The relationship among coronary artery disease (CAD), angina, and ischemic burden is complex. It is rendered more complex by continuing improvements in medical therapy, and it is further complicated by the vast diversity of other patient characteristics at the time of presentation. Symptoms of angina pectoris are pressing targets of therapy and important determinants of guideline recommendations for revascularization. Although the presence of ongoing symptoms in spite of medical therapy is a common indication for revascularization and a strong determinant of other health resource utilization, the severity of presenting angina pectoris also typically dictates the pace with which revascularization options are pursued. This is based on the well-documented superiority of combination medical and revascularization therapy for rapid symptom relief, even though this benefit of added revascularization is lost fairly rapidly within the first year as compared with medical therapy alone. However, other underlying motivations exist, including the assumptions that 1) the severity of symptoms is linked to the underlying amount of viable and ischemic myocardium, 2) the latter, when documented through stress testing, is likely to result from more extensive coronary disease, and 3) the uncovering of high-risk anatomy will result in superior outcome with revascularization. It is important to re-examine these truisms because there is nothing more fundamental or more commonplace in the practice of cardiology than the assessment and management of patients with stable ischemic heart disease.

Recently reported data from the CLARIFY (Prospective Observational Longitudinal Registry of Patients With Stable Coronary Artery Disease) registry are quite provocative and instructive regarding symptoms of angina.¹ This registry of over 32,000 patients with a median follow-up of 2 years strikingly showed that in outpatients with known CAD and stable symptoms, those with angina at baseline had a higher event rate than those without angina. This was the case regardless of underlying ischemia. Even though the presence of both features showed slightly but not significantly higher risk, this effect was entirely attributable to angina because ischemia alone did not predict cardiovascular-related death, nonfatal myocardial infarction (MI), stroke, or all-cause death. In an analysis of the Heart and Soul Study of patients with known CAD, treated and observed over a median follow-up of 8.9 years, angina was associated with higher rates of secondary cardiovascular events and death, independent of the objective measure of disease severity, including presence of ischemia.²

It is important to recognize that these registry observations have important limitations and must be viewed in light of the fact that all patients were treated as deemed appropriate, including with revascularization. Although there are multiple randomized clinical trials (RCTs) in patients with stable ischemic heart disease, there are surprisingly little data from RCTs that assess the interaction between angina and outcome or its potential interaction with randomized therapy. A recent analysis from the STICH (Comparison of Surgical Treatment of Ischemic Heart Failure) trial showed that with background medical therapy in all patients, presenting angina did not predict all-cause mortality, nor did it identify a greater survival benefit from coronary artery bypass grafting in patients with known CAD and severely depressed left ventricular function.³ Thus, presence or absence of angina could not be used as a discriminating factor to decide for or against revascularization as an initial, elective strategy in patients with ischemic cardiomyopathy. Similar findings in patients without ischemic cardiomyopathy were reported in an analysis of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation) study wherein an initial strategy of optimal medical therapy alone for patients with Canadian Cardiovascular Society Class III angina or stabilized Class IV angina did not result in increased death or MI at 4.6 years of follow-up when compared to an initial medical-plus-angioplasty strategy.⁴ In patients with type 2 diabetes in the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial, symptom status also had no impact on cardiovascular events and death.⁵ Even asymptomatic patients at entry were at the same relatively high risk as patients with angina or angina-equivalent symptoms. In both the COURAGE and BARI 2D analyses, however, higher crossover or first revascularization rates were understandably seen in those with more severe angina at the time of enrolment.

