European Heart Journal Supplements (2010) 12 (Supplement C), C2–C10

doi:10.1093/eurheartj/suq014

Coronary artery disease in 2010

Downloaded from https://academic.oup.com/eurheartjsupp/article-abstract/12/suppl_C/C2/422543 by guest on 12 October 2019

Jean-Claude Tardif *
Department of Medicine, Montreal Heart Institute and Université de Montréal, 5000 Belanger Str, Montreal, Canada
H1T 1C8

KEYWORDS The burden of coronary artery disease (CAD) remains high across Europe and the rest
Coronary disease; of the world. CAD continues to be the main cause of death and a major cause of mor-
Atherosclerosis; bidity and loss of quality of life. The decline in age-standardized mortality rates and in
Angina; incidence of CAD in many countries illustrates the potential for prevention of prema-
Socioeconomic costs;
ture deaths and for prolonging life expectancy. New therapeutic options for preven-
Heart rate
tion and treatment of CAD have resulted in an increasing number of patients who
survive a cardiovascular event; in developed countries the burden has shifted from
the middle-aged to the elderly and the prevalence of CAD increases exponentially
with aging. CAD is a leading public health problem accounting for a significant pro-
portion of total societal costs and representing 27% of total cardiovascular disease
costs. Together with cerebrovascular diseases, CAD accounts for 64% of all cardiovas-
cular deaths. There are a number of lifestyle changes that can be implemented to
improve the prognosis of patients with stable CAD, including smoking cessation, adop-
tion of a Mediterranean diet, body weight reduction, and increased physical activity.
Concomitant risk factors such as diabetes, dyslipidaemia, and hypertension should be
managed aggressively. Current treatment options for stable CAD involve a two-
pronged approach combining antianginal treatment to improve symptoms and
quality of life along with a cardioprotective treatment to prevent cardiovascular
events. Optimal medical treatment should be the initial management approach in
the majority of patients with stable CAD, even if extensive and multi-vessel athero-
sclerosis is involved. A large body of evidence suggests that high resting heart rate
(HR) is a potential risk factor for mortality and morbidity in various populations, includ-
ing patients with CAD. Experimental evidence indicates that high HR plays a role in
endothelial dysfunction and atherosclerosis progression. An HR ≥70 b.p.m. is associ-
ated with an increased cardiovascular risk. Ongoing randomized trials are evaluating
the role of selective HR reduction in improving cardiovascular outcomes. These trial
data will be complemented by CLARIFY, a large-scale international registry of outpati-
ents with stable CAD which will analyse not only the baseline characteristics and man-
agement practices but will also capture all suspected important determinants of
outcomes including resting HR.

Epidemiology of coronary artery disease Registry is a contemporary community registry used to

The incidence of coronary artery disease (CAD) is appar-
ent from community surveys. The Bromley Coronary
* Corresponding author. Tel:+1 514 376 3330 ext. 3612, Fax: +1 514
593 2500, Email: jean-claude.tardif@icm-mhi.org
identify all symptomatic medical presentations of CAD
in one population.1 All incident (first) presentations of
exertional angina, acute coronary syndromes, and
sudden cardiac death were recorded for the Bromley
Health Authority in South East London (population
186 053, in men and women aged 25–74 years) for the

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010.
For permissions please email: journals.permissions@oxfordjournals.org.
Coronary artery disease in 2010
period from 1996 to 1998. In the ARIC study in partici-
pants aged from 45 to 64 years, the average age-adjusted
CAD incidence rates per 1000 person-years were 12.5 in
white men and 10.6 in black men.2 According to AHA
Heart Disease and Stroke statistics, it is estimated that
770 000 Americans had a new coronary attack in 2008,
and 430 000 had a recurrent attack. It is estimated that
190 000 additional silent first acute myocardial infarc-
tions (MIs) occur each year. Approximately every 26 s,
an American will have a coronary event, and about
every minute someone will die of one.3
There are marked variations in the epidemic of CAD
among regions of the world, nations, and even between
regions within a country.4 The age-standardized death
rates from CAD are declining in many developed
countries, but are increasing in developing and transi-
tional countries, partly as a result of demographic
changes, urbanization, and lifestyle changes. Nowadays
3.8 million men and 3.4 million women worldwide die
each year from CAD.5 According to the Global Burden of
Disease Study,6 the developing countries contributed
3.5 million of the total number of 6.2 million deaths
from CAD in 1990. The projections estimate that these
countries will account for 7.8 million of the 11.1 million
deaths due to CAD in 2020. According to global and
regional projections of mortality and burden of disease,
CAD will remain the leading cause of death for the next
20 years.7 In the USA and in most countries in the Euro-
pean Union, the age-standardized CAD mortality rates
have decreased significantly. This may lead paradoxically
to an increase in the prevalence of CAD; indeed a better
survival of CAD patients and demographic changes result
in more elderly people suffering from CAD. Today CAD is
the most important major killer of both American men
and women, causing approximately one of every five
deaths in the USA in 2005.8 Approximately 37% of the
people who have a coronary event in a given year will
die of it. In 2005 the overall CAD death rate was 144.4
per 100 000 population. The death rates were 187.7 for
white males and 213.9 for black males; for white
females the rate was 110.0 and for black females
140.99. In the European Union, CAD is also the single
most common cause of death. One in five to one in
seven women die of CAD; in men CAD accounts for one
in four to one in six of all deaths. Age-standardized and
gender-specific CAD mortality rates have significantly
decreased during recent decades in many countries in
the north, west and south of Europe. However, the
decline was less apparent or absent in central and
eastern Europe. Thus, the Russian Federation, Belarus,
Ukraine, and Central Asian republics show the highest
CAD mortality rates ever seen, significantly higher even
than recognized peaks in the USA, Australia, New
Zealand, Finland, and Scotland.9,10 Furthermore, popu-
lation aging represents a major challenge. Thus, even if
age-specific mortality rates continue to decline, the
absolute number of cardiovascular disease (CVD) deaths
will increase. Predictions up to 2030 suggest that even
with an annual decline in mortality rates of about 1%,
the absolute number of deaths will increase, attributable
solely to population aging.7
C3
It has been estimated that 30–43% of patients who
were asymptomatic after an MI had silent myocardial
ischaemia in the initial 30-day period after the infarct,
based on stress test data or Holter monitoring.11,12 A
recently published analysis in 937 outpatients with
stable CAD from the Heart and Soul Study demonstrated
that 14% of outpatients had angina alone, 20% had indu-
cible ischaemia alone, and 4% had both angina and
ischaemia. Recurrent CAD events occurred in 7% of par-
ticipants without angina or inducible ischaemia, 10% of
those with angina alone, 21% of those with inducible
Downloaded from https://academic.oup.com/eurheartjsupp/article-abstract/12/suppl_C/C2/422543 by guest on 12 October 2019
ischaemia alone, and 23% of those with both angina and
inducible ischaemia.13
Coronary atherosclerosis most commonly presents in the
community as angina pectoris, followed by acute coronary
syndromes (MI and unstable angina), and finally as sudden
cardiac death. When the acute manifestations of CAD—
sudden cardiac death and MI—are considered together,
one in two patients with new or recurrent disease die
within 30 days of their acute clinical presentation.14–17
About 69% die in the community, 29% die in hospital, and
the other 2% die within 30 days of discharge. The prognosis
of patients with chronic CAD is not uniform. It depends
on several factors, including the underlying coronary
anatomy, left ventricular (LV) function, and comorbidities.
