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

doi:10.1093/eurheartj/suq014

Coronary artery disease in 2010

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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

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

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010.
For permissions please email: [email protected].
Coronary artery disease in 2010 C3

period from 1996 to 1998. In the ARIC study in partici- It has been estimated that 30–43% of patients who
pants aged from 45 to 64 years, the average age-adjusted were asymptomatic after an MI had silent myocardial
CAD incidence rates per 1000 person-years were 12.5 in ischaemia in the initial 30-day period after the infarct,
white men and 10.6 in black men.2 According to AHA based on stress test data or Holter monitoring.11,12 A
Heart Disease and Stroke statistics, it is estimated that recently published analysis in 937 outpatients with
770 000 Americans had a new coronary attack in 2008, stable CAD from the Heart and Soul Study demonstrated
and 430 000 had a recurrent attack. It is estimated that that 14% of outpatients had angina alone, 20% had indu-
190 000 additional silent first acute myocardial infarc- cible ischaemia alone, and 4% had both angina and
tions (MIs) occur each year. Approximately every 26 s, ischaemia. Recurrent CAD events occurred in 7% of par-
an American will have a coronary event, and about ticipants without angina or inducible ischaemia, 10% of
every minute someone will die of one.3 those with angina alone, 21% of those with inducible

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There are marked variations in the epidemic of CAD ischaemia alone, and 23% of those with both angina and
among regions of the world, nations, and even between inducible ischaemia.13
regions within a country.4 The age-standardized death Coronary atherosclerosis most commonly presents in the
rates from CAD are declining in many developed community as angina pectoris, followed by acute coronary
countries, but are increasing in developing and transi- syndromes (MI and unstable angina), and finally as sudden
tional countries, partly as a result of demographic cardiac death. When the acute manifestations of CAD—
changes, urbanization, and lifestyle changes. Nowadays sudden cardiac death and MI—are considered together,
3.8 million men and 3.4 million women worldwide die one in two patients with new or recurrent disease die
each year from CAD.5 According to the Global Burden of within 30 days of their acute clinical presentation.14–17
Disease Study,6 the developing countries contributed About 69% die in the community, 29% die in hospital, and
3.5 million of the total number of 6.2 million deaths the other 2% die within 30 days of discharge. The prognosis
from CAD in 1990. The projections estimate that these of patients with chronic CAD is not uniform. It depends
countries will account for 7.8 million of the 11.1 million on several factors, including the underlying coronary
deaths due to CAD in 2020. According to global and anatomy, left ventricular (LV) function, and comorbidities.
regional projections of mortality and burden of disease, The data concerning prognosis in clinical trials are of
CAD will remain the leading cause of death for the next limited value due to the highly selective nature of popu-
20 years.7 In the USA and in most countries in the Euro- lations included in such studies. Large population-based
pean Union, the age-standardized CAD mortality rates studies could help to increase our understanding of the
have decreased significantly. This may lead paradoxically differences in prognosis between CAD manifestations.
to an increase in the prevalence of CAD; indeed a better The recently published data on cardiovascular event rates
survival of CAD patients and demographic changes result from the REACH (Reduction of Atherothrombosis for Contin-
in more elderly people suffering from CAD. Today CAD is ued Health) registry in stable CAD outpatients (n ¼ 38 602
the most important major killer of both American men patients) has confirmed that patients with established
and women, causing approximately one of every five stable CAD had the highest non-fatal MI rate and the
deaths in the USA in 2005.8 Approximately 37% of the highest non-fatal stroke rate. The registry reported
people who have a coronary event in a given year will annual event rates of 15.2% for death, stroke, MI, or hospi-
die of it. In 2005 the overall CAD death rate was 144.4 talization for an atherothrombotic event, 6.4% for unstable
per 100 000 population. The death rates were 187.7 for angina, 4.5% for death, acute MI, and stroke, and 3.8% for
white males and 213.9 for black males; for white revascularization by percutaneous coronary intervention
females the rate was 110.0 and for black females (PCI).18 Thus, 3 of 20 patients with established CAD had
140.99. In the European Union, CAD is also the single a major event or had been hospitalized within a year of
most common cause of death. One in five to one in follow-up. The high event rates observed in the subgroup
seven women die of CAD; in men CAD accounts for one of patients with established CAD in this large contemporary
in four to one in six of all deaths. Age-standardized and cohort indicate that continued efforts are needed to
gender-specific CAD mortality rates have significantly improve secondary prevention and clinical outcomes.
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 Financial burden
eastern Europe. Thus, the Russian Federation, Belarus,
Ukraine, and Central Asian republics show the highest The appropriate management of CAD entails costs for non-
CAD mortality rates ever seen, significantly higher even invasive diagnostic and follow-up tests, as well as for
than recognized peaks in the USA, Australia, New medical and interventional therapy. All these factors
Zealand, Finland, and Scotland.9,10 Furthermore, popu- lead to significant direct and indirect costs. The treatment
lation aging represents a major challenge. Thus, even if of stable CAD aims to prevent serious cardiovascular events
age-specific mortality rates continue to decline, the such as MI or death and to improve quality of life by redu-
absolute number of cardiovascular disease (CVD) deaths cing the symptoms caused by myocardial ischaemia. The
will increase. Predictions up to 2030 suggest that even economic costs of CAD include health care expenditure
with an annual decline in mortality rates of about 1%, and non-health service costs. Health care expenditures
the absolute number of deaths will increase, attributable comprise primary care activities, accident and emergency
solely to population aging.7 care, hospital inpatient care, outpatient care, and
C4 J.-C. Tardif

