14
Članek prispel / Received
16. 8. 2020
Članek sprejet / Accepted
18. 3. 2021
Abstract
Purpose: There are no data demon-
strating that a decrease in heart rate 
reduces periprocedural myocardial inju-
ry (PMI) in patients undergoing electi-
ve percutaneous coronary intervention 
(PCI). Ivabradine is an established an-
ti-ischemic drug that reduces heart rate 
(HR) and subsequently alleviates symp-
toms of angina. The present study sou-
ght to determine whether HR reduction 
via ivabradine attenuates PMI.
Methods: Forty patients with stable 
angina and a resting HR of >70 bpm 
were administered 5 mg of ivabradine 
twice daily. The control group consisted 
of 40 patients with a resting HR of >70 
bpm. All patients were monitored for 
Izvleček
Namen: V literaturi zaenkrat ni po-
datkov, ki bi dokazovali, da znižanje 
srčne frekvence zmanjša periprocedu-
ralno poškodbo miokarda pri bolnikih, 
ki imajo opravljen perkutani koronarni 
interventni poseg. Ivabradin je uvelja-
vljeno protiishemično zdravilo, ki znižu-
je srčno frekvenco in posledično izboljša 
simptome angine pektoris. V pričujoči 
raziskavi nas je zanimalo, ali znižanje 
srčne frekvence z ivabradinom zmanjša 
periproceduralno poškodbo miokarda. 
Metode: 40 bolnikom s stabilno an-
gino pektoris in utripom v mirovanju 
nad 70 udarcev na minuto smo pred-
pisali ivabradin 2x5 mg dnevno. V 
kontrolni skupini je bilo 40 bolnikov z 
Ključne besede: 
srčna frekvenca, koronarna 
angiografija, periproceduralna 
poškodba miokarda
Key words: 
heart rate, coronary angiography, 
myocardial periprocedural injury 
Znižanje srčne frekvence z ivabradinom zmanjša 
periproceduralno poškodbo srčne mišice po 
koronarnem posegu in izboljša simptome angine 
pektoris pri bolnikih s stabilno koronarno boleznijo
Heart rate reduction using ivabradine protects 
against periprocedural myocardial injury and angina 
symptoms in patients with stable coronary disease 
undergoing coronary intervention
Avtor / Author Franjo Naji1,2,  Marcel Berro1, David Suran1,2, Vojko Kanic1,2
Ustanova / Institute 1University Medical Centre Maribor, Clinic for Internal Medicine, Department for Cardiology 
and Angiology, Maribor, Slovenia; 2University of Maribor, Faculty of Medicine, Department of 
Internal Medicine, Maribor, Slovenia
1Univerzitetni klinični center Maribor, Klinika za interno medicino, Oddelek za kardiologijo 
in angiologijo, Maribor, Slovenija; 2Univerza v Mariboru, Medicinska fakulteta, Katedra za 
interno medicino, Maribor, Slovenija
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INTRODUCTION
Periprocedural myocardial injury (PMI) is frequent 
in patients undergoing elective percutaneous 
coronary intervention (PCI). The main reasons for 
this collateral damage are occlusion of small side 
branches during stent deployment and peripheral 
embolization via dislodged debris that also takes place 
during stent positioning and balloon inflation (1). 
It has been previously demonstrated that the extent 
of troponin leakage after the procedure is associated 
with a worse patient prognosis (2). PMI is defined in 
the latest universal definition of myocardial infarction 
as an elevation of troponin above the 99th percentile 
Naslov za dopisovanje /  
Correspondence
Doc.dr.Franjo Naji, dr.med., 
Univerzitetni klinični center Maribor, 
Klinika za interno medicino, Oddelek za 
kardiologijo in angiologijo, Ljubljanska 
5, 2000 Maribor, Slovenija 
Telefon: +386 23212371
E pošta: franjo.naji@yahoo.com
utripom v mirovanju nad 70 udarcev 
na minuto. Vsi bolniki so bili vključeni 
mesec dni pred predvidenim posegom. 
Vrednosti troponina I smo določili pred 
posegom in 24 ur po posegu. Spremljali 
smo tudi simptome angine pektoris v 
obeh skupinah.
Rezultati: Med obema skupinama 
bolnikov ni bilo statistično pomembnih 
razlik. Opažali smo pomembno zniža-
nje srčne frekvence in pomembno manj 
simptomov angine pektoris v skupini, 
zdravljeni z ivabradinom (62.3±7.1 
utripov na minuto vs.79±10.2 utripov 
na minuto; P<0.05 in 0.5±0.1 vs. 
