Background and Rationale

Coronary artery disease (CAD) is the third leading cause of mortality worldwide and associated with 17.8 million deaths annually.1 In patients with obstructive CAD, invasive interventions such as revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery has been effective in reducing cardiovascular events and improving quality of life.2 However, in those with stable CAD and moderate or severe ischemia, the clinical outcomes associated with invasive intervention compared to medical therapy is still uncertain. The ISCHEMIA trial (NCT01471522) was hence designed to determine the best management strategy for higher-risk patients with stable CAD and moderate or severe ischemia. This study, as the largest clinical trial in patient with CAD, randomised 5179 individuals to either invasive strategy (medical therapy plus PCI or CABG) or conservative strategy (medical therapy only). The principal results of the SCHEMIA trials were published last year in the New England Journal of Medicine.3 At 4 years of follow-up, there was no evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the primary outcomes (absolute difference, –2.2%; 95% CI, –4.4 to 0; adjusted HR = 0.93; 95% CI, 0.8-1.08).3

Prior studies have demonstrated that a complete revascularization (CR) improved cardiovascular outcomes when compared to incomplete revascularization. However, achieving CR by PCI or CABG surgery, might not be always feasible owing to patient comorbidities, anatomical factors, and technical or procedural considerations.2 Besides, “all the prior trials were limited; most of them did not use a sophisticated core lab analysis to really rigorously assess the completeness of revascularization”, said Dr Gregg Stone, one of the SCHEMIA investigators and professor of Medicine and director of Transcatheter Cardiovascular Therapeutics. He continued “there was never really a comparator arm to see how much CR could affect outcomes compared to a conservative approach”. Therefore, in an exploratory analysis of ISCHEMIA, both anatomic (³ 50% blockage in any vessel ³ 2mm) and functional (every ischemic blockage) completeness of revascularization and their impacts on the outcomes compared to the conservative approach were investigated.

Data and interpretation

The findings were presented at the American College of Cardiology (ACC) 2021 Scientific Session. Among 2296 patients randomized to invasive therapy, 44% achieved anatomic CR and 58% achieved functional CR, both of which were associated with better outcomes compared to incomplete revascularization, but associations were only significant when anatomic CR achieved. Looking at the numbers at 4 years, the primary outcome occurred in 15.4 % patients with conservative treatment compared to 11.9% in those with anatomic CR (-3.5% (-7.4% to 0.1%)) and 13.1% in those with functional CR (-2.3% (-5.4% to 0.8%)) arms. “Whereas in the main trial, at the end of four years, there was about a 2.2% benefit, if you achieve complete anatomic revascularization that [is] increased to about 3.5% whereas achieving complete functional revascularization, didn't make a major difference to the overall outcomes [non-significant reduction of 2.3%]” explained Dr Stone. He added “so you can't just focus on the most severe lesions” and as the other lesions including those that are “not ischemia producing” seem to have an impact on long-term cardiovascular mortality and myocardial infarction hence should be revascularized as well.

This analysis strongly supports that the outcomes of an invasive strategy, using PCI or CABG are significantly improved, if a complete anatomic revascularization is achieved. This is an important factor in clinical decision-making when choosing between invasive approach or medical therapy for patients with chronic coronary syndromes. But the main question remains whether interventionalists and surgeons can “safely” achieve complete anatomic revascularization? “You can get a good sense” said Dr Stone, adding “when you see one or two major large lesions that are short and focal, you're pretty sure you're going to be able to safely revascularize those lesions. In contrast, when you see long, diffuse disease in the arteries, then you may not be able to completely revascularize,” in which case, doctors should guide their patients towards a conservative approach, as the long-term outcomes might not be achieved for these patients, and withhold the invasive strategy for real breakthrough symptoms.

Limitations and take-home message

While the study results were robust, “these conclusions are not definitive” and do not apply to all patients’ sub-groups (e.g. highly symptomatic patients, patients with acute coronary syndromes within 2 months, or those with left main disease, heart failure or reduced LVEF). But “I think the real take home message here is that patients will have different thresholds for wanting an invasive or conservative approach, and we always have to really listen to the patient and understand their wishes” elaborated Dr Stone. After all, if there is a really good chance to completely and anatomically revascularize the patient, then “there's even more of a likelihood that their late outcomes might be better with an invasive approach”.

References

1. GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736-1788.

2. Gaba P, Gersh BJ, et al. Complete versus incomplete coronary revascularization: definitions, assessment and outcomes. Nature Reviews Cardiology. 2021;18:155-168

3. Maron DJ, Hochman JS, et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med 2020; 382:1395-1407