medications. Non-health service costs comprise informal Dietary therapy for all patients should include reduced
care costs, and productivity costs attributable to mortality intake of saturated fats (to ,7% of total calories),
and morbidity. Informal care costs are equivalent to the trans fatty acids, and cholesterol. Daily physical activity
opportunity cost of unpaid care, i.e. the time (work and/ and weight management are recommended for all
or leisure) that carers forego, valued in monetary terms, patients. Statin therapy should always be considered
to provide unpaid care for relatives suffering from CAD. for patients with established CAD, based on their benefits
Productivity costs include the foregone earnings related in the reduction of the risk of atherosclerotic compli-
to CAD-attributable mortality and morbidity. A recent cations. Current European guidelines on CVD prevention
study estimated economic costs of CVD in the enlarged suggest a target value of ,4.5 mmol/L (175 mg/dL) for
European Union and the proportion of these costs attribu- total cholesterol with an option of 4.0 mmol/L (155 mg/
table to CAD.19 CAD cost the health care systems of the dL) if feasible, and 2.5 mmol/L (10 mg/dL) for LDL

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European Union just under 23 billion euros in 2003. The cholesterol an option of 2.0 mmol/L (80 mg/dL) if feas-
major component of health expenditure was inpatient ible in patients with established CVD.20
care, which accounted for 62% (14 billion euros) of costs, Physical activity should be encouraged, as it increases
followed by pharmaceutical expenditure which rep- exercise tolerance, reduces symptoms of angina, and
resented 23% (5.4 billion euros) of total health care has a favourable effect on weight, blood lipids, blood
costs. Primary, outpatient, and emergency care accounted pressure, glucose tolerance, and insulin sensitivity. The
for 16% of health care costs. Over 678 000 people pro- recent ACC/AHA update of the Guidelines for the Man-
vided care to CAD patients, representing 702 million agement of Patients With Chronic Stable Angina rec-
hours of care, which was estimated to cost the European ommends physical activity of 30–60 min, 7 days per
Union 6.8 billion euros. Approximately one million week (minimum 5 days per week).22 All patients should
working years were lost because of CAD mortality, account- be encouraged to do 30–60 min of moderate-intensity
ing for 44% of all working years lost because of cardiovascu- aerobic activity, such as brisk walking, on most and pre-
lar deaths, with a cost of 11.7 billion euros. Additionally, ferably all days of the week, supplemented by an
90 million working days were lost because of CAD morbid- increase in daily activities (walking breaks at work, gar-
ity, representing a cost of 3.5 billion euros after adjusting dening, or household work). Patients should be advised
costs using the friction period. Overall, CAD is estimated to to adopt a ‘Mediterranean’ diet, with vegetables, fruit,
have cost European Union 45 billion euros in 2003—one- fish, and poultry. Body mass index and waist circumfer-
quarter of the overall cost of CVD. Over half of these ence should be assessed regularly. On each patient
costs (51%) were incurred in health care, 34% in pro- visit, it is useful to consistently encourage weight main-
ductivity losses, and 15% in informal care. tenance/reduction through an appropriate balance of
physical activity, caloric intake, and formal behavioural
programmes when indicated to achieve and maintain a
Management of traditional risk factors body mass index between 18.5 and 24.9 kg/m2. Diabetes
management should include lifestyle and pharmacother-
Risk factor control in patients with established CAD apy measures to achieve a near-normal HbA1c. In type 1
