EXCEL

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Stone GW, et al. "Everolimus-eluting stents or bypass surgery for left main coronary artery disease". The New England Journal of Medicine. 2016. 375(23):2223-35.
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Clinical Question

In patients with left main coronary artery disease and low to intermediate anatomic complexity (SYNTAX score ≤ 32), is contemporary PCI with second-generation drug-eluting stents (DES) noninferior to coronary artery bypass surgery (CABG) in regards to long-term cardiovascular outcomes?

Bottom Line

Patients with left main CAD and low-intermediate anatomic complexity, PCI with 2nd generation DES is noninferior to CABG with respect to a primary outcome of death, stroke, or myocardial infarction at 3 years, though with a nonsignificant trend towards increased mortality.

Major Points

While the standard of care for patients presenting with symptomatic CAD attributable to left main coronary artery disease has been surgical revascularization with CABG, this practice has been based on older RCT data using bare-metal stents or 1st generation DES.

In 2012, the SYNTAX trial demonstrated that only in patients with high anatomic complexity (based on SYNTAX score) did CABG demonstrate superiority to PCI in left main disease. On the strength of this evidence, the 2012 guidelines listed PCI as a reasonable alternative to CABG in left main disease if SYNTAX score is low and surgical risk is elevated (Class IIa, Level B) or if SYNTAX score is intermediate and surgical risk is elevated (Class IIb, Level B). Notably, the SYNTAX data are limited in that only 40% of patients in the SYNTAX trial had left main disease, and that this analysis was performed in a subgroup of a subgroup. As a result, further prospective validation was required.

The 2016 EXCEL trial randomized 1905 patients with left main CAD to PCI (with 2nd-generation DES) vs. CABG, examining 30 day and 3 year outcomes. At 3 years, PCI was noninferior with respect to its composite primary outcome (of death, MI, or stroke), however with a small trend towards increased harm (15.4% vs. 14.7%) driven by a nonsignificant trend towards increased mortality (8.2% vs 5.9%; P=0.11). Notably, patients randomized to DES had improved short-term outcomes, with a 3% absolute reduction in death, MI, or stroke at 30 days (driven by decrease in periprocedural MI).

Ultimately, these data cautiously support the practice of PCI with 2nd-generation DES as a reasonable option in patients with left main CAD with low or intermediate anatomic complexity at a tertiary academic center. Long-term safety data is still needed to ensure the trend in increased mortality is not significant. Post-hoc analysis suggests there may be a trade-off in short-term benefit from PCI (fewer peri-procedural MI) vs. long-term durability with CABG (lower rates of ischemia-guided revascularization). In particular, patients at higher risk for operative complications from CABG should be considered for PCI even in the setting of LM disease.

Guidelines

As of December 2016, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, randomized, open-label trial
  • Patients randomized 1:1 to CABG or PCI
    • CABG (N=957)
    • PCI (N=948)
  • Setting: 126 centers in 17 countries
  • Enrollment: September 29, 2010 - March 6, 2014
  • Median follow-up: 3 years
  • Analysis: Intention-to-treat
  • Primary Outcome: Death, stroke, or MI

Population

Inclusion Criteria

  • Unprotected left main CAD with angiographic stenosis ≥ 70% or angiographic stenosis ≥ 50% with one or more of the following:
    • Non-invasive evidence of ischemia referable to a hemodynamically significant left main lesion
    • IVUS MLA ≤ 6.0 mm^2
    • FFR ≤ 0.80
  • Left main equivalent disease
  • Clinical and anatomic eligibility for both PCI and CABG as agreed to by the local Heart Team
  • Age ≥ 18 years
  • Ability to sign informed consent and comply with all study procedures

Exclusion Criteria

  • Prior PCI or the left main at any point
  • Prior PCI of any non-left main coronary artery within 1 year
  • Prior CABG at any point
  • Need for concomitant cardiac surgery other than CABG
  • Presence of any clinical conditions that dictate stronger indication for CABG and/or PCI
  • Subjects unable to tolerate, obtain, or comply with dual antiplatelet therapy for at least one year
  • Subjects requiring or may require additional surgery within 1 year
  • CK-MB greater than normal or recent MI with CK-MB levels still elevated
  • Pregnancy or intent to become pregnant
  • Non-cardiac co-morbidities with life expectancy < 3 years
  • Current participation in another clinical trial
  • Angiographic exclusions
    • Left main diameter stenosis < 50% unless left main equivalent disease is present
    • SYNTAX score ≥ 33
    • Visually estimated left main reference vessel diameter < 2.25mm or > 4.25mm

Baseline Characteristics

From the PCI group.

