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Original Article
Short‑Term Effects of Ivabradine in Patients with Chronic
Stable Ischemic Heart Disease
Hosam Zaky, Hind Elzein, Alawi A. Alsheikh‑Ali1, Arif Al‑Mulla
Dubai Heart Center, Division of Cardiology, Dubai Hospital, Dubai Health Authority, Dubai, 1Cardiac Arrhythmia Service,
Heart and Vascular Institute, Sheikh Khalifa Medical City, Abu Dhabi, UAE
ABSTRACT
Introduction: Ivabradine is a novel selective If current inhibitor with anti‑ischemic and antianginal activity.
Objectives: To assess the effect of the selective If current inhibitor ivabradine on heart rate, angina pectoris, and functional
capacity in stable patients with chronic coronary artery disease on maximally tolerated medical therapy.
Materials and Methods: Consecutive patients from the out‑patient cardiology clinic with stable coronary artery disease
documented by coronary angiography were included. Patients had to be on maximally tolerated medical therapy with b‑blockers,
angiotensin‑converting enzyme inhibitors or receptor blockers (ACE‑I or ARB), antiplatelets, statins, nitrates, and anti‑metabolics
with a baseline heart rate of at least 70 beats per minute. All patients underwent assessment of angina (Canadian Cardiovascular
Society Angina Class: CCS I to IV) and functional capacity (using a validated self‑administered questionnaire), at baseline and
after 4 months of ivabradine therapy.
Results: Twenty patients were enrolled (mean age 47 ± 7 years, all male, 60% with hypertension, 30% with diabetes mellitus). Patients were
on optimal medical regimen of aspirin (100%), b‑blocker (100%), statins (100%), clopidogrel (90%), nitrates (35%), anti‑metabolics (90%),
and ACE‑I or ARB (95%). At baseline, the majority of patients (90%) were in CCS class II–IV. All patients were started on ivabradine
5 mg twice daily, and in 12 patients the dose was increased to 7.5 mg twice daily. After 4 months of treatment, the heart rate was
significantly reduced from an average of 82 ± 8 to 68 ± 6 bpm (P < 0.001). The reduction in heart rate was accompanied by a significant
improvement in functional capacity (score 3.5 ± 0.9 to 4.7 ± 0.7, P < 0.001) and angina classification; at baseline 10% of the patients
were in CCS class I compared to 50% after 4 months of therapy (P = 0.01). No symptomatic bradycardia was reported with ivabradine.
Conclusion: The addition of ivabradine to optimal medical therapy in patients with stable coronary artery disease is associated
with significant improvement in anginal symptoms and functional capacity.
Key words: Heart rate, ischemic heart disease, ivabradine
How to cite this article: Zaky H, Elzein H, Alsheikh-Ali AA, Al-Mulla A. Short-term effects of ivabradine in patients with chronic stable ischemic
heart disease. Heart Views 2013;14:53-5. © Gulf Heart Association 2013.
INTRODUCTION
A
ngina pectoris is typically caused by myocardial
ischemia owing to an imbalance between
myocardial perfusion and oxygen demand.
Elevated heart rate increases myocardial oxygen
demand and limits tissue perfusion, the latter by reducing
the duration of diastole during which most myocardial
perfusion occurs.[1] In current clinical practice, however,
many patients with stable angina pectoris require
treatment with more than one anti‑anginal drug, in
addition to short‑acting nitrates. [2‑5] Ivabradine is a
pure heart rate‑lowering agent that acts by inhibiting
If, an important ionic current channel involved in the
Address for correspondence: Dr. Hosam Zaky,
P.O. Box 21910, Dubai, UAE.
E‑mail: [email protected]
53
pacemaker activity in cells of the sinoatrial node. [6]
Ivabradine reduces the slope of spontaneous diastolic
depolarization in these cells and lowers the heart rate at
rest and during exercise. Ivabradine has demonstrated
anti‑ischemic and anti‑anginal efficacy in randomized
trials in patients with chronic stable angina pectoris
when compared with placebo. [7] It has also been
shown to be non‑inferior to atenolol[8] or amlodipine[9]
in controlling anginal symptoms.
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DOI:
10.4103/1995-705X.115495
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Zaky, et al.: Ivabradine in chronic ischemic heart disease
We examined the effects of ivabradine in patients
with stable ischemic heart disease on maximally
tolerated medical therapy, with regard to resting heart
rate, angina class, and quality of life.
MATERIALS AND METHODS
Twenty patients were enrolled in the study from the
out‑patient cardiology clinic according to the following
inclusion criteria:
• Proof of significant coronary heart disease by
coronary arteriography.
• Symptoms of angina pectoris.
• Stable treatment with maximally tolerated medical
therapy.
• Heart rate in sinus rhythm of at least 70 beat per
minute.
