Clinical profile of contemporary patients with stable coronary artery disease



by M. Tendera, Poland

Michal TENDERA, MD
3rd Department of Cardiology,
Medical University of Silesia
Katowice, POLAND

Recent registries have provided an opportunity to analyze the clinical profiles of contemporary patients with stable coronary artery disease (SCAD). SCAD patients enrolled in randomized clinical trials tend to have similar characteristics than those included in registries. Patients with SCAD enrolled in recent studies are older, and have a higher prevalence of past myocardial infarction, heart failure, diabetes, and other comorbidities than those enrolled in earlier studies. These findings suggest that the management of outpatients with SCAD is now more complex. Although there have been improvements in the use of therapies advocated by international guidelines, many SCAD patients are still receiving suboptimal treatment. The prevalence of symptoms and major cardiovascular risk factors and their control vary markedly worldwide, reflecting the different clinical profiles of SCAD patients and the varying levels of availability of diagnostic procedures and treatments. The aim of this review is to discuss the clinical characteristics of contemporary patients with SCAD, analyze the factors influencing prognosis, and assess the changes in patient characteristics that occurred over the last decades.

Patients with stable coronary artery disease (SCAD) form a nonuniform group encompassing individuals with stable angina, those with a history of acute coronary syndrome, percutaneous coronary intervention (PCI), or coronary artery bypass graft surgery (CABG), or with >50% stenosis in a major coronary artery, regardless of the presence or absence of symptoms.

Although myocardial ischemia causes typical angina in the majority of patients with significant obstructive coronary lesions, many patients may have less specific symptoms or may be asymptomatic. In order to identify patients with obstructive CAD, several diagnostic algorithms have been proposed, depending on the pretest probability of having the disease.1-3 These algorithms have two main drawbacks: they only include symptomatic subjects, and they assume that patients whose calculated risk is less than 15% do not have CAD and do not require further work-up. The latter is based on the assumption that around 15% of patients falling into that category would have false positive noninvasive tests.4 This may, however, mean that some theoretically low-risk patients are underdiagnosed. On the other hand, higher- risk patients with false positive or ambivalent noninvasive tests for ischemia may be over diagnosed. These considerations pertain to patients with obstructive CAD. However, myocardial ischemia may also be present in patients who do not present significant coronary vessel lesions on coronary angiography.5,6 All these factors contribute to making it difficult to accurately define the population of patients with SCAD.

Data from randomized controlled trials (RCTs) are generally regarded as being of limited value here, since RCTs usually have extensive lists of exclusion criteria that may eliminate patients with comorbidities, often seen in everyday practice. For this reason, registries are considered to best reflect the demographics, treatment patterns, and outcomes of patient populations. It must be emphasized, however, that the recent SIGNIFY study (Study Assessing the Morbidity-Mortality Benefits of the If inhibitor Ivabradine in Patients with Coronary Artery Disease)7 included patients with a higher prevalence of risk factors and more comorbidities than any of the global surveys conducted so far. Therefore, in SCAD, the differences in patient populations, treatment patterns, and outcomes between RCTs and surveys may not be pronounced.

Over the last 15 years several registries of SCAD patients differing in terms of geographical coverage, inclusion criteria, environment (in- or out-patients; specialist vs non specialist care), and outcomes measured have provided a comprehensive description of the real-life SCAD patient population.8-21 The aim of this paper is to review the clinical profiles of patients with SCAD, together with treatment patterns and outcomes, and to analyze the changes that have occurred over time.

Clinical profiles of contemporary SCAD patients

Two recent large surveys, the CLARIFY registry (prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease)8,9 and the REACH registry (REduction of Atherothrombosis for Continued Health),11 have provided a global overview of patients with SCAD.

