Ivabradine; A treatment option for Angina pectoris
AhmedKamel989034
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Jul 15, 2024
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About This Presentation
Ivabradine as a treatment option for AP
Slide Content
Role of
Ivabradine
in The
Management of
Angina Pectoris
Ahmed Kamel
02–Aug–2023
Ivabradine
in The
Management of
Angina Pectoris
Ahmed Kamel
02–Aug–2023
Epidemiological Facts
Introduction to AP
Role of Ivabradine in The Management of AP
Table of contents
Introduction to AP
Role of Ivabradine in The Management of AP
Table of contents
Epidemiolo
gical Facts
gical Facts
Global cv diseases epidemiology
Prevalence & Mortality Rates of CVDs in 2020
Age-standardized global prevalence rates of CVDs per 100,000
for both sexes
Age-standardized global mortality rates of CVDs per 100,000
for both sexes
Tsao C.W. et al, Circulation. 2023;147:e93–e621.
Prevalence & Mortality Rates of CVDs in 2020
Age-standardized global prevalence rates of CVDs per 100,000
for both sexes
Age-standardized global mortality rates of CVDs per 100,000
for both sexes
Tsao C.W. et al, Circulation. 2023;147:e93–e621.
Global IHD epidemiology
Prevalence & Mortality Rates of IHDs in 2020
Age-standardized global prevalence rates of IHDs per 100,000
for both sexes
Age-standardized global mortality rates of IHDs per 100,000 for
both sexes
Tsao C.W. et al, Circulation. 2023;147:e93–e621.
Prevalence & Mortality Rates of IHDs in 2020
Age-standardized global prevalence rates of IHDs per 100,000
for both sexes
Age-standardized global mortality rates of IHDs per 100,000 for
both sexes
Tsao C.W. et al, Circulation. 2023;147:e93–e621.
CV Diseases in the us
Tsao C.W. et al, Circulation. 2023;147:e93–e621.
Population
group
Total CVD prevalence,*
2017–2020: ≥20 y of age
Prevalence, 2017–
2020: ≥20 y of age†
Mortality, 2020: all
ages‡
Hospital discharges,
2019: all ages
Cost, 2018–2019
Both sexes 127,900,000 (48.6%) 28,600,000 (9.9%) 928,741 5,134,000 $407.3 Billion
Males 65,400,000 (52.4%) 14,800,000 (10.9%) 487,209 (52.5%)
§ --- $253.9 Billion
Females 62,500,000 (44.8%) 13,800,000 (9.2%) 441,532 (47.5%)
§ --- $153.5 Billion
COVID-19 indicates coronavirus disease 2019; CVD, cardiovascular disease; ellipses (…), data not available; NHANES, National Health and Nutrition Examination Survey; and NH, non-Hispanic.
*Total CVD prevalence includes coronary heart disease, heart failure, stroke, and hypertension. CVD prevalence rates do not include peripheral artery disease (PAD) because the ankle-
brachial index measurement used to ascertain PAD was discontinued after the NHANES 2003 to 2004 cycle.
†Prevalence excluding hypertension.
‡Mortality for Hispanic, American Indian or Alaska Native, and Asian and Pacific Islander people should be interpreted with caution because of inconsistencies in reporting Hispanic origin or race
on the death certificate compared with censuses, surveys, and birth certificates. Studies have shown underreporting on death certificates of American Indian or Alaska Native, Asian and Pacific
Islander, and Hispanic decedents, as well as undercounts of these groups in censuses.
§These percentages represent the portion of total CVD mortality that is attributable to males versus females.
Tsao C.W. et al, Circulation. 2023;147:e93–e621.
Population
group
Total CVD prevalence,*
2017–2020: ≥20 y of age
Prevalence, 2017–
2020: ≥20 y of age†
Mortality, 2020: all
ages‡
Hospital discharges,
2019: all ages
Cost, 2018–2019
Both sexes 127,900,000 (48.6%) 28,600,000 (9.9%) 928,741 5,134,000 $407.3 Billion
Males 65,400,000 (52.4%) 14,800,000 (10.9%) 487,209 (52.5%)
§ --- $253.9 Billion
Females 62,500,000 (44.8%) 13,800,000 (9.2%) 441,532 (47.5%)
§ --- $153.5 Billion
COVID-19 indicates coronavirus disease 2019; CVD, cardiovascular disease; ellipses (…), data not available; NHANES, National Health and Nutrition Examination Survey; and NH, non-Hispanic.
*Total CVD prevalence includes coronary heart disease, heart failure, stroke, and hypertension. CVD prevalence rates do not include peripheral artery disease (PAD) because the ankle-
brachial index measurement used to ascertain PAD was discontinued after the NHANES 2003 to 2004 cycle.
†Prevalence excluding hypertension.
‡Mortality for Hispanic, American Indian or Alaska Native, and Asian and Pacific Islander people should be interpreted with caution because of inconsistencies in reporting Hispanic origin or race
on the death certificate compared with censuses, surveys, and birth certificates. Studies have shown underreporting on death certificates of American Indian or Alaska Native, Asian and Pacific
Islander, and Hispanic decedents, as well as undercounts of these groups in censuses.
§These percentages represent the portion of total CVD mortality that is attributable to males versus females.
AP
* Diseases in the us
Tsao C.W. et al, Circulation. 2023;147:e93–e621.
Population group
Prevalence, 2017–2020,
age ≥20 y
Hospital discharges,
2019, all ages
Both sexes
10,800,000 (3.9%)
[95% CI, 3.3%–4.5%]
14,000
Males 5,600,000 (4.3%)
Females 5,200,000 (3.6%)
NH White males 4.7% ---
NH White females 3.5% ---
NH black males 2.7% ---
NH black females 4.1% ---
Hispanic males 3.6% ---
Hispanic females 4.3% ---
NH Asian or Pacific
Islander males
2.7% ---
NH Asian or Pacific
Islander females
2.7% ---
Prevalence of AP by age and sex, US (NHANES, 2017–2020)
In March 2020, the COVID-19 pandemic halted NHANES field operations. Because data collected in the partial 2019 to 2020 cycle are not nationally representative, they were combined with previously released 2017 to
2018 data to produce nationally representative estimates.131 AP includes people who either answered “yes” to the question of ever having angina or AP or being diagnosed
with Rose angina (the Rose questionnaire is administered only to survey participants >40 years of age).
AP indicates angina pectoris; COVID-19, coronavirus disease 2019; ellipses (…), data not available; NH, non-Hispanic; and NHANES, National Health and Nutrition Examination Survey.
*AP is chest pain or discomfort that results from insufficient blood flow to the heart muscle. Stable AP is predictable chest pain on exertion or under mental or emotional stress. The incidence estimate is for AP without
myocardial infarction..
* Diseases in the us
Tsao C.W. et al, Circulation. 2023;147:e93–e621.
Population group
Prevalence, 2017–2020,
age ≥20 y
Hospital discharges,
2019, all ages
Both sexes
10,800,000 (3.9%)
[95% CI, 3.3%–4.5%]
14,000
Males 5,600,000 (4.3%)
Females 5,200,000 (3.6%)
NH White males 4.7% ---
NH White females 3.5% ---
NH black males 2.7% ---
NH black females 4.1% ---
Hispanic males 3.6% ---
Hispanic females 4.3% ---
NH Asian or Pacific
Islander males
2.7% ---
NH Asian or Pacific
Islander females
2.7% ---
Prevalence of AP by age and sex, US (NHANES, 2017–2020)
In March 2020, the COVID-19 pandemic halted NHANES field operations. Because data collected in the partial 2019 to 2020 cycle are not nationally representative, they were combined with previously released 2017 to
2018 data to produce nationally representative estimates.131 AP includes people who either answered “yes” to the question of ever having angina or AP or being diagnosed
with Rose angina (the Rose questionnaire is administered only to survey participants >40 years of age).
AP indicates angina pectoris; COVID-19, coronavirus disease 2019; ellipses (…), data not available; NH, non-Hispanic; and NHANES, National Health and Nutrition Examination Survey.
*AP is chest pain or discomfort that results from insufficient blood flow to the heart muscle. Stable AP is predictable chest pain on exertion or under mental or emotional stress. The incidence estimate is for AP without
myocardial infarction..
Mortality rates of CHD
Tsao C.W. et al, Circulation. 2023;147:e93–e621.
Percentage breakdown of deaths attributable to CVD, United States,
2020.
Death rates per 100 000 population for CHD in selected countries for
adults 35 to 74 years of age, 2020.
A Closer Look
Tsao C.W. et al, Circulation. 2023;147:e93–e621.
Percentage breakdown of deaths attributable to CVD, United States,
2020.
Death rates per 100 000 population for CHD in selected countries for
adults 35 to 74 years of age, 2020.
A Closer Look
Introduction to
Angina Pectoris
Angina Pectoris
What is AP?
•Angina pectoris is one of the classic symptoms of coronary artery
disease (CAD).
•Although angina represents the most identifiable symptom in
patients with ischemic heart disease, it is causally related to the
presence and development of obstructive coronary atherosclerosis.
•Angina is caused when required oxygen demand of the
myocardium cannot be met. The most common cause for this is
atherosclerotic lesions within the coronary arteries leading to flow
limitation.
•Angina is not specific to atherosclerosis and the symptoms can
also be caused by: coronary spasm, aortic valve disease,
microvascular coronary dysfunction, esophageal spasm and reflux,
and anemia.
Rev Cardiovasc Med. 2013;14(suppl 1):S3-S10 doi: 10.3909/ ricm13S1S0003
•Angina pectoris is one of the classic symptoms of coronary artery
disease (CAD).
•Although angina represents the most identifiable symptom in
patients with ischemic heart disease, it is causally related to the
presence and development of obstructive coronary atherosclerosis.
•Angina is caused when required oxygen demand of the
myocardium cannot be met. The most common cause for this is
atherosclerotic lesions within the coronary arteries leading to flow
limitation.
•Angina is not specific to atherosclerosis and the symptoms can
also be caused by: coronary spasm, aortic valve disease,
microvascular coronary dysfunction, esophageal spasm and reflux,
and anemia.
Rev Cardiovasc Med. 2013;14(suppl 1):S3-S10 doi: 10.3909/ ricm13S1S0003
Endothelial dysfunction
Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction. A marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003;23:168–75. http://dx.doi.org/10.1161/01.ATV.0000051384.43104.FC
Endothelial dysfunction has been referred to as “the risk of the risk factors”, since it has been shown to occur in the presence of conventional,
modifiable risk factors (e.g. cigarette smoking, high blood pressure, hyperlipidemia and diabetes). These risk factors are, in turn, associated with a
state of increased oxidative stress and the overproduction of reactive oxygen species. This all contributes to the complex interplay of endothelial
dysfunction since reactive oxygen species can themselves lead to abnormal NO metabolism
The Risk of Risk Factors
Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction. A marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003;23:168–75. http://dx.doi.org/10.1161/01.ATV.0000051384.43104.FC
Endothelial dysfunction has been referred to as “the risk of the risk factors”, since it has been shown to occur in the presence of conventional,
modifiable risk factors (e.g. cigarette smoking, high blood pressure, hyperlipidemia and diabetes). These risk factors are, in turn, associated with a
state of increased oxidative stress and the overproduction of reactive oxygen species. This all contributes to the complex interplay of endothelial
dysfunction since reactive oxygen species can themselves lead to abnormal NO metabolism
The Risk of Risk Factors
CMD and myocardial ischemia
•Ischemic heart disease can result from several mechanisms,
including atheromatous plaques occluding the epicardial coronary
arteries, coronary artery spasm, and coronary microvascular
dysfunction (CMD).
•CMD can lead to myocardial ischemia by impairing the ability of
the coronary circulation to increase coronary blood flow in response
to an increased myocardial oxygen demand.
•CMD can result from an abnormal vasodilatory ability of the
microvasculature, compressive external forces affecting the
intramural microvessels, or microvascular spasm.
•CMD is typically the cause of myocardial ischemia in individuals with
angina despite completely normal coronary arteriograms (primary
microvascular angina), but it can also trigger myocardial ischemia in
several other clinical conditions, including patients with
cardiomyopathies and those with obstructive coronary artery
disease.
Circulation. 2018;138:1463–1480.
•Ischemic heart disease can result from several mechanisms,
including atheromatous plaques occluding the epicardial coronary
arteries, coronary artery spasm, and coronary microvascular
dysfunction (CMD).
•CMD can lead to myocardial ischemia by impairing the ability of
the coronary circulation to increase coronary blood flow in response
to an increased myocardial oxygen demand.
•CMD can result from an abnormal vasodilatory ability of the
microvasculature, compressive external forces affecting the
intramural microvessels, or microvascular spasm.
•CMD is typically the cause of myocardial ischemia in individuals with
angina despite completely normal coronary arteriograms (primary
microvascular angina), but it can also trigger myocardial ischemia in
several other clinical conditions, including patients with
cardiomyopathies and those with obstructive coronary artery
disease.
Circulation. 2018;138:1463–1480.
Initial Diagnostic Algorithm
In Patients with Angina and Suspected CAD
a
If the diagnosis of CAD is uncertain, establishing a diagnosis
using non-invasive functional imaging for myocardial ischemia
before treatment may be reasonable.
b
May be omitted in very young and healthy patients with a high
suspicion of an extracardiac cause of chest pain, and in
multimorbid patients in whom the echocardiography result has no
consequence for further patient management.
c
Consider exercise ECG to assess symptoms, arrhythmias,
exercise tolerance, BP response, and event risk in selected
patients.
d
Ability to exercise, individual test-related risks, and likelihood of
obtaining diagnostic test result.
e
High clinical likelihood and symptoms inadequately responding to
medical treatment, high event risk based on clinical evaluation
(such as ST-segment depression, combined with symptoms at a
low workload or systolic dysfunction indicating CAD), or uncertain
diagnosis on non-invasive testing.
f
Functional imaging for myocardial ischaemia if coronary CTA has
shown CAD of uncertain grade or is non-diagnostic.
g
Consider also angina without obstructive disease in the epicardial
coronary arteries
ACS = acute coronary syndrome; BP = blood pressure; CAD = coronary artery disease; CTA = computed tomography angiography; ECG =
electrocardiogram; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; LVEF = left ventricular ejection fraction.
