'Angina pectoris' was first described in 1772 by William Heberden.¹ Although Dr. Heberden was unsure about the pathology underlying this symptom, we now know it to be most commonly reflective of myocardial ischemia. The underlying cause of the ischemia is coronary atherosclerosis leading to inadequate coronary blood flow during periods of increased myocardial oxygen demand.² The diagnosis of chronic stable angina is made primarily by history and physical, making the agnosis somewhat subjective. Though subjective, angina is the first symptom of coronary artery disease in about 50% of patients and has been studied extensively over the past 50 years.

The prevalence and incidence of angina has varied by twofold among different reports.^3,4,5 It is estimated that nine million adults in the United States have chronic angina.⁶ It does appear that the prevalence of chronic stable angina has decreased since the 1970's based on more recent population studies.⁷ The prevalence of chronic stable angina increases with age for women, but peaks between 55 and 65 years of age for men and then declines.⁸ Whether or not the incidence is declining, the costs of this entity are staggering. The direct and indirect costs of coronary artery disease is estimated to have topped $177 billion in 2010.⁹ It should come as no surprise that this is one of the most studied clinical entities.

The past three decades have seen multiple studies explore the prognostic value of angina in patients with coronary artery disease. Cohn et al, found that annual mortality was twice as high (5.4% vs 2.7%), for patients with angina than a cohort of matched asymptomatic patients.¹⁰ A study of patients within the Veterans' Affairs system found that self-reported angina predicted risk of cardiovascular death. Those patients with severe symptoms had a four-fold increase in risk of death when compared to those with minimal symptoms.¹¹ These findings were replicated in women by a sub-study of the Australian Longitudinal Study on Women's Health. In this study, the frequency of angina was associated with increased all-cause mortality. Those patients with the most frequent and limiting angina had five times the risk of all-cause mortality.¹² A population study done using the Finnish healthcare system found 5-year mortality to be 4.4% in men and 5.4% in women. A subsequent study found that 10-year risk of death and non-fatal MI were greater than 10% in women requiring nitrates for their angina.¹³ In the United States, data from the Framingham Heart Study has shown the two-year incidence of non-fatal MI and coronary heart disease (CHD) death were 14.3 and 5.5% in men and 6.2 and 3.8% in women with an initial presentation of stable angina.¹⁴

Not all patients with coronary artery disease experience angina. Multiple studies in the 1980's explored the prognostic implications of asymptomatic patients with known coronary disease. The Coronary Artery Surgery Study(CASS) assigned patients to three groups, normal left ventricular(LV) function with Class I or II angina, reduced LV function with Class I or II angina and no angina. These groups were then randomized to surgery or medical therapy. At a mean follow up of six years there was no significant difference in survival or non-fatal MI among the three groups.¹⁵

The clinical outcomes for patients with chronic stable angina can vary greatly depending on patient characteristics. Over the past 15 years, multiple trials have compared treatment strategies for chronic stable angina. These trials have proved useful as the number and cost of treatment options have expanded. It is possible to assess outcomes for patients with chronic stable angina by reviewing the primary endpoints for placebo groups in secondary prevention trials. The HOPE trial compared outcomes among patients with stable coronary disease who had diabetes and at least one other risk factor who were treated with angiotensin-converting-enzyme inhibitors (ACEi). More than 50% of patients randomized had stable angina. A total of 9297 patients were enrolled with an endpoint of death from a cardiovascular cause occurring in 6.1% of the treatment arm, and 8.1% of the placebo arm over a mean of 4.5 years.¹⁶ The PEACE trial enrolled over 8200 patients with stable coronary artery disease and LV dysfunction, 70% of whom had angina. The trial compared addition of angiotensin converting enzyme inhibitor to standard medical therapy. In the placebo arm, death occurred in 3.7% of patients and non-fatal MI in 5.3% after a mean of 4.8 years.¹⁷ The ACTION trial compared outcomes in patients with symptomatic stable angina and hypertension in patients treated with nifedipine versus standard care. Over 7000 patients participated and over 90% of patients had angina at baseline. An end-point of death from any cause was reached in 1.64% of the treatment arm and 1.53% of the placebo arm after a mean follow-up of 1.1 years. The patients in this trial had symptoms of angina, plus prior MI event, positive stress test or angiographic evidence of CAD.¹⁸ Declining prevalence of stable ischemic disease may be secondary to more aggressive and successful medical management. As a point of reference, the last full ACC/AHA Guideline on chronic stable angina was published in 1999. The last update was published in 2002.