CLARIFY is an ongoing, prospective, observational, longitudinal cohort study of outpatients with SCAD with a 5-year follow- up.8 Between November 2009 and July 2010, a total of 33 438 patients were recruited in 45 countries in Africa, Asia, Australia, Europe, the Middle East, and the Americas (excluding the United States). In order to be eligible for the study, the patients had to meet at least one of the following criteria: documented myocardial infarction (MI) >3 months ago; >50% coronary stenosis on angiography; chest pain with myocardial ischemia confirmed by a stress test, and a history of PCI or CABG >3 months ago.8,9 The mean age of patients was 64±10 years and 78% of them were male. A majority of them had a history of MI (60%) and/or myocardial revascularization (59% PCI, 23% CABG). Only 16% of all patients had CCS class II, III, or IV angina. Comorbid conditions were frequent; hypertension was present in 71% of patients, lipid abnormalities in 75%, heart failure in 15%, diabetes in 29%, peripheral artery disease in 10%, asthma/chronic obstructive pulmonary disease (COPD) in 7%,9 and chronic renal disease in 22%.22 There were significant geographical variations in the prevalence of cardiovascular risk factors.10 Clinical presentation also differed between the regions. The prevalence of MI ranged from 50% in East Asia to 79% in Eastern Europe; while angina was present in 10% of patients from the Middle East or Central/South America and in 78% of those from Eastern Europe. While the use of guideline-advocated medication was generally good, risk factors were not adequately controlled. There were also sex- and age-related differences in terms of clinical presentation and management.23 Female patients were older than male patients, and were more likely to have diabetes and hypertension. Smoking and a history of MI were more common in men. Women were more likely to have angina, but underwent fewer revascularizations. Patients aged >75 years were less likely to be treated with aspirin, β-blockers, and angiotensin-converting enzyme (ACE) inhibitors.

The worldwide REACH registry, which recruited a total of 68 236 outpatients from 29 countries between December 2003 and June 2004, comprised patients with a wider spectrum of atherothrombotic conditions: coronary artery disease, cerebrovascular disease, peripheral artery disease, or multiple risk factors for atherosclerosis.11 More than 45 000 patients were included in the 4-year follow-up analysis, of whom over 37 000 had either a history of MI or documented CAD.11 Within the CAD group, males were more prevalent (70% vs 65%) and heart failure more frequent (18% vs 12%) among patients with a history of MI than in patients with no prior acute event. The mean age was similar (68 years vs 69 years), and so was the prevalence of hypertension (79% vs 80%), hypercholesterolemia (67% vs 70%), diabetes (36% vs 37%), and current smoking (14% vs 15%). Within the entire spectrum of patients, those with a prior ischemic event at baseline had a higher risk of having a new atherothrombotic event than those with stable coronary, cerebrovascular, or peripheral artery disease (18.3 vs 12.2%; P<0.001). Like CLARIFY, the REACH registry showed that risk factor control remains suboptimal.11,24





Table I. Characteristics of patients in major SCAD registries.
Abbreviations: CABG, coronary artery bypass grafting; CASS, Coronary Artery Surgery Study; CLARIFY, ProspeCtive observational LongitudinAl RegIstry oF patients
with stable coronary arterY disease; COPD, chronic obstructive pulmonary disease; EHS, EuroHeart Survey; EurObs, EURObservational Research Programme;
MI, myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; REACH, Reduction of Atherothrombosis for Continued Health;
SD, standard deviation.




In the randomized, placebo-controlled SIGNIFY study7—which was conducted in 51 countries worldwide and enrolled 19 102 patients between October 2009 and April 2012—the age and sex distribution (mean age 65 years, 73% males) was similar to that of recent surveys, with a very high prevalence of hypertension (86%), dyslipidemia (72%), current smoking (24%), angina (75%), diabetes (43%), and peripheral artery disease (21%) (see Table I for comparative data). Patients enrolled in SIGNIFY received excellent background drug therapy (98% of them were on antiplatelet or anticoagulant therapy, 79% took a β-blocker, and 84% were treated with an ACE inhibitor or an ARB; see Table II, page 8).