European Heart Journal (2020) 41, 407477
In Patients with Angina and Suspected CAD
a
If the diagnosis of CAD is uncertain, establishing a diagnosis
using non-invasive functional imaging for myocardial ischemia
before treatment may be reasonable.
b
May be omitted in very young and healthy patients with a high
suspicion of an extracardiac cause of chest pain, and in
multimorbid patients in whom the echocardiography result has no
consequence for further patient management.
c
Consider exercise ECG to assess symptoms, arrhythmias,
exercise tolerance, BP response, and event risk in selected
patients.
d
Ability to exercise, individual test-related risks, and likelihood of
obtaining diagnostic test result.
e
High clinical likelihood and symptoms inadequately responding to
medical treatment, high event risk based on clinical evaluation
(such as ST-segment depression, combined with symptoms at a
low workload or systolic dysfunction indicating CAD), or uncertain
diagnosis on non-invasive testing.
f
Functional imaging for myocardial ischaemia if coronary CTA has
shown CAD of uncertain grade or is non-diagnostic.
g
Consider also angina without obstructive disease in the epicardial
coronary arteries
ACS = acute coronary syndrome; BP = blood pressure; CAD = coronary artery disease; CTA = computed tomography angiography; ECG =
electrocardiogram; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; LVEF = left ventricular ejection fraction.
European Heart Journal (2020) 41, 407477
Main diagnostic pathways
In Patients with Suspected Obstructive CAD
European Heart Journal (2020) 41, 407477
•Through each pathway, both
functional and anatomical information
is gathered to inform an appropriate
diagnostic and therapeutic strategy.
•Risk-factor modification should be
considered in all patients.
In Patients with Suspected Obstructive CAD
European Heart Journal (2020) 41, 407477
•Through each pathway, both
functional and anatomical information
is gathered to inform an appropriate
diagnostic and therapeutic strategy.
•Risk-factor modification should be
considered in all patients.
Ivabradine in The
Management of
AP
Management of
AP
Ivabradine
The indications for the use of ivabradine have evolved over time and differ based on region
Koruth, J.S. et al. J Am Coll Cardiol. 2017;70(14):1777–84.
•As a unique pharmacological agent that is
specifically able to reduce the heart rate
unaccompanied by side effects common to
other similar medications, the expectations
of its potential impact within cardiovascular
medicine were high.
•Several small and large studies have
evaluated this drug as a therapeutic agent
targeting disease conditions in all 3 major
branches of cardiology (i.e., coronary
artery disease, heart failure [HF], and
electrophysiology).
•Since it was first approved for use in
angina by the European Medicines Agency
(EMA) in 2005, the findings of several
RCTs have resulted in expanded
indications to include select heart failure
patients and only recent approval by the
U.S. Food and Drug Administration (FDA)
for this indication
The indications for the use of ivabradine have evolved over time and differ based on region
Koruth, J.S. et al. J Am Coll Cardiol. 2017;70(14):1777–84.
•As a unique pharmacological agent that is
specifically able to reduce the heart rate
unaccompanied by side effects common to
other similar medications, the expectations
of its potential impact within cardiovascular
medicine were high.
•Several small and large studies have
evaluated this drug as a therapeutic agent
targeting disease conditions in all 3 major
branches of cardiology (i.e., coronary
artery disease, heart failure [HF], and
electrophysiology).
•Since it was first approved for use in
angina by the European Medicines Agency
(EMA) in 2005, the findings of several
RCTs have resulted in expanded
indications to include select heart failure
patients and only recent approval by the
U.S. Food and Drug Administration (FDA)
for this indication
Ivabradine
Therapeutic Indications
Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery
disease adults with normal sinus rhythm and heart rate ≥ 70 bpm.
Procoralan, INN-ivabradine. Summary of Product Characteristics. European Medicines Agency. 2021
Ivabradine is indicated:
In adults unable to
tolerate or with a
contraindication to the
use of beta-blockers
or in combination with
beta-blockers in patients
inadequately controlled
with an optimal beta-
blocker dose
Therapeutic Indications
Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery
disease adults with normal sinus rhythm and heart rate ≥ 70 bpm.
Procoralan, INN-ivabradine. Summary of Product Characteristics. European Medicines Agency. 2021
Ivabradine is indicated:
In adults unable to
tolerate or with a
contraindication to the
use of beta-blockers
or in combination with
beta-blockers in patients
inadequately controlled
with an optimal beta-
blocker dose
Ivabradine
Mechanism of Action
(A)Ivabradine’s primary mechanism of action on
cardiac tissue is on the sinoatrial (SA) node, which
occupies a predominantly subepicardial position at
the junction of the superior vena cava (SVC) and
the right atrium (RA).
(B)In the sinoatrial node, ivabradine blocks the
intracellular aspect of the hyperpolarization-
activated cyclic nucleotide–gated (HCN)
transmembrane channel, which is responsible for
the transport of sodium (Na
+) and potassium (K
+)
ions across the cell membrane, in the open state.
This results in inhibition of the inward funny
current (I
f
), which is specifically activated at
hyperpolarized membrane potentials.
(C)By selectively inhibiting If, there is a reduction in the
slope of diastolic depolarization of the pacemaker
action potential (shaded region) and an increase in
the duration of diastole, without altering other
phases of the action potential. This results in heart
rate reduction
Koruth, J.S. et al. J Am Coll Cardiol. 2017;70(14):1777–84.
Ao= aorta; IVC= inferior vena cava; PA= pulmonary artery; RV= right ventricle
Mechanism of Action
(A)Ivabradine’s primary mechanism of action on
cardiac tissue is on the sinoatrial (SA) node, which
occupies a predominantly subepicardial position at
the junction of the superior vena cava (SVC) and
the right atrium (RA).
(B)In the sinoatrial node, ivabradine blocks the
intracellular aspect of the hyperpolarization-
activated cyclic nucleotide–gated (HCN)
transmembrane channel, which is responsible for
the transport of sodium (Na
+) and potassium (K
+)
ions across the cell membrane, in the open state.
This results in inhibition of the inward funny
current (I
f
), which is specifically activated at
hyperpolarized membrane potentials.
(C)By selectively inhibiting If, there is a reduction in the
slope of diastolic depolarization of the pacemaker
action potential (shaded region) and an increase in
the duration of diastole, without altering other
phases of the action potential. This results in heart
rate reduction
Koruth, J.S. et al. J Am Coll Cardiol. 2017;70(14):1777–84.
Ao= aorta; IVC= inferior vena cava; PA= pulmonary artery; RV= right ventricle
Ivabradine
Posology and Method of Administration
Procoralan, INN-ivabradine. Summary of Product Characteristics. European Medicines Agency. 2021
Starting Dose
5 mg twice daily
•If the patient is still symptomatic
•If the initial dose is well tolerated
•If resting heart rate remains above 60
bpm
3-4 weeks
Maintenance Dose
2.5 mg twice daily
or
5 mg twice daily
should not exceed 7.5 mg
twice daily
If there is no improvement in symptoms of angina within 3 months after start of treatment, treatment
of ivabradine should be discontinued
In patients aged
below 75 years
Posology and Method of Administration
Procoralan, INN-ivabradine. Summary of Product Characteristics. European Medicines Agency. 2021
Starting Dose
5 mg twice daily
•If the patient is still symptomatic
•If the initial dose is well tolerated
•If resting heart rate remains above 60
bpm
3-4 weeks
Maintenance Dose
2.5 mg twice daily
or
5 mg twice daily
should not exceed 7.5 mg
twice daily
If there is no improvement in symptoms of angina within 3 months after start of treatment, treatment
of ivabradine should be discontinued
In patients aged
below 75 years
Borer J.S. et al. Circulation. 2003;107: 817-823.
Methodology
Borer J.S. et al. Circulation. 2003;107: 817-823.
Withdrawn (n = 3)
Completed (n = 87)
Adverse events (n = 1)
Worsening angina (n = 1)
Non-medical (n = 1)
Non-eligible (n=129)
Target disease not proven (n=101)
Unstable CAD (n=8)
Consent withdrawn (n=7)
Other (n=13)
Selection, wash-out, and run-in phase
Placebo
(n = 529)
Double blinded, dose-ranging phase
Randomized
(n = 360)
Ivabradine 5 mg bid
(n = 91)
Ivabradine 2.5 mg bid
(n = 90)
Ivabradine 10 mg bid
(n = 88)
Withdrawn (n = 4)
Completed (n = 87)
Adverse events (n = 1)
Worsening angina (n = 1)
Protocol deviation (n = 1)
Non-medical (n =1)
Withdrawn (n = 3)
Completed (n = 85)
Adverse events (n = 2)
Worsening angina (n = 1)
Placebo
(n = 91)
Withdrawn (n = 1)
Completed (n =
90)
Adverse events (n = 1)
Open-label extension Phase
Ivabradine 10 mg bid (n = 173)
Completed (n = 161)
Withdrawn (n = 12)
Adverse events (n = 1) Worsening angina (n =
1)
Non-medical (n = 1)
Not included (n=40)
Negative ETT at D
○
(n=23)
Unstable CAD (n=5)
Unstable ETT results (n=3)
Consent withdrawn (n=2)
Other (n=7)
Selected
(n =400)
Objectives
To evaluate the antianginal and anti-ischemic effects of ivabradine,
a new heart rate–lowering agent that acts specifically on the
sinoatrial node, in patients with stable angina.
Study Design
•A randomized, double-blind, placebo-
controlled, parallel-arm trial was
performed to investigate the effects of
ivabradine on time to 1-mm ST-
segment depression and time to
limiting angina during standardized
bicycle exercise tolerance tests (ETT).
•Patients were randomly assigned to
receive ivabradine (2.5, 5, or 10 mg
BID) or placebo for 2 weeks, followed
by an open-label 2- or 3-month
extension on ivabradine (10 mg BID)
and a 1-week randomized withdrawal
to ivabradine (10 mg BID) or placebo.
AE indicates adverse event; CAD, coronary artery disease; ETT, exercise tolerance test.
Randomized
Withdrawal
Phase
(n = 157)
Ivabradine 10 mg bid (n = 77)
Completed (n = 161)
Withdrawn (n = 12)
Placebo (n = 80)
Completed (n = 161)
Withdrawn (n = 12)
Borer J.S. et al. Circulation. 2003;107: 817-823.
Withdrawn (n = 3)
Completed (n = 87)
Adverse events (n = 1)
Worsening angina (n = 1)
Non-medical (n = 1)
Non-eligible (n=129)
Target disease not proven (n=101)
Unstable CAD (n=8)
Consent withdrawn (n=7)
Other (n=13)
Selection, wash-out, and run-in phase
Placebo
(n = 529)
Double blinded, dose-ranging phase
Randomized
(n = 360)
Ivabradine 5 mg bid
(n = 91)
Ivabradine 2.5 mg bid
(n = 90)
Ivabradine 10 mg bid
(n = 88)
Withdrawn (n = 4)
Completed (n = 87)
Adverse events (n = 1)
Worsening angina (n = 1)
Protocol deviation (n = 1)
Non-medical (n =1)
Withdrawn (n = 3)
Completed (n = 85)
Adverse events (n = 2)
Worsening angina (n = 1)
Placebo
(n = 91)
Withdrawn (n = 1)
Completed (n =
90)
Adverse events (n = 1)
Open-label extension Phase
Ivabradine 10 mg bid (n = 173)
Completed (n = 161)
Withdrawn (n = 12)
Adverse events (n = 1) Worsening angina (n =
1)
Non-medical (n = 1)
Not included (n=40)
Negative ETT at D
○
(n=23)
Unstable CAD (n=5)
Unstable ETT results (n=3)
Consent withdrawn (n=2)
Other (n=7)
Selected
(n =400)
Objectives
To evaluate the antianginal and anti-ischemic effects of ivabradine,
a new heart rate–lowering agent that acts specifically on the
sinoatrial node, in patients with stable angina.
Study Design
•A randomized, double-blind, placebo-
controlled, parallel-arm trial was
performed to investigate the effects of
ivabradine on time to 1-mm ST-
segment depression and time to
limiting angina during standardized
bicycle exercise tolerance tests (ETT).
•Patients were randomly assigned to
receive ivabradine (2.5, 5, or 10 mg
BID) or placebo for 2 weeks, followed
by an open-label 2- or 3-month
extension on ivabradine (10 mg BID)
and a 1-week randomized withdrawal
to ivabradine (10 mg BID) or placebo.
AE indicates adverse event; CAD, coronary artery disease; ETT, exercise tolerance test.
Randomized
Withdrawal
Phase
(n = 157)
Ivabradine 10 mg bid (n = 77)
Completed (n = 161)
Withdrawn (n = 12)
Placebo (n = 80)
Completed (n = 161)
Withdrawn (n = 12)
Methodology
Borer J.S. et al. Circulation. 2003;107: 817-823.
Primary Endpoint
•Changes in time to 1-mm horizontal or down-sloping ST-segment
depression ≥0.08 seconds after the J point and performed at the
trough of drug activity (12 hours after last drug administration)
•Changes in time to limiting angina during ETT performed at the
trough of drug activity
Secondary Endpoints
•Changes in ETT at peak drug activity (4 hours after drug administration)
•Angina attack frequency
•Safety and adverse events
Eligibility Criteria
Eligible patients aged ≥18 years
with
A ≥ 3- month history of chronic stable effort-induced angina, relieved
by rest or nitroglycerine, without:
•prior mechanical therapy, or
•>3 months after CABG, or
•>6 months after PTCA
Catheterization-documented coronary artery disease or previous
myocardial infarction ≥3 months before random assignment
all patients needed to manifest positive ETT, female participants
needed to be of non-childbearing potential
Patients were
excluded if they had
Inability to perform ETT
Unstable angina, Prinzmetal angina or ‘microvascular angina’
2
nd or 3
rd degree AV block
Significant valvular disease, AF/ flutter, pacemaker, or indwelling
pacemaker
Exclusion Criteria
Borer J.S. et al. Circulation. 2003;107: 817-823.
Primary Endpoint
•Changes in time to 1-mm horizontal or down-sloping ST-segment
depression ≥0.08 seconds after the J point and performed at the
trough of drug activity (12 hours after last drug administration)
•Changes in time to limiting angina during ETT performed at the
trough of drug activity
Secondary Endpoints
•Changes in ETT at peak drug activity (4 hours after drug administration)
•Angina attack frequency
•Safety and adverse events
Eligibility Criteria
Eligible patients aged ≥18 years
with
A ≥ 3- month history of chronic stable effort-induced angina, relieved
by rest or nitroglycerine, without:
•prior mechanical therapy, or
•>3 months after CABG, or
•>6 months after PTCA
Catheterization-documented coronary artery disease or previous
myocardial infarction ≥3 months before random assignment
all patients needed to manifest positive ETT, female participants
needed to be of non-childbearing potential
Patients were
excluded if they had
Inability to perform ETT
Unstable angina, Prinzmetal angina or ‘microvascular angina’
2
nd or 3
rd degree AV block
Significant valvular disease, AF/ flutter, pacemaker, or indwelling
pacemaker
Exclusion Criteria
Baseline characteristics
Borer J.S. et al. Circulation. 2003;107: 817-823.
