By its definition, chronic stable coronary artery disease (CAD) refers predominantly to patients who have a prior history of or current demonstrable obstructive atherosclerotic disease of the epicardial coronary arteries and who are either asymptomatic, or have stable symptoms, with no evidence of recent symptomatic, hemodynamic, or electrical decompensation. Because the process of atherosclerosis usually evolves over several decades, the natural history of CAD typically involves long periods during which patients are asymptomatic, minimally symptomatic, or have stable symptoms that can be effectively managed; however, these periods of clinical stability can rapidly transition to acute coronary syndromes (ACSs), resulting in serious, and sometimes fatal, adverse cardiac events. The major goals of treating patients with chronic stable CAD are, therefore, 2-fold. One is to prolong life and prevent or reduce major adverse cardiovascular events. The second, and equally important, goal is to control symptoms of CAD—primarily angina—with the purpose of improving symptoms, functional status, and quality of life, as well as reducing hospitalizations. These goals are achieved, in part, by administering evidence-based medical therapies that have been proven to provide prognostic benefit, improve symptoms of angina, or achieve both goals; and by identifying (through appropriate testing) a subgroup of patients that may derive a prognostic benefit from coronary revascularization. This section will summarize the key therapeutic approaches to achieving these goals and direct the reader to additional details for each of the treatment strategies in other chapters.
Improving Survival and Prevention of Major Adverse Cardiac Events
Lifestyle Interventions
Numerous prior studies have documented the positive impact of dietary interventions and physical activity on surrogate markers of cardiovascular risk (such as blood pressure, lipids, blood glucose, and weight), and meta-analyses suggest that an intensive lifestyle intervention program may have a modest beneficial effect on cardiovascular mortality and prevention of myocardial infarction (MI). Multiple beneficial effects of cardiac rehabilitation programs have also been demonstrated in several prior studies, and they are endorsed by professional guidelines in patients who have sustained an ACS or have had a revascularization procedure. See Chapter 18 for more on this topic.
Medical Therapy
Few treatment approaches have been definitively shown to reduce mortality and prevent Major Adverse Cardiac Events (MACE) in patients with chronic stable CAD. Although β-blockers are a mainstay of therapy in chronic stable CAD, little evidence exists that their prolonged use results in improved survival or lower MACE rate. A meta-analysis of older clinical trials demonstrated an overall 23% relative risk reduction in mortality in patients following acute MI; however, this meta-analysis primarily included studies performed before the modern era of coronary revascularization/reperfusion and medical therapy and did not examine truly long-term treatment (median duration of follow-up was 1.4 years). Data from the REduction of Atherothrombosis for Continued Health (REACH) registry, which included over 20,000 propensity-matched patients that were and were not treated with β-blockers, demonstrated no statistically significant difference in the rates of MACE between patients with established CAD and no prior MI during a median follow up of nearly 4 years. Among patients with previous history of MI, the outcomes were numerically favorable in patients with versus without β-blocker use, but this difference was not statistically significant. Other large observational studies also suggest a modest benefit in patients with a recent MI, but not in those without prior acute MI. As a result, current guidelines for chronic stable CAD management give a strong recommendation for the use of β-blockers in patients with prior MI or history of heart failure, but not in other patients with chronic stable CAD.
Other medical therapies used for treating symptoms of CAD, such as calcium-channel blockers, nitrates, and ranolazine, have not been shown to have an effect on survival or MACE events. In randomized clinical trials, neither nifedipine nor amlodipine was shown to reduce the rates of cardiovascular death or MI. In the Metabolic Efficiency with Ranolazine for Less Ischemia in Non−ST-Elevation Acute Coronary Syndromes (MERLIN-TIMI36) trial, which was performed in patients stabilized after an ACS event, ranolazine did not significantly reduce the primary endpoint of cardiovascular death, MI, or recurrent ischemia compared with placebo. No cardiovascular outcomes trials have ever been performed with long- or short-acting nitrates in this patient population.
Antiplatelet therapy has been proven to improve outcomes in patients with established CAD and is endorsed by practice guidelines. The Antithrombotic Trialists’ Collaboration meta-analysis of over 135,000 patients, which included those with prior vascular events but also patients with previous coronary revascularization procedures and/or stable angina, demonstrated a significant reduction in MACE (nonfatal MI, nonfatal stroke, or vascular death) with antiplatelet therapy, primarily aspirin There was no difference in efficacy or safety between low-dose (75 to 150 mg daily) and higher-dose aspirin. The use of thienopyridines, such as clopidogrel, instead of aspirin may provide an additional modest benefit, but is not recommended unless patients are unable to tolerate aspirin. The use of dual antiplatelet therapy (aspirin plus P2Y12 receptor blocker) in patients with chronic stable CAD (and without another indication, such as recent coronary stent implantation) is more controversial; an in-depth discussion of antiplatelet therapy, as well as anticoagulants, is provided in Chapter 21 .