remains poor, especially for obesity, smoking, and blood diabetes, glycemic control requires appropriate insulin
pressure, in spite of guidelines. The 2007 European therapy and concomitant professional dietary therapy.
Guidelines on CVD prevention in clinical practice have In type 2 diabetes, professional dietary advice, weight
adopted a more aggressive approach for the treatment reduction, and increased physical activity should be the
of cardiovascular risk factors.20 Smoking cessation and first treatment, followed by pharmacological treatment
avoidance of exposure to environmental tobacco smoke (oral hypoglycemic treatment and insulin when needed)
at work and home is recommended. Follow-up, referral aiming at good glucose control. Current European
to special programs, and/or pharmacotherapy (including guidelines on CVD prevention suggest a target HbA1c
nicotine replacement) are recommended, as is a stepwise value of ,6.5% if feasible, ,6.0 mmol/L (110 mg/dL)
strategy for smoking cessation. Patients should initiate for fasting/preprandial plasma glucose and ,7.5 mmol/L
and/or maintain lifestyle modifications—weight control, (135 mg/dL) for postprandial plasma glucose if feasible.20
increased physical activity, moderation of alcohol con- In addition, psychological risk factors should also be
sumption, limited sodium intake, and maintenance of a addressed, such as excessive anxiety or depression.
diet high in fresh fruits, vegetables, and low-fat dairy
products. Combination antihypertensive treatment is fre-
quently needed to control blood pressure. Drugs that Heart rate as an emerging cardiovascular
have a long-lasting effect and a documented ability risk factor
to lower blood pressure effectively over 24 h with
once-a-day administration are preferred. Long-acting Heart rate (HR), a simple and easily measurable clinical
drugs also minimize blood pressure variability and this parameter, has been found to be a risk predictor of mor-
may offer protection against progression of target-organ tality and morbidity in various populations. Heart rate
damage and risk of cardiovascular events. According to has already appeared in European guidelines on CVD pre-
Joint National Conference VII guidelines, blood pressure vention.20 This consideration is based on a large body of
,140/90 mmHg, or ,130/80 mmHg for patients with evidence from epidemiological studies reporting an
diabetes or chronic kidney disease, is recommended.21 association between elevated HR and increased risk of
Coronary artery disease in 2010 C5

all-cause mortality and cardiovascular mortality and mor- and left ventricULar dysfunction) investigators have
bidity in the general population, hypertensives, dia- also added to current knowledge concerning the prognos-
betics, and those with CAD.23 The relationship between tic value of elevated HR by conducting a prospective
HR and cardiovascular mortality has been shown in 14 analysis of the data from the placebo arm of the study
epidemiological studies over the last 25 years carried to assess the association of HR with different clinical
out in the general population and in subjects with hyper- outcomes.31 The results of this analysis in the placebo
tension, including a total of more than 155 000 patients arm (n ¼ 5438) showed that an elevated resting HR
followed up for between 8 and 36 years.24 The Framing- (≥70 b.p.m.) is a strong predictor of outcome in patients
ham study, which included 5070 subjects followed up with stable CAD and LV dysfunction. This was the case for
for 30 years, evidenced a progressive and significant all of the outcomes assessed in the study. Patients with an
increase in all-cause mortality in relation to HR in both HR of 70 b.p.m. or more were 34% more likely to die of

