Physiology of Revascularization
Emergence of Clinical Ischemia as Important in Revascularization
This anatomy-based framework for revascularization was adopted from surgery by the interventional community. The finding of anatomic lesions, assessed subjectively via the 'oculostenotic' reflex, coupled with the lack of collaborative oversight in the decision-making process, led to an explosion of intervention with stents. A small number of noninferiority clinical trials compared PCI versus CABG, in lower-risk patients with less complex anatomic disease than the observational database cohorts of patients undergoing CABG 'in the real world'.[29,30] These anatomy-based trials, as a group, were not linked to the underlying presence of ischemia, now recognized as a significant limitation in their interpretation. However, one very real consequence of these trials was to drive both PCI and CABG underneath the umbrella of 'revascularization,' with important consequences for the designs of the SYNTAX, FREEDOM and ISCHEMIA trials (Box 1).[31]
Into this milieu, the COURAGE trial established the importance of OMT in SIHD.[32] This trial also helped accelerate the transition from 'chronic angina' (often without objective evidence of real angina substrate) to 'SIHD', and demonstrated that, in many cases, it could be treated by medication alone. This transition also highlighted that revascularization intervention should be based on more than just anatomy alone.[33]
Studies addressing myocardial integrity (diabetes, viability, consequences of prior injury including nonviability/scar and collateral development) produced equally surprising results in support of medical therapy. In the BARI-2D trial, where selected patients were randomly assigned after angiography, the rates of death and MI did not differ between the overall revascularization (CABG or PCI) and medical therapy groups.[34] In a similar fashion, the results of the STICH trial surprisingly failed to produce a better primary outcome (all-cause death) in patients with heart failure and reduced LV systolic function (LV ejection fraction ≤0.35) when CABG was compared with OMT.[35,36] However, in BARI-2D the CABG subset of patients with three-vessel disease demonstrated improved mortality.[34]
Into this confusing picture, the link of SIHD revascularization with ischemia came from a COURAGE substudy by Shaw et al., where they demonstrated that patients with significant (>5%) ischemia by serial myocardial perfusion scintigraphy had a significant reduction in ischemic burden when revascularization was added to OMT.[37] Moreover, the reduction of ischemia (>5%) was a marker for improved event-free survival up to 5 years in the PCI group.
Supporting this were two studies from Cedars Sinai. Hachamovitch et al. retrospectively studied 10,267 patients who underwent stress single-photon emission computed tomography myocardial perfusion scintigraphy, and were followed for a mean of 1.9 ± 0.6 years.[38] Revascularization compared with medical therapy had greater survival benefit in patients with moderate (>10%) to large ischemia, and the benefit was greater in patients with increasing levels of ischemia. Importantly, intervention in patients with <10% ischemia had poorer outcomes than medical therapy alone. In patients with >20% ischemia, revascularization was associated with a lower mortality than medical therapy (2.0 vs 6.7%; p < 0.02). Interestingly, 60% of the revascularization procedures were CABG. The authors duplicated these results in a larger (n > 13,000) patient population with >8-year follow-up.[39]
Emergence of Objective Ischemia Documentation as Important in Revascularization
Over this same decade, physiologic evaluation in the catheterization laboratory established the possibility of generating more information than just the anatomic definition of stenoses during diagnostic evaluation.[40,41] In PCI-based revascularization, the FAME (fractional flow reserve [FFR] vs angiography for multivessel disease) 1 and 2 studies and the DEFER studies[42,43] have created a paradigm shift from anatomy to 'functional anatomy' as the basis for PCI.[44–46] FFR is measured as a pressure drop across an anatomic stenosis at maximal coronary vasodilation, where a drop of >20% (FFR <0.8) is considered clinically significant as indicating a perfusion deficit and/or ischemia in the myocardium supplied by the TVECA with the anatomic stenosis. These studies demonstrated that intervention on anatomic stenoses without functionality was associated with poorer clinical outcomes and increased healthcare costs.[47]
Broadening the revascularization paradigm from anatomy alone to anatomy plus functionality has been slow to develop in the surgical arena, for several reasons. First, the improvement in surgical outcomes over time has dissuaded surgeons from deviating from the status quo. Second, the technique of traditional CABG with cardiopulmonary bypass (on-pump CABG) does not engender evaluation beyond anatomy alone; in the heart arrested with cardioplegic solution to provide a bloodless field and still heart, anatomy remains the only framework for technical execution of the operation. Paradoxically, this highly effective surgical framework has uncoupled the direct link between TVECA revascularization and the direct impact on the myocardium supplied by that target vessel. The threshold of 10–12.5% of ischemia established the importance of both anatomy (percentage anatomic stenosis) and functionality, which is regional ischemia associated with the TVECA in revascularization.
Broadening the revascularization paradigm also supports the importance of both short- and long-term mortality outcomes following intervention. Both the SYNTAX and FREEDOM trials showed a late (5-year) survival advantage in patients with three-vessel and complex two-vessel disease versus PCI using anatomy alone (the SYNTAX score) as the basis for revascularization intervention.[23,24,48] It is interesting to speculate how the SYNTAX results might be different under this more broad context for revascularization. For example, if the improved outcomes with physiologic-based revascularization versus anatomic-based revascularization seen in FAME were applied to the PCI arm of SYNTAX, would these late mortality differences have emerged?
Examination of ways to further quantify functional anatomy beyond percentage of ischemia in patients with SIHD is ongoing.[41] In the catheterization laboratory, new technologies measuring coronary blood flow, flow resistance and myocardial resistances under a variety of ischemic conditions have been reported. Determination of the perfusion deficit without maximal hyperemia using instant wave-free ratio is generating considerable controversy.[49–51] All of these efforts attempt to better understand the physiology of blood flow and perfusion in various clinical circumstances of SIHD and acute coronary syndromes.
Quantified functional anatomic assessment is being tested in the ongoing ISCHEMIA trial,[101] wherein a SIHD threshold of 10% or greater is required on prerandomization testing to identify patients eligible for trial enrollment. This enrollment ischemia criteria threshold needs to be met prior to a blinded cardiac computed tomographic angiography, which eliminates patients at either end of the anatomic spectrum for applicability and safety reasons. The remaining patients have documented ischemia and are then suitable for random assignment to conservative (OMT) or invasive (OMT plus revascularization) treatment arms, prior to defining their coronary anatomy, to prevent knowledge of coronary anatomy from biasing provider care delivery decisions. If they randomize to the conservative arm, no anatomy is defined unless clinically indicated.
Future Cardiol. 2014;10(1):63-79. © 2014 Future Medicine Ltd.
