Gregg W. Stone, M.D., presenting the EXCEL data at TCT 2016 during a standing room only late-breaking trial session.
The biggest news from the 2016 Transcatheter Cardiovascular Therapeutics (TCT) meeting this past fall was the results of the EXCEL (Evaluation of Xience versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) Trial, which compared the latest generation Xience V drug-eluting stents (DES) to coronary artery bypass surgery (CABG). The result of the 1,905-patient study was that both revascularization strategies have comparable outcomes using the latest techniques and technology in patients with a blockage in the left main coronary artery. Left main lesions have traditionally been the exclusive realm of cardiac surgeons.
The trial highlighted the progress of percutaneous coronary intervention (PCI) in achieving the same clinical results in what can sometimes amount to an outpatient procedure, as compared to the gold standard of open-heart surgery.
“The patients are getting sicker and the outcomes are getting better with PCI,” said David Kandzari, M.D., director of interventional cardiology and chief scientific officer, Piedmont Heart Institute, Atlanta, Ga. He was the principal U.S. investigator in the trial. “However, [the EXCEL Trial] is not a statement that PCI is taking over all of bypass surgery by any means, but the left main artery has always been the domain of surgeons.”
He said guidelines to treat the left main have recommended CABG only. In 2011, the guidelines changed to allow PCI in the left main for some patients at high surgical risk. “Today, what the guidelines have not addressed is what EXCEL has, which is what to recommend for patients who qualify for either PCI or bypass. Hopefully this trial will advance the guidelines even further and allow PCI as an alternative standard of care to bypass surgery…In terms of the really meaningful endpoints of death, stroke and myocardial infarction, EXCEL underscores similarity with PCI compared to surgery. There are also other advantages of PCI, including avoiding periprocedural complications, the need for excessive blood transfusions, atrial fibrillation and sternal wound infection, so it is a positive step forward to be sure.”
“Our study has shown that many patients with left main coronary artery disease who prefer a minimally invasive approach can now rest assured that a stent is as effective as bypass surgery for at least three years, and is initially safer, with fewer complications from the procedure,” said first author Gregg W. Stone, M.D., professor of medicine at Columbia University Medical Center and director of cardiovascular research and education at the Center for Interventional Vascular Therapy at NewYork-Presbyterian/Columbia. Stone presented the EXCEL data at TCT during a standing-room-only session, packed with several thousand cardiologists.
EXCEL Trial Details
Between September 2010 and March 2014, 2,905 patients with left main coronary artery disease were recruited at 126 sites in 17 countries, including 1,905 randomized and 1,000 registry patients. Eligible patients (n=1,905) with LMCAD and low or intermediate coronary artery disease complexity (SYNTAX score ≤32) were randomized to revascularization with fluoropolymer-based cobalt-chromium everolimus-eluting stents (EES; n=948) or CABG (n=957). The primary endpoint was the three-year composite rate of death, stroke or myocardial infarction (MI), powered for noninferiority testing. Major secondary outcomes included this endpoint at 30 days, and the composite rate of death, stroke, MI or ischemia-driven revascularization at three years.
At three years, the primary endpoint of death, stroke or MI occurred in 15.4 percent of EES patients and 14.7 percent of CABG patients (difference [upper 97.5% confidence limit] = 0.7% [4.0%], Pnoninferiority=0.018; HR [95%CI] = 1.00 [0.79, 1.26], Psuperiority=0.98). The secondary endpoint of death, stroke or MI at 30 days occurred in 4.9 percent EES patients and 7.9 percent CABG patients (Psuperiority=0.008). Death, stroke, MI or ischemia-driven revascularization at three years occurred in 23.1 percent EES patients and 19.1 percent CABG patients (Pnoninferiority=0.01; Psuperiority=0.10). Patients treated with PCI rather than CABG had fewer MIs and less bleeding, infections, arrhythmias and renal failure within 30 days, although more repeat revascularization procedures at three years. Fewer patients developed definite stent thrombosis after PCI than symptomatic graft occlusion after PCI at 30 days and three years.
In the three-year follow-up period, the trial added an additional endpoint of target lesion revascularization. “Even with the inclusion of death, stroke, myocardial infarction and repeat revascularization, PCI was still statistically similar to surgical outcomes,” Kandzari said. “By three years, the combined primary endpoint of death, stroke and myocardial infarction was statistically similar and it achieved its non-inferiority endpoint between the two treatment arms.”
He said one notable event in the trial was the CABG symptomatic graft occlusion rate, which was used as a comparator to PCI stent thrombosis. Kandzari explained the graft occlusion rate was 5.4 percent, while the rate of stent thrombosis was only 0.7 percent.
“We found that approximately 15 percent of patients in both groups had a heart attack, stroke or died within three years,” said Stone. “In other words, stents were equally effective as bypass surgery.”
The researchers also analyzed what happened to the patients in the first 30 days after treatment, when serious complications are most likely to occur. Within that period, stent patients had a significantly lower incidence (4.9 percent) of death, stroke, heart attack or revascularization than those who had bypass surgery (7.9 percent). In addition, fewer stent patients had major bleeding, infections, kidney failure or severe abnormal heart rhythms compared to those treated with surgery.