Randomly Assigned Population
(n=360)
Per-Protocol Population
(n=257)
Age, y 58.5±9.2 (35–86) 58.1±8.9 (37–86)
Male sex, % 89.7 90.7
Weight, kg 79.0±11.2 (50–118) 79.6±11.1 (57–118)
Supine SBP, mm Hg 133.7±16.3 (95–197) 132.7±16.3 (95–197)
Supine DBP, mm Hg 81.3±8.2 (55–112) 81.2±7.9 (55–100)
Supine heart rate, bpm 69.7±10.3 (47–106) 69.1±9.7 (47–104)
Coronary artery disease duration, mo 68.1±63.9 (2–300) 69.7±61.2 (3–300)
Mean frequency of angina attacks per wk 5.3±7.9 (0–78) 5.4±8.2 (0–78)
Mean consumption of short-acting nitrates, U/wk 3.4±7.6 (0–80) 3.4±7.9 (0–80)
Previous MI, n (%) 218 (60.6) 152 (59.1)
Previous CABG, n (%) 59 (16.4) 43 (16.7)
Previous PTCA, n (%) 66 (18.3) 39 (15.2)
DBP indicates diastolic blood pressure; MI, myocardial infarction; and SBP, systolic blood pressure.
Borer J.S. et al. Circulation. 2003;107: 817-823.
Randomly Assigned Population
(n=360)
Per-Protocol Population
(n=257)
Age, y 58.5±9.2 (35–86) 58.1±8.9 (37–86)
Male sex, % 89.7 90.7
Weight, kg 79.0±11.2 (50–118) 79.6±11.1 (57–118)
Supine SBP, mm Hg 133.7±16.3 (95–197) 132.7±16.3 (95–197)
Supine DBP, mm Hg 81.3±8.2 (55–112) 81.2±7.9 (55–100)
Supine heart rate, bpm 69.7±10.3 (47–106) 69.1±9.7 (47–104)
Coronary artery disease duration, mo 68.1±63.9 (2–300) 69.7±61.2 (3–300)
Mean frequency of angina attacks per wk 5.3±7.9 (0–78) 5.4±8.2 (0–78)
Mean consumption of short-acting nitrates, U/wk 3.4±7.6 (0–80) 3.4±7.9 (0–80)
Previous MI, n (%) 218 (60.6) 152 (59.1)
Previous CABG, n (%) 59 (16.4) 43 (16.7)
Previous PTCA, n (%) 66 (18.3) 39 (15.2)
DBP indicates diastolic blood pressure; MI, myocardial infarction; and SBP, systolic blood pressure.
Efficacy Results
ETT Parameters at Trough of Drug Activity During Double-Blind, Dose-Ranging Phase
Borer J.S. et al. Circulation. 2003;107: 817-823.
Parameter
Placebo
(n=68)
Ivabradine 2.5 mg BID
(n=64)
Ivabradine 5 mg BID
(n=59)
Ivabradine 10 mg BID
(n=66)
Between-
Group
P
Time to 1-mm ST-depression, s
D0
D14
D14-D0
369.1 ± 119.0
378.0 ± 124.2
9.0 ± 63.6
343.7 ± 120.7
375.7 ± 121.2
32.0 ± 74.3
364.1 ± 119.3
408.2 ± 122.8
44.1 ± 80.1*
370.2 ± 120.8
416.4 ± 155.7
46.2 ± 78.2* 0.016
Time to limiting angina, s
D0
D14
D14-D0
417.8 ± 115.6
430.5 ± 119.0
12.7 ± 51.3
402.5 ± 121.0
425.0 ± 116.4
22.5 ± 55.4
432.8 ± 124.0
460.0 ± 115.1
27.2 ± 56.8
430.5 ± 125.4
471.3 ± 148.4
40.8 ± 69.3* 0.049
Time to angina onset, s
D0
D14
D14-D0
352.8 ± 98.2
377.5 ± 116.3
24.7 ± 64.2
330.5 ± 105.4
368.1 ± 112.5
37.6 ± 57.7
355.6 ± 110.9
394.4 ± 132.3
38.8 ± 81.7
351.5 ± 123.1
420.8 ± 148.8
69.4 ± 74.8* 0.003
RPP at peak of exercise, bpm/mm Hg
D0
D14
D14-D0
23057 ± 5498
23323 ± 5488
266 ± 3074
23924 ± 4885
23187± 5052
-737 ± 2950
24772 ± 5757
23630 ± 5253
-1142 ± 3354*
24183 ± 4623
22640 ± 4540
-1543 ± 3526* 0.011
Total work performed, W/min
D0
D14
D14-D0
501.7 ± 246.2
529.1 ± 256.8
27.4 ± 104.7
473.9 ± 240.6
515.6 ± 241.8
41.7 ± 112.7
538.0 ± 269.6
588.3 ± 260.2
50.3 ± 122.4
534.0 ± 278.8
633.1 ± 373.5
99.1 ± 192.0* 0.019
*Significantly different from placebo in pairwise comparison.
RPP indicates rate-pressure product.
ETT Parameters at Trough of Drug Activity During Double-Blind, Dose-Ranging Phase
Borer J.S. et al. Circulation. 2003;107: 817-823.
Parameter
Placebo
(n=68)
Ivabradine 2.5 mg BID
(n=64)
Ivabradine 5 mg BID
(n=59)
Ivabradine 10 mg BID
(n=66)
Between-
Group
P
Time to 1-mm ST-depression, s
D0
D14
D14-D0
369.1 ± 119.0
378.0 ± 124.2
9.0 ± 63.6
343.7 ± 120.7
375.7 ± 121.2
32.0 ± 74.3
364.1 ± 119.3
408.2 ± 122.8
44.1 ± 80.1*
370.2 ± 120.8
416.4 ± 155.7
46.2 ± 78.2* 0.016
Time to limiting angina, s
D0
D14
D14-D0
417.8 ± 115.6
430.5 ± 119.0
12.7 ± 51.3
402.5 ± 121.0
425.0 ± 116.4
22.5 ± 55.4
432.8 ± 124.0
460.0 ± 115.1
27.2 ± 56.8
430.5 ± 125.4
471.3 ± 148.4
40.8 ± 69.3* 0.049
Time to angina onset, s
D0
D14
D14-D0
352.8 ± 98.2
377.5 ± 116.3
24.7 ± 64.2
330.5 ± 105.4
368.1 ± 112.5
37.6 ± 57.7
355.6 ± 110.9
394.4 ± 132.3
38.8 ± 81.7
351.5 ± 123.1
420.8 ± 148.8
69.4 ± 74.8* 0.003
RPP at peak of exercise, bpm/mm Hg
D0
D14
D14-D0
23057 ± 5498
23323 ± 5488
266 ± 3074
23924 ± 4885
23187± 5052
-737 ± 2950
24772 ± 5757
23630 ± 5253
-1142 ± 3354*
24183 ± 4623
22640 ± 4540
-1543 ± 3526* 0.011
Total work performed, W/min
D0
D14
D14-D0
501.7 ± 246.2
529.1 ± 256.8
27.4 ± 104.7
473.9 ± 240.6
515.6 ± 241.8
41.7 ± 112.7
538.0 ± 269.6
588.3 ± 260.2
50.3 ± 122.4
534.0 ± 278.8
633.1 ± 373.5
99.1 ± 192.0* 0.019
*Significantly different from placebo in pairwise comparison.
RPP indicates rate-pressure product.
Efficacy Results
Borer J.S. et al. Circulation. 2003;107: 817-823.
*P<0.05 vs placebo in pairwise comparison.
Changes in heart rate at rest and at peak exercise During Double-Blind, Dose-Ranging Phase
Borer J.S. et al. Circulation. 2003;107: 817-823.
*P<0.05 vs placebo in pairwise comparison.
Changes in heart rate at rest and at peak exercise During Double-Blind, Dose-Ranging Phase
Efficacy Results
Borer J.S. et al. Circulation. 2003;107: 817-823.
Data for the 10% of patients for whom open-label extension ended after 2 months were pooled with those for whom
the extension ended after 3 months.
Ivabradine-mediated improvements in the double-blind phase were maintained in the open-label
phase;
Borer J.S. et al. Circulation. 2003;107: 817-823.
Data for the 10% of patients for whom open-label extension ended after 2 months were pooled with those for whom
the extension ended after 3 months.
Ivabradine-mediated improvements in the double-blind phase were maintained in the open-label
phase;
Efficacy Results
Changes in ETT Parameters, Measured at Trough of Drug Activity, During Randomized Withdrawal*
Borer J.S. et al. Circulation. 2003;107: 817-823.
Parameter
Ivabradine 10 mg BID
(n=59)
Placebo
(n=65)
Between- Group
P
Heart rate at rest, bpm -0.44 ± 5.6 13.3 ± 8.8 <0.001
Maximal heart rate, bpm -1.31 ± 7.48 12.3 ± 8.8 <0.001
Time to 1-mm ST-segment depression, s 4.25 ± 59.7 -32.0 ± 73.7 0.003
Time to limiting angina, s -0.78 ± 48.8 -25.2 ± 63.9 0.018
Time to angina onset, s 2.1 ± 59.1 -36.05 ± 76.7 0.002
RPP at rest, bpm · mm Hg -26 ± 1207 1487 ± 1628 <0.001
RPP at peak of exercise, bpm · mm Hg -180 ± 3195 1813 ± 3331 <0.001
*Expressed as value at end of the randomized withdrawal phase minus value at end of the open-label extension.
RPP indicates rate-pressure product.
Changes in ETT Parameters, Measured at Trough of Drug Activity, During Randomized Withdrawal*
Borer J.S. et al. Circulation. 2003;107: 817-823.
Parameter
Ivabradine 10 mg BID
(n=59)
Placebo
(n=65)
Between- Group
P
Heart rate at rest, bpm -0.44 ± 5.6 13.3 ± 8.8 <0.001
Maximal heart rate, bpm -1.31 ± 7.48 12.3 ± 8.8 <0.001
Time to 1-mm ST-segment depression, s 4.25 ± 59.7 -32.0 ± 73.7 0.003
Time to limiting angina, s -0.78 ± 48.8 -25.2 ± 63.9 0.018
Time to angina onset, s 2.1 ± 59.1 -36.05 ± 76.7 0.002
RPP at rest, bpm · mm Hg -26 ± 1207 1487 ± 1628 <0.001
RPP at peak of exercise, bpm · mm Hg -180 ± 3195 1813 ± 3331 <0.001
*Expressed as value at end of the randomized withdrawal phase minus value at end of the open-label extension.
RPP indicates rate-pressure product.
Efficacy Results
Changes in ETT Parameters, Measured at Trough of Drug Activity, During Double-Blind Dose Ranging*
Borer J.S. et al. Circulation. 2003;107: 817-823.
Parameter
Placebo
(n=68)
Ivabradine 2.5
mg BID
(n=64)
Ivabradine 5 mg
BID
(n=59)
Ivabradine 10 mg
BID
(n=66)
Between-
Group P
Time to 1-mm ST-segment depression, s 9.9±68.5 32.6±76.4 62.8±79.7† 69.6±78.5† <0.001
Time to limiting angina, s 7.4±50.5 23.1±60.3 41.0±71.1† 54.9±74.4† <0.001
Time to angina onset, s 28.9±66.5 44.9±69.0 72.1±83.1† 94.9±88.5† <0.001
RPP at rest, bpm . mm Hg 167±1952 -740±1696† -1740±2059† -2621±1672† <0.001
RPP at peak of exercise, bpm . mm Hg 765±3389 -931±3730† -1490±3774† 2148±3057† <0.001
RPP indicates rate-pressure product.
*Expressed as value on D14 minus value on D0.
†Significantly different from placebo in pairwise comparison.
Changes in ETT Parameters, Measured at Trough of Drug Activity, During Double-Blind Dose Ranging*
Borer J.S. et al. Circulation. 2003;107: 817-823.
Parameter
Placebo
(n=68)
Ivabradine 2.5
mg BID
(n=64)
Ivabradine 5 mg
BID
(n=59)
Ivabradine 10 mg
BID
(n=66)
Between-
Group P
Time to 1-mm ST-segment depression, s 9.9±68.5 32.6±76.4 62.8±79.7† 69.6±78.5† <0.001
Time to limiting angina, s 7.4±50.5 23.1±60.3 41.0±71.1† 54.9±74.4† <0.001
Time to angina onset, s 28.9±66.5 44.9±69.0 72.1±83.1† 94.9±88.5† <0.001
RPP at rest, bpm . mm Hg 167±1952 -740±1696† -1740±2059† -2621±1672† <0.001
RPP at peak of exercise, bpm . mm Hg 765±3389 -931±3730† -1490±3774† 2148±3057† <0.001
RPP indicates rate-pressure product.
*Expressed as value on D14 minus value on D0.
†Significantly different from placebo in pairwise comparison.
Safety Results
Borer J.S. et al. Circulation. 2003;107: 817-823.
Open-label Extension Phase
•The pattern of adverse events was similar, with 31 patients (17.9%)
having visual symptoms (graded as mild for 29 patients).
Randomized Withdrawal Phase
•1 patient had visual symptoms.
Study Withdrawals
•3 patients withdrew from the study because of visual symptoms;
these withdrawals all were voluntary rather than at the investigators’
insistence because of safety concerns.
Double-blind Dose-ranging Phase
•The incidence of adverse events was low and generally similar to placebo in all treatment groups.
•The only exception was visual symptoms photopsia [n= 10], stroboscopic effect [n= 4], nontypical blurred vision [n= 1]), which
were reported by no patients in the placebo group, by 1 patient in each of the ivabradine 2.5 and 5 mg BID groups, and by 13
patients (14.8%) in the 10 mg BID ivabradine group and were commonly associated with abrupt changes in light intensity.
Borer J.S. et al. Circulation. 2003;107: 817-823.
Open-label Extension Phase
•The pattern of adverse events was similar, with 31 patients (17.9%)
having visual symptoms (graded as mild for 29 patients).
Randomized Withdrawal Phase
•1 patient had visual symptoms.