Lowering of low-density lipoprotein cholesterol (LDL-C) with statin therapy is a mainstay of chronic stable CAD management. Numerous clinical trials and multiple meta-analyses have demonstrated the benefits of LDL-C lowering—specifically with statins—on cardiovascular outcomes. Specifically, both in trials of statins versus placebo, and in trials of more intensive versus less intensive statin regimens, a consistent benefit of intensive statin therapy is observed in patients with established CAD, including reductions in cardiovascular and all-cause mortality, and MI, and, therefore, clinical guidelines strongly endorse high-intensity statin treatment for all eligible patients with established CAD. For patients with established CAD that require additional LDL lowering despite maximally tolerated statin therapy, several options for nonstatin LDL-C lowering exist; however, only ezetimibe has been shown to provide additional, modest clinical benefit in combination with a statin. Of note, the modest benefit with ezetimibe was observed in patients in whom treatment was initiated following an ACS event and was predominantly seen in the subgroup of patients with type 2 diabetes; whether these data can be extrapolated to patients with chronic stable CAD without prior ACS is unclear. Therapies aimed at raising high-density lipoprotein (HDL) and/or lowering triglycerides have so far failed to provide additional clinical benefit in recent clinical trials. The effects of LDL cholesterol lowering therapies in patients with established CAD are discussed in detail elsewhere ( Chapter 30 ).
In the broad population of patients with stable CAD, angiotensin-converting enzyme inhibitor (ACE-I), angiotensin receptor blocker (ARB), and mineralocorticoid receptor antagonists have not been consistently demonstrated to improve outcomes above and beyond blood pressure lowering; however, these agents have important benefits (including reduction in total mortality, MI, stroke, and heart failure) in several key subgroups of patients, such as those after acute MI with reduced left ventricular ejection fraction (LVEF), symptomatic heart failure, and high-risk diabetes, and may also improve renal outcomes in patients with chronic kidney disease (CKD) (particularly diabetic nephropathy). Medical therapy is discussed in more detail in Chapter 20 .
Coronary Revascularization
A benefit of coronary revascularization ( Chapter 23 ) on death and MI has been difficult to demonstrate in patients with stable CAD, except in select patient populations (high-grade left main disease, multivessel disease with reduced LVEF and/or large ischemic burden, etc.) in whom coronary artery bypass graft (CABG) surgery is indicated. Percutaneous coronary intervention (PCI), even with the latest generation drug-eluting stents, has not been shown to improve the natural history of stable CAD. This contrasts with evidence in patients with ACS, where routine use of PCI lowers the risk of recurrent ischemic events.
An important goal of management is to identify the minority of patients with stable ischemic heart disease (IHD) who have clear indications for coronary revascularization. Multiple noninvasive testing options are available for risk stratification, including standard stress electrocardiography ( Chapter 10 ), echocardiography and stress echocardiography ( Chapter 11 ), nuclear and positron emission tomography (PET) imaging ( Chapter 12 ) and cardiac computed tomography (CT), and magnetic resonance imaging (MRI) ( Chapter 13 ). Selection among the different testing options should be based on individual patient factors, local expertise, and cost considerations. ( Chapter 15 ). When high-risk findings are found on noninvasive testing, coronary angiography is generally indicated. Incorporation of functional assessment of the impact of coronary stenoses using hemodynamic assessments such as fractional flow reserve ( Chapter 14 ) improves decision-making regarding coronary revascularization, allowing deferral of revascularization for lesions with minimal hemodynamic significance.
Improving Symptoms and Quality of Life
Importance of Angina as Outcome in Patients with Chronic Stable CAD
Whereas prolonging survival and reducing the risk of recurrent adverse cardiac events are important, many of the treatments used for chronic CAD are used for the explicit purpose of reducing angina and improving quality of life. Despite improvements in interventional techniques and medications to reduce the burden of atherosclerosis, angina continues to be a substantial issue for many patients with chronic CAD. Understanding the burden and impact of angina on our patients and working to reduce that burden remain important goals of treatment of chronic CAD. Among patients with CAD, those with more frequent angina and more physical limitations due to angina are more likely to be hospitalized for an ACS and are more likely to die, as compared with those with minimal angina, even after adjusting for demographic and clinical factors. Among 5558 patients with CAD, nearly 20% of those who reported severe functional limitations due to angina died by 2 years versus less than 5% of those who reported minimal limitations from angina ( Fig. 16.1 ).
Importantly, treatment of angina in patients with chronic CAD, either with medications or revascularization, has not been shown to improve prognosis except in rare circumstances (e.g., large ischemic burden, disease in the proximal left anterior descending coronary artery). As such, the association of burden of angina with increased risk of mortality is likely more of a marker of a higher risk patient, as opposed to a mediator of poor outcomes that can be modulated. However, there are other benefits of aggressively treating angina, namely in improving quality of life and reducing healthcare utilization. Angina is not only associated with substantial impairment in disease-specific and generic quality of life, but relief of angina after revascularization has been shown to be the primary determinant of improvement in quality of life.
