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The evolving nature of coronary artery disease

Philippe G. Steg, Stephen H. Dorman
DOI: http://dx.doi.org/10.1093/eurheartj/sur018 C14-C18 First published online: 31 August 2011


Epidemiological studies have demonstrated a substantial decline in cardiovascular mortality in industrialized countries over the last 10 years. Improvements in primary prevention and in management of acute coronary syndromes account for this decline. Despite this spectacular progress, cardiovascular disease remains the number one cause of mortality worldwide and in low- and middle-income countries. ‘Westernized’ urban lifestyle in emerging countries and the epidemic of obesity and metabolic syndrome in North America appear to be challenging this positive trend, with evidence of adverse age- and sex-adjusted mortality rates from coronary artery disease (CAD) starting to emerge. In parallel, changes in the epidemiology of CAD are being mirrored by changes in the nature of its clinical presentation. Existing randomized trials in this area have limited generalizability and our contemporary understanding of CAD is reliant on registry data. These registries have shown that cardiovascular event rates in the outpatient population with CAD are predictable and overall remain high, although a clear spectrum of risk exists. Importantly, event rates can be modified by adherence to guideline-based therapy. Consequently, optimal secondary prevention and eliminating variation in sex- and age-based patterns of investigation remain a priority. Further studies of unselected outpatient CAD populations, such as the CLARIFY registry, will help improve understanding of the prognostic determinants and inform therapeutic strategies.

  • Coronary artery disease
  • Myocardial infarction
  • Heart rate
  • Outpatients

The changing epidemiology of coronary artery disease

Over the past four decades, there have been major advances in the prevention and cure of cardiovascular diseases in general and coronary artery disease (CAD) in particular. These changes have resulted in a spectacular decline of cardiovascular mortality in industrialized countries (Figure 1)1 and have been major contributors to the increase in life expectancy in the same geographic areas.2 Refined analyses of the explanations for these major epidemiologic changes have consistently found that progress could be ascribed to improved prevention for almost half (as evidenced by a lower incidence of acute coronary events) and to improved curative treatment of coronary events for an additional 25–40% (as shown by a lower case-fatality rate).1 There is strong evidence from convergent sources that the mortality of patients with acute coronary syndromes (ACS) in general and acute myocardial infarction (MI) in particular is dwindling: registries, whether population-based or not, have documented a steady decline in the acute mortality of patients with acute MI3 (although sometimes post-discharge mortality increases) including for elderly patients.4 Data from more recent sources even indicate that in the past 10 years the decline has continued: the age- and sex-adjusted rates of acute MI have diminished steadily in the past 10 years in the USA5 (Figure 2). The in-hospital mortality of patients with ACS was almost halved in 5 years in centres participating in the GRACE registry of ACS,6 and 30-day and 1-year mortality of all types of ACS diminished steadily and rapidly in the comprehensive Swedish RIKS-HIA registry of ACS across all age categories.7 In addition to a decline in the incidence and lethality of acute coronary events, there is also a shift in the type of events, with an increasing proportion of patients presenting with non-ST elevation ACS, and, pari passu, a corresponding reduction in the proportion of ST-segment elevation MI (STEMI). This probably reflects not only the ageing of the population but also the increasing propensity over time for patients with CAD to survive an inaugural episode of STEMI and to experience subsequent recurrent ACS episodes in the form of non-ST segment elevation ACS.

Figure 1

Decline in age-adjusted coronary artery disease mortality in men and women in the USA from 1980 to 2002 (from ref. (1)).

Figure 2

Decline in age- and sex-adjusted rates of acute myocardial infarction from 1999 to 2008 in the USA (ref. (5)).