Study Withdrawals
•3 patients withdrew from the study because of visual symptoms;
these withdrawals all were voluntary rather than at the investigators’
insistence because of safety concerns.
Double-blind Dose-ranging Phase
•The incidence of adverse events was low and generally similar to placebo in all treatment groups.
•The only exception was visual symptoms photopsia [n= 10], stroboscopic effect [n= 4], nontypical blurred vision [n= 1]), which
were reported by no patients in the placebo group, by 1 patient in each of the ivabradine 2.5 and 5 mg BID groups, and by 13
patients (14.8%) in the 10 mg BID ivabradine group and were commonly associated with abrupt changes in light intensity.
Conclusion
•Ivabradine produces dose-dependent improvements in
exercise tolerance and time to development of ischemia during
exercise.
•These results suggest that ivabradine, representing a novel
class of antianginal drugs, is effective and safe during 3
months of use.
•Longer-term safety requires additional assessment.
Borer J.S. et al. Circulation. 2003;107: 817-823.
•Ivabradine produces dose-dependent improvements in
exercise tolerance and time to development of ischemia during
exercise.
•These results suggest that ivabradine, representing a novel
class of antianginal drugs, is effective and safe during 3
months of use.
•Longer-term safety requires additional assessment.
Borer J.S. et al. Circulation. 2003;107: 817-823.
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Methodology
Objectives
To compare the anti anginal and anti ischemic effects of ivabradine and the beta-blocker atenolol on exercise capacity in patients with
stable angina.
Study Design
A randomized double-blinded, parallel-group,
trial involving 144 centers in 21 countries was
performed to compare the effects of 4 weeks of
5 mg ivabradine bid vs. 50 mg atenolol qid and
12 additional weeks of 7.5 or 10 mg ivabradine
bid vs. 100 mg atenolol qid
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Pre-selection
(n=1789)
Selection
ETT
M
1
ETT
M
4
ETT
Randomization= M
○
Inclusion ETT (n=1789)
Ivabradine
5 mg bid
(n=315)
Ivabradine
5 mg bid
(n=317)
Atenolol 50
mg qid
(n=307)
Placebo
Ivabradine
7.5 mg bid
Ivabradine
10 mg bid
Atenolol
100 mg qid
Placebo
Placebo
50 mg qid
25 mg qid
2-7 days7 days 4 weeks 12 weeks 14 days
Wash-out Run-in Initial
treatment
period
Second
treatment
period
Run-out
Objectives
To compare the anti anginal and anti ischemic effects of ivabradine and the beta-blocker atenolol on exercise capacity in patients with
stable angina.
Study Design
A randomized double-blinded, parallel-group,
trial involving 144 centers in 21 countries was
performed to compare the effects of 4 weeks of
5 mg ivabradine bid vs. 50 mg atenolol qid and
12 additional weeks of 7.5 or 10 mg ivabradine
bid vs. 100 mg atenolol qid
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Pre-selection
(n=1789)
Selection
ETT
M
1
ETT
M
4
ETT
Randomization= M
○
Inclusion ETT (n=1789)
Ivabradine
5 mg bid
(n=315)
Ivabradine
5 mg bid
(n=317)
Atenolol 50
mg qid
(n=307)
Placebo
Ivabradine
7.5 mg bid
Ivabradine
10 mg bid
Atenolol
100 mg qid
Placebo
Placebo
50 mg qid
25 mg qid
2-7 days7 days 4 weeks 12 weeks 14 days
Wash-out Run-in Initial
treatment
period
Second
treatment
period
Run-out
Methodology
TED: Total Exercise Duration, ETT: Exercise Tolerance Test, TST: time to 1 mm ST-segment depression
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Primary Endpoint
The change in TED during ETT from
inclusion (M0) to end of treatment (M4)
performed at trough of drug activity.
Secondary Endpoints
•Changes in time to limiting angina (TLA)
•Changes in time to angina onset (TAO)
•Changes in TST, HR, rate pressure product (RPP), TED and other ETT criteria at peak of drug activity
A history of stable effort angina for ≥3 months prior to study entry
Eligibility Criteria
Eligible patients were aged ≥18
years with
Evidence of CAD manifested by ≥1 of five criteria:
1.Myocardial infarction ≥3 months before study entry
2.Coronary angioplasty ≥6 months before entry
3.Bypass surgery ≥3 months before entry
4.Coronary angiogram showing ≥1 diameter stenosis ≥50%
5.Scintigraphic/ echocardiographic evidence of exercise-induced
reversible myocardial ischemia
Two positive exercise tolerance tests (ETT) prior to randomization*
time to 1 mm ST-segment depression (TST) of the two ETTs within
+/- 20% or +/- 1 min of each other.
Exclusion Criteria
Patients were excluded if they had
Significant heart disease other than CAD
Known high-grade left main CAD
Symptomatic hypotension or uncontrolled hypertension or CHF stage
III/IV NYHA
AF/ flutter, pacemaker, or implanted defibrillator
2
nd/ 3
rd degree AV block, resting HR <50 bpm or sick sinus syndrome
Any condition that interferes with ability to perform or interpret exercise
tests
Contraindications to atenolol; recent treatment with amiodarone (<3
months) or bepridil (<7 days)
TED: Total Exercise Duration, ETT: Exercise Tolerance Test, TST: time to 1 mm ST-segment depression
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Primary Endpoint
The change in TED during ETT from
inclusion (M0) to end of treatment (M4)
performed at trough of drug activity.
Secondary Endpoints
•Changes in time to limiting angina (TLA)
•Changes in time to angina onset (TAO)
•Changes in TST, HR, rate pressure product (RPP), TED and other ETT criteria at peak of drug activity
A history of stable effort angina for ≥3 months prior to study entry
Eligibility Criteria
Eligible patients were aged ≥18
years with
Evidence of CAD manifested by ≥1 of five criteria:
1.Myocardial infarction ≥3 months before study entry
2.Coronary angioplasty ≥6 months before entry
3.Bypass surgery ≥3 months before entry
4.Coronary angiogram showing ≥1 diameter stenosis ≥50%
5.Scintigraphic/ echocardiographic evidence of exercise-induced
reversible myocardial ischemia
Two positive exercise tolerance tests (ETT) prior to randomization*
time to 1 mm ST-segment depression (TST) of the two ETTs within
+/- 20% or +/- 1 min of each other.
Exclusion Criteria
Patients were excluded if they had
Significant heart disease other than CAD
Known high-grade left main CAD
Symptomatic hypotension or uncontrolled hypertension or CHF stage
III/IV NYHA
AF/ flutter, pacemaker, or implanted defibrillator
2
nd/ 3
rd degree AV block, resting HR <50 bpm or sick sinus syndrome
Any condition that interferes with ability to perform or interpret exercise
tests
Contraindications to atenolol; recent treatment with amiodarone (<3
months) or bepridil (<7 days)
Baseline characteristics
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Ivabradine 5/7.5 mg
(n = 315)
Ivabradine 5/10 mg
(n = 317)
Atenolol 50/100 mg
(n = 307)
Age, year 60.8 +/- 8.5 61.1 +/- 8.4 61.6 +/- 6.6
Male, n (%) 266 (84.4) 275 (86.8) 257 (83.7)
Angina class
I 64 (20.3) 68 (21.5) 62 (20.2)
II 225 (71.4) 222 (70.0) 215 (70.0)
III 26 (8.3) 27 (8.5) 30 (9.8)
Previous MI, n (%) 168 (53.3) 171 (53.9) 167 (54.4)
Previous PCI, n (%) 65 (20.6) 73 (23.0) 48 (15.6)
Previous CABG, n (%) 60 (19.0) 63 (19.9) 52 (16.9)
Supine BP (mmHg) systolic 135.6 +/- 16.5 136.5 +/- 16.9 136.3 +/- 17.3
Supine BP (mmHg) diastolic 80.8 +/- 8.9 81.5 +/- 9.4 81.0 +/- 8.8
Total exercise duration (s)
Mean + SD 592.1 +/- 145.4 590.7 +/- 144.9 575.7 +/- 148.4
Min–max 232–1025 86–1054 163–929
Time to limiting angina (s)
Mean + SD 584.0 +/- 141.2 583.5 +/- 140.7 565.0 +/- 144.6
Min–max 232–980 86–1069 163–929
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Ivabradine 5/7.5 mg
(n = 315)
Ivabradine 5/10 mg
(n = 317)
Atenolol 50/100 mg
(n = 307)
Age, year 60.8 +/- 8.5 61.1 +/- 8.4 61.6 +/- 6.6
Male, n (%) 266 (84.4) 275 (86.8) 257 (83.7)
Angina class
I 64 (20.3) 68 (21.5) 62 (20.2)
II 225 (71.4) 222 (70.0) 215 (70.0)
III 26 (8.3) 27 (8.5) 30 (9.8)
Previous MI, n (%) 168 (53.3) 171 (53.9) 167 (54.4)
Previous PCI, n (%) 65 (20.6) 73 (23.0) 48 (15.6)
Previous CABG, n (%) 60 (19.0) 63 (19.9) 52 (16.9)
Supine BP (mmHg) systolic 135.6 +/- 16.5 136.5 +/- 16.9 136.3 +/- 17.3
Supine BP (mmHg) diastolic 80.8 +/- 8.9 81.5 +/- 9.4 81.0 +/- 8.8
Total exercise duration (s)
Mean + SD 592.1 +/- 145.4 590.7 +/- 144.9 575.7 +/- 148.4
Min–max 232–1025 86–1054 163–929
Time to limiting angina (s)
Mean + SD 584.0 +/- 141.2 583.5 +/- 140.7 565.0 +/- 144.6
Min–max 232–980 86–1069 163–929
Baseline characteristics
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Ivabradine 5/7.5 mg
(n = 315)
Ivabradine 5/10 mg
(n = 317)
Atenolol 50/100 mg
(n = 307)
Age, year 60.8 +/- 8.5 61.1 +/- 8.4 61.6 +/- 6.6
Male, n (%) 266 (84.4) 275 (86.8) 257 (83.7)
Angina class
I 64 (20.3) 68 (21.5) 62 (20.2)
II 225 (71.4) 222 (70.0) 215 (70.0)
III 26 (8.3) 27 (8.5) 30 (9.8)
Previous MI, n (%) 168 (53.3) 171 (53.9) 167 (54.4)
Previous PCI, n (%) 65 (20.6) 73 (23.0) 48 (15.6)
Previous CABG, n (%) 60 (19.0) 63 (19.9) 52 (16.9)
Supine BP (mmHg) systolic 135.6 +/- 16.5 136.5 +/- 16.9 136.3 +/- 17.3
Supine BP (mmHg) diastolic 80.8 +/- 8.9 81.5 +/- 9.4 81.0 +/- 8.8
Total exercise duration (s)
Mean + SD 592.1 +/- 145.4 590.7 +/- 144.9 575.7 +/- 148.4
Min–max 232–1025 86–1054 163–929
Time to limiting angina (s)
Mean + SD 584.0 +/- 141.2 583.5 +/- 140.7 565.0 +/- 144.6
Min–max 232–980 86–1069 163–929
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Ivabradine 5/7.5 mg
(n = 315)
Ivabradine 5/10 mg
(n = 317)
Atenolol 50/100 mg
(n = 307)
Age, year 60.8 +/- 8.5 61.1 +/- 8.4 61.6 +/- 6.6
Male, n (%) 266 (84.4) 275 (86.8) 257 (83.7)
Angina class
I 64 (20.3) 68 (21.5) 62 (20.2)
II 225 (71.4) 222 (70.0) 215 (70.0)
III 26 (8.3) 27 (8.5) 30 (9.8)
Previous MI, n (%) 168 (53.3) 171 (53.9) 167 (54.4)
Previous PCI, n (%) 65 (20.6) 73 (23.0) 48 (15.6)
Previous CABG, n (%) 60 (19.0) 63 (19.9) 52 (16.9)
Supine BP (mmHg) systolic 135.6 +/- 16.5 136.5 +/- 16.9 136.3 +/- 17.3
Supine BP (mmHg) diastolic 80.8 +/- 8.9 81.5 +/- 9.4 81.0 +/- 8.8
Total exercise duration (s)
Mean + SD 592.1 +/- 145.4 590.7 +/- 144.9 575.7 +/- 148.4
Min–max 232–1025 86–1054 163–929
Time to limiting angina (s)
Mean + SD 584.0 +/- 141.2 583.5 +/- 140.7 565.0 +/- 144.6
Min–max 232–980 86–1069 163–929
Efficacy Results
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Ivabradine 5/7.5 mg
(n = 315)
Ivabradine 5/10 mg
(n = 317)
Atenolol 50/100 mg
(n = 307)
Total exercise duration (s)
Baseline 594.9 +/- 141.6 590.8 +/- 142.9 578.2 +/- 144.2
Change 86.8 +/- 129.0 91.7 +/- 118.8 78.8 +/- 133.4
Difference
a
(SE) 10.3 (9.4) 15.7 (9.5)
95% CIs [-8.3; 28.8] [-2.9; 34.3]
P-value, non-inferiority P > 0.001 P > 0.001
Time to limiting angina (s)
Baseline 587.0 +/- 138.0 583.5 +/- 139.6 568.1 +/- 139.8
Change 91.8 +/- 131.1 96.9 +/- 121.2 85.4 +/- 133.7
Difference
a (SE) 9.3 (9.7) 15.1 (9.7)
95% CIs [-9.6; 28.3] [-3.9; 34.0]
P-value, non-inferiority P > 0.001 P > 0.001
SE= standard error.
a Ivabradine–atenolol, estimate adjusted for baseline and country factors.
Changes in exercise tests from M0 to M4 at trough of drug activity in the full analysis set
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Ivabradine 5/7.5 mg
(n = 315)
Ivabradine 5/10 mg
(n = 317)
Atenolol 50/100 mg
(n = 307)
Total exercise duration (s)
Baseline 594.9 +/- 141.6 590.8 +/- 142.9 578.2 +/- 144.2
Change 86.8 +/- 129.0 91.7 +/- 118.8 78.8 +/- 133.4
Difference
a
(SE) 10.3 (9.4) 15.7 (9.5)
95% CIs [-8.3; 28.8] [-2.9; 34.3]
P-value, non-inferiority P > 0.001 P > 0.001
Time to limiting angina (s)
Baseline 587.0 +/- 138.0 583.5 +/- 139.6 568.1 +/- 139.8
Change 91.8 +/- 131.1 96.9 +/- 121.2 85.4 +/- 133.7
Difference
a (SE) 9.3 (9.7) 15.1 (9.7)
95% CIs [-9.6; 28.3] [-3.9; 34.0]
P-value, non-inferiority P > 0.001 P > 0.001
SE= standard error.
a Ivabradine–atenolol, estimate adjusted for baseline and country factors.