At the European level, two studies were carried out by the European Society of Cardiology (ESC): the EuroHeart Survey, which recruited SCAD patients in 2002,12,13 and the EURObservational Research Programme, which recruited a pilot cohort of SCAD patients in 2013-2014.14 The recent pilot chronic ischemic cardiovascular disease registry (CICD-PILOT [Chronic Ischaemic Cardiovascular Disease Registry: Pilot phase]; part of the EURObservational Research Program) recruited 2420 subjects scheduled for elective PCI or medical treatment, including 1464 with SCAD,14 while the earlier EuroHeart Survey enrolled 3031 patients with SCAD12 (for the characteristics of both cohorts see Table I). The prevalence of comorbid conditions was much higher in CICD-PILOT, except for peripheral artery disease (PAD) and asthma/COPD. There was a noticeable improvement in secondary prevention in CICD-PILOT compared with the EuroHeart Survey (Table II). In addition to these registries there have been numerous country- specific surveys addressing different aspects of SCAD, such as risk factor prevalence and control, quality of life, and prognosis.16-21

Increased attention has recently been given to patients who have angina but do not have any visible obstructive changes on coronary arteriography.5,6 Most of these patients have occult functional or anatomical abnormalities that may be identified by additional testing.5 This subpopulation cannot be neglected because symptoms of angina pectoris increase the probability of disability and premature exit from the workforce even in the absence of obstructive coronary artery disease.6 However, since the population of patients with angina without obstructive coronary stenosis is rather poorly defined, it will not be further discussed in this paper.


Table II. Pharmacotherapy at baseline in patients included in SCAD registries.
Abbreviations: ACEi, angiotensin convertase enzyme inhibitor; ARB, angiotensin receptor blocker; CADENCE, Coronary Artery Disease in gENeral practice; CASS,
Coronary Artery Surgery Study; CLARIFY, ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease; CORONOR, Suivi d’une
cohorte de patients COROnariens stables en région NORd-pas-de-Calais (cohort study of coronary artery disease patients from Nord-Pas-de-Calais, France); EHS,
EuroHeart Survey; EurObs, EURObservational Research Programme; INDYCE, INsuffisance coronaire stable, DYsfonction ventriculaire gauche et fréquenCE cardiaque
(left ventricular dysfunction and heart rate in stable coronary artery disease patients [registry]); MI, myocardial infarction; SCAD, stable coronrary artery disease.



Clinical outcomes

Data from RCTs and surveys indicate that the annual mortality rate in patients with SCAD ranges from 1.2% to 2.4%, with an annual incidence of cardiac death between 0.6% and 1.4%, and an annual incidence of nonfatal MI between 0.6% and 2.7%.4 The incidence of cardiovascular or cardiac deaths differs between studies, depending on patient characteristics.

For example, in the COURAGE trial27 (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation) and in the CORONOR registry (Suivi d’une cohorte de patients COROnariens stables en région NORd-pas-de-Calais [cohort study of coronary artery disease patients from Nord-Pas-de- Calais, France])21 most deaths were noncardiovascular, 73% and 55%, respectively, while in the SIGNIFY trial,7 67% of deaths were cardiovascular, and 55% cardiac. When the proportion of noncardiovascular deaths is relatively low, the all-cause death rate in patients with SCAD may be similar to that in the age- and sex-matched general population.21 However, the risk of death in SCAD patients is not uniform; it is influenced by age, comorbidities such as heart failure, diabetes, renal insufficiency, PAD, and COPD,13,26,28 and also by CAD-specific characteristics such as the duration and severity of symptoms13 or a history of previous ischemic events.11

It has been suggested that female patients with CAD receive inadequate treatment and have worse outcomes than males.23,29 However, in the CLARIFY registry there were no sex related differences in outcome after one year of follow-up.30 CLARIFY also assessed the effect of angina and ischemia on clinical outcomes31; 65% of patients had neither angina nor ischemia, and 58% of primary outcome events—including cardiovascular death or nonfatal MI—occurred in this group. The presence of concomitant angina and ischemia, or of angina alone, was associated with a worse outcome (hazard ratio [HR], 1.45; 95% confidence interval [CI], 1.08-1.95; P=0.01; and HR, 1.75, 95% CI, 1.34-2.29; P<0.01, respectively). There was no increase in cardiovascular events in patients with silent ischemia. Increased heart rate is a major factor associated with ischemia and angina, and an important marker of risk. At the same time, there is a large body of evidence showing that heart rate control is inadequate in a high proportion of patients despite the widespread use of β-blockers.9,32 The results of the SIGNIFY study indicate that in patients who had SCAD without heart failure, heart rate is not a modifiable determinant of outcome.7 Thus, improving heart rate control is likely to improve the symptoms, but not the outcome.

tatins and antiplatelet agents improve the prognosis of patients with SCAD.4 Their use has universally increased over the years (Table II),11,13,16-21,25 but in many geographical areas their use is still suboptimal. Surgical revascularization has the potential to decrease cardiac mortality in SCAD patients with extensive ischemia,33 but so far there is no evidence that the same is true for PCI.27 The ongoing ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches; NCT01471522) is likely to provide definitive information.