Beyond its impact on quality of life, angina is also related to healthcare utilization. In a study of 5460 patients after a hospitalization for an ACS, residual angina was associated with a graded risk for both cardiovascular hospitalizations and increased resource utilization ( Fig. 16.2 ).
Patients with angina had incremental costs of approximately $125 (monthly angina) to $500 (daily angina) per month of follow-up over the monthly costs of those without residual angina, which were primarily driven by hospitalizations for recurrent acute coronary events or coronary revascularization. Whereas treatment of angina has not specifically been shown to reduce healthcare utilization, in an era of increasing capitation and reimbursement based on quality of care, interventions that effectively reduce the burden of angina, including disease management programs, could potentially reduce both morbidity and healthcare costs.
Measuring Angina Burden
A unique feature of angina is that there is no biologic or imaging assay that can quantify it. In research studies, semi-quantitative methods of treadmill testing with time to chest pain or ST-segment depression have been used as a means of quantifying the patient’s burden of angina and response to antianginal medications. However, these methods, although reasonably assessing ischemia, are artificial in their assessment of angina, as they do not represent patients’ daily lives nor are they practical to serially assess in clinical practice. Instead, the physician/patient interaction is the primary means by which physicians assess patients’ responses to therapy and the need for further testing or treatment. As such, the evaluation of angina is subject to all the limitations inherent in history taking, including physical and psychosocial barriers to the proper conveyance of information, preexisting biases on the part of both physicians and patients, and the inherent inter-rater variability across physicians. Studies have shown that both cardiologists and primary care doctors often underestimate the burden of angina of their patients when they rely on free-form interviews. In a multicenter, cross-sectional sample of patients with coronary artery disease, 42% of patients who reported chest pain in the prior month had their angina underrecognized by the treating physician. Few patient factors were associated with underrecognition; instead, it was explained by variation in the quality of physician assessment, with some physicians being quite good at angina recognition while others were poor (range of underrecognition rates of 0–86%). These data underscore that a more systematic approach is needed for assessing angina in patients with CAD.
Many physicians rely on Canadian Cardiovascular Society (CCS) grading of angina, which asks the physician to grade the level of activity that brings on chest pain, ranging from a score of 0 to 4 ( Table 16.1 ).
| Class 0 | Asymptomatic |
| Class I | Angina during strenuous or prolonged physical activity only |
| Class II | Angina with moderate physical activity, such as walking or climbing stairs briskly |
| Class III | Angina with ordinary physical activity, such as walking on level ground at normal pace |
| Class IV | Angina at rest or with minimal activity, such as dressing or showering |
This grading scale is used in the Appropriateness Criteria for coronary revascularization and is easy to calculate, as it arises simply from the information gathered in the physician/patient interview. However, similar to New York Heart Association functional class in heart failure, it does not provide any standardized assessment directly from the patient and, therefore, is susceptible to biases and errors. For example, in a clinical trial of patients undergoing revascularization, physicians tended to overestimate the burden of angina of their patients using CCS class when compared to a patient-reported measure prior to revascularization and underestimate residual angina after revascularization.
Assessing symptoms directly from patients with a validated instrument, such as the Seattle Angina Questionnaire (SAQ), provides more reliable and reproducible results than physician-derived scales. The SAQ has been used to document angina burden and disease-specific quality of life in patients with CAD in numerous clinical trials and registries and has been shown to correlate closely with daily angina and sublingual nitroglycerin diaries. Despite its established validity, its widespread use in research studies, and its promotion for clinical use by major societies, the routine clinical use of the SAQ (along with other similar health status measures for conditions such as heart failure and peripheral artery disease) has been hindered by logistic barriers. A shorter, seven-item version of the SAQ has been developed, which was designed to simplify this transition from being a research instrument to an effective clinical tool. The SAQ-7 is a reliable and valid measure of the burden of angina from the patient’s perspective and changes in scores over time (≥ 10 points on the SAQ angina frequency domain score or ≥ 5 points on the SAQ summary score) can support clinicians in their management of patients with CAD (e.g., up-titration of antianginal medications, referral for revascularization). However, moving patient-reported outcomes, such as the SAQ, into routine clinical care requires creative implementation strategies, including novel mechanisms to collect, score, and interpret these data, work that is on-going.
Medical Therapy to Treat Angina
Pharmacologic treatment is the mainstay of treatment of angina ( Chapter 20 ) and has been shown to reduce the frequency of angina, reduce the functional limitations due to angina, and improve quality of life. Medications to treat angina are generally grouped into those that decrease myocardial demand (e.g., β-blockers, calcium-channel blockers, ranolazine) and those that improve myocardial oxygen supply (e.g., calcium-channel blockers, long-acting nitrates) ( Table 16.2 ).
