The evolving clinical patterns of chronic coronary artery disease: clarifying the picture

Philippe Gabriel STEG,MD
Département de Cardiologie
Hôpital Bichat, Université
Paris-Diderot, INSERM U-698

The evolving clinical patterns of chronic coronary artery disease: clarifying the picturee

by P. G. Steg, France

Despite major advances in the prevention and acute management of coronary artery disease (CAD), the condition remains the number one cause of death worldwide. The presentation and management of patients with chronic CAD has changed drastically over the past decades. In the past, management of such patients largely involved measurement and control of anginal symptoms, with careful dosing of one or more antianginal agents. Over the years, however, the emergence of myocardial revascularization, improved secondary prevention measures, and the availability of novel potent antianginal agents have dramatically changed the clinical presentation of chronic CAD such that patients are now largely asymptomatic, with angina or ischemia rarely present; moreover, if angina or ischemia are identified, they often lead to delineation of the coronary anatomy by angiography with a view to revascularization. Yet, the clinical benefit of routine revascularization in patients with stable CAD is at best uncertain. The ongoing ISCHEMIA study (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) will determine the benefit of anatomical assessment of these patients compared with routine medical therapy alone. In the interim, the ongoing international observational registry CLARIFY (prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease), which was started in 2009-2010 in 46 countries, aims to collect contemporary information on the clinical characteristics, management, and outcomes (over a period of up to 5 years) of a large cohort (approximately 33 000 patients) representing a broad spectrum of stable outpatients with CAD. An ongoing analysis will describe the relative prevalence and prognostic impact of both anginal symptoms and the presence or absence of myocardial ischemia on noninvasive testing.

Medicographia. 2014;36:19-24 (see French abstract on page 24)

Changing epidemiology of coronary artery disease

There have been spectacular advances in the management of patients with coronary artery disease (CAD) over the past 3 decades, particularly in the field of acute coronary syndromes (ACS). The advent of effective reperfusion therapy, first with thrombolysis and subsequently with primary percutaneous coronary intervention (PCI), has been accompanied by steady progress in adjunctive antithrombotic therapy combining effective anticoagulant and antiplatelet therapy. There has also been progress in secondary prevention, with standardized management including liberal use of β-blockers, statins, angiotensin-converting enzyme inhibitors, and long-term antiplatelet therapy. Together, all of the aforementioned therapies have resulted in spectacular reductions in the lethality and complications of ACS. These reductions have been consistently documented in international registries, such as GRACE (the Global Registry of Acute Coronary Events),1 and national registries, such as SWEDEHEART/RIKS-HIA ([Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies]/ [Register of Information and Knowledge about Swedish Heart Intensive care Admissions]) in Sweden, the French acute myocardial infarction (AMI) registries, and the Danish registry in Denmark (Figure 1).2-4

Figure 1
Figure 1. Evolution of 30-day mortality in the French myocardial infarction registries from 1995 to 2010, as a function of the type of reperfusion therapy used.

Abbreviations: Adj, adjusted; CI, confidence interval; OR, odds ratio; PPCI, primary percutaneous coronary intervention.
After reference 3: Puymirat et al. JAMA. 2012;308 (10):998-1006. © 2012, American Medical Association.

In parallel with advances in the management of ACS, progress in prevention of cardiovascular events has also resulted in a reduction in the incidence of AMI and a decrease in deaths from coronary heart disease, at least in the “Western world.”5 Detailed analyses and modeling of such reductions have consistently shown that the bulk of these reductions is attributable to risk factor modifications, rather than acute treatment.5

However, despite this encouraging news, the epidemiology of CAD also shows worrisome signals: first, CAD is no longer solely a “disease of the West.” In fact, data show that the global burden of CAD has shifted to low- and middle-income countries, which account for the vast majority of cardiovascular deaths worldwide.6 For example, CAD mortality rates are much higher in Turkmenistan than in Western Europe or North America.7 This is related to the epidemiological transition that is occurring in many of the low- and middle-income countries, and to their large weighting in terms of the overall world population. This explains why, despite all of the progress that has been made, CAD remained the leading cause of death worldwide in 2010, ahead of stroke and chronic obstructive pulmonary disease.8,9 There are other worrying signals beyond the mortality data: the proportion of younger women among patients hospitalized for AMI is increasing, which parallels the increase in smoking prevalence among younger women and the increasing prevalence of obesity in the young.3,5