Although the prognostic role of ischemia in patients without known CAD is not the focus of this brief overview, the prognostic role of ischemia in RCTs of patients with known CAD who are treated with medical therapy is critical, is associated with much more heated debate than is the role of angina symptoms, and is especially contentious regarding its putative role in selecting an optimal management strategy. In this arena, there is one ongoing trial, ISCHEMIA (the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches),⁶ that grew directly from consideration of the results of the COURAGE trial⁷ and particularly from an early, prespecified nuclear substudy that included 314 patients who underwent stress single-photon emission computed tomography imaging at baseline and again at 6–18 months while on optimal medical therapy.⁸ The least provocative finding was that stress-induced ischemia was reduced more effectively in patients undergoing percutaneous coronary intervention in addition to receiving optimal medical therapy. A hypothesis-generating observation was that patients who had a >5% reduction in ischemia at the time of follow-up, regardless of randomization, and a moderate defect at baseline had lower event rates after the follow-up scan. These results were significant only in unadjusted analyses (not in adjusted analyses).

It must be emphasized that the prior substudy assessed outcome after the follow-up scan. A subsequent analysis from the COURAGE trial that used observations from the time of randomization did not show a predictive role of baseline extent of ischemia.⁹ And another study, a direct comparison within a subgroup of COURAGE patients with core laboratory measures of reversible ischemia, coronary anatomy, and ejection fraction (to account for scar or potentially nonviable myocardium) also failed to show a prognostic role for reversible ischemia or an interaction predicting a better treatment strategy (Figure 1).¹⁰ The latter study did show an interaction between severity of reversible ischemia and angiographic burden of disease with respect to overall higher risk of death, MI, or non-ST elevation acute coronary syndromes, as one would expect (Figure 2). But there was no interaction with randomized therapy even when the two variables were combined. The only other RCT evidence using follow-up from the time of randomization to assess the role of baseline ischemia was an analysis from the STICH trial.¹¹ It also failed to show a prognostic effect of presenting ischemia. Thus, these three analyses from RCTs show consistent results that do not support the role of ischemia as a predictor of outcome or as a determinant of a preferred management strategy when aggressive medical therapy is initiated promptly and when revascularization is performed either promptly or when medically refractory symptoms warrant.

These analyses remain only hypothesis generating for many reasons, the most important of which are diversity of patients, assessment methods, ongoing changes in medical and revascularization decisions (e.g., use of fractional flow reserve at the time of angiography), lack of randomization based on presence and severity of ischemia at baseline, and underpowering of subgroups with high-risk coronary anatomy or moderate to severe ischemia. The importance, therefore, of the successful completion of the ISCHEMIA trial is underscored by these provocative but limited studies pertaining to the most commonplace aspect of day-to-day cardiology practice. In essence, ISCHEMIA is designed to test the hypothesis that patients with moderate amounts of inducible ischemia as determined by stress testing will have superior outcomes with a strategy of initial catheterization and optimal revascularization plus optimal medical therapy as compared with optimal medical therapy alone.⁶ Thus, the most concrete conclusion from this brief overview is that clinicians who are able to support recruitment into the ISCHEMIA trial should emphatically do so as much as possible.

Beyond that, it is also important to speculate on the implications of the observations to date. Absence of a predictive effect of baseline ischemia may indicate that current medical-plus-revascularization therapies, as applied through clinical judgment in the case of registries or in RCTs allowing for crossover when symptoms are medically refractory, is a form of practice that adequately abrogates the prognostic importance of ischemia itself for predicting hard clinical events.^9-11 Despite this, substantial residual risk is present due to many factors, including the risk inherent in underlying, diffuse atherosclerosis and determinants of progression and destabilization.¹² The biologic effects on atherosclerosis of risk factor management and medications such as acetylsalicylic acid, statins, angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, and perhaps also beta blockers is profound but so far unable to eliminate residual risk. The extent to which these medications affect and improve the biology of the vasculature, of lesions not severe enough to induce ischemia or to warrant revascularization, or of lesions appearing severe but not associated with ischemia (e.g., lesions with normal fractional flow reserve) are plausible reasons for the lack of connection between baseline ischemia that is treated adequately but with remaining underlying atherosclerosis that is not fully rendered quiescent, even with modern medical therapy.

