This study investigated the effects of intracoronary nicorandil and tirofiban on no-reflow phenomenon and clinical outcomes in 438 patients with acute coronary syndrome undergoing percutaneous coronary intervention. Both nicorandil and tirofiban improved TIMI blood flow grades after PCI, with TIMI grade 3 flow in 85.2% and 81.4% of patients respectively. There was no significant difference in major adverse cardiac events between the two groups. The study concluded that intracoronary nicorandil can improve coronary perfusion in ACS patients, but its effect on long-term prognosis requires further research.

1. 209
OBJECTIVE: To investigate the effects of nicorandil and
tirofiban on no-reflow and postoperative outcome in pa­
tients with acute coronary syndrome (ACS) undergoing
percutaneous coronary intervention.
STUDY DESIGN: A total of 438 patients with ACS
diagnosed by the second Hospital of Shanxi Medical
University from January 2019 to December 2020 were
divided into two groups: nicorandil group (n=223)
and tirofiban group (n=215). The nicorandil group was
injected with 2 mg nicorandil 2 mm before coronary
occlusion before balloon dilation, and the tirofiban group
received 10 µg/kg intravenous injection during opera-
tion. Measurement of thrombolysis grade (thrombolysis
in myocardial infarction [TIMI]), corrected TIMI frame
count, and major adverse vascular events were recorded
30 days after operation in patients with ACS.
RESULTS: Both nicorandil and tirofiban could improve
the TIMI grade, and TIMI grade 3 blood flow was
obtained in 190 cases (85.2%) and 175 cases (81.4%),
respectively. There was no significant difference in the
incidence of major adverse cardiac events (14.3% vs.
13.5%, score 0.13).
CONCLUSION: Intracoronary use of nicorandil in pa-
tients with ACS can improve coronary perfusion, but the
improvement of prognosis needs further study. (Anal
Quant Cytopathol Histpathol 2021;43:209–215)
Keywords: coronary perfusion, myocardial infarc-
tion, nicorandil, no-reflow phenomenon, percuta-
neous coronary intervention, repercussion.
Percutaneous coronary intervention (PCI) refers to
the method of improving myocardial perfusion by
dredging the stenotic or even obstructed coronary
artery lumen by cardiac catheterization, which be-
longs to one of the re-canalization and is the least
invasive method in myocardial revascularization.1
PCI is one of the most effective treatments for
acute coronary syndrome, and early patency by
obstructing blood vessels can reduce myocar-
dial infarction area, cardiac death, and hospital
events.2,3 Although PCI theoretically achieves
epicardial coronary reperfusion, myocardial reper-
fusion is difficult to achieve, and prolonged myo-
cardial ischemia usually destroys coronary micro­
vessels, resulting in a significant reduction in blood
flow into the infarcted myocardium.4 This clini-
cally frequently observed impairment of myocar-
Analytical and Quantitative Cytopathology and Histopathology®
0884-6812/21/4304-0209/$18.00/0 © Science Printers and Publishers, Inc.
Analytical and Quantitative Cytopathology and Histopathology®
Effect of Intracoronary Application of
Nicorandil and Tirofiban on No-Reflow
Phenomenon in Patients with Acute
Coronary Syndrome
Feng Yan, M.M., Qian Wang, M.M., Junnan Li, M.M., and Hui Lv, M.D.
From the Department of Cardiology, Second Hospital of Shanxi Medical University, Taiyuan City, Shanxi Province, PR China.
Feng Yan is Attending Physician.
Qian Wang is Attending Physician.
Junnan Li is Attending Physician.
Hui Lv is Associate Chief Physician.
Address corresponding to: Hui Lv, M.D., No. 382 Wuyi Road, Xinghualing District, Taiyuan City, Shanxi Province, PR China (lv1870
3513006@163.com).
Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.