The emergence of revascularization

Another major change in the management of CAD has been the emergence of revascularization, particularly PCI, as a “dominant” modality for treatment. This stems from the documented mortality benefit of primary PCI for ST-segment elevation AMI,10,11 but also from the established clinical benefits of PCI in moderate-to-high–risk ACS.12-14 With the clear demonstration of these benefits, many countries and hospitals have worked to establish solid PCI centers that are able to provide round-the-clock access to effective PCI. Obviously, the availability of PCI for ACS opens the door to performing routine PCI for stable CAD. Paradoxically, however, at the same time as PCI has emerged as the standard of care for management of most patients with ACS, data regarding the use of PCI for stable CAD have failed to demonstrate a clear benefit in terms of clinical outcomes.15,16 Randomized trials performed in the 20th century that compared PCI with conservative medical therapy did not show a reduction in death or in the composite end point of cardiac death and myocardial infarction (MI).17 Later, the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation) compared optimal medical therapy (OMT) alone with OMT plus PCI. While approximately one-third of patients who were initially managed with medical therapy ultimately required intervention, there was no difference between the 2 study arms in clinical outcomes over 5 years.18 The only benefit of routine early PCI was a modest, but significant, reduction in anginal symptoms; however, this did not remain significant after 3 years.19

The results of COURAGE were subsequently confirmed by the BARI 2D trial (Bypass Angioplasty Revascularization Investigation 2 Diabetes), which was performed in 2368 patients with diabetes and stable CAD (of whom 82% were symptomatic with angina) and compared revascularization with medical therapy.20 Again, after 5 years of follow-up, there was no difference between the study arms in terms of survival, or survival without major adverse cardiovascular events. Thus, overall, routine PCI has not demonstrated any clinical benefit over modern medical therapy in the large randomized clinical trials powered for clinical outcomes. Obviously, while PCI techniques and outcomes have improved tremendously, this also is the case for medical therapy, which has become remarkably effective. Another consideration to keep in mind is that in both COURAGE and BARI 2D, randomization occurred after patients had undergone coronary angiography and the coronary anatomy had been defined. This opened the door to potential selection of lower-risk patients for revascularization and exclusion of patients with advanced or severe CAD and high risk, the very patients most likely to derive benefit from intervention. Indeed, there is data to support the concept that revascularization may be beneficial in stable CAD, provided the baseline risk and extent of ischemia is sufficient.21 The hypothetical benefit of the revascularization procedure over OMT alone is countered by the risk of harm induced by the revascularization procedure itself (such as periprocedural MI, stroke, or stent thrombosis). Hence, it is possible that for revascularization to be superior to OMT in terms of mortality and MI reduction, patients must be above a certain risk threshold that relates mainly to the extent of ischemia, the coronary anatomy, and possibly to clinical characteristics. This will be tested in the upcoming ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches; number NCT01471522).

ISCHEMIA will randomize 8000 patients with documented moderate-to-severe ischemia (involving >10% of the myocardium) in several hundred sites worldwide to either an invasive strategy plus OMT or to a conservative strategy of OMT alone, in which cardiac catheterization and revascularization will be reserved for patients with refractory angina or clinical events. In contrast with COURAGE and BARI 2D, randomization of patients will be performed before determination of coronary anatomy by angiography in an attempt to minimize any potential selection bias that would exclude higher-risk patients. So far, the only trial to test the value of revascularization that has randomized patients prior to performance of coronary angiography is TIME (Trial of Invasive vs Medical therapy in Elderly patients).22 However, in TIME, this resulted in enrolment of some patients who either had too little angiographic disease to warrant revascularization or, conversely, patients whose disease was too extensive to be amenable to revascularization. These concerns will in large part be mitigated in ISCHEMIA, as coronary computed tomography angiography will be performed prior to coronary angiography. This is designed to exclude patients with left main disease and also those without obstructive CAD, to minimize the dilutional impact of randomizing patients to invasive treatment who are not candidates for revascularization.

