Ischemic and Anatomic Burden in Coronary Artery Disease and the Role of the Oculostenotic Reflex


Despite the emergence of percutaneous coronary intervention in the management of acute coronary syndrome, its role in coronary artery disease and stable angina in addition to optimal medical therapy has been questioned. The role of ischemic burden as assessed by nuclear studies in these patients has been studied in a limited fashion. As such, this study aimed to explore the role of ischemic burden in determining death, MI or non-ST segment elevation acute coronary syndrome (NSTE-ACS) in patients with stable coronary disease and its potential synergistic role with anatomic burden of disease.


Out of 2287 patients enrolled in the COURAGE trial, 621 had baseline quantitative nuclear single-photon emission computed tomography (SPECT) and quantitative coronary angiography for analysis. Multiple logistic survival analysis was utilized to determine independent predictors of the primary composite endpoint of death, MI, and NSTE-ACS. Predictors examined included ischemic burden (defined from SPECT analysis), anatomic burden (derived from QCA analysis and an "anatomic burden score"), left ventricular ejection fraction, and assignment to OMT with or without PCI.


Of 621 patients examined, 313 were randomized to PCI + OMT as compared to 308 randomized to OMT alone. There were no differences in baseline characteristics between groups, however compared to the original COURAGE cohort, there were fewer white, more hypertensive, more diabetic, more prior coronary artery bypass graft surgery, fewer Canadian Cardiovascular Society class II and III, and more triple-vessel disease patients. In both groups, there were 185 primary events, with a raw incidence of 29.8%.

Multiple logistic survival analyses were performed for each independent variable tested. The first contained only the variables of interest, whereas the other two examined interactions between the variables and the treatment given in addition to between the variables themselves. Across all three models, LVEF and anatomic burden of disease were consistent predictors of the primary outcome (p = 0.0095 and 0.002, respectively). Conversely, treatment assignment and ischemic burden of disease did not predict outcomes in any model. Of note, there were no statistically significant interactions between any of the variables tested, although there was a correlation between ischemic and anatomic burden (p = 0.03). Further, a history of hypertension and CABG surgery were consistent independent predictors of the primary outcome, but did not change the significance of the aforementioned results when accounted for.


In patients receiving OMT for stable coronary artery disease, anatomic burden was a consistent predictor of death, MI and NSTE-ACS, whereas ischemic burden was not. Moreover ischemic burden, either in isolation or in conjunction with anatomic burden, did not identify patients who could preferentially benefit from an initial invasive strategy with PCI in combination with OMT.


Since the advent of coronary angiography, physicians have struggled with the role of percutaneous coronary interventions. While PCI has been shown to be beneficial in high-risk patients with acute coronary syndromes, extrapolation of its utility to stable ischemic heart disease (SIHD) has been more problematic.1 This population is not small, with a prevalence of 7.8 million (3.2% of the population) and an annual incidence of 565,000 as of 2014.2 As such, the question of how to optimally care for these patients has been debated, in particular the role of surgical or percutaneous revascularization in conjunction with optimal medical therapy.

The COURAGE trial, published in 2007, was one of the first major trials to evaluate this issue, comparing treatment of 2287 patients with SIHD with OMT + PCI versus OMT alone.3 Ultimately, no difference in the incidence of MI or death was observed (HR = 1.05; 95% confidence interval, 0.87 to 1.27; p = 0.62). Similarly, the BARI2D study examined 2386 patients with SIHD and type II diabetes and randomized them to OMT alone or in combination with either CABG or PCI.4 Like the COURAGE trial, there were no significant overall differences in mortality or major cardiovascular events. The STICH trial examined 1212 patients with SIDH and HFrEF, EF ≤ 35%, who were randomized to CABG + OMT versus OMT alone.5 This trial too demonstrated no statistical difference in mortality in the intention-to-treat analysis (HR = 0.86; 95% confidence interval, 0.72 to 1.04; p = 0.12). Indeed, these outcomes have been supported by meta-analyses as well.6

Some criticisms have arisen regarding the aforementioned trials. These studies focused either solely on coronary anatomy or coronary anatomy with only qualitative measures of ischemia. This raises questions about whether a higher risk patient population, perhaps with moderate to severe ischemia, could have benefited from PCI.