2. dial perfusion associated with poor prognosis is
known as no-reflow phenomenon (NRP).5 NRP is
a myocardial microcirculatory disturbance caused
by blood reperfusion failure after physical obstruc-
tion of the ischemic area is relieved after PCI or
thrombolysis, and its coronary angiography does
not show stenosis, but there is hypoperfusion of
cardiomyocytes, chest pain symptoms, and dy-
namic evolution of the electrocardiogram.6 NRP is
based on reperfusion microcirculatory disturbance
and is one of the main factors of impaired cardiac
function in acute coronary syndrome during the
recovery period.7 The incidence of NRP is as high
as more than 30% in patients undergoing PCI for
acute myocardial infarction, and its occurrence
and development predict the occurrence of many
clinical events, including cardiovascular compli-
cations such as ventricular systolic dysfunction,
impaired cardiac function, malignant arrhythmias,
and sudden cardiac death.8 A variety of factors
and mechanisms can affect the occurrence of NRP
in PCI, including age, reperfusion time, high throm-
bus burden, and long-term use of catheters.9 Since
NRP occurs at the level of the microvasculature,
its mainstay of treatment is drug therapy.10 Current
drugs that are effective in preventing and treating
patients associated with NPR to improve prog­
nosis include adenosine, nitroprusside, nicorandil,
shuangdamo, epinephrine, and cyclosporine.11,12
Among them, nicorandil can activate ATP-
sensitive potassium channels and was originally
used as an adjunct to primary PCI for acute myo­
cardial infarction, and its mechanism of action
includes dilation of small coronary vessels of 100
µm, exerting a role similar to nitrates, produc-
ing NO thereby dilating coronary microcircula-
tion, improving ischemia, and reducing ischemia-
reperfusion injury.13,14 Previous clinical studies
have been controversial regarding whether nicor­
andil can improve coronary blood flow and ven-
tricular function,15,16 and few studies have explored
the safety and efficacy of intracoronary injection
of nicorandil in patients with acute coronary syn-
drome. Based on this, the aim of this study was
to evaluate the therapeutic effect of nicorandil on
slow flow in patients with ACS undergoing PCI.
Materials and Methods
Drugs
The following drugs were used in this study:
nicorandil (Sihuan Kebao Pharmaceutical Co., Ltd.,
China), teicoplanin (Patheon Pharmaceutical Co.,
Ltd., North Carolina, USA), aspirin (Zhongxin
Pharmaceutical Co., Ltd., China), teicoplanin (Xin-
litai Pharmaceutical Co., Ltd., China), clopidogrel
(Hengrui Pharmaceutical Co., Ltd., China), and
atorvastatin (Qilu Pharmaceutical Co., Ltd., China).
Study Subjects
Patients who visited the Second Hospital of Shan-
xi Medical University from January 2019 to Decem-
ber 2020 and were diagnosed with acute coro-
nary syndrome and who underwent primary PCI
were selected. Inclusion criteria were as follows:
patients with acute ST-elevation myocardial infarc-
tion, non-ST-elevation myocardial infarction, and
unstable angina. Exclusion criteria were as follows:
cardiogenic shock, severe hypertension, tachycar-
dia, history of severe bleeding, liver and kidney
dysfunction, need for coronary artery bypass, pres-
ence of contraindications to antithrombotic ther-
apy, and previous history of myocardial infarc-
tion. This study has been approved by the Ethics
Committee of the Second Hospital of Shanxi Med-
ical University, and informed consent has been
granted.
Coronary Artery Surgery and Compatible Drug
Therapy
All patients received conventional antithrombotic
therapy before PCI, including aspirin 300 mg, tica-
grelor 180 mg or clopidogrel 450 mg, and atorvas-
tatin 20 mg. Conventional coronary angiography
and PCI were performed to manage the culprit
vessel. The right radial artery approach was used
for surgery. A total of 438 patients were enrolled
and divided into the nicorandil group (223 pa-
tients) and the teicoplanin group (215 patients).
In the nicorandil group, 2 mg nicorandil was ad-
ministered 2 mm before the site of the culprit
vessel obstruction before balloon predilation. In
the teicoplanin group, teicoplanin 10 µg/kg was
intravenously injected into the catheter for 3 min-
utes followed by intravenous infusion at a rate of
0.15 µg/kg/min for 12 hours. After surgery, long-
term oral aspirin, ticagrelor 90 mg twice a day or
clopidogrel 75 mg once a day and atorvastatin 20
mg once a night were administered. Beta-blockers,
ACEI drugs, and other antihypertensive and hypo-
glycemic drugs were also given according to clini-
cal conditions.
Coronary Flow Evaluation
Coronary thrombolysis in myocardial infarction
210 Analytical and Quantitative Cytopathology and Histopathology®
Yan et al

3. (TIMI) classification was evaluated immediately
after primary PCI by two senior cardiology inter-
ventionalists, correcting for TIMI frame number.