Because of the focus on myocardial revascularization in the management of CAD, the management of chronic CAD has largely shifted from long-term management of anginal symptoms to a focus on detection and treatment of myocardial ischemia, regardless of whether the ischemia is symptomatic or not. This is based on the concept that myocardial ischemia is prognostic,23 and that anginal symptoms are unreliable and correlate poorly with ischemia24 or with prognosis, particularly— but not solely—among diabetics.25 The dominant view is that ischemia—rather than symptoms—is the main determinant of prognosis,26 and it determines the potential benefit derived from revascularization.21 A recent analysis from the Heart and Soul Study examined outcomes as a function of the presence or absence of anginal symptoms and myocardial ischemia.26 The results showed that relative to patients with neither angina nor ischemia, angina conferred a modest increase in risk, but ischemia—particularly if it was symptomatic— was more important in driving prognosis (Figure 2, page 22).26 Indeed, recent studies do suggest that when revascularization is guided by a physiological assessment of coronary anatomy that is able to detect ischemia-generating lesions, such as fractional flow reserve assessment,27 revascularization is more likely to improve clinical outcomes.28 This has also resulted in a dramatic shift in the clinical presentation of patients with stable CAD. In the past, most patients with chronic CAD suffered from “chronic stable angina,” and physicians spent time and effort in measuring the burden of their angina and prescribing appropriate doses of antianginal agents, alone or in combination, to achieve optimal symptomatic relief. Instructions on proper prophylactic and therapeutic use of nitroglycerin or its derivatives and measurements of weekly and monthly use of short-acting sublingual nitrates were key elements of clinical management. Today, far fewer patients are symptomatic, as symptoms—particularly if associated with ischemia—are viewed as a clear indication for coronary angiography with a view to revascularization. Yet, angina remains a simple clinical indicator of outcomes, and the presence and severity of anginal symptoms parallels the burden of hospitalization and costs.29

Figure 2
Figure 2. Clinical patterns of coronary
artery disease in stable outpatients.

Data from the Heart and Soul Study, which included
937 outpatients with stable coronary heart disease
and 3.9 years of follow-up.Thirty-eight percent of outpatients
with stable coronary artery disease have
angina or ischemia or both.
Abbreviations: CHD, coronary heart disease;
MI, myocardial infarction.
Based on data from reference 26: Gehi et al. Arch
Intern Med. 2008;168(13):1423-1428.

The CLARIFY registry

Because of these major changes in the clinical presentation, management, and prognosis of patients with stable CAD, collection of representative and contemporary data on the current profiles, management, and outcomes of patients with stable CAD is of key importance. CLARIFY (the prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease) was established as a large-scale prospective international observational registry of outpatients with stable CAD, defined as any of the following 4 criteria (which are not mutually exclusive): history of previous MI (more than 3 months ago), presence of chest pain with objective evidence of myocardial ischemia on noninvasive testing, evidence of angiographic coronary artery stenosis of >50%, or history of previous myocardial revascularization with either PCI or coronary artery bypass grafting (more than 3 months ago). The exclusion criteria were minimized in order to enroll a broadly representative population. Patients were excluded if they had been hospitalized for cardiovascular disease in the previous 3 months, if they had planned 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 (eg, advanced heart failure, severe valve disease, history of valve repair/replacement, etc).

To ensure selection of a population that was representative of stable CAD outpatients, the selection of participating sites involved selection of predefined physician types and practice settings in each participating country. In addition, a short enrolment period was given to each site to enroll 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 to 50). Data are being collected anonymously through an annual visit that will take place for 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 is performed on-site at 5% of sites chosen at random in each country.

At these sites, 100% of case record forms are monitored for source documentation and accuracy. The data are collected and analyzed anonymously by an independent statistics center at the Robertson Center for Biostatistics (University of Glasgow, UK). Recruitment began in November 2009 and concluded in July 2010. Overall, 2898 investigators located at 2343 sites in 46 countries have enrolled more than 33 000 patients. Patients will be followed up on a yearly basis with a clinic visit, with interim 6-month phone calls every year, for up to 5 years. The large size, broad geographic scope, representativeness of the sample, and contemporary nature of the registry are important strengths of the data set.

Some of the baseline results from CLARIFY have already been published: there are important sex-related differences in clinical characteristics and management across all age groups in outpatients with stable CAD.30 However, although the baseline risk profiles of men and women differ substantially, 1-year outcomes were similar (even though fewer women underwent revascularization).31 Finally, despite a high rate of use of blockers, stable CAD patients frequently have an elevated resting heart rate of ≥70 beats per minute, which, in CLARIFY, is associated with an overall worse health status, more frequent angina, and ischemia.32

Another important issue in stable CAD is risk stratification. While several tools exist to allow risk assessment in patients with ACS (such as the GRACE or TIMI [Thrombolysis In Myocardial Infarction] risk scores),33,34 there is no such risk engine for patients with stable CAD, with the exception of the REACH (REduction of Atherothrombosis for Continued Health) risk score for atherothrombosis35; unfortunately, REACH did not include an assessment of heart rate, which has since emerged as a potentially important determinant of outcomes in patients with stable angina.36,37 At the end of the CLARIFY follow-up, a robust risk model to predict risk of adverse cardiovascular outcomes will be computed, which will allow incorporation of baseline demographics, clinical and biological examination findings, including heart rate, and, if appropriate, key elements of management. This tool will be important to identify those patients with stable CAD who are at high risk, and who may deserve more intensive evaluation and treatment.

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Keywords: angina, ischemia, prognosis, registry, revascularization