The data concerning prognosis in clinical trials are of
limited value due to the highly selective nature of popu-
lations included in such studies. Large population-based
studies could help to increase our understanding of the
differences in prognosis between CAD manifestations.
The recently published data on cardiovascular event rates
from the REACH (Reduction of Atherothrombosis for Contin-
ued Health) registry in stable CAD outpatients (n ¼ 38 602
patients) has confirmed that patients with established
stable CAD had the highest non-fatal MI rate and the
highest non-fatal stroke rate. The registry reported
annual event rates of 15.2% for death, stroke, MI, or hospi-
talization for an atherothrombotic event, 6.4% for unstable
angina, 4.5% for death, acute MI, and stroke, and 3.8% for
revascularization by percutaneous coronary intervention
(PCI).18 Thus, 3 of 20 patients with established CAD had
a major event or had been hospitalized within a year of
follow-up. The high event rates observed in the subgroup
of patients with established CAD in this large contemporary
cohort indicate that continued efforts are needed to
improve secondary prevention and clinical outcomes.
Financial burden
The appropriate management of CAD entails costs for non-
invasive diagnostic and follow-up tests, as well as for
medical and interventional therapy. All these factors
lead to significant direct and indirect costs. The treatment
of stable CAD aims to prevent serious cardiovascular events
such as MI or death and to improve quality of life by redu-
cing the symptoms caused by myocardial ischaemia. The
economic costs of CAD include health care expenditure
and non-health service costs. Health care expenditures
comprise primary care activities, accident and emergency
care, hospital inpatient care, outpatient care, and
C4
medications. Non-health service costs comprise informal
care costs, and productivity costs attributable to mortality
and morbidity. Informal care costs are equivalent to the
opportunity cost of unpaid care, i.e. the time (work and/
or leisure) that carers forego, valued in monetary terms,
to provide unpaid care for relatives suffering from CAD.
Productivity costs include the foregone earnings related
to CAD-attributable mortality and morbidity. A recent
study estimated economic costs of CVD in the enlarged
European Union and the proportion of these costs attribu-
table to CAD.19 CAD cost the health care systems of the
European Union just under 23 billion euros in 2003. The
major component of health expenditure was inpatient
care, which accounted for 62% (14 billion euros) of costs,
followed by pharmaceutical expenditure which rep-
resented 23% (5.4 billion euros) of total health care
costs. Primary, outpatient, and emergency care accounted
for 16% of health care costs. Over 678 000 people pro-
vided care to CAD patients, representing 702 million
hours of care, which was estimated to cost the European
Union 6.8 billion euros. Approximately one million
working years were lost because of CAD mortality, account-
ing for 44% of all working years lost because of cardiovascu-
lar deaths, with a cost of 11.7 billion euros. Additionally,
90 million working days were lost because of CAD morbid-
ity, representing a cost of 3.5 billion euros after adjusting
costs using the friction period. Overall, CAD is estimated to
have cost European Union 45 billion euros in 2003—one-
quarter of the overall cost of CVD. Over half of these
costs (51%) were incurred in health care, 34% in pro-
ductivity losses, and 15% in informal care.
Management of traditional risk factors
Risk factor control in patients with established CAD
remains poor, especially for obesity, smoking, and blood
pressure, in spite of guidelines. The 2007 European
Guidelines on CVD prevention in clinical practice have
adopted a more aggressive approach for the treatment
of cardiovascular risk factors.20 Smoking cessation and
avoidance of exposure to environmental tobacco smoke
at work and home is recommended. Follow-up, referral
to special programs, and/or pharmacotherapy (including
nicotine replacement) are recommended, as is a stepwise
strategy for smoking cessation. Patients should initiate
and/or maintain lifestyle modifications—weight control,
increased physical activity, moderation of alcohol con-
sumption, limited sodium intake, and maintenance of a
diet high in fresh fruits, vegetables, and low-fat dairy
products. Combination antihypertensive treatment is fre-
quently needed to control blood pressure. Drugs that
have a long-lasting effect and a documented ability
to lower blood pressure effectively over 24 h with
once-a-day administration are preferred. Long-acting
drugs also minimize blood pressure variability and this
may offer protection against progression of target-organ
damage and risk of cardiovascular events. According to
Joint National Conference VII guidelines, blood pressure
,140/90 mmHg, or ,130/80 mmHg for patients with
diabetes or chronic kidney disease, is recommended.21
J.-C. Tardif
Dietary therapy for all patients should include reduced
intake of saturated fats (to ,7% of total calories),
trans fatty acids, and cholesterol. Daily physical activity
and weight management are recommended for all
patients. Statin therapy should always be considered
for patients with established CAD, based on their benefits
in the reduction of the risk of atherosclerotic compli-
cations. Current European guidelines on CVD prevention
suggest a target value of ,4.5 mmol/L (175 mg/dL) for
total cholesterol with an option of 4.0 mmol/L (155 mg/
dL) if feasible, and 2.5 mmol/L (10 mg/dL) for LDL
Downloaded from https://academic.oup.com/eurheartjsupp/article-abstract/12/suppl_C/C2/422543 by guest on 12 October 2019
cholesterol an option of 2.0 mmol/L (80 mg/dL) if feas-
ible in patients with established CVD.20
Physical activity should be encouraged, as it increases
exercise tolerance, reduces symptoms of angina, and
has a favourable effect on weight, blood lipids, blood
pressure, glucose tolerance, and insulin sensitivity. The
recent ACC/AHA update of the Guidelines for the Man-
agement of Patients With Chronic Stable Angina rec-
ommends physical activity of 30–60 min, 7 days per
week (minimum 5 days per week).22 All patients should
be encouraged to do 30–60 min of moderate-intensity
aerobic activity, such as brisk walking, on most and pre-
ferably all days of the week, supplemented by an
increase in daily activities (walking breaks at work, gar-
dening, or household work). Patients should be advised
to adopt a ‘Mediterranean’ diet, with vegetables, fruit,
fish, and poultry. Body mass index and waist circumfer-
ence should be assessed regularly. On each patient
visit, it is useful to consistently encourage weight main-
tenance/reduction through an appropriate balance of
physical activity, caloric intake, and formal behavioural
programmes when indicated to achieve and maintain a
body mass index between 18.5 and 24.9 kg/m2. Diabetes
management should include lifestyle and pharmacother-
apy measures to achieve a near-normal HbA1c. In type 1
diabetes, glycemic control requires appropriate insulin
therapy and concomitant professional dietary therapy.