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men and women.25 Several studies of healthy men and cardiovascular causes (P ¼ 0.0041) and 53% more likely
women found that elevated resting HR was an indepen- to be hospitalized for new or worsening heart failure
dent risk predictor of sudden death. A recently published (P,0.0001) than those with values ,70 b.p.m. Similarly,
study of 5139 healthy French men found that resting HR an elevated HR (≥70 b.p.m.) was associated with a 46%
and its change over 5 years were both predictors of increase in the risk of fatal and non-fatal MI (P ¼
death, independent of standard risk factors.26 After 0.0066) and a 38% increase in the need for coronary
adjustments were made for confounding factors, includ- revascularization (P ¼ 0.037). These data were adjusted
ing baseline HR at rest, and compared with subjects for all the variables that differed between the two
with unchanged HR, those with HR that decreased groups at baseline, including beta-blocker intake and
during the 5 years had a 14% decreased mortality risk other background therapy.
(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- Role of heart rate in the development of
strated that in-hospital mortality and post-discharge atherosclerosis and coronary events
mortality increased with increasing HR on admission.
Total mortality was 15% for patients with an admission The most common coronary manifestations of athero-
HR ranging between 50 and 60 b.p.m., 41% for HR . sclerosis are stable angina pectoris and acute coronary syn-
90 b.p.m. and 48% for HR . 110 b.p.m. Mortality from dromes. The role of HR in myocardial ischaemia in patients
hospital discharge to 1 year was also related to the with stable angina and those who suffer an MI is well known.
maximal HR observed in the coronary care unit and to An increased HR contributes to an imbalance between myo-
the HR at discharge. The prognostic significance of HR cardial oxygen demand and supply, by causing both an
was also assessed in the GISSI-2 study in 8915 patients increase in myocardial oxygen demand and a decrease in
with acute MI and treated with fibrinolytic therapy.28 coronary blood supply (the latter via a shorter duration of
Increased HR on admission was associated with a diastole, the period during which most of the myocardial
progressive increase in in-hospital mortality (from 7.1% perfusion occurs). Thus, the likelihood of myocardial
for HR , 60 b.p.m. to 23.4% for HR . 100 b.p.m.). ischaemia is related to baseline resting HR, and is two
A progressive increase of 6-month mortality was noted times higher in patients with baseline HR of 89 b.p.m. or
with increasing HR at discharge (from 0.8% for HR ≤ more compared with those with HR of 60 b.p.m.32 Exper-
60 b.p.m. to 14.3% for HR . 100 b.p.m.). Tardif and col- imental evidence also supports the role of HR in endothelial
leagues29 found that resting HR was an independent risk dysfunction and progression of atherosclerosis. A higher HR
predictor of total and cardiovascular mortality in 24 913 is associated with a shortened diastole and more time spent
men and women with suspected or proved CAD followed in systole during which coronary shear stress is lower.33
for an average of 14 years. The prognostic value of HR Reduced shear stress is associated with enhanced endo-
held true when controlling for hypertension, diabetes, thelial expression of pro-inflammatory molecules and pre-
and smoking, as well as powerful markers such as the LV disposition to atherosclerosis. An increased HR may also
ejection fraction and the number of diseased coronary be involved at the later stages of atherosclerosis and has
vessels. Patients with an HR ≥ 83 b.p.m. also had a signifi- been associated with greater risk of plaque rupture.34 Con-
cantly higher risk of hospital admissions for cardiovascular sistent with this understanding of the importance of HR in
causes than those with an HR , 62 b.p.m. In a post hoc the pathophysiology of CAD, HR reduction is considered as
analysis from the INVEST (INternational VErapamil-SR/ a potential therapeutic goal in coronary patients; the short-
Trandolapril) study, the relationships between resting HR term implication is prevention of ischaemia, and the long-
at baseline and at follow-up and adverse outcomes (all- term implication is potential prevention of cardiovascular
cause death, non-fatal MI, and non-fatal stroke) were events.
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, Heart rate reduction and decreased
and on-treatment HR was even more predictive than cardiovascular risk
baseline resting HR.30
The BEAUTIFUL (MorBidity-mortality EvAlUaTion of the Several studies have shown that beta-blockers are able to
If inhibitor Ivabradine in patients with coronary disease reduce total mortality and sudden cardiac death after MI.
C6 J.-C. Tardif