Ivabradine was prescribed to all patients. Patients’
evaluation at baseline was used as the control and at
4 months as the active intervention. They were then
evaluated at 1 and 4 months. Parameters measured
before and after treatment with ivabradine were quality
of life score,[10] Canadian Cardiac Society (CCS) class of
anginal chest pain,[11] and resting heart rate. The dose of
ivabradine was 5 mg twice daily that could be uptitrated
to 7.5 mg twice daily in 4 weeks time. Patients were
excluded from the study if they had one of the following:
• Acute coronary syndrome.
• Acute decompensated heart failure.
• Heart rate less than 70 beat per minute.
• Chronic or paroxysmal atrial fibrillation.
All patients had signed a consent agreeing to join
the study. The protocol of the study was approved by
the ethical committee of our institution.
RESULTS
We enrolled 20 consecutive patients with documented
coronary artery disease. All were male with an average
age of 47 ± 7 years. Nearly two‑thirds of the patients
had a history of hypertension and one‑third had a
history of diabetes mellitus [Table 1]. All patients were
on aspirin, statin, and b‑blocker, and the majority
were on clopidogrel and an angiotensin‑converting
enzyme inhibitor/angiotensin receptor blocker [Table 1].
One‑third of the patients were also on a long‑acting
nitrate. The resting heart rate decreased significantly
from a mean of 82 ± 8 at baseline to 68 ± 6 bpm at
the 4 months visit, P < 0.0001 [Table 1]. The reduction
in heart rate was accompanied by improvement in
angina symptoms [Figure 1]. The CCS class of chest
pain [Table 2, Figure 1] improved in 16/20 patients by
one or two classes; in the four patients whose CCS class
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did not improve, two were class 1 and they had residual
single vessel disease after PCI, and two were class II
due to extensive underlying ischemic heart disease that
was not amenable to revascularization. The quality of
life score improved significantly from 3.46 ± 0.87 at the
first visit to 4.67 ± 0.71 at 4 months visit, P < 0.0001.
DISCUSSION
We prospectively studied the effects of ivabradine in
20 patients with coronary artery disease and stable
angina despite maximally tolerated medical therapy
followed in routine clinical practice. The addition of
ivabradine to their regimen significantly lowered the
resting heart rate, improved the Canadian class of chest
Figure 1: Canadian Cardiovascular Society Angina class
Table 1: Patients’ characteristics and medications
Heart rate
Age
Gender
Hypertension (%)
Diabetes mellitus (%)
Chronic kidney disease (%)
Medication (%)
Aspirin
Clopidogrel
Statin
β‑blocker*
Angiotensin converting
enzyme inhibitor
Angiotensin receptor blocker
Daily long‑acting nitrates
82±8 beats per minute
47±7 years
100% males
12/20 (60)
6/20 (30)
1/20 (5)
20/20 (100)
18/20 (90)
20/20 (100)
20/20 (100)
15/20 (75)
4/20 (20)
7/20 (35)
*β‑blocker doses: Atenolol 100 mg one patient, 50 mg 6 patients, bisoprolol 5 mg
3 patients, and bisoprolol 2.5 mg 10 patients
Table 2: Change in Canadian Cardiac Society Angina class
Class I
Class II
Class III
Class IV
Baseline (number of patients)
2
9
6
3
4 months
10
8
2
0
54
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Zaky, et al.: Ivabradine in chronic ischemic heart disease
pain in the majority of patients, and improved the quality
of life score in comparison to baseline.
A high resting heart rate is a potentially modifiable
cardiovascular risk factor, both in the general population
and in patients with cardiovascular disease.[4,12,13]
In our study, the heart rate dropped significantly by 14
bpm in comparison to baseline which was in agreement with
other authors.[7,14,15] In the study of Fox, et al. (BEAUTIFUL
Trial) in the prespecified subgroup of patients with the
heart rate of 70 bpm or greater, ivabradine treatment did
not affect the primary composite outcome, cardiovascular
death, or admission to hospital for new‑onset or worsening
heart failure. However, it did reduce secondary endpoints:
Admission to hospital for fatal and nonfatal myocardial
infarction and coronary revascularization.
In our study, we analyzed the Canadian class
of angina before and after the start of ivabradine. At
baseline, 10% of patients were in CCS class I compared
to 50% after 4 months of therapy (P = 0.01). Other
authors used objective measures of angina provocation
by the exercise tolerance test, total exercise time, and
time to limiting angina, which were shown to improve
after using ivabradine.[8,16]
With decreasing heart rate, the quality of life
questionnaire showed significant improvement mostly
related to improvement in angina class. The ADDITIONS
Trial showed similar significant improvement in quality of life
after 4 months of starting procoralan therapy with a mean
score rising from 0.66 at baseline to 0.83 at 4 months.[17]
Our limitations in this study were the small number
studied, no control group, lack of objective assessment,
and the short follow‑up time.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
CONCLUSION
The addition of ivabradine to maximally tolerated medical
therapy in patients with stable coronary artery disease
is associated with significant decreases in resting
heart rate and improvements in angina symptoms and
quality of life. Despite our study being limited, subjective
assessment of patient symptoms is important.
15.
16.
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Source of Support: Nil, Conflict of Interest: None declared.
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