In type 2 diabetes, professional dietary advice, weight
reduction, and increased physical activity should be the
first treatment, followed by pharmacological treatment
(oral hypoglycemic treatment and insulin when needed)
aiming at good glucose control. Current European
guidelines on CVD prevention suggest a target HbA1c
value of ,6.5% if feasible, ,6.0 mmol/L (110 mg/dL)
for fasting/preprandial plasma glucose and ,7.5 mmol/L
(135 mg/dL) for postprandial plasma glucose if feasible.20
In addition, psychological risk factors should also be
addressed, such as excessive anxiety or depression.
Heart rate as an emerging cardiovascular
risk factor
Heart rate (HR), a simple and easily measurable clinical
parameter, has been found to be a risk predictor of mor-
tality and morbidity in various populations. Heart rate
has already appeared in European guidelines on CVD pre-
vention.20 This consideration is based on a large body of
evidence from epidemiological studies reporting an
association between elevated HR and increased risk of
Coronary artery disease in 2010
all-cause mortality and cardiovascular mortality and mor-
bidity in the general population, hypertensives, dia-
betics, and those with CAD.23 The relationship between
HR and cardiovascular mortality has been shown in 14
epidemiological studies over the last 25 years carried
out in the general population and in subjects with hyper-
tension, including a total of more than 155 000 patients
followed up for between 8 and 36 years.24 The Framing-
ham study, which included 5070 subjects followed up
for 30 years, evidenced a progressive and significant
increase in all-cause mortality in relation to HR in both
men and women.25 Several studies of healthy men and
women found that elevated resting HR was an indepen-
dent risk predictor of sudden death. A recently published
study of 5139 healthy French men found that resting HR
and its change over 5 years were both predictors of
death, independent of standard risk factors.26 After
adjustments were made for confounding factors, includ-
ing baseline HR at rest, and compared with subjects
with unchanged HR, those with HR that decreased
during the 5 years had a 14% decreased mortality risk
(P ¼ 0.05), whereas men whose HR increased over the
5 years had a 19% increased mortality risk (P ¼ 0.012).
In patients with acute MI, Hjalmarson et al.27 demon-
strated that in-hospital mortality and post-discharge
mortality increased with increasing HR on admission.
Total mortality was 15% for patients with an admission
HR ranging between 50 and 60 b.p.m., 41% for HR .
90 b.p.m. and 48% for HR . 110 b.p.m. Mortality from
hospital discharge to 1 year was also related to the
maximal HR observed in the coronary care unit and to
the HR at discharge. The prognostic significance of HR
was also assessed in the GISSI-2 study in 8915 patients
with acute MI and treated with fibrinolytic therapy.28
Increased HR on admission was associated with a
progressive increase in in-hospital mortality (from 7.1%
for HR , 60 b.p.m. to 23.4% for HR . 100 b.p.m.).
A progressive increase of 6-month mortality was noted
with increasing HR at discharge (from 0.8% for HR ≤
60 b.p.m. to 14.3% for HR . 100 b.p.m.). Tardif and col-
leagues29 found that resting HR was an independent risk
predictor of total and cardiovascular mortality in 24 913
men and women with suspected or proved CAD followed
for an average of 14 years. The prognostic value of HR
held true when controlling for hypertension, diabetes,
and smoking, as well as powerful markers such as the LV
ejection fraction and the number of diseased coronary
vessels. Patients with an HR ≥ 83 b.p.m. also had a signifi-
cantly higher risk of hospital admissions for cardiovascular
causes than those with an HR , 62 b.p.m. In a post hoc
analysis from the INVEST (INternational VErapamil-SR/
Trandolapril) study, the relationships between resting HR
at baseline and at follow-up and adverse outcomes (all-
cause death, non-fatal MI, and non-fatal stroke) were
evaluated in 22 192 patients with hypertension and CAD
treated either with verapamil or with atenolol. Resting
HR was found in this study to predict adverse events,
and on-treatment HR was even more predictive than
baseline resting HR.30
The BEAUTIFUL (MorBidity-mortality EvAlUaTion of the
If inhibitor Ivabradine in patients with coronary disease
C5
and left ventricULar dysfunction) investigators have
also added to current knowledge concerning the prognos-
tic value of elevated HR by conducting a prospective
analysis of the data from the placebo arm of the study
to assess the association of HR with different clinical
outcomes.31 The results of this analysis in the placebo
arm (n ¼ 5438) showed that an elevated resting HR
(≥70 b.p.m.) is a strong predictor of outcome in patients
with stable CAD and LV dysfunction. This was the case for
all of the outcomes assessed in the study. Patients with an
HR of 70 b.p.m. or more were 34% more likely to die of
Downloaded from https://academic.oup.com/eurheartjsupp/article-abstract/12/suppl_C/C2/422543 by guest on 12 October 2019
cardiovascular causes (P ¼ 0.0041) and 53% more likely
to be hospitalized for new or worsening heart failure
(P,0.0001) than those with values ,70 b.p.m. Similarly,
an elevated HR (≥70 b.p.m.) was associated with a 46%
increase in the risk of fatal and non-fatal MI (P ¼
0.0066) and a 38% increase in the need for coronary
revascularization (P ¼ 0.037). These data were adjusted
for all the variables that differed between the two
groups at baseline, including beta-blocker intake and
other background therapy.
Role of heart rate in the development of
atherosclerosis and coronary events
The most common coronary manifestations of athero-
sclerosis are stable angina pectoris and acute coronary syn-
dromes. The role of HR in myocardial ischaemia in patients
with stable angina and those who suffer an MI is well known.