2.4±2.1; P<0.05). Vrednosti troponi-
na I so bile pomembno nižje v skupini, 
zdravljeni z ivabradinom v primerjavi s 
kontrolno skupino (0.12±0.03 ng/mL 
vs. 0.44±0.08 ng/mL; P<0.05). Ko 
smo dodatno analizirali faktorje vpliva, 
smo ugotovili da na periproceduralno 
poškodbo miokarda vplivata le srčna 
frekvenca pod 70 utripov na minuto 
(razmerje obetov 7.0; interval zaupa-
nja od 1.2 od 41.7; P=0.03) in število 
vstavljenih žilnih opornic (razmerje obe-
tov 4.4; 95% interval zaupanja 1.1 to 
17.3; P=0.03). 
Zaklju~ek: Znižanje srčne frekvence 
z ivabradinom zmanjša periprocedural-
no poškodbo miokarda pri bolnikih ob 
opravljenem perkutanem koronarnem 
interventnem posegu.
one month before the scheduled interven-
tion. After admission, troponin I levels 
were measured before and 24 h after the 
procedure. Data on any change in symp-
toms were also collected in both groups.
Results: There were no significant 
differences between the groups. A signi-
ficant reduction in HR and angina epi-
sodes per week was noted in the ivabra-
dine group (62.3±7.1 bpm vs.79±10.2 
bpm; P<0.05 and 0.5±0.1 vs. 2.4±2.1; 
P<0.05). The mean troponin I levels 
after the procedure were significantly 
lower in the ivabradine group compared 
to the control group (0.12±0.03 ng/
mL vs. 0.44±0.08 ng/mL; P<0.05). 
When analyzing patients after corona-
ry intervention, heart rate of <70 bpm 
(OR 7.0; CI 1.2 to 41.7; P=0.03) and 
number of deployed stents (OR 4.4; 
95% CI 1.1 to 17.3; P=0.03).were the 
only significant predictors of PMI after 
adjustment for potential confounders in 
a multivariable logistic model.
Conclusion: HR reduction achieved 
by ivabradine reduces PMI in patients 
undergoing elective PCI.
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of the upper level of normal (ULN) in the case 
with normal preprocedural values (3). Among risk 
factors associated with PMI, previous reports have 
mentioned age, N-terminal–pro-brain natriuretic 
peptide, hemoglobin, number of target vessels, type 
of lesion (B2 or C), number of stents, and presence 
of aortic valve calcification, just to name few (1,4,5,6). 
In terms of the other established atherosclerosis 
risk factors, it has been shown that preprocedural 
non-high-density lipoprotein cholesterol levels are 
associated with PMI (7). However, there are no data 
showing that heart frequency is connected to PMI. It 
was previously shown that elevated heart frequency is 
involved in atherosclerosis progression, although the 
pathophysiologic rationale for this phenomenon is 
still lacking (8). The present study hypothesized that 
heart rate (HR) reduction in patients with elevated 
heart frequency of >70 bpm attenuates PMI.
MATERIALS AND METHODS 
Patients scheduled for elective PCI were evaluated in this 
study, which was approved by the Institutional Ethics 
Committee. Inclusion criteria included suspected or 
preestablished coronary artery disease, presence of sinus 
rhythm, and resting heart frequency of >70 bpm. Exclusion 
criteria included previous pacemaker implantation, 
symptoms and signs of heart failure, left ventricle ejection 
fraction of <50%, creatinine levels above ULN, and prior 
ivabradine treatment. Patients were invited to participate 
in the study after the inclusion criteria were satisfied. 
Informed consent was obtained, and patients were 
instructed to come for the first time one month before 
the planned procedure. The heart rate was reassessed at 
the first visit. Patients were asked about their usual therapy 
adherence and then instructed to rest for 5 min. A twelve-
lead electrocardiogram (ECG) was recorded and eligible 
(HR>70 bpm) patients were then randomly assigned to 
one of two groups. Patients in group 1 were prescribed 
5 mg of ivabradine twice daily on top of their standard 
therapy. Patients in group 2 received no additional 
treatment. Patients were reassessed upon admission and 
data including history of angina and any ivabradine side 
effect symptoms were obtained. A twelve-lead ECG was 
recorded and resting heart frequency was measured. 
Fasting state blood was collected upon admission 
using standard medical techniques. Additional blood 
samples were obtained 24 h after the procedure. 
Troponin I levels were analyzed using cardiac troponin 
I assay (Siemens Healthcare Diagnostics) with a limit of 
detection of 0.006 μg/L, 99th percentile cut-off point of 
0.04 μg/L, and coefficient of variation of <10% at 0.03 
μg/L as specified by the manufacturer (9,10).
PCI was performed by an experienced interventional 
cardiologist who was blinded to the study protocol. 