Yet, despite such spectacular progress, there is serious cause for concern regarding the epidemiology of CAD: first, while both incidence and lethality of acute coronary events have declined in the Western world, the latest data suggest that the decline has abated and that we may be on the verge of witnessing a rebound of cardiovascular mortality: when the trends in coronary-related mortality in the USA are analysed by gender and age class, it is apparent that among younger patients, the decline has stopped. In fact, among younger women, we may already be witnessing an increasing coronary mortality1 (Figure 3). The explanations for this may relate to the ongoing epidemic of obesity and attendant diabetes in North America. In addition, it is important to remember that, contrary to widespread perceptions, CAD (and for that matter cardiovascular disease) is not a disease of the affluent countries: there are far more deaths related to cardiovascular disease among ‘emerging’ countries than in the high-income countries,8 which explains why cardiovascular diseases are (and are expected to remain) the number one cause of death worldwide and among low- and middle-income countries.9 The rapidly increasing burden of cardiovascular disease in emerging countries is probably related largely to the epidemiologic transition from a traditional rural lifestyle to the so-called ‘modern’ Westernized urban lifestyle, with a decrease in physical activity and major increases in the rates of obesity, dyslipidemia, diabetes, hypertension, and smoking.

Figure 3

Trends in coronary mortality by age category in the USA (ref. (1)).

Among industrialized countries, the successes of prevention and treatment have involved improved preventive measures against CAD, with effective blood pressure control, active measures to curb smoking, the advent of statins very effective at lowering LDL cholesterol and preventing first and recurrent cardiovascular events, and the modern treatment of diabetes. Regarding treatment of established disease, a major change has been the widespread availability of myocardial revascularization using percutaneous coronary interventions, both in the setting of ACS and as a treatment for stable CAD. These new preventive and curative measures have completely changed the epidemiology of CAD.

The changing clinical picture of coronary artery disease

There are few sources of contemporary information on the current clinical presentation and management of outpatients with CAD. Most of the data available originate from randomized clinical trials, which tend to enrol highly selected patient populations.10 Some large registries have collected information in less selected settings but most (e.g. the GRACE registry, the CRUSADE registry, the get with the Guidelines/Action registry) focus on patients with acute coronary events. Among the best available sources, the Euro-Heart survey of stable angina in 2003 examined the investigation, management and outcome of a large cohort of ambulatory patients from 36 countries, presenting to a cardiologist as an outpatient, with new-onset stable angina.11 This relatively young population (mean age 61 years) had a high prevalence of modifiable risk factors. The majority underwent further risk stratification with exercise ECG and coronary angiography (CAG) was planned or performed in 41%, although with significant national variations. Exercise ECG and CAG were performed less commonly in the elderly and in women. Interestingly, these tests more often yielded abnormal results within the elderly population than in their younger counterparts, although in women significant coronary narrowings were less common than in men. Secondary prevention, in particular antiplatelet and statin therapy, was suboptimal and a clear reduction in death and MI during follow-up was observed as the intensity of guideline-compliant therapy increased (HR: 0.68; 95% CI: 0.49–0.95 per unit increase in treatment score). Some element of selection is, of course, present in the above findings as in routine clinical practice many patients with CAD will be asymptomatic because of silent ischaemia, successful medical treatment, or following revascularization therapy post-ACS. In addition, these registries exclude a small but significant cohort of patients with CAD who do not seek medical attention for their symptoms or are managed directly in primary care without onward cardiological referral.

Another important source of information is the international REduction of Atherothrombosis in Continued Health (REACH) registry, which prospectively enrolled 68 236 patients with either established atherosclerotic arterial disease or at least three risk factors for atherothrombosis, from physician practices in 44 countries from 2003 to 2004. Among some of the key findings from that registry are the following observations:

  • – cardiovascular event rates remain high among stable outpatients with atherothrombosis in general and CAD in particular,12

  • – event rates are largely predicted by a few simple clinical descriptors, such as the presence of multivessel disease, history of MI, particularly if it occurred in the previous 12 months, and diabetes.13

Interestingly, while secondary prevention patients are traditionally considered to be at uniformly high risk of adverse cardiac events, data from the REACH registry demonstrated that there is actually a whole spectrum of risk with event rates at 4 years ranging from 9.1 to 25.0% according to the various clinical risk predictors.13 In summary, large registries have shown that cardiovascular event rates in the outpatient population with CAD are predictable and overall remain high, although a clear spectrum of risk exists. These event rates can be modified by adherence to guideline-based therapy and consequently optimal secondary prevention and the elimination of variations in sex- and age-based patterns of investigation remains a priority.