  • Demographics: age 66 years, male 76.2%, white 91.5%, BMI 28.6
  • Comorbidities: DM 30.2%, HTN 74.5%, HLD 71.5%, smoker 24.1%, prior MI 18.1%, prior PCI 18.4%, CHF 7.1%, prior stroke/TIA 5.5%, PAD 10.3%, COPD 6.9%, CKD 17.6%, anemia 26.9%, thrombocytopenia 7.0%
  • Clinical presentation: Recent MI 15.0%, STEMI 1.4%, NSTEMI 13.2%, unstable angina 24.2%, stable angina 53.1%, silent ischemia 7.7%
  • Cardiac: LVEF 57.0, SYNTAX score 20.6

Interventions

  • Patients were assessed for eligibility by a heart team comprised of an interventional cardiologist and a cardiac surgeon
  • Randomization to PCI or CABG was stratified by the presence of diabetes, high/low SYNTAX score, and study center
  • ECG was performed within 24 hours of procedure, at discharge, and 1 year
  • Levels of CK-MB were measured at baseline, 12 hours after procedure, and 24 hours after procedure
  • Clinical follow-up was performed at 1 month, 6 months, and 1 year and then annually through 5 years
  • Guideline-directed medical therapy was recommended for all the patients, and risk factors were managed as described previously
  • Routine angiographic follow-up was not permitted
  • PCI protocol
    • Goal of PCI was complete revascularization of all ischemic territories using 2nd-generation DES
    • Intravascular ultrasound was strongly recommended
    • The use of heparin or bivalirudin was allowed, and the use of glycoprotein IIb/IIIa inhibitors was discouraged
    • Dual antiplatelet therapy was initiated before PCI and continued for 1 year minimum following PCI
  • CABG protocol
    • CABG was performed with or without bypass at the discretion of the operator
    • Goal of CABG was complete anatomical revascularization of all vessels 1.5mm or larger in diameter in which the angiographic diameter stenosis was 50% or more
    • The use of arterial grafts was strongly recommended
    • Epiaortic ultrasound and TEE were recommended to assess the ascending aorta and ventricular/valvular function
    • ASA was administered perioperatively, and dual antiplatelet therapy was allowed but not mandatory
  • Study monitors collected source documents for all primary and secondary endpoint events for adjudication by an independent events committee
  • Extent of disease and SYNTAX score were assessed at an angiographic core laboratory

Outcomes

Comparisons are PCI vs. CABG

Primary Outcomes

Death, stroke, or MI (3 years)
15.4% vs. 14.7% (absolute difference +0.7 [97.5% CI <0.0 to -4.0]; noninferiority P=0.02)

84% vs. 64% (HR 0.37; 95% CI 0.26-0.55; P<0.001)

Secondary Outcomes

Death, stroke, or MI (30 days)
4.9% vs. 7.9% (absolute difference -3.1 [95% CI <0.0 to -1.2]; noninferiority P<0.001)
Death, stroke, MI or ischemia-driven revascularization (3 years)
23.1% vs. 19.1% (absolute difference +4.0 [95% CI <0.0 to 7.2]; noninferiority P=0.01)
Mortality (3 years)
8.2% vs 5.9% (HR 1.34; CI 0.94-1.91; P=0.11)

Subgroup Analyses

The relative treatment effect for the primary end point was consistent across prespecified subgroups, including the subgroup defined according to the presence or absence of diabetes.

Adverse Events

BARC criteria bleeding
69 (7.3%) vs. 123 (13.0%); HR 0.55 [95% CI 0.41-0.74]; p < 0.001
TIMI criteria bleeding
35 (3.7%) vs. 85 (9.0%); HR 0.0.41 [95% CI 0.27-0.60]; p < 0.001

Criticisms

  • Medical management and optimization differed between PCI and CABG groups due to common post-procedural practice, with an unclear contribution to overall results (e.g. asymmetric DAPT use)
  • Patients and operators were not blinded to treatment assignment, and so some degree of event ascertainment bias cannot be excluded
  • Trend toward increased mortality from PCI is obscured by the noninferiority design and having a composite primary outcome

Funding

  • Trial sponsored by Abbott Vascular, which participated in the design of the protocol and in the selection and management of the sites but was not involved in the writing of the drafts of the manuscript or in the management or analysis of the data, although it had the right to a nonbinding review
  • Authors with multiple ties to industry

Further Reading