Significant left main coronary artery disease (LMD) carries important therapeutic and prognostic implications given the large amount of myocardium at risk. Current clinical practice guidelines from both the American College of Cardiology/American Heart Association and the European Society of Cardiology recommend revascularization for all patients with ≥50% stenosis irrespective of symptomatic status or associated ischemic burden.[1,2] These recommendations are largely based on post hoc analyses of 185 patients from 2 randomized trials of coronary artery bypass grafting in comparison with medical therapy and registry data, which showed improved survival over 5–10 years in the coronary artery bypass grafting arm. Notably, medical therapy was modest compared with contemporary standards, with <20% of patients on aspirin, only two-thirds on beta-blockers, and statins not in common use.
More recently, the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial showed that in patients with stable ischemic heart disease and moderate to severe ischemia on noninvasive stress testing, routine invasive therapy failed to reduce major adverse cardiac events compared with optimal medical therapy. An important exclusion from the trial was patients with >50% LMD as noted on computed tomography angiography (CTA) (8% of all enrolled patients), in addition to those with left ventricular ejection fraction <35%, advanced chronic kidney disease (estimated glomerular filtration rate <30 mL/1.73 m2 body surface area), recent acute coronary syndrome, New York Heart Association functional class III or IV heart failure and unacceptable angina despite maximal medical therapy. In a way, ISCHEMIA results were like those from the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial from more than a decade ago, where upfront percutaneous coronary intervention did not reduce the risk of death or myocardial infarction compared with optimal medical therapy.
Predicting or ruling out LMD with accuracy has long been known to be the Achilles' heel of noninvasive stress imaging. Existing data is limited to smaller studies with significant heterogeneity. In this issue of the Journal, Senior et al present findings from post hoc analysis of the ISCHEMIA trial to explore the markers of LMD (defined as >50% stenosis on coronary CTA). Using clinical and noninvasive functional parameters as seen on single-photon emission computed tomography, positron-emission tomography, dobutamine stress echocardiography, and exercise treadmill test (ETT) in ISHCEMIA trial participants, the authors aimed to help identify patients with highly probable LMD or a low risk of LMD, which could potentially obviate the need for anatomical imaging. The authors need to be commended on their investigation given the paucity of quality data in this cohort, which is not uncommonly encountered in clinical practice, but the findings need to be interpreted keeping study design in mind.
In their post hoc analysis of 5,146 patients from the ISCHEMIA trial, 414 (8%) had LMD. Older age, male sex, absence of prior myocardial infarction, transient ischemic dilation on stress echocardiography, magnitude of ST-segment depression, and peak METS achieved on ETT were all significantly associated with LMD; however, logistic regression models were weakly predictive of LMD. Interestingly, nuclear stress testing parameters were not independently associated with LMD. Similarly, the ability of predictive models to exclude LMD was modest. The question becomes, is LMD indeed unable to be predicted using clinical and noninvasive stress testing and clinical parameters, with anatomical imaging being the only choice? Before fully committing to the results of the study, some factors need to be considered, most of which are well acknowledged by the authors. First and foremost, this is a post hoc analysis to study an association that was not the major focus in the ISCHEMIA trial. The noninvasive assessment before enrollment was geared toward detection of moderate to severe ischemia, rather than specifically looking for global ischemia or LMD. It is for this reason, in this post hoc analysis, when we examine predictive factors for LMD some well-known predictors of LMD on noninvasive testing, such as aVR lead elevation during ETT or right ventricular tracer uptake during single-photon emission computed tomography, are not included.[7,8] If these additional parameters during noninvasive testing were taken into consideration, the overall predictive power for LMD may have been stronger with a higher C-index than what was noted. Second, it must also be pointed out that because an inclusion criterion of the ISCHEMIA trial was moderate to severe ischemia on noninvasive testing, patients with mild or no ischemia who may also have LMD were not enrolled. Although ~8% of patients with moderate to severe ischemia were found to have LMD, we do not know how many patients with mild or no ischemia on noninvasive stress testing in a similar population would have had LMD. Those patients may have had different profiles, and hence, the demographic predictors of LMD may have been different. In the current analysis, the only demographic predictors of LMD were age, male sex, and absence of prior myocardial infarction. For certain other parameters, such as advanced chronic kidney disease, recent acute coronary syndrome, severe left ventricular dysfunction, and other exclusion criteria from ISCHEMIA, we cannot deduce from this analysis, because these patients were excluded and may well have been independent, even stronger, predictors of LMD. It is interesting, however, that 8% LMD incidence, as seen by the authors, is close to the 5%-7% incidence of LMD as seen in "all comers." Third, using 50% diameter stenosis on CTA alone as a cut off for significance may have affected the findings as well, as not infrequently, LMD that appears visually significant may not be physiologically significant and ischemia generating, and therefore can be missed on noninvasive stress testing. Senior et al performed separate analyses on patients with >70% left main stenosis, which also did not reveal any significant association. Last, although cardiac CTA can detect stenosis of large caliber proximal coronary arteries (including left main coronary artery) well with a high degree of concordance with invasive angiography, certain limitations can affect the interpretation. Increased heart rates, obesity, and stents or significant calcification in the left main coronary artery can lead to suboptimal visualization. Whereas patients with cardiac CTA-detected LMD will invariably need angiographic evaluation and frequently use of intravascular ultrasound or fractional flow reserve, computed tomography–derived fractional flow reserve may become a useful tool in the future, but larger studies are needed.
So, the questions become what more does an analysis that "failed" to show an association add to our knowledge, and what are we to do next time we want to rule out LMD in our clinical practice before starting a patient with moderate to severe ischemia to medical therapy? Sometimes, it is equally important to know what one does not know. Senior et al help generate more questions and will help lay the foundation for future investigations. As for the clinical question, based on this and all prior evidence, the answer remains that we need to apply all tools at hand. A careful assessment of a patient's risk factor profile and noninvasive imaging results can help guide, but to accurately rule out LMD, for now anatomical imaging remains the modality of choice.
J Am Coll Cardiol. 2022;79(5):662-664. © 2022 American College of Cardiology Foundation