reflow Phenomenon in Young Patients With Acute ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. Angiology. 2016;67(7):683–689.

19.

Zimarino

, Affinito

. The prognosis of periprocedural myocardial infarction after percutaneous coronary interventions. Cardiovascular Revascularization Medicine: Including Molecular Interventions. 2013;14(1):32–36.

20.

Reffelmann

, Kloner

. The “no-reflow” phenomenon: basic science and clinical correlates. Heart. 2002;87(2):162–168.

21.

, Lv

, Sun

, et al. Role of TLR4/MyD88/NF-kappaB signaling pathway in coronary microembolization-induced myocardial injury prevented and treated with nicorandil. Biomedicine & Pharmacotherapy=Biomedecine & Pharmacotherapie. 2018;106:776–784.

22.

Binder

, Ali

, Chawla

, et al. Myocardial protection from ischemia-reperfusion injury post coronary revascularization. Expert Review of Cardiovascular Therapy. 2015;13(9):1045–1057.

23.

Djaballah

, Muller

, Angioi

, et al. Nitrate-enhanced gated SPECT in patients with primary angioplasty for acute myocardial infarction: evidence of a reversible and nitrate-sensitive impairment of myocardial perfusion. Eur J Nucl Med Mol Imaging. 2007;34(12):1981–1990.

24.

Olivier

, Catalina

, Eric

. Myocardial no-reflow treatment. Curr Vasc Pharmacology. 2013;11:278–285.

25.

Yamada

, Isobe

, Ishii

, et al. Impacts of nicorandil on infarct myocardium in comparison with nitrate: assessed by cardiac magnetic resonance imaging. Heart and Vessels. 2015;31(9):1430–1437.

26.

, Niu

, Chen

, et al. Intracoronary Nicorandil and the Prevention of the No-Reflow Phenomenon During Primary Percutaneous Coronary Intervention in Patients with Acute ST-Segment Elevation Myocardial Infarction. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2018;24:2767–2776.

27.

Tarkin

J M

, Kaski

J C

. Nicorandil and Long-acting Nitrates: Vasodilator Therapies for the Management of Chronic Stable Angina Pectoris. European Cardiology. 2018;13(1):23–28.

28.

, Liu

, Peng

, et al. Nicorandil improves clinical outcomes in patients with stable angina pectoris requiring PCI: a systematic review and meta-analysis of 14 randomized trials. 2018;11(9):855–865.

29.

Suleimani

, Eshraghi

, Daloee

, et al. Effect of nicorandil on QT dispersion in patients with stable angina pectoris undergoing elective angioplasty: A triple-blind, randomized, placebo-controlled study. Electronic Physician. 2017;9(8):4934–4941.

30.

, Zhang

, Lu

, et al. The effect of nicorandil in patients with acute myocardial infarction undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Irish Journal of Medical Science. 2020;189(1):119–131.

31.

Wang

, Fan

, Feng

, et al. Nicorandil alleviates myocardial injury and post-infarction cardiac remodeling by inhibiting Mst1. Biochemical and Biophysical Research Communications. 2018;495(1):292–299.

32.

Chen

, Wang

, Zou

, et al. Effects of intracoronary injection of nicorandil and tirofiban on myocardial perfusion and short-term prognosis in elderly patients with acute ST-segment elevation myocardial infarction after emergency PCI. World Journal of Emergency Medicine. 2020;11(3):157–163.

33.

de Lemos

, Antman

, Giugliano

, et al. ST-segment resolution and infarct-related artery patency and flow after thrombolytic therapy. Thrombolysis in Myocardial Infarction (TIMI) 14 investigators. The American Journal of Cardiology. 2000;85(3):299–304.

34.

Tomaszuk-Kazberuk

, Musial

, Dobrzycki

, et al. Normalisation of elevated ST segment predicts return of left ventricular systolic function and improved outcome in patients with acute myocardial infarction, treated with primary coronary angioplasty. Kardiologia Polska. 2004;60(6):541–549.

35.

Miyazawa

, Ikari

, Tanabe

, et al. Intracoronary nicorandil prior to reperfusion in acute myocardial infarction. EuroIntervention: Journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2006;2(2):211–217.

Effect of intravenous application of nicorandil on area of myocardial infarction in patients with STEMI during the perioperative stage of PCI

Abstract

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1 Introduction

2 Materials and methods

2.1 Study objects

2.2 Diagnostic criteria of STEMI

2.3 Method of determining the area of myocardial infarction

2.4 Method of determining the area of myocardial edema

2.5 Inclusion and exclusion criteria

2.5.1 Inclusion criteria

2.5.2 Exclusion criteria

2.6 Research drugs

2.7 Research design

2.8 Indexes for detection

2.8.1 Observation of therapeutic effects

2.8.2 Evaluation of the safety

3 Results

3.1 Comparison of the baseline data

3.4 Comparison of cardiac enzymes and troponins between the two groups of patients

3.7 Comparison of the incidence of slow flow/no reflow between the two groups post operation

3.9 Comparison of the occurrence of composite cardiovascular events during the study period between the two groups

Table 6 Comparison of the incidence of MACE in both groups Events/Grouping Group A (n = 59) Group B (n = 60) P All-cause death, n (%) 0 0 – Cardiovascular death, n (%) 0 0 – Unplanned hospitalization for heart failure, n (%) 0 0 – Blood reconstruction, n (%) 0 0 – Total MACE, n (%) 0 0 –

4 Discussion

References