An increased HR contributes to an imbalance between myo-
cardial oxygen demand and supply, by causing both an
increase in myocardial oxygen demand and a decrease in
coronary blood supply (the latter via a shorter duration of
diastole, the period during which most of the myocardial
perfusion occurs). Thus, the likelihood of myocardial
ischaemia is related to baseline resting HR, and is two
times higher in patients with baseline HR of 89 b.p.m. or
more compared with those with HR of 60 b.p.m.32 Exper-
imental evidence also supports the role of HR in endothelial
dysfunction and progression of atherosclerosis. A higher HR
is associated with a shortened diastole and more time spent
in systole during which coronary shear stress is lower.33
Reduced shear stress is associated with enhanced endo-
thelial expression of pro-inflammatory molecules and pre-
disposition to atherosclerosis. An increased HR may also
be involved at the later stages of atherosclerosis and has
been associated with greater risk of plaque rupture.34 Con-
sistent with this understanding of the importance of HR in
the pathophysiology of CAD, HR reduction is considered as
a potential therapeutic goal in coronary patients; the short-
term implication is prevention of ischaemia, and the long-
term implication is potential prevention of cardiovascular
events.
Heart rate reduction and decreased
cardiovascular risk
Several studies have shown that beta-blockers are able to
reduce total mortality and sudden cardiac death after MI.
C6
These beneficial effects have been ascribed at least in
part to the reduction of HR.35 Furthermore, a recent
meta-regression of randomized clinical trials of beta-
blockers and calcium channel blockers in post-MI patients
strongly suggests that resting HR reduction could be a
major determinant of the clinical benefits seen in these
trials.36 Recently, the BEAUTIFUL investigators have con-
tributed to the understanding of the importance of HR
reduction for prevention of coronary events. Treatment
with ivabradine, a pure HR-reducing agent, provides an
opportunity to assess the effects of selectively lowering
HR without altering other aspects of cardiac function.37
The prospective analysis of data from the placebo arm
of BEAUTIFUL demonstrated that elevated resting HR
(≥70 b.p.m.) is a strong independent predictor of clinical
outcomes. Consistent with these data, ivabradine signifi-
cantly improved coronary outcomes in these patients
with an HR ≥70 b.p.m. Compared with placebo, there
was a 36% reduction in relative risk of hospitalization
for fatal and non-fatal MI in these patients with HR ≥
70 b.p.m. treated with ivabradine (P ¼ 0.001) and a
30% relative risk reduction in coronary revascularization
(P ¼ 0.016). Treatment with ivabradine was also associ-
ated with a 22% reduction in the relative risk of the com-
posite endpoint of hospitalization for fatal and non-fatal
MI and unstable angina pectoris (P ¼ 0.023) as compared
with placebo.
Pharmacologic therapy
Antiplatelet agents
Aspirin irreversibly inhibits platelet cyclooxygenase
and, as a consequence, reduces the synthesis of throm-
boxane. At low doses (75–150 mg/day), chronic therapy
with aspirin remains the best pharmacological option for
the prevention of arterial thrombosis.38 Outside this
dose range, the advantage conferred by treatment
with aspirin may be lower.39 Low-dose aspirin is there-
fore to be recommended in all patients, provided they
do not present specific contraindications.38 The antipla-
telet agents clopidogrel and ticlopidine are more
expensive than aspirin, but have a similar overall
safety profile and may be good options in cases of
aspirin intolerance (e.g. patients with bronchospasm).
They have antithrombotic effects comparable to
those of aspirin.40 The CAPRIE trial demonstrated the
benefits of long-term treatment with clopidogrel by
reducing the combined risk of ischaemic stroke, MI, or
vascular death.41 High-risk patients may benefit from
combination of aspirin with an anticoagulant agent
such as warfarin. However, unless there is a specific
separate indication, anticoagulants should be avoided
in stable CAD.
Lipid-lowering drugs
There is a strong association between increased low-
density lipoprotein (LDL) cholesterol levels and the
risk of CVD.42 Cholesterol lowering reduces the risk
J.-C. Tardif
of atherosclerosis progression43 and the currently
recommended treatment goals are lower for patients
with established CAD and those considered to be at
high risk. The Heart Protection Study clearly demon-
strated that lipid-lowering treatment was beneficial in
patients with a history of CAD, and such therapy should
be an integral part of the management of all CAD
patients.44 Statins have been reported to decrease cardi-
ovascular complications by up to 30%, even in the elderly
(.70 years) and patients with diabetes.44,45 It is known
that the deleterious effects of serum cholesterol begin
Downloaded from https://academic.oup.com/eurheartjsupp/article-abstract/12/suppl_C/C2/422543 by guest on 12 October 2019
at low-normal levels,46 and pre-treatment cholesterol
level does not determine the benefits of long-term
statin therapy; treatment is therefore useful in patients
with normal cholesterol levels but high cardiovascular
risk.47 This explains why it is currently recommended to
treat patients at high cardiovascular risk with a statin,
even if they have normal or near-normal LDL cholesterol
levels.
Angiotensin-converting enzyme inhibitors
Angiotensin-converting enzyme (ACE) inhibitors are
widely used in the treatment of hypertension and heart
failure. Trials in patients with heart failure and post-MI
reported reduced cardiac mortality and MI with ACE inhi-
bition,48–50 which ultimately led to the investigation of
the role of these agents in secondary prevention for
CAD patients without heart failure. In the EUropean
trial of Reduction Of cardiac events with Perindopril in
stable coronary Artery disease (EUROPA), there was a
20% relative risk reduction in the composite primary end-
point of cardiovascular death, MI, or resuscitated cardiac
arrest in the perindopril treatment group.48 Results in
favour of ACE inhibition also came from the Heart Out-
comes Prevention Evaluation (HOPE) study with ramipril,
in which there was a 22% reduction in the composite
primary endpoint of cardiovascular death, MI, and
stroke.49 The conclusion drawn from these studies is
that ACE inhibition with perindopril or ramipril could
have additional cardiovascular effects via mechanisms
other than reduction of blood pressure.51–53 Secondary
prevention with ACE inhibition is therefore recommended
for patients with proved CAD, if they have had a previous
MI, or have diabetes, concomitant hypertension, heart
failure, or asymptomatic LV dysfunction.38
Beta-blockers
Beta-blockers can reduce the risk of cardiovascular death
or MI by about 30% in post-MI populations.54 Beta-
blockers are currently recommended in such patients,
and in patients with heart failure. Beta-blockers reduce
HR at rest and during exercise, and are the standard
choice for the symptomatic treatment of stable angina
and ischaemia, provided the agent is initiated carefully
and titrated progressively to full dose to achieve resting
HR less than 60 b.p.m.55 Uptitration of beta-blockers
might be limited by side effects, such as fatigue,
depression, lethargy, insomnia, nightmares, and worsen-
ing claudication.