The CLARIFY registry

In order to overcome the limitations of the aforementioned studies, new studies are needed to enroll a population of unselected outpatients with symptomatic or asymptomatic stable CAD, from a broad geographic base and with longitudinal follow-up. It is important to capture all important determinants of outcomes in this population in order to analyse not only the demographic, clinical characteristics, and management practices, but also outcomes and prognostic determinants. Among these, heart rate has emerged as a potentially important determinant of long-term outcomes in patients with CAD.14 Yet the measurement of heart rate is not well standardized and results can fluctuate very substantially. Therefore, the availability of a large data set in which heart rate is measured in a reliable and standardized fashion, using both the electrocardiogram and clinical measurement, will be critical to the assessment of the precise prognostic role of resting heart rate in CAD.

One of the principal aims of the CLARIFY registry (ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease) is to provide worldwide contemporary data in stable CAD outpatients.15 Participants were outpatients with stable CAD defined as the presence of at least one of the following criteria:

  • – documented MI (more than 3 months ago);

  • – coronary artery stenosis >50%, proven by CAG;

  • – chest pain with myocardial ischaemia, proven by stress ECG, stress echocardiography or myocardial imaging;

  • – coronary artery bypass grafting (CABG), surgery or percutaneous coronary intervention (>3 months ago).

The exclusion criteria were minimized, in order to enrol a broadly representative population. Patients were excluded if they had been hospitalized for cardiovascular disease in the previous 3 months, if they were scheduled for revascularization, or if they had conditions hampering participation or follow-up, such as limited cooperation, limited legal capacity, serious noncardiovascular disease, or conditions interfering with life expectancy (such as cancer, drug abuse) or severe cardiovascular disease (e.g. advanced heart failure, severe valve disease, history of valve repair/replacement, etc.).

To ensure selection of a population representative of stable CAD outpatients, the selection of participating sites involved predefined selection of physician types and practice settings in each participating country. In addition, a short enrolment period was given to each site to enrol a maximum of 15 patients, in order to maximize consecutive or near-consecutive enrolment. Finally, to ensure a balanced representation of participating countries, a general target of 25 patients per million inhabitants was used (with a range of 12.5–50). Data were collected anonymously at an annual visit each year up to 5 years of follow-up with a 6-month phone call between annual visits, in order to maximize follow-up and increase retention rates. Quality control was performed onsite at 5% of the sites chosen at random in each country. At these sites, 100% of case report forms were monitored for source documentation and accuracy. The data were collected and analysed anonymously by the independent Robertson Centre for Biostatistics (University of Glasgow, UK). Recruitment began in November 2009 and ended in July 2010. Overall, 2898 investigators at 2343 sites in 45 countries enrolled more than 33 000 patients. Results for the baseline cohort are forthcoming.


The epidemiology and clinical presentation of CAD are changing significantly. Contemporary studies such as the CLARIFY registry, involving unselected outpatient CAD cohorts, will help to improve our understanding of this disease and its treatment.


S.H.D has the following disclosure: Fellowship grant from Abbott Vascular.

P.G.S. has the following disclosures: Research grant (to institution): Servier; Speaking or consulting: Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo/Lilly, Eisai, GlaxoSmithKline, Merck Sharp and Dohme, Novartis, Nycomed, sanofi-aventis, Sankyo, Servier, The Medicines Company; Stockholding: Aterovax.


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