These beneficial effects have been ascribed at least in of atherosclerosis progression43 and the currently
part to the reduction of HR.35 Furthermore, a recent recommended treatment goals are lower for patients
meta-regression of randomized clinical trials of beta- with established CAD and those considered to be at
blockers and calcium channel blockers in post-MI patients high risk. The Heart Protection Study clearly demon-
strongly suggests that resting HR reduction could be a strated that lipid-lowering treatment was beneficial in
major determinant of the clinical benefits seen in these patients with a history of CAD, and such therapy should
trials.36 Recently, the BEAUTIFUL investigators have con- be an integral part of the management of all CAD
tributed to the understanding of the importance of HR patients.44 Statins have been reported to decrease cardi-
reduction for prevention of coronary events. Treatment ovascular complications by up to 30%, even in the elderly
with ivabradine, a pure HR-reducing agent, provides an (.70 years) and patients with diabetes.44,45 It is known
opportunity to assess the effects of selectively lowering that the deleterious effects of serum cholesterol begin

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HR without altering other aspects of cardiac function.37 at low-normal levels,46 and pre-treatment cholesterol
The prospective analysis of data from the placebo arm level does not determine the benefits of long-term
of BEAUTIFUL demonstrated that elevated resting HR statin therapy; treatment is therefore useful in patients
(≥70 b.p.m.) is a strong independent predictor of clinical with normal cholesterol levels but high cardiovascular
outcomes. Consistent with these data, ivabradine signifi- risk.47 This explains why it is currently recommended to
cantly improved coronary outcomes in these patients treat patients at high cardiovascular risk with a statin,
with an HR ≥70 b.p.m. Compared with placebo, there even if they have normal or near-normal LDL cholesterol
was a 36% reduction in relative risk of hospitalization levels.
for fatal and non-fatal MI in these patients with HR ≥
70 b.p.m. treated with ivabradine (P ¼ 0.001) and a Angiotensin-converting enzyme inhibitors
30% relative risk reduction in coronary revascularization
(P ¼ 0.016). Treatment with ivabradine was also associ- Angiotensin-converting enzyme (ACE) inhibitors are
ated with a 22% reduction in the relative risk of the com- widely used in the treatment of hypertension and heart
posite endpoint of hospitalization for fatal and non-fatal failure. Trials in patients with heart failure and post-MI
MI and unstable angina pectoris (P ¼ 0.023) as compared reported reduced cardiac mortality and MI with ACE inhi-
with placebo. 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
Pharmacologic therapy trial of Reduction Of cardiac events with Perindopril in
stable coronary Artery disease (EUROPA), there was a
Antiplatelet agents 20% relative risk reduction in the composite primary end-
point of cardiovascular death, MI, or resuscitated cardiac
Aspirin irreversibly inhibits platelet cyclooxygenase arrest in the perindopril treatment group.48 Results in
and, as a consequence, reduces the synthesis of throm- favour of ACE inhibition also came from the Heart Out-
boxane. At low doses (75–150 mg/day), chronic therapy comes Prevention Evaluation (HOPE) study with ramipril,
with aspirin remains the best pharmacological option for in which there was a 22% reduction in the composite
the prevention of arterial thrombosis.38 Outside this primary endpoint of cardiovascular death, MI, and
dose range, the advantage conferred by treatment stroke.49 The conclusion drawn from these studies is
with aspirin may be lower.39 Low-dose aspirin is there- that ACE inhibition with perindopril or ramipril could