Coronary artery disease in 2010
If current inhibitor ivabradine
If current inhibitor ivabradine selectively inhibits the If
cardiac pacemaker current, thus exerting selective HR
reduction while preserving LV contractility and relax-
ation.56 It provides powerful anti-ischaemic and antiangi-
nal efficacy in patients with stable angina.57–60 The
recent ASSOCIATE study clearly demonstrated that treat-
ment with ivabradine in patients with stable angina
receiving the beta-blocker atenolol resulted in a signifi-
cant reduction in HR and improvement in all parameters
of exercise capacity.61 The results of the BEAUTIFUL
study suggest that ivabradine has the ability to affect
not only symptoms of myocardial ischaemia, but also
potentially to improve coronary outcomes in patients
with elevated HR (≥70 b.p.m.), which makes it an inter-
esting agent for the management of patients with CAD.37
Calcium channel blockers
Calcium channel blockers (CCBs), through selective inhi-
bition of the L-type calcium channels, lead to dilation of
the coronary and other arteries, which decreases cardiac
work and counteracts vasospasm. The non-dihydropyridine
CCBs (e.g. verapamil and diltiazem) reduce HR, myocar-
dial contractility, and atrioventricular nodal conduction.
Calcium channel blockers reduce the frequency and sever-
ity of anginal attacks, but there is no evidence supporting
their use to improve prognosis in stable CAD patients.
ACTION (A Coronary disease Trial Investigating Outcome
with Nifedipine gastrointestinal therapeutic system)
found no benefit of nifedipine over placebo in stable
angina in terms of composite endpoints, including death,
MI, refractory angina, and heart failure.62
Nicorandil
Nicorandil is a potassium channel opener with a nitrate-
like effect. The IONA (Impact Of Nicorandil in Angina)
study showed fewer major coronary events in patients
treated with nicorandil vs. placebo, but significance
was driven mainly by a reduction in ‘hospital admission
for cardiac chest pain’. The risk of death and non-fatal
MI was unaffected.63
Myocardial revascularization
Revascularization includes either PCI, usually with stent
implantation, or coronary artery bypass graft (CABG)
surgery. The results of the Clinical Outcomes Utilizing
Revascularization and Aggressive Drug Evaluation
(COURAGE) trial, published in 2007, showed no benefit in
terms of all-cause mortality, MI, or other major cardiovas-
cular events of adding PCI in stable CAD patients receiving
optimized medical therapy.64 Moreover, the marginal
quality of life benefit obtained by revascularization in
that trial had completely disappeared after 3 years.65 A
remarkable finding from COURAGE is that the majority of
patients had substantial improvements in health status
(with contemporary treatment) that were sustained for
C7
several years. At the same time, the rapid improvement
with optimal medical therapy alone suggests that antian-
ginal medications are underused in practice. The
COURAGE trial redefines the contemporary roles of
optimal medical therapy and PCI in the management of
patients with stable CAD. It suggests the complementary
role of optimal medical therapy as first-line therapy,
with PCI reserved for patients who do not respond or
who have severe symptoms. In some circumstances, for
example in patients with severe lesions in coronary
arteries that supply a large area of the myocardium, revas-
Downloaded from https://academic.oup.com/eurheartjsupp/article-abstract/12/suppl_C/C2/422543 by guest on 12 October 2019
cularization can improve prognosis by increasing the
effectiveness of the existing perfusion or providing
alternative routes of perfusion. Whatever the decision—
to revascularize or not—the patient should be advised
that secondary preventative pharmacological therapy
will continue to be necessary, even after the intervention.
The risks and benefits of surgery or PCI should also be care-
fully discussed with the patient.
The CLARIFY registry: rationale and objectives
Coronary artery disease is and will remain for the fore-
seeable future the first cause of death worldwide. With
improvements in treatment, an increasing number of
patients survive acute coronary syndromes and will live
as outpatients with or without anginal symptoms.
Need for worldwide contemporary data on
outpatients with stable coronary artery disease
Data available today on disease presentation and man-
agement of patients with stable CAD come mainly from
clinical trials or registries. Clinical trials often have strin-
gent inclusion and exclusion criteria, and thus do not
adequately represent populations with stable CAD, par-
ticularly in terms of age, comorbidity, and concomitant
therapy, and often do not reflect daily practice. This is
emphasized by the under-representation of women and
ethnic minorities in trial populations, and by the ten-
dency for trial patients to be free from important comor-
bidities. Furthermore, patients followed up in the large
centres typically participating in clinical trials may not
resemble those in the outpatient community. However,
some registries have attempted to capture the patient
population with stable CAD, but often focus on a single
country or geographic region, or on acute manifestations
of the disease,66 or only on patients with anginal symp-
toms.67 In addition, some studies are cross-sectional
and therefore do not establish links between baseline
characteristics, management, and subsequent outcomes.
Therefore, the generalizability of findings from random-
ized clinical trials and most registries is often limited.
Finally, due to the important changes in management
and outcome of CAD patients, there is a need for contem-
porary data. It is therefore important to have longitudi-
nal observations of a representative large cohort of
patients with stable CAD, spanning several geographic
regions, focusing on stable outpatients (as opposed to
patients hospitalized or recently discharged from hospital
C8
for acute manifestations of the disease), and including
both symptomatic and asymptomatic patients.
Need to evaluate determinants of long-term
prognosis, including heart rate, in patients with
stable coronary artery disease
It is also important that such a database captures all sus-
pected important determinants of outcomes in order to
analyze not only the baseline characteristics and manage-
ment practices, but also outcomes and prognostic determi-
nants including resting HR. In spite of extensive evidence
for the importance of HR in the prognosis of stable CAD,
HR is not yet a routine component of cardiovascular risk
assessment. We also lack data on HRs actually achieved
in practice. Therefore, using a dataset in which resting
HR is carefully and reliably measured will be critical
when trying to assess the role of HR in prognosis in stable
CAD patient populations. Therefore, large outpatient-
based registries are needed to increase understanding of
the characteristics, management, outcomes, and determi-
nants of prognosis, including HR, of contemporary outpati-
ents with stable CAD. The CLARIFY registry has been set up
to improve knowledge about the contemporary stable CAD
population.68 CLARIFY is an international, prospective,
observational, longitudinal registry in stable CAD outpati-
ents with 5-year follow-up. The study will be approved by
local institutional review boards and all patients will give
informed consent in accordance with national and local
guidelines. The registry will provide important data on
the demographic and clinical profile of the stable CAD out-
patient population, current treatment in daily practice,
adherence to guidelines, evidence-based practice, chan-
ging patterns of stable CAD management during registry
follow-up, variations in management of CAD patients
according to geography, type of physician, and patient
characteristics, and the determinants of long-term prog-
nosis, including the role of resting HR. The population of
CLARIFY is intended to reflect the entire spectrum of out-
patients with CAD. This information will help to improve
the management of patients with CAD.