Femoral or radial approach was used. All patients 
received unfractionated heparin at a standard dosage 
(30–100 IU/kg). The drug dosage and material selection 
were left to the operator’s discretion. The target lesions 
were pinpointed and PCI was performed after the 
coronary angiogram. Troponin I was reassessed 24 h 
after the procedure in all patients. PMI was defined 
as an elevation of troponin above the 99th percentile 
of ULN in the case of normal preprocedural values. 
This definition is in accordance with the 4th universal 
definition of myocardial infarction (3).
Student’s t-test was used to evaluate the differences 
between continuous variables. Chi-square test was 
used for analysis of categorical variables. Continuous 
data were expressed as mean ± standard deviation 
(SD), whereas categorical variables were expressed as 
percentages. Simple logistic regression method was 
used to assess the correlation between HR and PMI. 
Multivariate logistic regression was then used to adjust 
the significance for other potential confounders. 
Statistical analysis was performed using the SPSS 
statistical package.
RESULTS
There were slightly more patients with arterial 
hypertension in the ivabradine group. Otherwise, no 
significant differences were noted between the groups 
(Table 1: Clinical characteristics of both groups). A 
significant reduction in HR and angina episodes per 
week was present in the ivabradine group (62.3±7.1 
vs.79.3±10.2 bpm; P<0.05 and 0.5±0.1 vs. 2.4±2.1; 
P<0.05; Table 2: Clinical effects of ivabradine 
treatment after one month). The mean troponin I 
levels after the procedure were significantly lower in 
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the ivabradine group compared to the control group 
(0.12±0.03 ng/mL vs. 0.44±0.08 ng/mL; P<0.05; 
Table 3). Logistic regression model showed a positive 
correlation between HR≥70 bpm and PMI (odds ratio 
(OR) 5.8; 95% confidence interval (CI 1.2–26.9; 
P=0.01). In a multivariate model including all of the 
variables, the only significant predictors of PMI were 
HR≥70 bpm (OR 7.0; CI 1.2–41.7; P=0.03) and the 
number of deployed stents (OR 4.4; 95% CI 1.1–17.3; 
P=0.03; Tables 1, 3).
DISCUSSION
The present study showed that heart frequency has 
an impact on PMI in patients with coronary disease 
Table 1. Clinical characteristics of both groups
Baseline parameters Ivabradine group (N=40)
Control group 
(N=40) P value
Age (years) 56±13 57±11 0.9
Sex (Female) 17(42%) 16(40%) 0.9
Weight (kg) 88.8±16.5 83.2±21.6 0.2
Height (cm) 168.9±8.3 170.3±11.3 0.5
Pulse (per min) 79.4±10.2 78.3±7.9 0.6
Hypertension 36 (90%) 28 (70%) 0.05
Diabetes 11 (27%) 11 (27%) 1.0
Dyslipidemia 22 (55%) 27 (68%) 0.4
Antiagregation therapy 35 (87%) 30 (75%) 0.3
Beta-blockers 25 (62%) 22 (55%) 0.6
Statins 23 (58%) 26 (65%) 0.6
ACE inhibitors 31 (75%) 30 (78%) 1.0
Trimetazidine 6 (15%) 1 (3%) 0.1
Cholesterol (mmol/L) 5.0±1.4 4.9±1.5 0.7
Hemoglobin (g/L) 142.3±11.4 142.9±16.5 0.9
LDL cholesterol 
(mmol/L) 3.2±1.3 3.0±1.3 0.7
Troponin levels (ng/mL ) 0.03±0.01 0.02±0.01 0.7
ACE – angiotensin converting enzyme             
LDL – low density lipoprotein.
Table 3. Periprocedural and postprocedural parameters 
in both groups
After procedure Ivabradine group Control group P value
Troponin I levels (ng/
mL) 0.12±0.03 0.44±0.08 0.02 
Creatinine levels 
(µmol/L) 86.9±26.9 81.0±19.8 0.3 
Number of lesions per 
patient 1.1±0.3 1.1±1.0 0.9 
Lesion location –LAD 9 (23%) 8 (20%) 0.8 
Lesion location –LCX 4 (10%) 7 (18%) 0.5 
Lesion location RCA 7 (18%) 4 (10%) 0.3 
Lesion location other 1 (3%) 2 (5%) 1.0
Type B2/C lesion 
according to American 
Heart Association 
(AHA) 
12 (31%) 14 (35%) 0.8
PCIs per patient 0.4±0.05 0.6±0.05 0.1 
Stents per patient 0.5±0.08 0.6±0.08 0.5 
Cummulative mean stent 
length (mm) 30.1±16.1 24.6±9.7 0.2 
Cummulative mean stent 
diameter (mm) 3.0±0.4 2.7±0.7 0.1 
Maximum pressure (atm) 15.8±4.4 15.5±4.9 0.8 
Ballon inflation duration 
(sec) 29.1±16.9 27.0±14.3 0.7
Duration of procedure 
(min) 35.3±24.6 37.4±16.6 0.7
LAD – left anterior descending 
LCX – left circumflex
RCA – right coronary artery             
LDL – low density lipoprotein.