fore to be recommended in all patients, provided they have additional cardiovascular effects via mechanisms
do not present specific contraindications.38 The antipla- other than reduction of blood pressure.51–53 Secondary
telet agents clopidogrel and ticlopidine are more prevention with ACE inhibition is therefore recommended
expensive than aspirin, but have a similar overall for patients with proved CAD, if they have had a previous
safety profile and may be good options in cases of MI, or have diabetes, concomitant hypertension, heart
aspirin intolerance (e.g. patients with bronchospasm). failure, or asymptomatic LV dysfunction.38
They have antithrombotic effects comparable to
those of aspirin.40 The CAPRIE trial demonstrated the Beta-blockers
benefits of long-term treatment with clopidogrel by
reducing the combined risk of ischaemic stroke, MI, or Beta-blockers can reduce the risk of cardiovascular death
vascular death.41 High-risk patients may benefit from or MI by about 30% in post-MI populations.54 Beta-
combination of aspirin with an anticoagulant agent blockers are currently recommended in such patients,
such as warfarin. However, unless there is a specific and in patients with heart failure. Beta-blockers reduce
separate indication, anticoagulants should be avoided HR at rest and during exercise, and are the standard
in stable CAD. choice for the symptomatic treatment of stable angina
and ischaemia, provided the agent is initiated carefully
Lipid-lowering drugs and titrated progressively to full dose to achieve resting
HR less than 60 b.p.m.55 Uptitration of beta-blockers
There is a strong association between increased low- might be limited by side effects, such as fatigue,
density lipoprotein (LDL) cholesterol levels and the depression, lethargy, insomnia, nightmares, and worsen-
risk of CVD.42 Cholesterol lowering reduces the risk ing claudication.
Coronary artery disease in 2010 C7

If current inhibitor ivabradine several years. At the same time, the rapid improvement
with optimal medical therapy alone suggests that antian-
If current inhibitor ivabradine selectively inhibits the If ginal medications are underused in practice. The
cardiac pacemaker current, thus exerting selective HR COURAGE trial redefines the contemporary roles of
reduction while preserving LV contractility and relax- optimal medical therapy and PCI in the management of
ation.56 It provides powerful anti-ischaemic and antiangi- patients with stable CAD. It suggests the complementary
nal efficacy in patients with stable angina.57–60 The role of optimal medical therapy as first-line therapy,
recent ASSOCIATE study clearly demonstrated that treat- with PCI reserved for patients who do not respond or
ment with ivabradine in patients with stable angina who have severe symptoms. In some circumstances, for
receiving the beta-blocker atenolol resulted in a signifi- example in patients with severe lesions in coronary
cant reduction in HR and improvement in all parameters arteries that supply a large area of the myocardium, revas-

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of exercise capacity.61 The results of the BEAUTIFUL cularization can improve prognosis by increasing the
study suggest that ivabradine has the ability to affect effectiveness of the existing perfusion or providing
not only symptoms of myocardial ischaemia, but also alternative routes of perfusion. Whatever the decision—
potentially to improve coronary outcomes in patients to revascularize or not—the patient should be advised
with elevated HR (≥70 b.p.m.), which makes it an inter- that secondary preventative pharmacological therapy
esting agent for the management of patients with CAD.37 will continue to be necessary, even after the intervention.
The risks and benefits of surgery or PCI should also be care-
Calcium channel blockers fully discussed with the patient.