Changes in exercise tests from M0 to M4 at trough of drug activity in the full analysis set
Efficacy Results
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
SE= standard error.
a Ivabradine–atenolol, estimate adjusted for baseline and country factors.
Changes in exercise tests from M0 to M4 at trough of drug activity in the full analysis set
Ivabradine 5/7.5 mg
(n = 315)
Ivabradine 5/10 mg
(n = 317)
Atenolol 50/100 mg
(n = 307)
Time to angina onset (s)
Baseline 468.0 +/- 147.1 477.0 +/- 147.8 457.4 +/- 145.0
Change 145.2 +/- 153.4 139.6 +/- 140.6 135.2 +/- 154.7
Difference
a (SE) 12.1 (11.5) 10.1 (11.6)
95% CIs [-10.5; 34.7] [-12.5; 32.8]
P-value, non-inferiority P > 0.001 P > 0.001
Time to 1 mm ST depression (s)
Baseline 521.7 +/- 164.3 528.6 +/- 161.8 510.7 +/- 156.0
Change 98.0 +/- 153.7 86.9 +/- 128.2 95.6 +/- 147.5
Difference
a (SE) 4.3 (10.7) 23.3 (10.8)
95% CIs [-16.8; 25.3] [-24.4; 17.8]
P-value, non-inferiority P > 0.001 P = 0.002
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
SE= standard error.
a Ivabradine–atenolol, estimate adjusted for baseline and country factors.
Changes in exercise tests from M0 to M4 at trough of drug activity in the full analysis set
Ivabradine 5/7.5 mg
(n = 315)
Ivabradine 5/10 mg
(n = 317)
Atenolol 50/100 mg
(n = 307)
Time to angina onset (s)
Baseline 468.0 +/- 147.1 477.0 +/- 147.8 457.4 +/- 145.0
Change 145.2 +/- 153.4 139.6 +/- 140.6 135.2 +/- 154.7
Difference
a (SE) 12.1 (11.5) 10.1 (11.6)
95% CIs [-10.5; 34.7] [-12.5; 32.8]
P-value, non-inferiority P > 0.001 P > 0.001
Time to 1 mm ST depression (s)
Baseline 521.7 +/- 164.3 528.6 +/- 161.8 510.7 +/- 156.0
Change 98.0 +/- 153.7 86.9 +/- 128.2 95.6 +/- 147.5
Difference
a (SE) 4.3 (10.7) 23.3 (10.8)
95% CIs [-16.8; 25.3] [-24.4; 17.8]
P-value, non-inferiority P > 0.001 P = 0.002
Efficacy Results
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Changes in exercise tests from M0 to M4 at trough of drug activity in the full analysis set
Effects on total exercise duration at trough of drug activity Effects on time to 1 mm ST segment depression (TST) at trough of drug activity
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Changes in exercise tests from M0 to M4 at trough of drug activity in the full analysis set
Effects on total exercise duration at trough of drug activity Effects on time to 1 mm ST segment depression (TST) at trough of drug activity
Safety Results
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Ivabradine 5/7.5 mg
(n = 315)
Ivabradine 5/10 mg
(n = 317)
Atenolol 50/100 mg
(n = 307)
Withdrawal due to visual symptoms (n, %) 2 (0.6%) 3 (0.9%) 0 (0%)
Sinus bradycardia (n, %) 7 (2.2%) 17 (5.4%) 13 (4.3%)
Headache (n, %) 8 (2.6%) 15 (4.8%) 5 (1.6%)
The decrease in corrected QT interval (QTc)
from baseline till end of treatment (ms)
10 +/- 40 9 +/- 35 12 +/- 38
QTc increase by > 60 ms (n, %) 1 (0.3%) 2 (0.6%) 2 (0.7%)
Death (n, %) 2 (0.6%) 3 (0.9%) 1 (0.3%)
•Ivabradine was well-tolerated, with the most frequent adverse drug reaction being visual symptoms.
•Most of these were mainly phosphenes (luminous phenomena) described as increases in brightness in limited areas of the visual
field.
•These symptoms were transient, rated as non-serious, appeared on average after 40 days of treatment, occurred under well-defined
conditions, such as light variation, and did not disturb patients’ activities.
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
Ivabradine 5/7.5 mg
(n = 315)
Ivabradine 5/10 mg
(n = 317)
Atenolol 50/100 mg
(n = 307)
Withdrawal due to visual symptoms (n, %) 2 (0.6%) 3 (0.9%) 0 (0%)
Sinus bradycardia (n, %) 7 (2.2%) 17 (5.4%) 13 (4.3%)
Headache (n, %) 8 (2.6%) 15 (4.8%) 5 (1.6%)
The decrease in corrected QT interval (QTc)
from baseline till end of treatment (ms)
10 +/- 40 9 +/- 35 12 +/- 38
QTc increase by > 60 ms (n, %) 1 (0.3%) 2 (0.6%) 2 (0.7%)
Death (n, %) 2 (0.6%) 3 (0.9%) 1 (0.3%)
•Ivabradine was well-tolerated, with the most frequent adverse drug reaction being visual symptoms.
•Most of these were mainly phosphenes (luminous phenomena) described as increases in brightness in limited areas of the visual
field.
•These symptoms were transient, rated as non-serious, appeared on average after 40 days of treatment, occurred under well-defined
conditions, such as light variation, and did not disturb patients’ activities.
Conclusion
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
In conclusion, the I
f
inhibitor ivabradine is as
effective as atenolol, a well-established reference
drug for the treatment of stable angina
Tardif JC, et al. Eur Heart J. 2005 Dec;26(23):2529-36.
In conclusion, the I
f
inhibitor ivabradine is as
effective as atenolol, a well-established reference
drug for the treatment of stable angina
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Methodology
Reasons for noninclusion of screened patients:
Did not meet ETT criteria (n = 372)
Adverse events during washout/ run-in period (n = 30)
Consent withdrawn/nonmedical reason (n = 54)
Other (n = 42)
Screened
(n = 1693)
Selected
(n = 1318)
Randomized
(n = 1195)
Ivabradine 10mg bid
(n = 391)
Ivabradine 7.5mg bid
(n = 400)
Amlodipine 10mg od
(n = 404)
Completed
(n = 358)
Completed
(n = 363)
Completed
(n = 378)
Withdrawn (n = 37)
Adverse events (n = 30)
Nonmedical reason (n = 6)
Lack of efficacy (n = 1)
Withdrawn (n = 33)
Adverse events (n = 24)
Nonmedical reason (n = 6)
Protocol deviation (n = 2)
Lack of efficacy (n = 1)
Withdrawn (n = 26)
Adverse events (n = 21)
Nonmedical reason (n = 3)
Protocol deviation (n = 2)
Objectives
To compare the antianginal and anti-ischemic effects of the novel heart-rate-lowering
agent ivabradine and of the calcium channel antagonist amlodipine.
Study Design
A randomized, double-blind, three-arm parallel
group, international trial involving 133 centers was
performed to compare the effects of 3 months of
ivabradine 7.5 and 10mg twice daily with amlodipine
10mg once daily.
bid = twice daily; ETT = exercise tolerance test; od = once daily.
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Reasons for noninclusion of screened patients:
Did not meet ETT criteria (n = 372)
Adverse events during washout/ run-in period (n = 30)
Consent withdrawn/nonmedical reason (n = 54)
Other (n = 42)
Screened
(n = 1693)
Selected
(n = 1318)
Randomized
(n = 1195)
Ivabradine 10mg bid
(n = 391)
Ivabradine 7.5mg bid
(n = 400)
Amlodipine 10mg od
(n = 404)
Completed
(n = 358)
Completed
(n = 363)
Completed
(n = 378)
Withdrawn (n = 37)
Adverse events (n = 30)
Nonmedical reason (n = 6)
Lack of efficacy (n = 1)
Withdrawn (n = 33)
Adverse events (n = 24)
Nonmedical reason (n = 6)
Protocol deviation (n = 2)
Lack of efficacy (n = 1)
Withdrawn (n = 26)
Adverse events (n = 21)
Nonmedical reason (n = 3)
Protocol deviation (n = 2)
Objectives
To compare the antianginal and anti-ischemic effects of the novel heart-rate-lowering
agent ivabradine and of the calcium channel antagonist amlodipine.
Study Design
A randomized, double-blind, three-arm parallel
group, international trial involving 133 centers was
performed to compare the effects of 3 months of
ivabradine 7.5 and 10mg twice daily with amlodipine
10mg once daily.
bid = twice daily; ETT = exercise tolerance test; od = once daily.
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Methodology
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Primary Endpoint
The change from baseline in Total Exercise Duration (TED)
after 3 months of treatment
Secondary Endpoints
•Changes in time to angina onset at the trough of drug activity
•Changes in time to 1 mm ST-segment depression at the trough of drug activity
•Changes in time the rate pressure product (RPP) at the trough of drug activity
Eligibility Criteria
Eligible patients are Men or women
aged ≥18 and ≤90 of age with
A ≥ 3- month history of chronic stable effort-induced angina,
relieved by rest or short-acting nitrates
Coronary artery disease (CAD) documented by occurrence of a
myocardial infarction (MI) ≥3 months previously, or coronary
artery bypass graft surgery (CABG) ≥3 months previously, or
percutaneous coronary angioplasty (PTCA) ≥6 months
previously, or by coronary angiography, stress
echocardiography or scintigraphy
A positive bicycle exercise tolerance test (ETT) [with both
limiting angina and ST-segment depression ≥1mm compared
with rest] at selection (D–7) and at inclusion (M0). Patients were excluded if they had
Inability to perform ETT, ECG abnormalities confounding ETT interpretation
Unstable angina, Prinzmetal angina or ‘microvascular angina’
NYHA class III or IV heart failure
Symptomatic hypotension or uncontrolled hypertension
AF/ flutter, pacemaker, or indwelling pacemaker
Clinically significant heart disease other than CAD
treatment with defined unauthorized concomitant medications that could
interact with ivabradine or amlodipine
Contraindications to amlodipine; recent treatment with amiodarone (<3
months) or bepridil (<7 days) prior to selection
Exclusion Criteria
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Primary Endpoint
The change from baseline in Total Exercise Duration (TED)
after 3 months of treatment
Secondary Endpoints
•Changes in time to angina onset at the trough of drug activity
•Changes in time to 1 mm ST-segment depression at the trough of drug activity
•Changes in time the rate pressure product (RPP) at the trough of drug activity
Eligibility Criteria
Eligible patients are Men or women
aged ≥18 and ≤90 of age with
A ≥ 3- month history of chronic stable effort-induced angina,
relieved by rest or short-acting nitrates
Coronary artery disease (CAD) documented by occurrence of a
myocardial infarction (MI) ≥3 months previously, or coronary
artery bypass graft surgery (CABG) ≥3 months previously, or
percutaneous coronary angioplasty (PTCA) ≥6 months
previously, or by coronary angiography, stress
echocardiography or scintigraphy
A positive bicycle exercise tolerance test (ETT) [with both
limiting angina and ST-segment depression ≥1mm compared
with rest] at selection (D–7) and at inclusion (M0). Patients were excluded if they had
Inability to perform ETT, ECG abnormalities confounding ETT interpretation
Unstable angina, Prinzmetal angina or ‘microvascular angina’
NYHA class III or IV heart failure
Symptomatic hypotension or uncontrolled hypertension
AF/ flutter, pacemaker, or indwelling pacemaker
Clinically significant heart disease other than CAD
treatment with defined unauthorized concomitant medications that could
interact with ivabradine or amlodipine
Contraindications to amlodipine; recent treatment with amiodarone (<3
months) or bepridil (<7 days) prior to selection
Exclusion Criteria
Baseline characteristics
Ivabradine 7.5 mg bid (n =
400)
Ivabradine 10 mg bid
(n = 391)
Amlodipine 10 mg od (n =
404)
Age (y) 59.7 +/- 9.0 59.6 +/- 8.9 60.0 +/- 8.9
Male (%) 341 (85.3) 346 (88.5) 347 (85.9)
Caucasian (%) 99.8 100 100
Angina grade
a
I (%) 14.3 17.1 11.4
II (%) 66.0 63.4 72.5
III (%) 19.8 19.4 16.1
Disease duration (mo) 72.5 +/- 71 67.6 +/- 64 73.6 +/- 71
Previous MI (%) 43.8 42.7 45.5
Previous CABG (%) 13.3 15.1 13.9
Previous PTCA (%) 10.8 12.0 11.6
Heart rate at rest (beats/min)
b 79 +/- 13 78 +/- 14 79 +/- 13
Heart rate at peak of ETT (beats/min)
b 132 +/- 19 132 +/- 19 131 +/- 18
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
a Canadian Cardiovascular Society Functional Classification.
b Data obtained in the intention-to-treat population.
bid = twice daily; CABG = coronary artery bypass graft surgery; ETT exercise tolerance test; MI = myocardial infarction; od = once daily; PTCA = percutaneous transluminal coronary angioplasty.
Ivabradine 7.5 mg bid (n =
400)
Ivabradine 10 mg bid
(n = 391)
Amlodipine 10 mg od (n =
404)
Age (y) 59.7 +/- 9.0 59.6 +/- 8.9 60.0 +/- 8.9
Male (%) 341 (85.3) 346 (88.5) 347 (85.9)
Caucasian (%) 99.8 100 100
Angina grade
a
I (%) 14.3 17.1 11.4
II (%) 66.0 63.4 72.5
III (%) 19.8 19.4 16.1
Disease duration (mo) 72.5 +/- 71 67.6 +/- 64 73.6 +/- 71
Previous MI (%) 43.8 42.7 45.5
Previous CABG (%) 13.3 15.1 13.9
Previous PTCA (%) 10.8 12.0 11.6
Heart rate at rest (beats/min)
b 79 +/- 13 78 +/- 14 79 +/- 13
Heart rate at peak of ETT (beats/min)
b 132 +/- 19 132 +/- 19 131 +/- 18
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
a Canadian Cardiovascular Society Functional Classification.
b Data obtained in the intention-to-treat population.
bid = twice daily; CABG = coronary artery bypass graft surgery; ETT exercise tolerance test; MI = myocardial infarction; od = once daily; PTCA = percutaneous transluminal coronary angioplasty.
