51成人动漫

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WASHINGTON -- In lower surgical risk patients with left main coronary artery disease, stenting was on par with coronary artery graft surgery (CABG) in the EXCEL trial but not in the NOBLE trial, but many still saw the sum as a green light for percutaneous procedures.

Both well-powered trials -- designed to settle the issue raised by a subanalysis of the SYNTAX trial suggesting the stents matched surgery in low and intermediate SYNTAX score patients -- were presented here at the Transcatheter Cardiovascular Therapeutics meeting and simultaneously online, in the New England Journal of Medicine for EXCEL and The Lancet for NOBLE.

NOBLE randomized 1,201 patients in northern Europe to either stenting, primarily with the biolimus-eluting Biomatrix Flex or CABG. For the primary composite endpoint of all-cause mortality, nonprocedural MI, stroke, and repeat revascularization at 5 years, the rate with stenting was a relative 48% higher at a rate of 29% compared with 19%, a difference that exceeded the limit for noninferiority and met criteria for superiority of CABG over PCI (P=0.0079).

The difference was driven by significantly fewer clinically-apparent MIs and fewer repeat revascularizations with CABG,, of Aarhus University Hospital in Denmark, and colleagues reported.

EXCEL randomized 1,905 patients, largely in Europe and North America, to Xience drug-eluting stents or CABG. For the primary composite endpoint of death from any cause, stroke, or MI (including periprocedural events) at a median 3 years, the rates were similar between groups at 15.4% and 14.7%, respectively (P=0.02 for noninferiority, P=0.98 for superiority).

The rate at 30 days met superiority for stenting (4.9% vs 7.9%, P=0.008 for superiority), although superiority was not met when ischemia-driven revascularization was added to the composite at 3 years, reported, of New York-Presbyterian Hospital/Columbia University Medical Center in New York City and director of TCT.

Editorials looking at the two trials separately came to opposite conclusions:

"The take-home message from the EXCEL trial is that the majority of patients with unprotected left main coronary artery disease, which was a very serious, life-shortening, and disabling condition early in my professional lifetime, can now be managed equally well by means of two strategies of revascularization if carried out by expert, experienced teams such as those participating in the EXCEL trial," wrote , of Brigham and Women's Hospital in Boston. "The outcomes of shorter hospital stay, greater early safety benefit, and more rapid recovery and return to normal activity favor PCI over CABG."

However, surgeon , of Baylor Scott & White Health in Plano, Texas, and interventionalist , of the Mayo Clinic in Rochester, Minn., writing about NOBLE, concluded: "If a patient is a good surgical candidate, CABG should remain the mainstay of treatment.... In patients who are not good surgical candidates, PCI [percutaneous coronary intervention] is a reasonable alternative to CABG, albeit with a higher incidence of subsequent clinical events."

Opinions also varied widely on what impact the findings would have.

, of St. Luke's Hospital of Kansas City, Mo., noted the wide upper confidence interval margin allowed for noninferiority in EXCEL. Being up to 4.2% worse than CABG, "seems like a pretty big difference to me," he told 51成人动漫. "It will be interesting to see the quality of life results. But with these data, I would probably lean towards PCI given that more than 120 patients need to be treated with CABG for one not to have a primary even at 3 years, and I would vastly prefer the more rapid recovery of PCI (and I really fear a stroke)."

, of the Sanger Heart and Vascular Institute in Charlotte, N.C., and chair-elect of the American College of Cardiology board of governors, agreed that there would be a shift toward PCI.

"This is changing the thought process on how these patients are treated," he told 51成人动漫. "Currently the recommendation is with a team approach in left main coronary artery disease that there be a team evaluation and recommendation as to whether the patient has surgery versus PCI.... In the future for these lower risk patients that have less complex disease and left main disease, they may be simply treated with PCI."

Whereas ad hoc PCI has rarely been done for left main disease, Wilson, who was an EXCEL site investigator, predicted movement in that direction. "Essentially these studies will say as long as you're sure you're picking the right patients, you don't necessarily need to consult on these and that you can actually in low risk cases do ad hoc left main stenting."

Stone noted that, based on his group's findings and the registry of patients not included in EXCEL for various exclusion criteria, "the final conclusion is that 62% of the universe might be treated by PCI." But he argued that heart team involvement will still be important.

"It will depend on how the guidelines take this up," , also of St. Luke's, suggested at a press conference at which the EXCEL and NOBLE results were discussed. "If the guidelines don't support left main PCI beyond where they do currently, it puts the clinician is a very awkward position doing this on an ad hoc basis." While it's reasonable to say that there should still be heart team involvement, "I do think there will be some leakage."