The main objectives of CLARIFY are (i) to characterize
contemporary CAD patients in terms of demographic
characteristics, clinical profiles, management and out-
comes and to identify gaps between treatment and evi-
dence, and (ii) to determine the long-term prognostic
determinants in this population, including resting HR,
with a view to developing a risk prediction model.
CLARIFY study design
CLARIFY is an international, prospective, observational,
longitudinal registry in stable CAD outpatients, with
5-year follow-up. This observational registry is designed
to collect data on the current status of outpatients
with stable CAD, including their demographic character-
istics, clinical profiles, therapeutic strategies, and out-
comes. This is not an interventional study to assess the
impact of a predefined therapy. In this longitudinal
study, a minimum of 30 000 subjects will be followed up
J.-C. Tardif
for 5 years and data will be collected prospectively at
annual visits at 12, 24, 36, 48, and 60 months. Because
of substantial geographic variations in the epidemiology
of stable CAD, this registry will be international to gener-
ate data on various countries and regions of the world.
This strategy will enhance the value of the results and
yield data on international variability in disease presen-
tation and management.
Selection of subjects in the CLARIFY registry
Downloaded from https://academic.oup.com/eurheartjsupp/article-abstract/12/suppl_C/C2/422543 by guest on 12 October 2019
The registry will attempt to collect representative data
for each of the participating countries. Representative-
ness will be ensured by a two-tiered process: (i) determi-
nation of physician type in charge of CAD patients in a
given country and targeting of an appropriate proportion
of each of these physician specialties; (ii) enrolment
of consecutive eligible patients is planned for each
patient. Each physician will recruit 10–15 outpatients
with stable CAD as defined by the inclusion criteria.
Patients will be recruited at each practice setting over
a brief period of time, suggesting consecutive (or nearly
so) patient enrolment and ensuring representative
inclusion of the overall population in each practice
setting.
Inclusion and exclusion criteria
Outpatients with stable CAD proved by a history of at
least one of the following criteria are eligible to enter
CLARIFY: documented MI (more than 3 months ago), cor-
onary stenosis of more than 50% proved by coronary
angiography, chest pain with myocardial ischaemia
proved by stress ECG, stress echocardiography or myocar-
dial imaging, or CABG or PCI (more than 3 months ago).
Patients cannot enter the study if they were hospitalized
for CVD within the last 3 months before recruitment
(including revascularization), are scheduled for revascu-
larization, or have conditions hampering participation
in the 5-year follow-up, such as limited cooperation,
limited legal capacity, serious non-CVD or conditions
interfering with life expectancy (cancer, drug abuse,
etc.) or severe CVD (advanced heart failure, severe
valve disease, history of valve repair/replacement).
Data collection and evaluation in CLARIFY
The data are collected anonymously at baseline and annually
for 5 years to ascertain clinical events, hospitalization,
employment status, or sick leave. Evaluations at baseline
include demographic information, employment status,
medical history, risk factors, physical examination, HR,
pulse palpation, 12-lead electrocardiography (the most
recent ECG within 6 months in clinically stable patients),
laboratory values (if available), and current chronic
medical treatments. Evaluations at the annual follow-up
visit include clinical events occurring since last visit and
other cases of hospitalization, death, employment status,
medical history, physical examination, HR, pulse palpation,
Coronary artery disease in 2010
12-lead ECG, laboratory values (if available), and current
chronic medical treatments. A phone call between annual
visits will be made 6 months after each annual visit to ascer-
tain whether the patient has experienced major clinical
events or been hospitalized. This will help to limit missing
data and loss to follow-up. The main outcomes to be col-
lected in CLARIFY for 5 years of follow-up are cardiovascular
death [fatal MI, sudden death, and other cardiovascular
death (fatal stroke, heart failure, ruptured aneurysm,
pulmonary embolism, cardiac investigation/procedure/
operation)], non-cardiovascular death, and cardiovascular
morbidity [hospitalization for non-fatal MI, hospitalization
for unstable angina, hospitalization for new-onset or
worsening heart failure, coronary revascularization (PCI or
CABG), hospitalization for non-fatal stroke, and other
vascular events or procedures].
Conclusion
Cardiovascular diseases and CAD remain the leading
cause of mortality in the world. In addition to the life-
style and pharmacological approaches that are available
to prevent and treat CAD, HR is emerging as a potential
risk factor for CAD-related outcomes. Ongoing random-
ized trials are assessing the role of selective HR reduction
in improving outcomes in patients with CVDs. Results
from these trials will be complemented by CLARIFY, a
large-scale international registry of outpatients with
stable CAD that will assess baseline characteristics, man-
agement practices, and all potential outcome determi-
nants including HR.
Conflict of interest: J.-C.T. has received honoraria from Servier.
References
1. Sutcliffe SJ, Fox KF, Wood DA, Sutcliffe A, Stock K, Wright M, Akhras F,
Langford E. Incidence of coronary heart disease in a health authority
in London: review of a community register. Br Med J 2003;326:20.
2. Jones DW, Chambless LE, Folsom AR, Heiss G, Hutchinson RG,
Sharrett AR, Szklo M, Taylor H Jr. Risk factors for coronary heart
disease in African Americans: the Atherosclerotic Risk in Communities
Study, 1987–1997. Arch Intern Med 2002;162:2565–2571.
3. Heart disease and stroke statistics–2009 update: a report from the
American Heart Association Statistics Committee and Stroke Stat-
istics Subcommittee. Circulation 2009;119:e21–e181.
4. Allender S, Peto V, Scarborough P, Boxer A, Rayner M. Coronary Heart
Disease Statistics. 2007 ed. London: British Heart Foundation; 2007. UK.
5. WHO. The global burden of disease: 2004 update. www.who.int/
healthinfo/global_burden_disease/2004_report_update/en/index.
html.
6. Murray CJL, Lopez AD. The Global Burden of Disease: A Comprehen-
sive Assessment of Mortality and Disability From Disease, Injuries
and Risk Factors in 1990 and Projected to 2020. Boston, USA:
Harvard University Press; 1996.
7. Mathers CD, Loncar D. Projections of global mortality and burden of
disease from 2002 to 2030. PLoS Med 2006;3:e442.
8. Heron MP, Hoyert DL, Xu J, Scott C, Tejada-Vera B. Deaths: prelimi-
nary data for 2006. Natl Vital Stat Rep 2008;56:1–52.
9. Rea TD, Pearce RM, Raghunathan TE et al. Incidence of out-of-hospital
cardiac arrest. Am J Cardiol 2004;93:1455–1460.
10. Allender S, Peto V, Scarborough et al. Coronary Heart Disease Stat-
istics: 2007 edition. London: British Heart Foundation; 2007.