TIMI is classified as grade 0 (no perfusion), grade
1 (through no perfusion), grade 2 (partial perfu-
sion), and grade 3 (complete perfusion). The index
of infarct-related coronary flow was assessed in
the TFC by 1.7-fold in the anterior descending
artery compared with the circumflex artery and the
right coronary artery.
Major Adverse Cardiac Events Recording and
Clinical Follow-Up
Major adverse cardiac events (MACEs) were rec­
orded during hospitalization after primary PCI
and at the 3-month follow-up outside the hospital.
MACEs include life-threatening arrhythmias (ven-
tricular tachycardia and fibrillation), heart failure,
reinfarction, coronary revascularization, and sud-
den cardiac death.
Statistical Analysis
GraphPad Prism 7.0 statistical software (Graph Pad
Software Inc.) was used to analyze the data. The
measurement data conforming to normal distribu-
tion are expressed as mean ± standard deviation.
For the comparison, firstly, F test is used to com-
pare the homogeneity of data variance. If the over-
all variance is equal, t test is used. Enumeration
data were compared between the two groups using
χ2 test, and p>0.05 was considered statistically sig-
nificant.
Results and Discussion
Comparison of the Clinical Data of the Selected
Patients
A total of 438 patients with acute coronary syn-
drome who underwent primary PCI were enrolled
and divided into two groups: nicorandil group
(223 patients) and teicoplanin group (215 patients).
There was no significant difference in gender, age,
body mass index, previous history of myocardial
infarction, and biochemical tests between the two
groups. At the same time, there was no statistical-
ly significant difference in the timely limit of med­
ication categories between the two groups (p>0.05)
(Table I).
Nicorandil Reduces the Occurrence of NPR in
Patients with ACS
Previous studies by Iwakura have shown that the
use of nicorandil in patients with acute myocardial
infarction (AMI) reduces effective NPR.17 In our
study, the results of coronary angiography pro-
cess analysis showed that there was no statistical
difference in TIMI and cTFC data between the
two groups after PCI; after PCI, both nicorandil
and teicoplanin could improve TIMI grade, and
the proportions of patients achieving TIMI grade
3 flow were 85.2% and 81.4%, respectively, with
statistical difference. Patients in both groups of
cTFC decreased significantly, and the decrease was
more significant in the nicorandil group than in
the teicoplanin group (p>0.05) (Table II). The re­
sults of imaging examination showed that the
coronary no-reflow was significantly improved in
both the teicoplanin group (Figure 1) and the
nicorandil group (Figure 2) before and after in-
tracoronary use of drugs. In addition, in the treat­
ment of NPR, intracoronary administration is sig-
nificantly superior to intravenous administration
because higher plasma concentrations can be
achieved with intracoronary administration.18 Tra-
ditional administration to the coronary ostium has
disadvantages such as leakage of drugs into the
aortic root and reaching non-diseased vessels, and
our study ensured high concentrations of drugs
in the ischemic and infarcted areas before ad-
Volume 43, Number 4/August 2021 211
Nicorandil and Tirofiban in No-Reflow Phenomenon
Table I Comparison of Clinical Data Characteristics of Patients
Nicorandil Tirofiban
group group p Value
Male 145 144 0.47
Age (years) 59±6 60±8 0.17
BMI (kg/m2) 23.2±2.4 22.9±2.2 0.38
History of myocar-
dial infarction 5 3 0.71
History of hyper-
tension 104 106 0.56
History of hyper-
lipidemia 71 75 0.76
History of diabetes 73 77 0.64
Smoking history 75 83 0.23
Total cholesterol
(mg/dL) 182±36 173±37 0.67
Glycosylated
hemoglobin (%) 6.2±0.4 5.8±0.5 0.57
Serum creatinine
(mg/dL) 1.23±0.21 1.18±0.19 0.59
Medications
Aspirin 223 215 —
Clopidogrel/
Ticagrelor 223 215 —
Beta blockers 67 82 0.49
Atorvastatin 223 215 —

4. ministration to the predilated vessels.19 Therefore,
nicorandil effectively reduced the occurrence of
NPR in patients with ACS and significantly im-
proved TIMI flow and significantly reduced cTFC.
Kostic et al20 also showed that intracoronary use
of nicorandil in ST-segment elevation AMI can
significantly improve microcirculatory function by
reducing the microcirculatory resistance index and
increasing coronary flow reserve, consistent with
our findings.