Calcium channel blockers (CCBs), through selective inhi-

bition of the L-type calcium channels, lead to dilation of The CLARIFY registry: rationale and objectives
the coronary and other arteries, which decreases cardiac
work and counteracts vasospasm. The non-dihydropyridine Coronary artery disease is and will remain for the fore-
CCBs (e.g. verapamil and diltiazem) reduce HR, myocar- seeable future the first cause of death worldwide. With
dial contractility, and atrioventricular nodal conduction. improvements in treatment, an increasing number of
Calcium channel blockers reduce the frequency and sever- patients survive acute coronary syndromes and will live
ity of anginal attacks, but there is no evidence supporting as outpatients with or without anginal symptoms.
their use to improve prognosis in stable CAD patients.
ACTION (A Coronary disease Trial Investigating Outcome Need for worldwide contemporary data on
with Nifedipine gastrointestinal therapeutic system) outpatients with stable coronary artery disease
found no benefit of nifedipine over placebo in stable
angina in terms of composite endpoints, including death, Data available today on disease presentation and man-
MI, refractory angina, and heart failure.62 agement of patients with stable CAD come mainly from
clinical trials or registries. Clinical trials often have strin-
Nicorandil gent inclusion and exclusion criteria, and thus do not
adequately represent populations with stable CAD, par-
Nicorandil is a potassium channel opener with a nitrate- ticularly in terms of age, comorbidity, and concomitant
like effect. The IONA (Impact Of Nicorandil in Angina) therapy, and often do not reflect daily practice. This is
study showed fewer major coronary events in patients emphasized by the under-representation of women and
treated with nicorandil vs. placebo, but significance ethnic minorities in trial populations, and by the ten-
was driven mainly by a reduction in ‘hospital admission dency for trial patients to be free from important comor-
for cardiac chest pain’. The risk of death and non-fatal bidities. Furthermore, patients followed up in the large
MI was unaffected.63 centres typically participating in clinical trials may not
resemble those in the outpatient community. However,
some registries have attempted to capture the patient
Myocardial revascularization population with stable CAD, but often focus on a single
country or geographic region, or on acute manifestations
Revascularization includes either PCI, usually with stent of the disease,66 or only on patients with anginal symp-
implantation, or coronary artery bypass graft (CABG) toms.67 In addition, some studies are cross-sectional
surgery. The results of the Clinical Outcomes Utilizing and therefore do not establish links between baseline
Revascularization and Aggressive Drug Evaluation characteristics, management, and subsequent outcomes.
(COURAGE) trial, published in 2007, showed no benefit in Therefore, the generalizability of findings from random-
terms of all-cause mortality, MI, or other major cardiovas- ized clinical trials and most registries is often limited.
cular events of adding PCI in stable CAD patients receiving Finally, due to the important changes in management
optimized medical therapy.64 Moreover, the marginal and outcome of CAD patients, there is a need for contem-
quality of life benefit obtained by revascularization in porary data. It is therefore important to have longitudi-
that trial had completely disappeared after 3 years.65 A nal observations of a representative large cohort of
remarkable finding from COURAGE is that the majority of patients with stable CAD, spanning several geographic
patients had substantial improvements in health status regions, focusing on stable outpatients (as opposed to
(with contemporary treatment) that were sustained for patients hospitalized or recently discharged from hospital
C8 J.-C. Tardif

for acute manifestations of the disease), and including for 5 years and data will be collected prospectively at
both symptomatic and asymptomatic patients. annual visits at 12, 24, 36, 48, and 60 months. Because
of substantial geographic variations in the epidemiology
Need to evaluate determinants of long-term of stable CAD, this registry will be international to gener-
prognosis, including heart rate, in patients with ate data on various countries and regions of the world.
stable coronary artery disease This strategy will enhance the value of the results and
yield data on international variability in disease presen-
It is also important that such a database captures all sus- tation and management.
pected important determinants of outcomes in order to
analyze not only the baseline characteristics and manage-
ment practices, but also outcomes and prognostic determi- Selection of subjects in the CLARIFY registry

