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doi:10.1093/eurheartj/suq014
The burden of coronary artery disease (CAD) remains high across Europe and the rest
of the world. CAD continues to be the main cause of death and a major cause of morbidity and loss of quality of life. The decline in age-standardized mortality rates and in
incidence of CAD in many countries illustrates the potential for prevention of premature deaths and for prolonging life expectancy. New therapeutic options for prevention 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 signicant proportion of total societal costs and representing 27% of total cardiovascular disease
costs. Together with cerebrovascular diseases, CAD accounts for 64% of all cardiovascular deaths. There are a number of lifestyle changes that can be implemented to
improve the prognosis of patients with stable CAD, including smoking cessation, adoption 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 twopronged 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 atherosclerosis 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, including 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 associated 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 outpatients with stable CAD which will analyse not only the baseline characteristics and management practices but will also capture all suspected important determinants of
outcomes including resting HR.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010.
For permissions please email: journals.permissions@oxfordjournals.org.
KEYWORDS
Coronary disease;
Atherosclerosis;
Angina;
Socioeconomic costs;
Heart rate
Financial burden
The appropriate management of CAD entails costs for noninvasive diagnostic and follow-up tests, as well as for
medical and interventional therapy. All these factors
lead to signicant 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 reducing 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
period from 1996 to 1998. In the ARIC study in participants 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 rst acute myocardial infarctions (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 transitional 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 European Union, the age-standardized CAD mortality rates
have decreased signicantly. 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 ve
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 ve 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-specic CAD mortality rates have signicantly
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, signicantly higher even
than recognized peaks in the USA, Australia, New
Zealand, Finland, and Scotland.9,10 Furthermore, population aging represents a major challenge. Thus, even if
age-specic 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
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J.-C. Tardif
all-cause mortality and cardiovascular mortality and morbidity in the general population, hypertensives, diabetics, 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 hypertension, including a total of more than 155 000 patients
followed up for between 8 and 36 years.24 The Framingham study, which included 5070 subjects followed up
for 30 years, evidenced a progressive and signicant
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 independent 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, including 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 0.05), whereas men whose HR increased over the
5 years had a 19% increased mortality risk (P 0.012).
In patients with acute MI, Hjalmarson et al.27 demonstrated 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 signicance of HR
was also assessed in the GISSI-2 study in 8915 patients
with acute MI and treated with brinolytic 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 colleagues29 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 signicantly 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 (allcause 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
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Pharmacologic therapy
Antiplatelet agents
Aspirin irreversibly inhibits platelet cyclooxygenase
and, as a consequence, reduces the synthesis of thromboxane. At low doses (75150 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 therefore to be recommended in all patients, provided they
do not present specic contraindications.38 The antiplatelet agents clopidogrel and ticlopidine are more
expensive than aspirin, but have a similar overall
safety prole 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
benets of long-term treatment with clopidogrel by
reducing the combined risk of ischaemic stroke, MI, or
vascular death.41 High-risk patients may benet from
combination of aspirin with an anticoagulant agent
such as warfarin. However, unless there is a specic
separate indication, anticoagulants should be avoided
in stable CAD.
Lipid-lowering drugs
There is a strong association between increased lowdensity lipoprotein (LDL) cholesterol levels and the
risk of CVD.42 Cholesterol lowering reduces the risk
Beta-blockers
Beta-blockers can reduce the risk of cardiovascular death
or MI by about 30% in post-MI populations.54 Betablockers 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 worsening claudication.
J.-C. Tardif
Calcium channel blockers (CCBs), through selective inhibition 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, myocardial contractility, and atrioventricular nodal conduction.
Calcium channel blockers reduce the frequency and severity 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 benet 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 nitratelike effect. The IONA (Impact Of Nicorandil in Angina)
study showed fewer major coronary events in patients
treated with nicorandil vs. placebo, but signicance
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 benet in
terms of all-cause mortality, MI, or other major cardiovascular events of adding PCI in stable CAD patients receiving
optimized medical therapy.64 Moreover, the marginal
quality of life benet obtained by revascularization in
that trial had completely disappeared after 3 years.65 A
remarkable nding from COURAGE is that the majority of
patients had substantial improvements in health status
(with contemporary treatment) that were sustained for
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It is also important that such a database captures all suspected important determinants of outcomes in order to
analyze not only the baseline characteristics and management practices, but also outcomes and prognostic determinants 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 outpatientbased registries are needed to increase understanding of
the characteristics, management, outcomes, and determinants of prognosis, including HR, of contemporary outpatients 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 outpatients 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 prole of the stable CAD outpatient population, current treatment in daily practice,
adherence to guidelines, evidence-based practice, changing 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 prognosis, including the role of resting HR. The population of
CLARIFY is intended to reect the entire spectrum of outpatients 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 proles, management and outcomes and to identify gaps between treatment and evidence, and (ii) to determine the long-term prognostic
determinants in this population, including resting HR,
with a view to developing a risk prediction model.
J.-C. Tardif
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