There are several scores that can be used to predict the outcome in patients with established11,13,24,26 or suspected SCAD,3 but their clinical usefulness is limited. It is noteworthy that the outcomes of patients included in clinical trials may not be much different from what is experienced in real life, despite the fact that surveys tend to enroll more complex patients. For instance, the 4-year composite clinical outcome including death and nonfatal MI of the COURAGE trial27 was identical to that of the contemporary cohort of the Mayo Clinic registry.15

Changing characteristics of patients with SCAD over time

The first registries of patients with SCAD date back to the 1970s.15,25,26 Data from the CASS registry—which comprised almost 25 000 patients referred for coronary angiography who did not qualify for the CASS study (Coronary Artery Surgery Study)—was collected between 1975 and 1979.25 The Mayo Clinic Registry included over 8900 patients who underwent PCI at the Mayo Clinic in the years 1979-2006.15 The majority of later registries, run on a global, European, or single-country scale, focused on ambulatory patients with SCAD managed by cardiologists or primary care physicians.9,11,12,14,16-18,21 Despite their differences, these registries seem to accurately depict the changes in patient characteristics and treatment over time (see Table I).

Over time the mean age of patients has increased by more than 10 years and the proportion of female patients has increased. The initial studies included almost exclusively symptomatic patients with angina, while in the subsequent ones there was considerable variability in the proportion of symptomatic patients, which ranged from 16% to 85%. There has been a steady increase in the prevalence of comorbidities, including hypertension, lipid abnormalities, diabetes, history of MI, heart failure, and renal failure. The same seems to be true for peripheral artery disease and asthma/COPD, although the data from older studies tends to be incomplete. While these changes can be in part attributed to the ageing of the SCAD population and to changes in diagnostic criteria, they appear to be representative of the true differences between patient cohorts. Obviously, contemporary patients are more likely to have a history of coronary revascularization (PCI, CABG, or both).

Of interest, the longitudinal, single-center registry of consecutive patients undergoing PCI for SCAD at the Mayo Clinic— which took place over 27 years and was divided into four time periods—provided a good reflection of secular trends. It showed that age and the prevalence of diabetes, hypertension, and hyperlipidemia had all increased over each time period.15 Pharmacotherapy has also evolved over the years (Table II). When the early registries were set up, secondary prevention in its present form did not exist, and in a number of papers there was no mention of drug therapy. At the beginning of the 21st century, only a minority of patients in Europe were treated with a statin, β-blocker, and antiplatelet agent.13 Later registries showed a significant positive change in this respect, but there is still room for improvement.14,19-21

Summary

The populations of patients with SCAD included in observational registries and randomized clinical trials differ in terms of age, proportion of male to female patients, medical history, presence and characteristics of symptoms, and comorbidities. Generally, their prognosis is good, and in some studies it is not much different from the general age- and sex-matched population. However, patients of advanced age, with heart failure, renal dysfunction, diabetes, COPD, and PAD, as well as those with angina and ischemia or a previous ischemic event are at increased risk of an incident cardiovascular event.

Over the last decades, there has been a clear change in the characteristics of patients with SCAD. Compared with patients enrolled at the end of the 20th century, contemporary patients with SCAD are older and are more likely to have a history of MI and coronary revascularization (PCI, CABG, or both). The prevalence of heart failure, diabetes, chronic renal and pulmonary disease, and peripheral artery disease has increased substantially. Thus, today’s patients represent a higher-risk group and are more difficult to manage due to the increased complexity of their medical problems.

There is considerable geographical variation in the clinical presentation and management of patients with SCAD. Although preventive pharmacotherapy has improved, it is still inadequate in many areas; as a result, risk factor control remains suboptimal overall. ■


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