However, the possible prognostic importance of angina itself in the absence of demonstrable ischemia still remains puzzling. It is conceivable that the symptoms actually reflect underlying cardiac dysfunction manifesting as chest pain. Similarly, the chest pain may impair exercise capacity, thereby inhibiting detection of ischemia while still actually reflecting underlying CAD or ventricular dysfunction. One might also speculate that patients with persistent angina may have activation of other mechanisms seldom considered, such as those mediated through activation of the central and/or sympathetic nervous systems (i.e., "chronic stress") that could augment either cardiac dysfunction or atherosclerotic processes directly or indirectly through secondary pathways such as hormonal or inflammatory mechanisms. From this perspective, "angina" per se, not associated with ischemia, may represent an incompletely understood element of residual risk that requires innovative thinking beyond traditional approaches that address only augmentation of blood flow and/or rebalancing of supply and demand.

In summary, there remain many unanswered questions regarding the prognostic importance of angina and documented ischemia. Both appear to lose prognostic ability in an era of aggressive risk factor management and with ready access to elective revascularization or when symptoms warrant. This status is a cause for celebration. But residual risk is not eliminated. The ISCHEMIA trial will give us a clearer picture of whether moderate ischemic burden at presentation that is verified to be associated with definite but not left main coronary disease, identifies a preferred management pathway. The study will also allow a re-evaluation of the role of angina as a predictor of events and/or a preferred management strategy.

References

1. 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.
2. Beatty AL, Spertus JA, Whooley MA. Frequency of angina pectoris and secondary events in patients with stable coronary heart disease (from the Heart and Soul Study). Am J Cardiol 2014;114:997-1002.
3. Jolicœur EM, Dunning A, Castelvecchio S, et al. Importance of Angina in Patients With Coronary Disease, Heart Failure, and Left Ventricular Systolic Dysfunction: Insights From STICH. J Am Coll Cardiol 2015;66:2092-100.
4. Maron DJ, Spertus JA, Mancini GB, et al. Impact of an initial strategy of medical therapy without percutaneous coronary intervention in high-risk patients from the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial. Am J Cardiol 2009;104:1055-62.
5. Dagenais GR, Lu J, Faxon DP, et al. Prognostic impact of the presence and absence of angina on mortality and cardiovascular outcomes in patients with type 2 diabetes and stable coronary artery disease: results from the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. J Am Coll Cardiol 2013;61:702-11.
6. International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA). Available at: https://clinicaltrials.gov/ct2/show/NCT01471522?term=international+study+of+comparative+ischemia&rank=1. Accessed 11/08/2015.
7. Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503-16.
8. Shaw LJ, Berman DS, Maron DJ, et al. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation 2008;117:1283-91.
9. Shaw LJ, Weintraub WS, Maron DJ, et al. Baseline stress myocardial perfusion imaging results and outcomes in patients with stable ischemic heart disease randomized to optimal medical therapy with or without percutaneous coronary intervention. Am Heart J 2012;164:243-50.
10. 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.
11. Panza JA, Velazquez EJ, She L, et al. Extent of coronary and myocardial disease and benefit from surgical revascularization in ischemic LV dysfunction [Corrected]. J Am Coll Cardiol 2014;64:553-61.
12. Mancini GB, Hartigan PM, Bates ER, et al. Prognostic importance of coronary anatomy and left ventricular ejection fraction despite optimal therapy: assessment of residual risk in the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation Trial. Am Heart J 2013;166:481-7.

Keywords: Acute Coronary Syndrome, Angina Pectoris, Angiography, Angioplasty, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Aspirin, Atherosclerosis, Biological Products, Cardiomyopathies, Catheterization, Cicatrix, Coronary Artery Bypass, Coronary Artery Disease, Diabetes Mellitus, Type 2, Drug Evaluation, Health Resources, Heart Failure, Motivation, Myocardial Infarction, Myocardial Ischemia, Myocardium, Outpatients, Percutaneous Coronary Intervention, Prospective Studies, Random Allocation, Registries, Risk Factors, Stroke, Sympathetic Nervous System, Tomography, Emission-Computed, Ventricular Dysfunction, Ventricular Function, Left, Angina, Stable

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