Efficacy Results
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Variable
Amlodipine
10mg od
(n = 398)
Ivabradine
7.5mg bid
(n = 381)
Difference
vs
amlodipine,
E (SE)
a [95%
CI]
p-Value for
noninferiority
b
Ivabradine
10mg bid
(n = 376)
Difference vs
amlodipine, E
(SE)
a [95% CI]
p-Value for
noninferiorit
y
b
Total exercise duration (sec)
Baseline 400.1 +/- 131.9414.4 +/- 133.0 423.6 +/- 142.6
3 months
431.2 +/-
140.9
442.0 +/- 154.4 445.3 +/- 155.5
Change at 3 months 31.2 +/- 92.0 27.6 +/- 91.7
–1.8 (6.6)
[–14.6, 11.1]
<0.001 21.7 +/- 94.5
–6.6 (6.6)
[–19.5, 6.3]
<0.001
Time to angina onset (sec)
Baseline 313.0 +/- 121.8325.2 +/- 119.9 331.4 +/- 125.7
3 months 379.5 +/- 143.2389.9 +/- 156.4 391.1 +/- 157.2
Change at 3 months 66.6 +/- 99.1 64.7 +/- 104.9
–0.6 (7.4)
[–15.2, 14.0]
<0.001 59.7 +/- 110.8
–4.6 (7.5)
[–19.3, 10.1]
<0.001
Time to 1mm ST-segment depression (sec)
Baseline 347.4 +/- 123.9355.0 +/- 122.4 366.9 +/- 130.9
3 months 387.1 +/- 138.4400.0 +/- 152.2 401.5 +/- 149.6
Change at 3 months 39.7 +/- 103.2 44.9 +/- 98.6
6.5 (7.2)
[–7.6, 20.6]
<0.001 34.7 +/- 104.5
–1.8 (7.2)
[–16.0, 12.3]
<0.001
a E (SE) and CI of the difference between ivabradine effect and amlodipine effect, based on a covariance analysis adjusted on baseline and country factors. Other values are mean
+/- standard deviation.
b For a noninferiority margin of –30 seconds.
ETT parameters at baseline and 3 months in the ITT population, measured at trough of drug activity
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Variable
Amlodipine
10mg od
(n = 398)
Ivabradine
7.5mg bid
(n = 381)
Difference
vs
amlodipine,
E (SE)
a [95%
CI]
p-Value for
noninferiority
b
Ivabradine
10mg bid
(n = 376)
Difference vs
amlodipine, E
(SE)
a [95% CI]
p-Value for
noninferiorit
y
b
Total exercise duration (sec)
Baseline 400.1 +/- 131.9414.4 +/- 133.0 423.6 +/- 142.6
3 months
431.2 +/-
140.9
442.0 +/- 154.4 445.3 +/- 155.5
Change at 3 months 31.2 +/- 92.0 27.6 +/- 91.7
–1.8 (6.6)
[–14.6, 11.1]
<0.001 21.7 +/- 94.5
–6.6 (6.6)
[–19.5, 6.3]
<0.001
Time to angina onset (sec)
Baseline 313.0 +/- 121.8325.2 +/- 119.9 331.4 +/- 125.7
3 months 379.5 +/- 143.2389.9 +/- 156.4 391.1 +/- 157.2
Change at 3 months 66.6 +/- 99.1 64.7 +/- 104.9
–0.6 (7.4)
[–15.2, 14.0]
<0.001 59.7 +/- 110.8
–4.6 (7.5)
[–19.3, 10.1]
<0.001
Time to 1mm ST-segment depression (sec)
Baseline 347.4 +/- 123.9355.0 +/- 122.4 366.9 +/- 130.9
3 months 387.1 +/- 138.4400.0 +/- 152.2 401.5 +/- 149.6
Change at 3 months 39.7 +/- 103.2 44.9 +/- 98.6
6.5 (7.2)
[–7.6, 20.6]
<0.001 34.7 +/- 104.5
–1.8 (7.2)
[–16.0, 12.3]
<0.001
a E (SE) and CI of the difference between ivabradine effect and amlodipine effect, based on a covariance analysis adjusted on baseline and country factors. Other values are mean
+/- standard deviation.
b For a noninferiority margin of –30 seconds.
ETT parameters at baseline and 3 months in the ITT population, measured at trough of drug activity
Efficacy Results
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Changes in HR and RPP (mean +/- SD) at 3 months in the ITT population, measured at trough of drug activity
Variable
Amlodipine 10mg od
(n = 398)
Ivabradine 7.5 mg
bid (n = 381)
Difference vs
amlodipine E (SE)
a
[95% CI]
Ivabradine 10mg bid
(n = 376)
Difference vs
amlodipine E (SE)
a
[95% CI]
Heart rate at rest
Baseline 78.8 +/- 13.4 78.6 +/- 13.0 78.1 +/-14.1
3 months 78.6 +/- 13.2 67.4 +/- 11.8 65.1 +/- 12.8
Change at 3 months –0.2 +/- 12.2 –11.2 +/- 12.5 –11.1 (0.8) –13.1 +/- 13.5 –13.1 (0.8)
[95% CI]
b [–1.5, 1.0] [–12.5, –10.0] [–12.6, –9.6] [–14.4, –11.8] [–14.7, –11.6]
p-Value
c vs baseline p = 0.720 p < 0.001 p < 0.001
p-Value
d vs amlodipine p < 0.001 p < 0.001
Heart rate at peak of exercise
Baseline 131.0 +/- 18.4 132.1 +/- 18.9 132.1 +/- 18.8
3 months 130.8 +/- 17.5 119.7 +/- 7.1 117.0 +/- 17.6
Change at 3 months –0.2 +/- 12.8 –12.4 +/- 15.3 –11.8 (0.9) –15.1 +/- 14.4 –14.5 (0.9)
[95% CI]
b [–1.6, 1.3] [–13.9, –11.0] [–13.6, –10.1] [–16.5, –13.4] [–16.3, –12.7]
p-Value
c vs baseline p = 0.829 p < 0.001 p < 0.001
p-Value
d vs amlodipine p < 0.001 p < 0.001
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Changes in HR and RPP (mean +/- SD) at 3 months in the ITT population, measured at trough of drug activity
Variable
Amlodipine 10mg od
(n = 398)
Ivabradine 7.5 mg
bid (n = 381)
Difference vs
amlodipine E (SE)
a
[95% CI]
Ivabradine 10mg bid
(n = 376)
Difference vs
amlodipine E (SE)
a
[95% CI]
Heart rate at rest
Baseline 78.8 +/- 13.4 78.6 +/- 13.0 78.1 +/-14.1
3 months 78.6 +/- 13.2 67.4 +/- 11.8 65.1 +/- 12.8
Change at 3 months –0.2 +/- 12.2 –11.2 +/- 12.5 –11.1 (0.8) –13.1 +/- 13.5 –13.1 (0.8)
[95% CI]
b [–1.5, 1.0] [–12.5, –10.0] [–12.6, –9.6] [–14.4, –11.8] [–14.7, –11.6]
p-Value
c vs baseline p = 0.720 p < 0.001 p < 0.001
p-Value
d vs amlodipine p < 0.001 p < 0.001
Heart rate at peak of exercise
Baseline 131.0 +/- 18.4 132.1 +/- 18.9 132.1 +/- 18.8
3 months 130.8 +/- 17.5 119.7 +/- 7.1 117.0 +/- 17.6
Change at 3 months –0.2 +/- 12.8 –12.4 +/- 15.3 –11.8 (0.9) –15.1 +/- 14.4 –14.5 (0.9)
[95% CI]
b [–1.6, 1.3] [–13.9, –11.0] [–13.6, –10.1] [–16.5, –13.4] [–16.3, –12.7]
p-Value
c vs baseline p = 0.829 p < 0.001 p < 0.001
p-Value
d vs amlodipine p < 0.001 p < 0.001
Efficacy Results
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Changes in HR and RPP (mean +/- SD) at 3 months in the ITT population, measured at trough of drug activity
Variable
Amlodipine 10mg od
(n = 398)
Ivabradine 7.5 mg
bid (n = 381)
Difference vs
amlodipine E (SE)
a
[95% CI]
Ivabradine 10mg bid
(n = 376)
Difference vs
amlodipine E (SE)
a
[95% CI]
Heart rate at rest
Baseline 78.8 +/- 13.4 78.6 +/- 13.0 78.1 +/-14.1
3 months 78.6 +/- 13.2 67.4 +/- 11.8 65.1 +/- 12.8
Change at 3 months –0.2 +/- 12.2 –11.2 +/- 12.5 –11.1 (0.8) –13.1 +/- 13.5 –13.1 (0.8)
[95% CI]
b [–1.5, 1.0] [–12.5, –10.0] [–12.6, –9.6] [–14.4, –11.8] [–14.7, –11.6]
p-Value
c vs baseline p = 0.720 p < 0.001 p < 0.001
p-Value
d vs amlodipine p < 0.001 p < 0.001
Heart rate at peak of exercise
Baseline 131.0 +/- 18.4 132.1 +/- 18.9 132.1 +/- 18.8
3 months 130.8 +/- 17.5 119.7 +/- 7.1 117.0 +/- 17.6
Change at 3 months –0.2 +/- 12.8 –12.4 +/- 15.3 –11.8 (0.9) –15.1 +/- 14.4 –14.5 (0.9)
[95% CI]
b [–1.6, 1.3] [–13.9, –11.0] [–13.6, –10.1] [–16.5, –13.4] [–16.3, –12.7]
p-Value
c vs baseline p = 0.829 p < 0.001 p < 0.001
p-Value
d vs amlodipine p < 0.001 p < 0.001
a E (SE) and CI of the difference between ivabradine effect and amlodipine effect, based on a covariance analysis adjusted on baseline and country factors. Other values are mean +/- standard
deviation.
b CI of the change within treatment group based on an analysis of variance without adjustment.
c Student’s t-test based on the overall general linear model (least-squares norm).
d
Student’s t-test based on the overall general linear model (least-squares norm) with baseline as a covariate and country as a random factor.
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Changes in HR and RPP (mean +/- SD) at 3 months in the ITT population, measured at trough of drug activity
Variable
Amlodipine 10mg od
(n = 398)
Ivabradine 7.5 mg
bid (n = 381)
Difference vs
amlodipine E (SE)
a
[95% CI]
Ivabradine 10mg bid
(n = 376)
Difference vs
amlodipine E (SE)
a
[95% CI]
Heart rate at rest
Baseline 78.8 +/- 13.4 78.6 +/- 13.0 78.1 +/-14.1
3 months 78.6 +/- 13.2 67.4 +/- 11.8 65.1 +/- 12.8
Change at 3 months –0.2 +/- 12.2 –11.2 +/- 12.5 –11.1 (0.8) –13.1 +/- 13.5 –13.1 (0.8)
[95% CI]
b [–1.5, 1.0] [–12.5, –10.0] [–12.6, –9.6] [–14.4, –11.8] [–14.7, –11.6]
p-Value
c vs baseline p = 0.720 p < 0.001 p < 0.001
p-Value
d vs amlodipine p < 0.001 p < 0.001
Heart rate at peak of exercise
Baseline 131.0 +/- 18.4 132.1 +/- 18.9 132.1 +/- 18.8
3 months 130.8 +/- 17.5 119.7 +/- 7.1 117.0 +/- 17.6
Change at 3 months –0.2 +/- 12.8 –12.4 +/- 15.3 –11.8 (0.9) –15.1 +/- 14.4 –14.5 (0.9)
[95% CI]
b [–1.6, 1.3] [–13.9, –11.0] [–13.6, –10.1] [–16.5, –13.4] [–16.3, –12.7]
p-Value
c vs baseline p = 0.829 p < 0.001 p < 0.001
p-Value
d vs amlodipine p < 0.001 p < 0.001
a E (SE) and CI of the difference between ivabradine effect and amlodipine effect, based on a covariance analysis adjusted on baseline and country factors. Other values are mean +/- standard
deviation.
b CI of the change within treatment group based on an analysis of variance without adjustment.
c Student’s t-test based on the overall general linear model (least-squares norm).
d
Student’s t-test based on the overall general linear model (least-squares norm) with baseline as a covariate and country as a random factor.
Efficacy Results
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Changes in anginal attack frequency and short-acting nitrate use in the ITT population
Variable
Amlodipine 10mg od
(n = 398)
Ivabradine 7.5mg bid
(n = 389)
Difference E (SE)
a
[95% CI]
Ivabradine 10mg
bid (n = 381)
Difference E
(SE)
a [95% CI]
Anginal attack frequency (attacks/week)
Run-in period 5.1 +/- 7.8 5.1 +/- 7.7 5.1 +/- 7.6
3 months 2.0 +/- 5.7 2.1 +/- 5.0 1.9 +/- 3.6
Change at 3 months –3.0 +/- 6.0 –3.0 +/- 5.0 0.1 (0.4) [–0.7, 0.9] –3.2 +/- 6.3
–0.2 (0.4)
[–1.0, 0.6]
p-Value
b vs baseline p < 0.001 p < 0.001 p < 0.001
p-Value
b vs amlodipine p = 0.564 p = 0.318
Short-acting nitrate use (units/week)
Run-in period 4.3 +/- 8.2 3.7 +/- 7.1 4.5 +/- 8.3
3 months 1.6 +/- 3.8 1.7 +/- 4.5 1.9 +/- 4.5
Change at 3 months –2.7 +/- 6.3 –1.9 +/- 4.5 0.8 (0.4) [–0.0, 1.6] –2.7 +/- 6.3
0.0 (0.4)
[–0.8, 0.9]
p-Value
b vs baseline p < 0.001 p < 0.001 p < 0.001
p-Value
b vs amlodipine p = 0.972 p = 0.541a E (SE) and CI of the difference between ivabradine effect and amlodipine effect, based on an analysis of variance without adjustment. Other values are mean +/- standard
deviation.
b Student’s t-test based on the overall general linear model (least-squares norm).