Revascularization is reserved for those that fail medical therapy, or have one of several specific subsets of coronary anatomy.¹⁹ Coronary revascularization relieves angina in up to 90% of patients. Despite this, there is little evidence to suggest it provides decreased morbidity and mortality outside of patients in whom CABG has already demonstrated clinical benefit.²⁰ It is worth noting that routine PCI is not recommended, based partly on the COURAGE trial. COURAGE compared 2287 patients with objective evidence of myocardial ischemia in the setting of angina randomized to optimal medical therapy plus PCI or optimal medical therapy alone. More than 80% of these patients reported at least Class I angina. An end-point of death and non-fatal myocardial infarction was reached in 19.0% in the PCI arm and 18.5% in the placebo group at a mean follow-up of 4.6 years.²¹ The COURAGE results are especially encouraging, as the study population had high rates of medical co-morbid illnesses, significant CAD by angiography and objective ischemia. A subsequent meta-analysis of ten prospective randomized control trials showed no significant difference between patients managed conservatively and those treated with percutaneous coronary intervention for end-points of all-cause mortality, CV mortality, MI and relief from angina.²² Taken together, the rate of death or non-fatal MI in these trials was less than 5% per year and often less than 2.5%.

With such a wide range of treatment options available, it is important to consider the cost of delivery of each treatment. Subsequent analysis of the COURAGE data found that the addition of PCI to optimal medical therapy cost an average of $10,000. There was no significant improvement in life years, or quality-adjusted life-years. More importantly, the average cost per patient to achieve an improvement in angina frequency was $154,580.²³

To conclude, adverse clinical outcomes are seen in patients with chronic stable angina at a rate of less than 5% per patient year when they are managed with guideline-directed medical therapy.

References

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3. Cannon PJ, Connell PA, Stockett IH et al. Prevalence of angina as assessed by a survey of prescriptions for nitrates. Lancet 1988;1:979-981.
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11. Mozaffarian D, Bryson CL, Spertus JA et al. Anginal symptoms consistently predict total mortality among outpatients with coronary artery disease. Am Heart J 2003;146:1015-1022.
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14. Murabito JM, Evans JC, Larson MG, Levy D. Prognosis after the onset of coronary heart disease. An investigation of differences in outcome between the sexes according to initial coronary disease presentation. Circulation 1993;88:2548–2555.
15. CASS Principal Investigators and Their Associates. Myocardial infarction and mortality in the Coronary Artery Surgery Study (CASS) Randomized Trial. N Engl J Med 1984; 310:750-758.
16. Yusuf et al. Effects of an angiotensin-converting-enzyme inhibitor, Ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342(3):145-53.
17. Braunwald et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;35(20): 2058-68.
18. Poole-Wilson PA, Lubsen J, Kirwan BA et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004;364:849-857.
19. Gibbons R, Chatterjee K, Daley J et al. ACC/AHA/ACP-ASIM Guidelines for the Management of Patients with Chronic Stable Angina: Executive Summary and Recommendations. Circulation 1999;99:2829-2848.
20. Thandani U. Current medical management of chronic stable angina. J Cardiovasc Pharmacol Ther 2004;9(suppl 1):11-20.
21. Boden WE, O'Rourke RA, Teo KK et al. Optimal medical therapy with or without PCI for stable coronary artery disease. N Engl J Med 2007;356:1503­16
22. Thomas S, Gokhale R, Boden WE, Devereaux PJ. A meta-analysis of randomized controlled trials comparing percutaneous coronary intervention with medical therapy in stable angina pectoris. Can J Cardiol 2013; 29:472-482.
23. Weintraub WS, Boden WE, Zhang Z et al. Cost-Effectiveness of Percutaneous Coronary Intervention in Optimally Treated Stable Coronary Patients. Circ Cardiovasc Qual Outcomes 2008; 1:12-20.

Keywords: Angina Pectoris, Angina, Stable, Angiography, Angiotensin-Converting Enzyme Inhibitors, Coronary Artery Disease, Coronary Disease, Diabetes Mellitus, Exercise Test, Follow-Up Studies, Hypertension, Incidence, Myocardial Infarction, Nifedipine, Nitrates, Oxygen, Percutaneous Coronary Intervention, Prevalence, Prospective Studies, Risk Factors, Secondary Prevention, Self Report, Veterans, Women's Health

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