C9
11. Greenland P, Gidding SS, Tracy RP. Commentary: lifelong prevention
of atherosclerosis: the critical importance of major risk factor
exposures. Int J Epidemiol 2002;31:1129–1134.
12. Cohn PF, Fox KM. Silent myocardial ischemia. Circulation 2003;108:
1263–1277.
13. Gehi AK, Ali S, Na B, Schiller NB, Whooley MA. Inducible ischemia and
the risk of recurrent cardiovascular events in outpatients with stable
coronary heart disease. The Heart and Soul Study. Arch Intern Med
2008;168:1423–1428.
14. Norris RM, on behalf of the United Kingdom Heart Attack Study Colla-
borative Group. Fatality outside hospital from acute coronary events
in three British health districts, 1994–95. Br Med J 1998;316:
1065–1070.
Downloaded from https://academic.oup.com/eurheartjsupp/article-abstract/12/suppl_C/C2/422543 by guest on 12 October 2019
15. Norris RM. Sudden Cardiac Death and Acute Myocardial Infarction in
Three British Health Districts: The UK Heart Attack Study. London:
British Heart Foundation; 1999. p61–64.
16. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D,
Rajakangas AM, Pajak A. Myocardial infarction and coronary deaths
in the World Health Organization MONICA Project. Registration pro-
cedures, event rates, and case-fatality rates in 38 populations from
21 countries in four continents. Circulation 1994;90:583–612.
17. Volmink JA, Newton JN, Hicks NR, Sleight P, Fowler GH, Neil HA. Cor-
onary event and case fatality rates in an English population: results of
the Oxford myocardial infarction incidence study. The Oxford Myocar-
dial Infarction Incidence Study Group. Heart 1998;80:40–44.
18. Steg PG, Bhatt DL, Wilson PW et al. One-year cardiovascular event
rates in outpatients with atherothrombosis. J Am Med Assoc 2007;
297:1197–1206.
19. Leal J, Luengo-Fernández R, Gray A, Petersen S, Rayner M. Economic
burden of cardiovascular diseases in the enlarged European Union.
Eur Heart J 2006;27:1610–1619.
20. Graham I, Atar D, Borch-Johnsen K et al. European guidelines on
cardiovascular disease prevention in clinical practice: executive
summary. Eur Heart J 2007;28:2375–2414.
21. Chobanian AV, Bakris GL, Black HR et al. Seventh report of the joint
national committee on prevention, detection, evaluation, and treat-
ment of high blood pressure. Hypertension 2003;42:1206–1252.
22. Fraker TD, Fihn SD. Chronic angina focused update of the ACC/AHA
2002 guidelines for the management of patients with chronic stable
angina. A report of the American College of Cardiology/American
Heart Association Task Force on practice guidelines writing group to
develop the focused update of the 2002 guidelines for the manage-
ment of patients with chronic stable angina. J Am Coll Cardiol
2007;23:2264–2274.
23. Fox K, Borer JS, Camm AJ et al. Resting heart rate in cardiovascular
disease. J Am Coll Cardiol 2007;50:823–830.
24. Aboyans V, Criqui MH. Can we improve cardiovascular risk prediction
beyond risk equations in the physician’s office? J Clin Epidemiol 2006;
59:547–558.
25. Kannel WB, Kannel CE, Paffenbarger R et al. Heart rate and cardio-
vascular mortality in the Framingham study. Am Heart J 1987;113:
1489–1494.
26. Jouven X, Empana JP, Escolano S et al. Relation of heart rate at rest
and long-term (.20 years) death rate in initially healthy middle-aged
men. Am J Cardiol 2009;103:279–283.
27. Hjalmarson A, Gilpin EA, Kjekshus J et al. Influence of heart rate on
mortality after acute myocardial infarction. Am J Cardiol 1990;65:
547–553.
28. Zuanetti G, Mantini L, Hernandez-Bernal F, Barlera S, di Gregorio D,
Latini R, Maggioni AP. Relevance of heart rate as a prognostic
factor in patients with acute myocardial infarction: insights from
the GISSI-2 study. Eur Heart J 1998;19 (Suppl. F):F19–F26.
29. Diaz A, Bourassa MG, Guertin MC et al. Long-term prognostic value of
resting heart rate in patients with suspected or proven coronary
artery disease. Eur Heart J 2005;26:967–974.
30. Kolloch R, Legler UF, Champion A et al. Impact of resting heart rate
on outcomes in hypertensive patients with coronary artery disease:
findings from the INternational VErapamil-SR/Trandolapril STudy
(INVEST). Eur Heart J 2008;29:1327–1334.
31. Fox K, Ford I, Steg PG et al. Heart rate as a prognostic risk factor in
patients with coronary artery disease and left-ventricular systolic
dysfunction (BEAUTIFUL): a subgroup analysis of a randomised con-
trolled trial. Lancet 2008;372:817–821.
C10
32. Andrews TC, Fenton T, Toyosaki N, Glasser SP, Young PM, MacCallum G
et al. Subsets of ambulatory myocardial ischemia based on heart rate
activity. Circadian distribution and response to antiischemic medi-
cation. The Angina and Silent Ischemia Study Group (ASIS). Circula-
tion 1993;88:92–100.
33. Giannoglou GD, Chatzizisis YS, Zamboulis C et al. Elevated heart rate
and atherosclerosis: An overview of the pathogenetic mechanisms.
Int J Cardiol 2008;126:302–312.
34. Heidland UE, Strauer BE. Left ventricular muscle mass and elevated
heart rate are associated with coronary plaque disruption. Circula-
tion 2001;104:1477–1482.
35. Kjekshus J. Importance of heart rate in determining beta-blocker
efficacy in acute and long-term myocardial infarction intervention
trials. Am J Cardiol 1986;57:43F–49F.
36. Cucherat M. Quantitative relationship between resting heart rate
reduction and magnitude of clinical benefits in post-myocardial
infarction: a meta-regression of randomized clinical trials. Eur
Heart J 2007;28:3012–3019.
37. Fox K, Ford I, Steg PG et al. Ivabradine for patients with stable cor-
onary artery disease and left ventricular dysfunction (Beautiful): a
randomized, double-blind, placebo-controlled trial. Lancet 2008;
372:807–816.
38. Fox K, Garcia MA, Ardissino D et al. Guidelines on the management of
stable angina pectoris: executive summary: the Task Force on the
Management of Stable Angina Pectoris of the European Society of
Cardiology. Eur Heart J 2006;27:1341–1381.
39. Collaborative meta-analysis of randomised trials of antiplatelet
therapy for prevention of death, myocardial infarction, and stroke
in high risk patients. Br Med J 2002;324:71–86.
40. Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-active
drugs: the relationships among dose, effectiveness, and side
effects: the Seventh ACCP Conference on Antithrombotic and Throm-
bolytic Therapy. Chest 2004;126:234S–264S.
41. A randomised, blinded, trial of clopidogrel versus aspirin in patients
at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.
Lancet 1998;348:1329–1339.
42. De Backer G, Ambrosioni E, Borch-Johnsen K et al. European guide-
lines on cardiovascular disease prevention in clinical practice: third
joint task force of European and other societies on cardiovascular
disease prevention in clinical practice (constituted by representa-
tives of eight societies and by invited experts). Eur J Cardiovasc
Prev Rehabil 2003;10:S1–S10.
43. Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical
trials for the National Cholesterol Education Program Adult Treat-
ment Panel III Guidelines. J Am Coll Cardiol 2004;44:720–732.
44. No authors listed. Randomised trial of cholesterol lowering in 4444
patients with coronary heart disease: the Scandinavian Simvastatin
Survival Study (4S). Lancet 1994;344:1383–1389.
45. Shepherd J, Blauw GJ, Murphy MB et al. Pravastatin in elderly individ-
uals at risk of vascular disease (PROSPER): a randomised controlled
trial. Lancet 2002;360:1623–1630.
46. Sangareddi V, Chockalingam A, Gnanavelu G, Subramaniam T,
Jagannathan V, Elangovan S. Canadian Cardiovascular Society classi-
fication of effort angina: an angiographic correlation. Coron Artery
Dis 2004;15:111–114.
47. MRC/BHF Heart Protection Study of cholesterol lowering with simvas-
tatin in 20,536 high-risk individuals: a randomised placebo controlled
trial. Lancet 2002;360:7–22.
48. Fox KM. EUropean trial on Reduction Of cardiac events with Perindo-
pril in stable coronary Artery Disease Investigators. Efficacy of peri-
ndopril in reduction of cardiovascular events among patients with
stable coronary artery disease: randomised, double-blind, placebo-
controlled, multicentre trial (the EUROPA study). Lancet 2003;362:
782–788.
49. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of
an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovas-
cular events in high-risk patients. The Heart Outcomes Prevention
Evaluation Study Investigators. N Engl J Med 2000;342:145–153.
J.-C. Tardif
50. Braunwald E, Domanski MJ, Fowler SE et al. Angiotensin-converting-
enzyme inhibition in stable coronary artery disease. N Engl J Med
2004;351:2058–2068.
51. Faggiotto A, Paoletti R. State-of-the-Art lecture. Statins and blockers
of the renin–angiotensin system: vascular protection beyond their
primary mode of action. Hypertension 1999;34:987–996.
52. Lonn EM, Yusuf S, Jha P et al. Emerging role of angiotensin-converting
enzyme inhibitors in cardiac and vascular protection. Circulation
1994;90:2056–2069.
53. Standards of medical care for patients with diabetes mellitus. Dia-
betes Care 2003;26(Suppl. 1):S33–S50.
54. Yusuf S, Wittes J, Friedman L. Overview of results of randomized
clinical trials in heart disease. I. Treatments following myocardial
Downloaded from https://academic.oup.com/eurheartjsupp/article-abstract/12/suppl_C/C2/422543 by guest on 12 October 2019
infarction. J Am Med Assoc 1988;260:2088–2093.
55. Gibbons RJ, Abrams J, Chatterjee K et al. ACC/AHA 2002 guideline
update for the management of patients with chronic stable angina–
summary article: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines (Com-
mittee on the Management of Patients With Chronic Stable Angina).
Circulation 2003;107:149–158.
56. DiFrancesco D, Camm JA. Heart rate lowering by specific and selec-
tive I(f) current inhibition with ivabradine: a new therapeutic per-
spective in cardiovascular disease. Drugs 2004;64:1757–1765.
57. Borer JS, Fox K, Jaillon P et al. Antianginal and antiischemic effects
of ivabradine, an If inhibitor, in stable angina: a randomized, double-
blind, multicentered, placebo-controlled trial. Circulation 2003;107:
817–823.
58. Ruzyllo W, Tendera M, Ford I et al. Antianginal efficacy and safety of
ivabradine compared with amlodipine in patients with stable effort
angina pectoris: a 3 month randomised, double-blind, multicentre,
noninferiority trial. Drugs 2007;67:393–405.
59. Tardif J-C, Ford I, Tendera M et al. Efficacy of ivabradine, a new
selective If inhibitor, compared with atenolol in patients with
chronic stable angina. Eur Heart J 2005;26:2529–2536.
60. López-Bescós L, Filipova S, Martos R. Long-term safety and efficacy of
ivabradine in patients with chronic stable angina. Cardiology 2007;
108:387–396.
61. Tardif JC, Ford I, Tendera M et al. Anti-anginal and anti-ischemic effi-
cacy of the If current inhibitor ivabradine versus atenolol in stable
angina. A 4-month randomized, double-blind, multicenter trial. Eur
Heart J 2005;26:2529–2537.
62. Poole-Wilson PA, Lubsen J, Kirwan BA et al. A Coronary disease Trial
Investigating Outcome with Nifedipine gastrointestinal therapeutic
system investigators. Effect of long-acting nifedipine on mortality
and cardiovascular morbidity in patients with stable angina requiring
treatment (ACTION trial): randomised controlled trial. Lancet 2004;
364:849–857.
63. IONA Study Group. Effect of nicorandil on coronary events in patients
with stable angina: the Impact Of Nicorandil in Angina (IONA) ran-
domised trial. Lancet 2002;359:1269–1275.
64. Boden WE, O’Rourke RA, Teo KK et al. Optimal medical therapy with
or without PCI for stable coronary disease. N Engl J Med 2007;356:
1503–1516.
65. Weintraub WS, Spertus JA, Kolm P et al. Effect of PCI on quality of
life in patients with stable coronary disease. N Engl J Med 2008;
359:677–687.
66. The GRACE Investigators. Rationale and design of the GRACE (Global
Registry of Acute Coronary Events) project: a multinational registry
of patients hospitalized with acute coronary syndromes. Am Heart
J 2001;141:190–199.
67. Daly CA, Clemens F, Sendon JL, Tavazzi L, Boersma E, Danchin N,
Delahaye F, Gitt A, Julian D, Mulcahy D, Ruzyllo W, Thygesen K,
Verheugt F, Fox KM. The clinical characteristics and investigations
planned in patients with stable angina presenting to cardiologists in
Europe: from the Euro Heart Survey of Stable Angina. Euro Heart
Survey Investigators. Eur Heart J 2005;26:996–1010.
68. Steg GP. Heart rate management in coronary artery desease: the
CLARIFY registry. Eur Heart J 2009;11 (Suppl. D):D13–D18.