"This trial [NOBLE] will add to the level of evidence but is not sufficient by itself to change present guidelines," predicted Mack and Holmes. At the press conference, Mack reiterated that, with the data taken as a whole, "it will be difficult to change the guidelines because you do have trials with very different results."

Points of Difference

One reason for the difference among the trials was suggested by Mack and Holmes in their editorial: that, in NOBLE, "the benefit of CABG was noted in all ranges of the SYNTAX score, which is contrary to the SYNTAX trial in which patients with less complex disease did as well with PCI as with CABG. This finding might partly be explained by the fact that 81% of the patients in NOBLE had bifurcation left main disease, which is more difficult to treat than ostial or trunk left main disease and might be associated with a worse outcome with PCI."

However, the evidence for use of the SYNTAX score is not high quality, but rather mainly based on post hoc analysis of the SYNTAX trial, cautioned , of Cedars-Sinai Medical Center in Los Angeles, in an email to 51成人动漫.

"SYNTAX score was not an effect modifier in NOBLE, EXCEL, and in the FREEDOM trial evaluating CABG vs PCI in patients with diabetes and multivessel disease (interaction P=0.58)," he said. "In contrast, SYNTAX score was an effect modifier in 5-year follow-up of SYNTAX trial (interaction P=0.07).... The preponderance of evidence does not support the use of SYNTAX score in making treatment recommendations in favor of PCI or CABG for either left main coronary artery disease or multivessel disease."

Stone pointed out differences that he saw as key to the difference in findings as lack of inclusion of procedural MIs in NOBLE; stroke rates substantially higher with PCI in that trial -- "we've never seen that in any study before"; and differences between stents used in the two trials, leading to three to four times the stent thrombosis rate as in EXCEL. "The trials are unfortunately not comparable," he concluded. "The late increase in MI we also saw in EXCEL, I do believe that is real. The 5% or 6% increase in target lesion revascularization is also not that different than what we saw. But the much higher stroke rates in NOBLE and lack of consideration of procedural MI I think bias the trial against PCI."

Christiansen noted that a post hoc analysis of his trial showed a rate of 7% vs 5% with PCI for postprocedural MI, which did not change the conclusion of the trial. Instead he cited the differences in follow-up time, looking at the Kaplan-Meier curves. "Maybe the differences are not that huge."

Cohen agreed. "I think there's more similarity than difference. If you look at the same endpoints, the curves are diverging late through 3 years in EXCEL. If you had taken out the periprocedural MIs [in NOBLE], they might have been crossed."

Kaul, too, agreed "I do not find the results of the two trials to be materially different."

"If one examines MACCE (which both trials report, EXCEL at 3 years and NOBLE at 5 years), the HR is 1.18, 95% CI 0.97-1.45 in EXCEL and 1.48, 95% CI 1.11-1.96 in NOBLE. They are directionally consistent with substantial overlap in 95% confidence intervals," Kaul wrote.

"Similar overlap is seen for all-cause mortality (HR of 1.34, 95% CI 0.94-1.91 in EXCEL and 1.07, 95% CI 0.67-1.72), spontaneous MI (HR 1.60, 95% CI 0.95-2.70 in EXCEL and 2.88, 95% CI 1.40-5.90 in NOBLE), and total revascularizations (HR 1.72, 95% CI 1.27-2.33 in EXCEL and 1.50, 95% CI 1.04-2.17 in NOBLE) all of which lean favorably for CABG. If one were to pool the outcomes of these two trials, one would see a statistically significant increase in all of these outcomes with PCI compared with CABG.... It is possible that longer follow-up in EXCEL might result in worsening of outcomes as is seen in NOBLE (5-year Kaplan-Meier estimates reported)."

Kaul concluded, "It is not reassuring to note that the Kaplan-Meier curves for all-cause mortality are already separating in EXCEL at 18 months with 2.3% absolute risk increase (albeit, nonsignificant) at 3 years."

Christiansen noted the high quality of PCI achieved in NOBLE, with IVUS guidance for about three-quarters of cases and only 7% not meeting criteria for good stent expansion. Also, the target vessel repeat revascularizations were largely outside the stented lesion, he noted.

Whatever one's view of the data, Mack and Holmes noted, "With trials of this magnitude costing tens of millions of U.S. dollars and none underway to our knowledge, it is probable that these two trials will serve as the evidence base for management of patients with left main disease for the foreseeable future."