January 27th, 2014

How “Compelling” Are Coronary Anatomy and Ischemic Burden When Considering an Invasive Strategy?

CardioExchange’s Richard Lange and David Hillis interviewed William E. Boden about his research group’s post hoc analysis of data from the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial. The study is published in JACC: Cardiovascular Interventions.

Lange and Hillis: Two interesting findings emerged from your analysis:

1. Baseline left ventricular ejection fraction and the anatomic burden of disease each significantly predicted incidence of the combined endpoint of death, myocardial infarction, or non–ST-segment elevation acute coronary syndromes — but baseline ischemic burden did not.
2. None of these baseline factors identified patients who would benefit from an initial invasive management strategy.

Given these results, should we be evaluating the extent of disease in patients with symptoms of or risk factors for CAD? If so, how? Does everyone (or anyone) need angiography, cardiac CT, etc.?

Boden: COURAGE has often been criticized because coronary angiography was, by trial design, obtained in all study patients. Also, because the trial’s primary endpoint did not show an incremental benefit of PCI + optimal medical therapy (OMT) compared with OMT alone, many have suggested that the results indicate we should not subject such patients to coronary angiography. Moreover, because all COURAGE participants had objective evidence of inducible myocardial ischemia by either standard exercise treadmill testing or myocardial perfusion imaging, the same argument has been used to question the need for ischemia testing.

A strength of COURAGE was that coronary anatomy was defined in all participants who had demonstrable ischemia. Canadian Cardiovascular Society class I–II angina, combined with objective findings of ischemia, warrant coronary angiography, given that we know some of these patients may exhibit high-risk anatomy. John Mancini’s recent post hoc analysis shows that an angiographic assessment of anatomic burden was more predictive of death, MI, or hospitalization for ACS than was an assessment of ischemic burden. However, neither modality could identify any subset of patients who appeared to benefit from PCI.

Why should this be, and why if an assessment of anatomic burden has value in defining late cardiovascular events, doesn’t PCI reduce the incidence of these events? I think the explanation is that late events are occurring from new plaque ruptures in non-instrumented coronary arteries, or in arteries where the coronary diameter reduction is less than 50%. That would explain why anatomy predicts subsequent events despite the fact that PCI does not necessarily result in better late outcomes — because “fixing” flow-limiting stenoses do nothing to mitigate the risk of vulnerable plaques in non–flow-limiting stenoses.

Lange and Hillis: Recent guidelines recommend revascularization for “compelling” coronary anatomy (i.e., three-vessel CAD, multivessel CAD involving the proximal left anterior descending, etc.). Given that anatomic burden does not identify patients who would benefit from an initial invasive strategy, should we abandon this?

Boden: Yes. The data do not support any clinical benefit of PCI in these patients with stable ischemic heart disease (SIHD), yet this is one of the most difficult paradoxes for clinicians to accept. Intuitively, we believe that stenosis severity drives events, but a separate paper by Mancini in 2013 showed that a quantitative coronary angiography analysis of all COURAGE angiograms could not identify even one anatomic subset of patients whose outcomes were better with PCI than with OMT. Like it or not — or believe it or not — the data are the data.

Lange and Hillis: Your results suggest that ischemia might be important in determining outcomes in patients with a more severe atherosclerotic burden. Might you speculate why ischemia predicts worse outcomes only in this group?

Boden: We really do not know whether moderate-to-severe ischemia predicts worse outcomes in SIHD patients. Two nuclear substudies from COURAGE showed opposite findings regarding whether PCI benefited SIHD patients. That conflicting information makes it difficult to interpret the significance of ischemia — even moderate-to-severe ischemia — and whether we should routinely recommend revascularization in these patients. The ongoing ISCHEMIA trial is targeting higher-risk SIHD patients, to determine whether revascularization yields better long-term outcomes in this patient subset.

In light of Dr. Boden’s analysis, share your assessment of the degree to which coronary anatomy and ischemic burden should factor into decisions about invasive management.

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