Angina pectoris is the most prevalent manifestation of myocardial ischemia and coronary artery disease (CAD), affecting up to 9 million patients in the United States. Compelling evidence suggests that the presence of limiting angina can have a profound impact on the quality of life of patients with stable CAD and may affect their prognoses.¹ The aims of this article are to review, in a contemporary setting, the prognosis associated with a clinical diagnosis of suspected angina and the main clinical and investigative predictors of outcomes in this condition.

Angina and Medical Outcomes

Several studies during the past three decades have explored the prognostic impact of angina in patients with CAD. In this area, compelling evidence shows that anginal symptoms among patients with stable CAD predict worse clinical outcomes. The HOPE (Heart Outcomes Prevention Evaluation) trial compared outcomes among patients with stable CAD who had diabetes and at least one other risk factor and who were randomly assigned to receive an angiotensin-converting-enzyme inhibitor or placebo. More than half of randomized patients had stable angina. A total of 9,297 patients were enrolled with the endpoint of death from a cardiovascular (CV) cause occurring in 6.1% of patients in the treatment group and 8.1% of those in the placebo group over a mean of 4.5 years. In a large registry of 2,376 patients with ischemic cardiomyopathy admitted at Duke University Medical Center from January 2000 to September 2009, Mentz et al. showed a strong association between angina pectoris and increased risks of CV death or CV rehospitalization.² In addition, persistent angina following cardiac catheterization was also independently associated with increased long-term major adverse cardiac events and rehospitalizations.³ In the HF-ACTION (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure) trial, in which 406 patients (17%) had angina at baseline (44% with Canadian Cardiovascular Society [CCS] classification score ≥II), angina status was associated with worse health-related quality of life and with 22% greater adjusted risk for all-cause mortality/hospitalizations.⁴ Finally, according to a sub-analysis of the prospective CLARIFY (Prospective Observational Longitudinal Registry of Patients With Stable Coronary Artery Disease) registry having included 20,291 patients with CAD, there was an elevated risk of CV death or nonfatal myocardial infarction (MI) among patients with angina compared with those without such symptoms.⁵

Main Predictors of Outcomes in Patients With Angina

Prognostic assessment is a crucial component of care in CV disease. Risk stratification is also of great importance in patients with angina. Long-term prognosis of patients with stable angina depends upon a number of factors, such as clinical and demographic variables, left ventricular (LV) function, stress testing results, and coronary anatomy.

The severity of angina is classically assessed using the four-level grading system of the CCS classification. In the ACRE (Appropriateness of Coronary Revascularisation) study, a prospective, population-based registry with a 2.5-year follow-up of 2,849 consecutive patients with angina, the CCS class was linearly associated with angiographic findings, revascularization rates, mortality, and nonfatal MI.⁶

Being a pivotal determinant of myocardial oxygen consumption, heart rate (HR) potentially also plays an important role in the development of adverse outcomes in patients with angina. In the randomized, controlled BEAUTIFUL (Effects of Ivabradine in Patients With Stable Coronary Artery Disease and Left Ventricular Systolic Dysfunction) study, an elevated HR (≥70 bpm) was associated with increased risks of CV death (34%), hospitalization for fatal or nonfatal MI (46%), and coronary revascularization.⁷

In the Euro Heart survey, Daly et al. investigated the prognosis of patients with stable angina. Stepwise regression identified co-morbidity, diabetes, recent onset of symptoms, more severe symptoms, and ST or T wave abnormalities on the resting electrocardiogram as the clinical variables most predictive of outcomes.⁸ In a multicenter cohort of 8,762 patients with suspected angina and a median follow-up of 10 years (and 233 coronary deaths), Sekhri et al. developed their prognostic model that showed strong associations with coronary mortality for age (older, HR = 2.33 per 10 years), sex (male, HR = 1.91), chest pain pattern (typical angina, HR = 1.59), smoking status (current smoking, HR = 1.64), diabetes (HR = 1.99), HR (HR = 1.22 per 10 bpm), and electrocardiogram findings (HR = 1.96).⁹

Another strong predictor of long-term survival in patients with angina and CAD is LV systolic function. In patients with stable CAD, it is well established that mortality increases as LV ejection fraction declines. In the CASS (Coronary Artery Surgery Study) registry, the following were 12-year survival rates of patients according to ejection fraction (p < 0.0001):¹⁰