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nants including resting HR. In spite of extensive evidence
for the importance of HR in the prognosis of stable CAD, The registry will attempt to collect representative data
HR is not yet a routine component of cardiovascular risk for each of the participating countries. Representative-
assessment. We also lack data on HRs actually achieved ness will be ensured by a two-tiered process: (i) determi-
in practice. Therefore, using a dataset in which resting nation of physician type in charge of CAD patients in a
HR is carefully and reliably measured will be critical given country and targeting of an appropriate proportion
when trying to assess the role of HR in prognosis in stable of each of these physician specialties; (ii) enrolment
CAD patient populations. Therefore, large outpatient- of consecutive eligible patients is planned for each
based registries are needed to increase understanding of patient. Each physician will recruit 10–15 outpatients
the characteristics, management, outcomes, and determi- with stable CAD as defined by the inclusion criteria.
nants of prognosis, including HR, of contemporary outpati- Patients will be recruited at each practice setting over
ents with stable CAD. The CLARIFY registry has been set up a brief period of time, suggesting consecutive (or nearly
to improve knowledge about the contemporary stable CAD so) patient enrolment and ensuring representative
population.68 CLARIFY is an international, prospective, inclusion of the overall population in each practice
observational, longitudinal registry in stable CAD outpati- setting.
ents with 5-year follow-up. The study will be approved by
local institutional review boards and all patients will give Inclusion and exclusion criteria
informed consent in accordance with national and local
guidelines. The registry will provide important data on Outpatients with stable CAD proved by a history of at
the demographic and clinical profile of the stable CAD out- least one of the following criteria are eligible to enter
patient population, current treatment in daily practice, CLARIFY: documented MI (more than 3 months ago), cor-
adherence to guidelines, evidence-based practice, chan- onary stenosis of more than 50% proved by coronary
ging patterns of stable CAD management during registry angiography, chest pain with myocardial ischaemia
follow-up, variations in management of CAD patients proved by stress ECG, stress echocardiography or myocar-
according to geography, type of physician, and patient dial imaging, or CABG or PCI (more than 3 months ago).
characteristics, and the determinants of long-term prog- Patients cannot enter the study if they were hospitalized
nosis, including the role of resting HR. The population of for CVD within the last 3 months before recruitment
CLARIFY is intended to reflect the entire spectrum of out- (including revascularization), are scheduled for revascu-
patients with CAD. This information will help to improve larization, or have conditions hampering participation
the management of patients with CAD. in the 5-year follow-up, such as limited cooperation,
The main objectives of CLARIFY are (i) to characterize limited legal capacity, serious non-CVD or conditions
contemporary CAD patients in terms of demographic interfering with life expectancy (cancer, drug abuse,
characteristics, clinical profiles, management and out- etc.) or severe CVD (advanced heart failure, severe
comes and to identify gaps between treatment and evi- valve disease, history of valve repair/replacement).
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. Data collection and evaluation in CLARIFY
The data are collected anonymously at baseline and annually
CLARIFY study design for 5 years to ascertain clinical events, hospitalization,
employment status, or sick leave. Evaluations at baseline
CLARIFY is an international, prospective, observational, include demographic information, employment status,
longitudinal registry in stable CAD outpatients, with medical history, risk factors, physical examination, HR,
5-year follow-up. This observational registry is designed pulse palpation, 12-lead electrocardiography (the most
to collect data on the current status of outpatients recent ECG within 6 months in clinically stable patients),
with stable CAD, including their demographic character- laboratory values (if available), and current chronic
istics, clinical profiles, therapeutic strategies, and out- medical treatments. Evaluations at the annual follow-up
comes. This is not an interventional study to assess the visit include clinical events occurring since last visit and
impact of a predefined therapy. In this longitudinal other cases of hospitalization, death, employment status,
study, a minimum of 30 000 subjects will be followed up medical history, physical examination, HR, pulse palpation,
Coronary artery disease in 2010 C9

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