The COURAGE investigators sought out to answer this question through a retrospective analysis performed in 2012 for those patients with pre- and post-randomization myocardial perfusion SPECT analysis.7 1381 patients treated with OMT alone or OMT + PCI were randomized into no to mild or moderate to severe ischemia based on their pre-randomization SPECT.8 No differences in death or non-fatal MI were observed in either grouping. The BARI2D investigators were able to evaluate the extent and severity of ischemia after randomization with SPECT analysis, again with no significant differences in death or non-fatal MI in patients undergoing either CABG or PCI.9 Moreover, randomization of 399 patients from the STICH trial with and without inducible ischemia to CABG + OMT versus OMT alone demonstrated no significant difference in all-cause mortality (HR = 1.08; 95% confidence interval: 0.77 to 1.50; p = 0.66).10

The results of these trials bring into question the validity of myocardial ischemia measured by non-invasive testing. Fractional-flow reserve (FFR) is a pressure-wire based index that represents the degree of maximal myocardial flow that can be achieved in the presence of coronary stenosis. The utility of FFR was evaluated in patients with SIHD who underwent diagnostic coronary angiography in the FAME 2 trial.11 Any patient with at least one functionally significant stenosis (FFR ≤ 0.80) was randomized to PCI + OMT versus OMT alone. However, here, there were significantly fewer patients who underwent PCI who reached the primary composite outcome (death, non-fatal MI, and urgent revascularization) as opposed to patients who received OMT alone. This was driven by less need for urgent revascularization, an outcome not previously evaluated in prior studies. While no differences were observed between groups with respect to non-fatal MI and death, the trial was terminated early as the primary composite endpoint was reached.

In the COURAGE Coronary Anatomy versus Ischemic burden trial, it appeared that ischemic burden assessed non-invasively did not reliably predict the risk of death, MI, and NSTE-ACS nor was there a benefit from PCI + OMT vs OMT. Notably, approximately 70% of the 621 patients had only minimal to mild ischemia on nuclear stress testing (< 10% perfusion defect). The low number of moderate to severely ischemic patients in the study could have impacted the results as it pertains to the degree of ischemia and the primary outcome. Indeed, the authors cite the lack of a more robust coronary anatomical score such as the SYNTAX score and lesion specific FFR measurements to better assess anatomic burden. Even though the authors created a novel anatomic score, the results did show that anatomy was predictive of cardiovascular events and ischemia was not predictive. The trial also revealed an interaction between ischemic and anatomic burden. The study is a post hoc analysis so the results have to be interpreted with caution. Nonetheless with greater ischemia for severe atherosclerotic disease, there was a trend towards increased death, MI, and NSTE-ACS. Still, there seems to be no benefit of adding PCI to OMT in this cohort of patients with SIHD.

The ongoing ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial (NCT01471522) will hopefully resolve the clinical equipoise. Coronary CT scanning will be utilized to exclude patients with significant left main disease and those with minimal atherosclerosis, and then only patients with moderate to severe ischemia on stress imaging will subsequently be randomized to revascularization (PCI or CABG as appropriate) + OMT versus OMT alone.

The optimal treatment for SIHD remains challenging and this trial has shed light on further risk stratifying patients. Based on the results of this trial, it seems that physicians may utilize non-invasive myocardial stress testing in conjunction with coronary angiography to identify SIHD patients at the highest cardiovascular risk. Since the best treatment modality is currently unknown, providers should individualize patient care in the high risk groups or enroll those patients in the ongoing ISCHEMIA trial. As data continually emerge, providers are justified in being concerned about severe obstructive coronary artery disease. Yet, at present, the oculostenotic reflex has not proved beneficial with the emergence of contemporary medication regimens in patients with SIHD.


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Keywords: Acute Coronary Syndrome, Angina Pectoris, Angina, Stable, Coronary Artery Disease, Coronary Disease, Percutaneous Coronary Intervention

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