Table 2. Clinical effects of ivabradine treatment after 
one month
Ivabradine group 1st visit After 1 month P value
Angina episodes per 
week 2.4±2.1 0.5±0.15 0.00 
Nitroglycerin per week 0.8±0.14 0.2±0.09 0.04 
CCS Scale 2.1±0.6 1.5±0.5 0.08 
Beats per minute 79.3±10.2 62.3±7.1 0.00 
CCS – Canadian Cardiovascular Society 
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undergoing PCI. There were no significant differences 
between the groups that could severely influence 
established results. The numbers of coronary lesions 
between both groups were comparable and there 
were no major differences in other angiographic 
and procedural parameters. Moreover, the included 
patients were all undergoing elective procedures. 
They had normal troponin I levels before the 
procedure and no signs of kidney failure before or 
after the procedure causing troponin I elevation. 
In addition, no differences in hemoglobin and low-
density cholesterol levels were present between both 
groups, even though it was recently shown that these 
two factors can have an influence on PMI. Therefore, 
it was suggested that reduced HR has an impact on 
troponin I level elevation after the procedure.
Previous studies have established that different factors 
mirroring endothelial damage (like microalbuminuria 
and hypercholesterolemia) are associated with PMI 
(7,11). It was also shown that patients with a greater 
myocardial enzyme leak during interventional 
procedures are prone to higher complication rates and 
worse prognosis (2). In addition, it was demonstrated 
that lesion complexity and stent position affect the 
post-procedural prognosis (12). Consequently, it 
would be of benefit to highlight different factors 
correlated with PMI. Since heart frequency is easy to 
measure and relatively simple to tackle, it is also of 
clinical benefit to know that lower HR is associated 
with better outcomes after PCI. 
It has been shown that elevated heart frequency in 
patients with established coronary disease is associated 
with a worse prognosis (8). The BASKET PROVE 
trial tried to elucidate whether HR in patients after 
PCI upon discharge from the hospital is associated 
with a worse outcome. It was demonstrated that 
patients with a higher HR had a higher all-cause 
mortality rate as well as a higher rate of myocardial 
infarction. Results were similar in groups of patients 
with acute coronary syndrome and in those with 
stable angina (13). However, positive results from 
large trials showing a possible benefit of HR reduction 
for prognosis of patients with heart disease are still 
lacking. The Signify Trial randomly assigned patients 
to the ivabradine or placebo groups to reduce HR to 
55–60 bpm. After a median follow up of 27.8 months, 
there were no clinical benefits from the ivabradine 
treatment, with a higher rate of bradycardia, atrial 
fibrillation, and QT prolongation observed in the 
treated group (14). However, subsequent subgroup 
analysis demonstrated that treatment with ivabradine 
reduced the frequency of angina episodes, which 
was also confirmed in the present study (15). Studies 
which address pathophysiological effects are urgently 
required as data on HR reduction using ivabradine are 
still conflicting as far as clinical benefits are concerned. 
Dillinger et al. have tried to evaluate the impact of HR 
reduction using ivabradine on central aortic blood 
pressure and myocardial perfusion. They showed 
that reduced HR improves the myocardial perfusion 
index and diastolic perfusion time without an effect 
on central aortic blood pressure (16). O’Connor 
et al. have studied the effect of HR  reduction with 
ivabradine on left ventricular remodelling measured 
by echo strain imaging in a pre-clinical setting. 
They were able to demonstrate that HR reduction 
attenuated infarct expansion and preserved remote-
zone contractile function and synchrony in a mouse 
model of myocardial infarction (17).
There are several limitations in this study. Because 
a placebo arm was not present, the clinical benefit 
could be biased by intention to treat. However, this 
did not influence biomarkers and troponin I levels 
in both groups. The study sample was also relatively 
small, although there were no large heterogeneities 
between the groups. We also could not measure 
other biomarkers of cardiac necrosis, such as creatine 
kinase enzyme, which could give further insight into 
myocardial damage after the procedure. Finally, 
it is also possible that other unidentified factors 
confounded the study results. To the best of our 
knowledge, all parameters previously demonstrated to 
have an impact on PMI were included in the study. 
CONCLUSIONS
In conclusion, we were able to show that HR reduction 
via ivabradine reduces PMI in patients undergoing 
elective PCI. Further clinical studies are needed to 
clarify this issue.
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