Ejection Fraction (%)	12-Year Survival Rate (%)
≥50	73
35-49	54
<35	21

CV risk stratification generally includes noninvasive assessment of myocardial ischemia and LV function and sometimes invasive assessment of coronary anatomy. Stress echocardiography is effective for stratifying patients with angina according to their risk of subsequent CV events. Patients with inducible wall motion abnormalities in ≥3 of the 17 segments of the standard LV model should be regarded as being at high risk of event.¹¹ Myocardial perfusion imaging using single-photon emission computed tomography (SPECT) is also a useful method of noninvasive risk stratification. Patients with stress-induced reversible perfusion deficits >10% of the total LV myocardium (≥2 of the 17 segments) represent a high-risk subset.¹² Finally, severity of luminal obstruction and extent of coronary disease on coronary arteriography have also been convincingly demonstrated to be important prognostic indicators in patients with angina. In the CASS registry of medically treated patients, the 12-year survival rate of patients with normal coronary arteries was 91%, compared with 74% for those with one-vessel disease, 59% for patients with two-vessel disease, and 50% for those with three-vessel disease (p < 0.001).¹¹ Furthermore, patients with severe stenosis of the left main coronary artery have a poor prognosis when treated medically.¹³ In large prospective trials investigating the prognostic value of coronary computed tomography angiography, patients with left main stenosis or proximal triple vessel disease have a univariate hazard ratio for all-cause mortality of 10.52, suggesting that risk defined by coronary computed tomography angiography is similar to that found in invasive coronary angiography studies.¹⁴ In the subset of 621 patients from the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial with both quantitative invasive coronary angiography and myocardial SPECT imaging at baseline, anatomic burden of CAD defined by invasive angiography was predictive of death, MI, and acute coronary syndrome, whereas ischemic burden of coronary disease defined by SPECT imaging was not.¹⁵

In conclusion, adverse clinical outcomes still occur in a sizeable proportion of patients with angina. Prognostic assessment is a pivotal step in the management of these patients. A variety of clinical and investigative characteristics mentioned in this article must be taken into account to determine the risk of adverse outcomes in patients with angina.

References

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2. Mentz RJ, Fiuzat M, Shaw LK, et al. Comparison of Clinical characteristics and long-term outcomes of patients with ischemic cardiomyopathy with versus without angina pectoris (from the Duke Databank for Cardiovascular Disease). Am J Cardiol 2012;109:1272-7.
3. Mentz RJ, Broderick S, Shaw LK, Chiswell K, Fiuzat M, O'Connor CM. Persistent angina pectoris in ischaemic cardiomyopathy: increased rehospitalization and major adverse cardiac events. Eur J Heart Fail 2014;16:854-60.
4. Parikh KS, Coles A, Schulte PJ, et al. Relation of Angina Pectoris to Outcomes, Quality of Life, and Response to Exercise Training in Patients With Chronic Heart Failure (from HF-ACTION). Am J Cardiol 2016;118:1211-6.
5. Steg PG, Greenlaw N, Tendera M, et al. Prevalence of anginal symptoms and myocardial ischemia and their effect on clinical outcomes in outpatients with stable coronary artery disease: data from the International Observational CLARIFY Registry. JAMA Intern Med 2014;174:1651-9.
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7. Fox K, Ford I, Steg PG, et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet 2008;372:817-21.
8. Daly CA, De Stavola B, Sendon JL, et al. Predicting prognosis in stable angina--results from the Euro heart survey of stable angina: prospective observational study. BMJ 2006;332:262-7.
9. Sekhri N, Perel P, Clayton T, Feder GS, Hemingway H, Timmis A. A 10-year prognostic model for patients with suspected angina attending a chest pain clinic. Heart 2016;102:869-75.
10. Emond M, Mock MB, Davis KB, et al. Long-term survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation 1994;90:2645-57.
11. Chelliah R, Anantharam B, Burden L, Alhajiri A, Senior R. Independent and incremental value of stress echocardiography over clinical and stress electrocardiographic parameters for the prediction of hard cardiac events in new-onset suspected angina with no history of coronary artery disease. Eur J Echocardiogr 2010;11:875-82.
12. Lin FY, Dunning AM, Narula J, et al. Impact of an automated multimodality point-of-order decision support tool on rates of appropriate testing and clinical decision making for individuals with suspected coronary artery disease: a prospective multicenter study. J Am Coll Cardiol 2013;62:308-16.
13. Califf RM, Armstrong PW, Carver JR, D'Agostino RB, Strauss WE. 27th Bethesda Conference: matching the intensity of risk factor management with the hazard for coronary disease events. Task Force 5. Stratification of patients into high, medium and low risk subgroups for purposes of risk factor management. J Am Coll Cardiol 1996;27:1007-19.
14. Min JK, Dunning A, Lin FY, et al. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol 2011;58:849-60.
15. Mancini GB, Hartigan PM, Shaw LJ, et al. Predicting outcome in the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation): coronary anatomy versus ischemia. JACC Cardiovasc Interv 2014;7:195-201.

Keywords: Angina, Stable, Diagnostic Imaging, Acute Coronary Syndrome, Angina, Stable, Benzazepines, Cardiac Catheterization, Cardiomyopathies, Constriction, Pathologic, Coronary Angiography, Coronary Artery Disease, Echocardiography, Stress, Electrocardiography, Heart Failure, Myocardial Infarction, Myocardial Ischemia, Myocardial Perfusion Imaging, Myocardium, Risk Factors, Tomography, Emission-Computed, Single-Photon

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