TIMI vascular grade reflects epicardial blood
perfusion, and intracoronary use of nicorandil can
effectively improve TIMI grade of coronary blood
flow and has the potential to further improve
ventricular function because nicorandil can inhibit
reperfusion injury.21 Nicorandil inhibits sarcoplas-
mic reticulum calcium release and less calcium in-
flux by opening potassium channels, thereby di-
lating coronary vessels with a diameter of >100
μm, reducing the production of oxygen free rad-
icals during mitochondrial reoxygenation in car-
diomyocytes and reducing ischemia-reperfusion–
induced polymorphonuclear leukocyte activation
through NO release and potassium channel cas-
cades.22,23 In addition, nicorandil can increase in-
tracellular cGMP and increase coronary blood flow
by activating guanylate cyclase on vascular smooth
muscle.24
Nicorandil Has High Safety
NRP is a marker of myocardial injury, ischemia,
and myocardial infarction and is also a predictor
of ventricular remodeling and myocardial insuf-
ficiency.25 A study by Durante et al indicated a
higher incidence of MACEs in patients with NPR
during PCI.26 Nicorandil can prevent no-flow/
slow-flow phenomena in AMI patients under-
going PCI, thereby reducing the occurrence of
212 Analytical and Quantitative Cytopathology and Histopathology®
Yan et al
Table II Comparison of Surgical Process Analysis
Nicorandil Tirofiban
group group
(223 cases) (215 cases) p Value
Preoperative TIMI
0 123 118 0.75
1 62 65 0.83
2 22 21 0.91
3 16 11 0.86
Postoperative TIMI
0 2 2 0.71
1 14 13 0.78
2 17 25 0.37
3 190 175 0.03
cTFC preoperatively 49±11 46±12 0.17
cTFC postoperatively 23±5 26±6 0.01
Figure 1 Images before and after intracoronary use of teicoplanin in patients with coronary no-reflow in the anterior descending artery
(frame 24) (1A is in patients with coronary no-reflow in the anterior descending artery [arrow], and 1B is in disappearance of no-reflow
after use of teicoplanin [arrow]).

5. MACEs, indicating that the drug is safe and does
not require intensive monitoring.27 And studies
have shown that nicorandil can reduce MACEs
by inhibiting inflammatory factors, reducing the
inflammatory response, and inhibiting platelet
activation, which in turn avoids causing intra-
coronary thrombosis and myocardial supply
reduction.28,29 It can reduce PCI-related myocardi-
al injury, improve endothelial function, stabilize
atheromatous plaques, and improve ventricu-
lar function.30 In our study, the incidence of in-
hospital MACEs was 12.1% and 10.3% in the
nicorandil group, respectively, with no statisti-
cally significant difference. After 3-month follow-
up outside the hospital, the incidence of MACEs
was also not significantly different, with an inci-
dence of 14.3% and 13.5%, respectively (p>0.05)
(Table III). The results showed that there was no
statistically significant difference in the incidence
of MACE after follow-up between the nicorandil
groups, which may be related to the small data
volume and observation time, once again confirm-
ing the safety of nicorandil.
Conclusion
Intracoronary administration of nicorandil can ef­
fectively reduce the occurrence of NPR in patients
with ACS, without intraoperative complications,
and the incidence of MACE is not significantly dif-
ferent from that of teicoplanin, which means that
it is an effective and safe treatment.
Acknowledgement
The authors thank Guangzhou Yujia Biotechnology
Co., Ltd., for excellent technical assistance.
Volume 43, Number 4/August 2021 213
Nicorandil and Tirofiban in No-Reflow Phenomenon
Figure 2 Images before and after coronary no-reflow intracoronary use of nicorandil (frame 29) (2A is the angiographic result of a patient
with no-reflow right coronary artery [arrow], and 2B is the no-reflow disappearance after the use of nicorandil [arrow]).
Table III Major Clinical Events and Follow-Up
Nicorandil Tirofiban
group group p Value
Hospital MACEs
Heart failure 11 10 0.36
Fatal arrhythmia 16 12 0.27
Recurrent
myocardial
infarction 0 0 —
Revascularization 0 0 —
Death 0 0 —
Out-of-hospital
MACEs
Heart failure 12 10 0.43
Fatal arrhythmia 13 11 0.56
Recurrent
myocardial
infarction 7 8 0.48
Revascularization 0 0 —
Death 0 0 —

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