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Changes in anginal attack frequency and short-acting nitrate use in the ITT population
Variable
Amlodipine 10mg od
(n = 398)
Ivabradine 7.5mg bid
(n = 389)
Difference E (SE)
a
[95% CI]
Ivabradine 10mg
bid (n = 381)
Difference E
(SE)
a [95% CI]
Anginal attack frequency (attacks/week)
Run-in period 5.1 +/- 7.8 5.1 +/- 7.7 5.1 +/- 7.6
3 months 2.0 +/- 5.7 2.1 +/- 5.0 1.9 +/- 3.6
Change at 3 months –3.0 +/- 6.0 –3.0 +/- 5.0 0.1 (0.4) [–0.7, 0.9] –3.2 +/- 6.3
–0.2 (0.4)
[–1.0, 0.6]
p-Value
b vs baseline p < 0.001 p < 0.001 p < 0.001
p-Value
b vs amlodipine p = 0.564 p = 0.318
Short-acting nitrate use (units/week)
Run-in period 4.3 +/- 8.2 3.7 +/- 7.1 4.5 +/- 8.3
3 months 1.6 +/- 3.8 1.7 +/- 4.5 1.9 +/- 4.5
Change at 3 months –2.7 +/- 6.3 –1.9 +/- 4.5 0.8 (0.4) [–0.0, 1.6] –2.7 +/- 6.3
0.0 (0.4)
[–0.8, 0.9]
p-Value
b vs baseline p < 0.001 p < 0.001 p < 0.001
p-Value
b vs amlodipine p = 0.972 p = 0.541a E (SE) and CI of the difference between ivabradine effect and amlodipine effect, based on an analysis of variance without adjustment. Other values are mean +/- standard
deviation.
b Student’s t-test based on the overall general linear model (least-squares norm).
Safety Results
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Adverse event (%)
a
Ivabradine 7.5mg bid
(n = 400)
Ivabradine 10mg bid
(n = 391)
Amlodipine 10mg od
(n = 404)
Visual symptoms 13.0 25.1 4.5
Peripheral oedema 0.8 1.3 7.9
Sinus bradycardia 6.5 10.5 1.7
Ventricular extrasystoles 4.5 4.1 2.7
a Percent patients reporting emergent adverse event.
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Adverse event (%)
a
Ivabradine 7.5mg bid
(n = 400)
Ivabradine 10mg bid
(n = 391)
Amlodipine 10mg od
(n = 404)
Visual symptoms 13.0 25.1 4.5
Peripheral oedema 0.8 1.3 7.9
Sinus bradycardia 6.5 10.5 1.7
Ventricular extrasystoles 4.5 4.1 2.7
a Percent patients reporting emergent adverse event.
Conclusion
•In patients with stable angina, Ivabradine 7.5mg or 10mg twice
daily was shown to have similar efficacy to Amlodipine 10mg
once daily in reducing anginal symptoms.
•Ivabradine was superior to amlodipine in reducing myocardial
oxygen consumption as demonstrated by the significantly
greater effect on the rate-pressure product.
•This study adds to the existing evidence that pure heart-rate
reduction with the specific and selective If inhibitor Ivabradine
represents a novel and attractive alternative for the treatment
of patients with CAD and stable angina.
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
•In patients with stable angina, Ivabradine 7.5mg or 10mg twice
daily was shown to have similar efficacy to Amlodipine 10mg
once daily in reducing anginal symptoms.
•Ivabradine was superior to amlodipine in reducing myocardial
oxygen consumption as demonstrated by the significantly
greater effect on the rate-pressure product.
•This study adds to the existing evidence that pure heart-rate
reduction with the specific and selective If inhibitor Ivabradine
represents a novel and attractive alternative for the treatment
of patients with CAD and stable angina.
Ruzyllo W, et al. Drugs 2007; 67 (3): 393-405
Fox K, et al. Lancet 2008; 372: 807–16
Methodology
Objectives
To test whether lowering the heart rate with ivabradine reduces cardiovascular death
and morbidity in patients with coronary artery disease and left-ventricular systolic
dysfunction.
Study Design
•A randomized, double-blind, placebo-controlled, parallel-group trial in 781
centers in 33 countries, patients were screened between Dec 2004, & Dec
2006.
•We enrolled 10,917 eligible patients who had CAD and a left-ventricular
ejection fraction of <40% 5,479 patients received 5 mg ivabradine, with the
intention of increasing to the target dose of 7·5 mg twice a day, and 5,438
received matched placebo in addition to appropriate CV medication.
1221 excluded
333 had inadequate echocardiographic data
183 had very low heart rate
27 had no sinus rhythm
83 for other cardiovascular reasons
300 withdrew consent
93 because laboratory criteria not fulfilled
55 had a serious adverse event
147 for other non-cardiovascular reasons
5,479 assigned to ivabradine
2 refused medication
115 had incomplete follow-up
114 withdrew consent
1 lost to follow-up
5,438 assigned to placebo
8 refused medication
105 had incomplete follow-up
102 withdrew consent
3 had incorrect randomisation*
5479 analysed 5438 analysed
12,473 assessed
335 excluded
12,138 screened
10,917 randomly assigned
Fox K, et al. Lancet 2008; 372: 807–16
1ry Endpoint 2ry Endpoint
A composite of:
•CV death
•Admission to hospital for
acute MI
•Admission to hospital for
new onset or worsening HF
•All-cause mortality
•CV death
•Cardiac death
•The composite of admission to hospital
for fatal and non-fatal acute MI or
unstable angina
•Coronary revascularization
•Admission to hospital for heart failure
•Admission to hospital for MI
*These three patients were randomized twice in two different centers.
Objectives
To test whether lowering the heart rate with ivabradine reduces cardiovascular death
and morbidity in patients with coronary artery disease and left-ventricular systolic
dysfunction.
Study Design
•A randomized, double-blind, placebo-controlled, parallel-group trial in 781
centers in 33 countries, patients were screened between Dec 2004, & Dec
2006.
•We enrolled 10,917 eligible patients who had CAD and a left-ventricular
ejection fraction of <40% 5,479 patients received 5 mg ivabradine, with the
intention of increasing to the target dose of 7·5 mg twice a day, and 5,438
received matched placebo in addition to appropriate CV medication.
1221 excluded
333 had inadequate echocardiographic data
183 had very low heart rate
27 had no sinus rhythm
83 for other cardiovascular reasons
300 withdrew consent
93 because laboratory criteria not fulfilled
55 had a serious adverse event
147 for other non-cardiovascular reasons
5,479 assigned to ivabradine
2 refused medication
115 had incomplete follow-up
114 withdrew consent
1 lost to follow-up
5,438 assigned to placebo
8 refused medication
105 had incomplete follow-up
102 withdrew consent
3 had incorrect randomisation*
5479 analysed 5438 analysed
12,473 assessed
335 excluded
12,138 screened
10,917 randomly assigned
Fox K, et al. Lancet 2008; 372: 807–16
1ry Endpoint 2ry Endpoint
A composite of:
•CV death
•Admission to hospital for
acute MI
•Admission to hospital for
new onset or worsening HF
•All-cause mortality
•CV death
•Cardiac death
•The composite of admission to hospital
for fatal and non-fatal acute MI or
unstable angina
•Coronary revascularization
•Admission to hospital for heart failure
•Admission to hospital for MI
*These three patients were randomized twice in two different centers.
Baseline characteristics
Ivabradine group
(n=5,479)
Placebo group
(n=5,438)
All patients
(N=10,917)
Demographic characteristics
Age (years) 65.3 (8.5) 65.0 (8.4) 65.2 (8.5)
Sex (male) 4540 (83%) 4507 (83%) 9047 (83%)
Smoking (current) 813 (15%) 834 (15%) 1647 (15%)
Body-mass index (kg/m
2) 28.4 (4.4) 28.5 (4.4) 28.5 (4.4)
Medical history
History of hypertension 3882 (71%) 3838 (71%) 7720 (71%)
History of diabetes 2017 (37%) 2019 (37%) 4036 (37%)
History of dyslipidemia 4289 (78%) 4278 (79%) 8567 (78%)
Previous MI 4828 (88%) 4817 (89%) 9645 (88%)
Previous PCI or CABG 2819 (51%) 2824 (52%) 5643 (52%)
Previous stroke 1020 (19%) 971 (18%) 1991 (18%)
Peripheral artery disease 692 (13%) 748 (14%) 1440 (13%)
Fox K, et al. Lancet 2008; 372: 807–16
Ivabradine group
(n=5,479)
Placebo group
(n=5,438)
All patients
(N=10,917)
Demographic characteristics
Age (years) 65.3 (8.5) 65.0 (8.4) 65.2 (8.5)
Sex (male) 4540 (83%) 4507 (83%) 9047 (83%)
Smoking (current) 813 (15%) 834 (15%) 1647 (15%)
Body-mass index (kg/m
2) 28.4 (4.4) 28.5 (4.4) 28.5 (4.4)
Medical history
History of hypertension 3882 (71%) 3838 (71%) 7720 (71%)
History of diabetes 2017 (37%) 2019 (37%) 4036 (37%)
History of dyslipidemia 4289 (78%) 4278 (79%) 8567 (78%)
Previous MI 4828 (88%) 4817 (89%) 9645 (88%)
Previous PCI or CABG 2819 (51%) 2824 (52%) 5643 (52%)
Previous stroke 1020 (19%) 971 (18%) 1991 (18%)
Peripheral artery disease 692 (13%) 748 (14%) 1440 (13%)
Fox K, et al. Lancet 2008; 372: 807–16
Baseline characteristics
Ivabradine group
(n=5,479)
Placebo group
(n=5,438)
All patients
(N=10,917)
Cardiac parameters
Heart rate (bpm) 71.5 (9.8) 71.6 (9.9) 71.6 (9.9)
Systolic blood pressure (mm Hg) 128.1 (15.7) 127.9 (15.5) 128.0 (15.6)
Diastolic blood pressure (mm Hg) 77.4 (9.3) 77.5 (9.2) 77.5 (9.3)
Left-ventricular ejection fraction (%) 32.4 (5.5) 32.3 (5.5) 32.4 (5.5)
NYHA class I heart failure 840 (15%) 840 (15%) 1680 (15%)
NYHA class II heart failure 3346 (61%) 3359 (62%) 6705 (61%)
NYHA class III heart failure 1293 (24%) 1239 (23%) 2532 (23%)
Medication at randomization
Aspirin or antithrombotic agent 5166 (94%) 5103 (94%) 10,269 (94%)
Statin 4064 (74%) 4032 (74%) 8096 (74%)
Angiotensin-converting enzyme inhibitor,
angiotensin II receptor blocker, or both
4917 (90%) 4873 (90%) 9790 (90%)
β blocker 4749 (87%) 4738 (87%) 9487 (87%)
Organic nitrates 2398 (44%) 2335 (43%) 4733 (43%)
Diuretics (excluding antialdosterone) 3232 (59%) 3194 (59%) 6426 (59%)
Antialdosterone agents 1487 (27%) 1466 (27%) 2953 (27%)
Fox K, et al. Lancet 2008; 372: 807–16 Data are number (%) or mean (SD).
Ivabradine group
(n=5,479)
Placebo group
(n=5,438)
All patients
(N=10,917)
Cardiac parameters
Heart rate (bpm) 71.5 (9.8) 71.6 (9.9) 71.6 (9.9)
Systolic blood pressure (mm Hg) 128.1 (15.7) 127.9 (15.5) 128.0 (15.6)
Diastolic blood pressure (mm Hg) 77.4 (9.3) 77.5 (9.2) 77.5 (9.3)
Left-ventricular ejection fraction (%) 32.4 (5.5) 32.3 (5.5) 32.4 (5.5)
NYHA class I heart failure 840 (15%) 840 (15%) 1680 (15%)
NYHA class II heart failure 3346 (61%) 3359 (62%) 6705 (61%)
NYHA class III heart failure 1293 (24%) 1239 (23%) 2532 (23%)
Medication at randomization
Aspirin or antithrombotic agent 5166 (94%) 5103 (94%) 10,269 (94%)
Statin 4064 (74%) 4032 (74%) 8096 (74%)
Angiotensin-converting enzyme inhibitor,
angiotensin II receptor blocker, or both
4917 (90%) 4873 (90%) 9790 (90%)
β blocker 4749 (87%) 4738 (87%) 9487 (87%)
Organic nitrates 2398 (44%) 2335 (43%) 4733 (43%)
Diuretics (excluding antialdosterone) 3232 (59%) 3194 (59%) 6426 (59%)
Antialdosterone agents 1487 (27%) 1466 (27%) 2953 (27%)
Fox K, et al. Lancet 2008; 372: 807–16 Data are number (%) or mean (SD).
Efficacy Results
Fox K, et al. Lancet 2008; 372: 807–16
A primary composite Endpoint
Ivabradine failed to show a significant clinical outcome vs. placebo on top of standard of care
Fox K, et al. Lancet 2008; 372: 807–16
A primary composite Endpoint
Ivabradine failed to show a significant clinical outcome vs. placebo on top of standard of care
Efficacy Results
Fox K, et al. Lancet 2008; 372: 807–16
Ivabradine
group
(N=5479)
Placebo
group
(N=5438)
HR (95% CI) p value
Ivabradine group
(N=2699)
Placebo
group
(N=2693)
HR (95% CI) p value
Primary composite endpoint
Cardiovascular death* or admission to hospital
for myocardial infarction or new-onset or
worsening heart failure†
844 (15·4%) 832 (15·3%)
1·00 (0·91–
1·10)
0·94 463 (17·2) 498 (18·5)
0·91 (0·81–
1·04)
0·17
Mortality endpoints
All-cause death 572 (10·4%) 547 (10·1%)
1·04 (0·92–
1·16)
0·55 331 (12·3) 324 (12·0)
1·02 (0·87–
1·19)
0·82
Cardiovascular death* 469 (8·6%) 435 (8·0%)
1·07 (0·94–
1·22)
0·32 269 (10·0) 263 (9·8)
1·02 (0·86–
1·21)
0·82
Cardiac death‡ 136 (2·5%) 151 (2·8%)
0·89 (0·71–
1·12)
0·33 82 (3·0) 97 (3·6)
0·84 (0·62–
1·12)
0·24
Heart failure endpoints
Admission to hospital for heart failure† 426 (7·8%) 427 (7·9%)
0·99 (0·86–
1·13)
0·85 268 (9·9) 271 (10·1)
0·97 (0·82–
1·15)
0·76
Cardiovascular death* or admission to hospital for
new-onset or worsening heart failure†
757 (13·8%) 723 (13·3%)
1·04 (0·94–
1·15)
0·48 436 (16·2) 442 (16·4) 0·97 (0·85–1·11) 0·71
Coronary endpoints
Admission to hospital for myocardial infarction*†199 (3·6%) 226 (4·2%)
0·87 (0·72–
1·06)
0·16 85 (3·1) 131 (4·9)
0·64 (0·49–
0·84)
0·001
Admission to hospital for myocardial infarction† or
unstable angina
303 (5·5%) 317 (5·8%)
0·95 (0·81–
1·11)
0·50 143 (5·3) 182 (6·8)
0·78 (0·62–
0·97)
0·023
Coronary revascularisation 155 (2·8%) 186 (3·4%)
0·83 (0·67–
1·02)
0·078 76 (2·8) 108 (4·0)
0·70 (0·52–
0·93)
0·016
Data are numbers of events (%), hazard ratios (HR) and 95% CIs, and p values. *Cardiac death, vascular procedure death, presumed arrhythmic death, stroke death, other vascular death, or sudden death of unknown
cause. †Admission to hospital for myocardial infarction or heart failure includes fatal and non-fatal events. ‡Death from myocardial infarction, heart failure, or cardiac procedures.