The researchers reported that bypass surgery should still be considered standard therapy for those with left main disease and extensive blockages in the remainder of the heart arteries, although the study did not include patients with severe disease.
“Our study establishes stents as an acceptable or preferred alternative for patients with left main coronary artery disease and low or moderate disease complexity in the other three coronary arteries — about two-thirds of all left main patients,” said Stone. “While bypass is still considered a more durable repair, patients and doctors may prefer a percutaneous treatment approach, which is associated with better upfront results, fewer complications and quicker recovery.”
Trial Designed as SYNTAX Rematch With Improved Stent
EXCEL was designed to be a rematch DES vs. CABG study using a stent that out performed the Taxus stent used in the earlier 2009 SYNTAX study. That trial used the Boston Scientific Taxus DES, at the time the stent with the best clinical outcomes, and it was widely expected to perform well against CABG. However, Taxus fell short of showing equal performance and showed clinical superiority with CABG.
“Since that time, stents have gotten better, and so has cardiac bypass surgery,” said Stone. “That required us to take a fresh look at the relative safety and effectiveness of the two approaches.”
In the head-to-head 2009 SPIRIT III Trial comparing the Abbott Xience V vs. Taxus, data showed Xience had better clinical outcomes. Abbott almost immediately announced plans to conduct the EXCEL trial to see if Xience could outperform CABG in a trial using an improved DES platform.
Questions Following NOBLE Trial Results
The Nordic–Baltic–British Left Main Revascularization Study (NOBLE) trial was also presented as a late-breaker at TCT 2016 and was similar to EXCEL, comparing use of a biolimus-eluting stent to CABG in patients with left main disease. However, despite similar mortality, the five-year risk of major adverse events was higher after PCI compared to CABG for the treatment of unprotected left main disease.
There were questions at TCT as to why one trial went so well and the other did not. Experts noted several differences in the trials, including the use of a different type of stent.
“[NOBLE] was a less rigorously designed trial and excluded endpoints like periprocedural myocardial infarction, and it had limitations on the completeness of follow-up,” Kandzari said.
However, he said a key takeaway in NOBLE was the low rate of target lesion revascularization, and the rates of cardiovascular death in both EXCEL and NOBLE were nearly identical.
NOBLE was a prospective, randomized, open label, clinical, non-inferiority trial that was conducted at 36 sites in Latvia, Estonia, Lithuania, Germany, Norway, Sweden, Finland, the United Kingdom and Denmark. Eligible patients had stable angina pectoris, unstable angina pectoris or non-ST elevation myocardial infarction. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE) — a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary revascularization and stroke.
The original primary endpoint was evaluation of non-inferiority of PCI to CABG assessed by MACCE at two years follow-up in the complete study cohort. Due to lower than expected endpoint rates, the primary endpoint assessment was ultimately changed to a median follow-up of three years.
A total of 1,201 patients were randomized 1:1 to PCI (598) or CABG (603), and 592 in each arm entered analysis by intention to treat. Kaplan-Meier five-year estimates of MACCE were 28.9% for PCI (121 events) and 19.1% for CABG (81 events), [HR 1.48 (95% CI 1.11-1.96)], exceeding the limit for non-inferiority and demonstrating superiority of CABG over PCI (P=0.0066). Comparing PCI with CABG, five-year estimates were 11.6% vs. 9.5% [HR 1.07 (95% CI 0.67-1.72), P=0.7701] for all-cause mortality; 6.9% vs. 1.9% [HR 2.88 (95% CI 1.40-5.90), P=0.0040] for non-procedural myocardial infarction; 16.2% vs. 10.4% [HR 1.50 (95% CI 1.04-2.17), P=0.0315] for any revascularization; and 4.9% vs. 1.7% [HR 2.25 (95% CI 0.93-5.48), P=0.0731] for stroke.
1. Gregg W. Stone, Joseph F. Sabik, Patrick W. Serruys, on behalf of the EXCEL investigators. “Everolimus-Eluting Stents or Bypass Surgery for Left Main Coronary Artery Disease.” N Engl J Med 2016; 375:2223-2235, December 8, 2016, DOI: 10.1056/NEJMoa1610227
2. Patrick W. Serruys, Marie-Claude Morice, A. Pieter Kappetein, for the SYNTAX Investigators. "Percutaneous Coronary Intervention versus Coronary-Artery Bypass Grafting for Severe Coronary Artery Disease." N Engl J Med 2009; 360:961-972, March 5, 2009 DOI: 10.1056/NEJMoa0804626
3. Stone GW, Midei M, Newman W, et al. “Randomized comparison of everolimus-eluting and paclitaxel-eluting stents: two-year clinical follow-up from the Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions (SPIRIT) III trial.” Circulation. 2009 Feb 10;119(5):680-6. doi: 10.1161/CIRCULATIONAHA.108.803528. Epub 2009 Jan 26.
4. Mäkikallio T, Holm NR, Lindsay M, et al., on behalf of the NOBLE Study Investigators. “Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial.” Lancet 2016;Oct 31:[Epub ahead of print].