Total study population (N=10 917)
Prespecified subgroup with heart rate of 70 bpm or greater
(N=5392)
Fox K, et al. Lancet 2008; 372: 807–16
Ivabradine
group
(N=5479)
Placebo
group
(N=5438)
HR (95% CI) p value
Ivabradine group
(N=2699)
Placebo
group
(N=2693)
HR (95% CI) p value
Primary composite endpoint
Cardiovascular death* or admission to hospital
for myocardial infarction or new-onset or
worsening heart failure†
844 (15·4%) 832 (15·3%)
1·00 (0·91–
1·10)
0·94 463 (17·2) 498 (18·5)
0·91 (0·81–
1·04)
0·17
Mortality endpoints
All-cause death 572 (10·4%) 547 (10·1%)
1·04 (0·92–
1·16)
0·55 331 (12·3) 324 (12·0)
1·02 (0·87–
1·19)
0·82
Cardiovascular death* 469 (8·6%) 435 (8·0%)
1·07 (0·94–
1·22)
0·32 269 (10·0) 263 (9·8)
1·02 (0·86–
1·21)
0·82
Cardiac death‡ 136 (2·5%) 151 (2·8%)
0·89 (0·71–
1·12)
0·33 82 (3·0) 97 (3·6)
0·84 (0·62–
1·12)
0·24
Heart failure endpoints
Admission to hospital for heart failure† 426 (7·8%) 427 (7·9%)
0·99 (0·86–
1·13)
0·85 268 (9·9) 271 (10·1)
0·97 (0·82–
1·15)
0·76
Cardiovascular death* or admission to hospital for
new-onset or worsening heart failure†
757 (13·8%) 723 (13·3%)
1·04 (0·94–
1·15)
0·48 436 (16·2) 442 (16·4) 0·97 (0·85–1·11) 0·71
Coronary endpoints
Admission to hospital for myocardial infarction*†199 (3·6%) 226 (4·2%)
0·87 (0·72–
1·06)
0·16 85 (3·1) 131 (4·9)
0·64 (0·49–
0·84)
0·001
Admission to hospital for myocardial infarction† or
unstable angina
303 (5·5%) 317 (5·8%)
0·95 (0·81–
1·11)
0·50 143 (5·3) 182 (6·8)
0·78 (0·62–
0·97)
0·023
Coronary revascularisation 155 (2·8%) 186 (3·4%)
0·83 (0·67–
1·02)
0·078 76 (2·8) 108 (4·0)
0·70 (0·52–
0·93)
0·016
Data are numbers of events (%), hazard ratios (HR) and 95% CIs, and p values. *Cardiac death, vascular procedure death, presumed arrhythmic death, stroke death, other vascular death, or sudden death of unknown
cause. †Admission to hospital for myocardial infarction or heart failure includes fatal and non-fatal events. ‡Death from myocardial infarction, heart failure, or cardiac procedures.
Total study population (N=10 917)
Prespecified subgroup with heart rate of 70 bpm or greater
(N=5392)
Results
Fox K, et al. Lancet 2008; 372: 807–16
A primary composite Endpoint in pre-specified subgroups
Fox K, et al. Lancet 2008; 372: 807–16
A primary composite Endpoint in pre-specified subgroups
Results
Fox K, et al. Lancet 2008; 372: 807–16
A primary composite Endpoint in pre-specified subgroups
Fox K, et al. Lancet 2008; 372: 807–16
A primary composite Endpoint in pre-specified subgroups
Safety Results
Borer J.S. et al. Circulation. 2003;107: 817-823.
•Ivabradine was well tolerated, with few side-effects, with
the exception of bradycardia, most of which was
asymptomatic.
•87% of the patients had study treatment in addition to
treatment with β blockers, and no safety concerns could be
identified.
Borer J.S. et al. Circulation. 2003;107: 817-823.
•Ivabradine was well tolerated, with few side-effects, with
the exception of bradycardia, most of which was
asymptomatic.
•87% of the patients had study treatment in addition to
treatment with β blockers, and no safety concerns could be
identified.
Conclusion
•These findings suggest that Ivabradine can be given safely to
patients with coronary artery disease and impaired left-
ventricular systolic function, and that it can be used in
conjunction with β blockers.
•Furthermore, a combination of ivabradine with β blockade was
not only safe, but also improved coronary artery disease
outcomes in patients with heart rates of 70 bpm or more. This
observation deserves confirmation in a prospective study.
Borer J.S. et al. Circulation. 2003;107: 817-823.
•These findings suggest that Ivabradine can be given safely to
patients with coronary artery disease and impaired left-
ventricular systolic function, and that it can be used in
conjunction with β blockers.
•Furthermore, a combination of ivabradine with β blockade was
not only safe, but also improved coronary artery disease
outcomes in patients with heart rates of 70 bpm or more. This
observation deserves confirmation in a prospective study.
Borer J.S. et al. Circulation. 2003;107: 817-823.
Discussion
•The absence of an association between ivabradine treatment
and clinical outcomes could have resulted from insufficient
reductions in heart rate or from very low heart rates at
baseline.
•A high heart rate in patients with coronary artery disease
increases cardiac work and myocardial oxygen consumption
and reduces diastolic myocardial perfusion time. This can
produce an imbalance between myocardial oxygen demand
and supply, leading to ischemia.
•High heart rate could also accelerate the progression of
coronary atherosclerosis and can cause disruption of
atherosclerotic plaque in stenosed coronary arteries.
Borer J.S. et al. Circulation. 2003;107: 817-823.
•The absence of an association between ivabradine treatment
and clinical outcomes could have resulted from insufficient
reductions in heart rate or from very low heart rates at
baseline.
•A high heart rate in patients with coronary artery disease
increases cardiac work and myocardial oxygen consumption
and reduces diastolic myocardial perfusion time. This can
produce an imbalance between myocardial oxygen demand
and supply, leading to ischemia.
•High heart rate could also accelerate the progression of
coronary atherosclerosis and can cause disruption of
atherosclerotic plaque in stenosed coronary arteries.
Borer J.S. et al. Circulation. 2003;107: 817-823.
Ivabradine
ESC 2019 recommendations for use in Angina/ ischemia relief
European Heart Journal (2020) 41, 407477
Angina/ Ischemia
c
relief
Nicorandil,
ranolazine,
ivabradine,
or trimetazidine should be considered as a second-line treatment to reduce angina frequency and improve
exercise tolerance in subjects who cannot tolerate, have contraindications to, or whose symptoms are not adequately controlled by beta-blockers,
CCBs, and long-acting nitrates.
IIa B
In selected patients, the combination of a beta-blocker or a CCB with second-line drugs (ranolazine, nicorandil, ivabradine, and
trimetazidine) may be considered for first-line treatment according to heart rate, BP, and tolerance.
IIb B
C
No demonstration of benefit on prognosis.
•In 10,917 patients with limiting previous angina enrolled in the morbidity mortality evaluation of the BEAUTIFUL (I
f
Inhibitor Ivabradine in Patients With
Coronary Artery Disease and Left Ventricular Dysfunction) trial, ivabradine did not reduce the composite primary endpoint of cardiovascular death,
hospitalization with MI, or HF.
• Also, in the SIGNIFY (Study Assessing the Morbidity Mortality Benefits of the I
f
Inhibitor Ivabradine in Patients with Coronary Artery Disease) study,
consisting of 19,102 patients with CAD without clinical HF and a heart rate ≥70 b.p.m. there was no significant difference between the ivabradine group
and the placebo group in the incidence of the primary composite endpoint of death from cardiovascular causes or non-fatal MI.
•Ivabradine was associated with an increase in the incidence of the primary endpoint among 12,049 patients with activity-limiting angina but not among
those without activity-limiting angina (P=0.02 for interaction).
•In 2014, the European Medicines Agency issued recommendations to reduce the risk of bradycardia and placed ivabradine under additional monitoring.
In aggregate, these results support the use of ivabradine as a second-line drug in patients with Chronic Coronary Syndrome.
ESC 2019 recommendations for use in Angina/ ischemia relief
European Heart Journal (2020) 41, 407477
Angina/ Ischemia
c
relief
Nicorandil,
ranolazine,
ivabradine,
or trimetazidine should be considered as a second-line treatment to reduce angina frequency and improve
exercise tolerance in subjects who cannot tolerate, have contraindications to, or whose symptoms are not adequately controlled by beta-blockers,
CCBs, and long-acting nitrates.
IIa B
In selected patients, the combination of a beta-blocker or a CCB with second-line drugs (ranolazine, nicorandil, ivabradine, and
trimetazidine) may be considered for first-line treatment according to heart rate, BP, and tolerance.
IIb B
C
No demonstration of benefit on prognosis.
•In 10,917 patients with limiting previous angina enrolled in the morbidity mortality evaluation of the BEAUTIFUL (I
f
Inhibitor Ivabradine in Patients With
Coronary Artery Disease and Left Ventricular Dysfunction) trial, ivabradine did not reduce the composite primary endpoint of cardiovascular death,
hospitalization with MI, or HF.
• Also, in the SIGNIFY (Study Assessing the Morbidity Mortality Benefits of the I
f
Inhibitor Ivabradine in Patients with Coronary Artery Disease) study,
consisting of 19,102 patients with CAD without clinical HF and a heart rate ≥70 b.p.m. there was no significant difference between the ivabradine group
and the placebo group in the incidence of the primary composite endpoint of death from cardiovascular causes or non-fatal MI.
•Ivabradine was associated with an increase in the incidence of the primary endpoint among 12,049 patients with activity-limiting angina but not among
those without activity-limiting angina (P=0.02 for interaction).
•In 2014, the European Medicines Agency issued recommendations to reduce the risk of bradycardia and placed ivabradine under additional monitoring.
In aggregate, these results support the use of ivabradine as a second-line drug in patients with Chronic Coronary Syndrome.
Step-wise treatment strategy
For long term anti-ischemic drug therapy in patients with chronic coronary syndromes
European Heart Journal (2020) 41, 407477
BB= beta-blocker; bpm= beats per minute; CCB= [any class of] calcium channel blocker; DHP-CCB= dihydropyridine calcium channel blocker; HF= heart failure; LAN= long-acting nitrate; LV= left ventricular; non-DHP-CCB= non-dihydropyridine calcium
channel blocker.
a
Combination of a BB with a DHP-CCB should be considered as first step; combination of a BB or a CCB with a second-line drug may be considered as a first step
b
The combination of a BB and non-DHP-CCB should initially use low doses of each drug under close monitoring of tolerance, particularly heart rate and blood pressure
c
Low-dose BB or low-dose non-DHP-CCB should be used under close monitoring of tolerance, particularly heart rate and blood pressure
d
Ivabradine should not be combined with non-DHP-CCB
e
Consider adding the drug chosen at step 2 to the drug tested at step 1 if blood pressure remains unchanged.
For long term anti-ischemic drug therapy in patients with chronic coronary syndromes
European Heart Journal (2020) 41, 407477
BB= beta-blocker; bpm= beats per minute; CCB= [any class of] calcium channel blocker; DHP-CCB= dihydropyridine calcium channel blocker; HF= heart failure; LAN= long-acting nitrate; LV= left ventricular; non-DHP-CCB= non-dihydropyridine calcium
channel blocker.
a
Combination of a BB with a DHP-CCB should be considered as first step; combination of a BB or a CCB with a second-line drug may be considered as a first step
b
The combination of a BB and non-DHP-CCB should initially use low doses of each drug under close monitoring of tolerance, particularly heart rate and blood pressure
c
Low-dose BB or low-dose non-DHP-CCB should be used under close monitoring of tolerance, particularly heart rate and blood pressure
d
Ivabradine should not be combined with non-DHP-CCB
e
Consider adding the drug chosen at step 2 to the drug tested at step 1 if blood pressure remains unchanged.
Ivabradine
A suggested starting dose and drug titration approach
Normal Starting Dose
oPatients with conduction
defects
oPatients in whom
bradycardia could lead to
hemodynamic compromise
Initiate at:
5 mg
twice
daily
2.5 mg
twice
daily
or
Assess in
2-4 weeks
If heart rate >60 bpm and well tolerated
Increase each dose by 2.5 mg
If heart rate 50-60 bpm
Maintain the dose
If heart rate <50 bpm or not tolerated
Decease each dose by 2.5 mgThe suggested starting dose and approach for drug titration are shown.
Drug titration is dependent on clinical response and heart rate.
Koruth, J.S. et al. J Am Coll Cardiol. 2017;70(14):1777–84.
A suggested starting dose and drug titration approach
Normal Starting Dose
oPatients with conduction
defects
oPatients in whom
bradycardia could lead to
hemodynamic compromise
Initiate at:
5 mg
twice
daily
2.5 mg
twice
daily
or
Assess in
2-4 weeks
If heart rate >60 bpm and well tolerated
Increase each dose by 2.5 mg
If heart rate 50-60 bpm
Maintain the dose
If heart rate <50 bpm or not tolerated
Decease each dose by 2.5 mgThe suggested starting dose and approach for drug titration are shown.
Drug titration is dependent on clinical response and heart rate.
Koruth, J.S. et al. J Am Coll Cardiol. 2017;70(14):1777–84.
CREDITS: This presentation template was
created by Slidesgo, including icons by
Flaticon, and infographics & images by
Freepik and illustrations by Stories
THANK you!
Does anyone have any questions?
Ahmed Kamel
[email protected]
+20 1019005220
Medical Affairs Direcror
DataClin CRO
created by Slidesgo, including icons by
Flaticon, and infographics & images by
Freepik and illustrations by Stories
THANK you!
Does anyone have any questions?
Ahmed Kamel
[email protected]
+20 1019005220
Medical Affairs Direcror
DataClin CRO
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