UPDATED January 8, 2020 // Five-year findings from the NOBLE trial demonstrate that percutaneous coronary intervention (PCI) is not as effective as coronary artery bypass grafting (CABG) in reducing the risk of death, myocardial infarction, repeat revascularization, and stroke in patients with left main disease.
Kaplan-Meier 5-year estimates of major adverse cardiac or cerebrovascular events (MACCE) were 28% for PCI and 19% for CABG, yielding a hazard ratio (HR) of 1.58, which exceeded the prespecified limit of 1.35 set for noninferiority of PCI. Instead, CABG was found to be superior to PCI for the primary composite endpoint (P = .0002).
"The most important finding is that, with complete 5-year follow-up, the MACCE rate after PCI was not shown to be noninferior to the MACCE rate after CABG," reported senior author Evald H. Christiansen, PhD, Aarhus University Hospital, Denmark. Christiansen has reported receiving grant support from Biosensors, which also provided an unrestricted institutional research grant to support this investigator-initiated trial.
"In fact, CABG was superior to PCI," he told theheart.org | Medscape Cardiology, with the difference mainly driven by higher rates of spontaneous MI and a greater need for repeat revascularization after PCI.
Although no difference was seen in all-cause mortality (9% for each group) or stroke (4% and 2%; P = .11), rates of nonprocedural MI (8% vs 3%; HR, 2.99; P = .0002) and total repeat revascularization (17% vs 10%; HR, 1.73; P = .0009) both favored CABG.
"Up to 5 years, these events (spontaneous MI and repeat revascularization) did not translate into differences in mortality," Christiansen commented in an email.
However, the NOBLE investigators emphasize some other outcomes that weigh against CABG, including a higher need for reoperation for bleeding (4% vs < 1% for PCI; P < .0001) and a more than fourfold longer length of stay for the index treatment (9 days vs 2 days; P < .0001).
"Some endpoints were not captured in the conventional MACCE endpoint, including longer hospital stay after CABG, the greater need for blood transfusion, and reoperations for bleeding and sternum infections. These endpoints are important to some patients and the selection of revascularization modus should therefore be individualized," Christiansen said.
"Also, although stroke did not differ in NOBLE, stroke rates are typically increased after CABG compared to after PCI," he added.
The NOBLE trial randomly assigned 1201 patients from 36 hospitals in nine northern European countries to PCI or CABG. All had left main coronary artery disease requiring revascularization.
These newest findings, published December 23 in the Lancet, land in the middle of an ongoing controversy over the conduct and reporting of the EXCEL trial, which also tested PCI and CABG in patients with left main disease.
The controversy — which with a BBC Newsnight report on December 9 has exploded into the public realm — revolves around allegations about the interpretation and reporting of data from the EXCEL trial in the New England Journal of Medicine 5-year publication that gave parity to PCI and CABG for the primary composite outcome of death, stroke, and MI at 5 years. The trialists have responded to these claims in writing.
Since then, the European Association for Cardio-Thoracic Surgery (EACTS) withdrew its endorsement of the 2018 EACTS-European Society of Cardiology clinical guidelines section covering left main coronary disease that was based on EXCEL results.
The unreported data and other issues have also led the American Association for Thoracic Surgery to issue a statement acknowledging the possibility of misguided treatment recommendations, and therefore patient care, stemming from incomplete reporting in EXCEL.
Of note, both trials were sponsored by stent manufacturers, Biosensors in the case of NOBLE and Abbott Vascular for EXCEL.
Same Data, Different Interpretations
To William Boden, MD, Boston University School of Medicine and VA New England Healthcare System, there is nothing in the NOBLE 5-year findings that dissuade him from considering CABG and optimal medical therapy the best choice for most left main patients.
"For me, the most important determinant of which procedure to choose has to do with clinical outcomes, and by that I mean survival, freedom from MI, and whether that can best be achieved with CABG or PCI," Boden, who was not involved in either study, said in an interview.
"To camouflage some of these decisions by saying, 'well, the length of stay is longer and there's more bleeding and more need for transfusion with CABG,' is really muddying the waters here."
While mortality was similar between CABG and PCI in NOBLE, it was higher for PCI in EXCEL (HR, 1.38), Boden noted.
"In NOBLE, spontaneous (nonprocedural) MI was almost threefold higher with PCI, while in EXCEL, the definition used to define procedural MI used a biomarker threshold that biased that end point against CABG," he asserted.
Also commenting for theheart.org | Medscape Cardiology, Marc Ruel, MD, MPH, a cardiac surgeon at the University of Ottawa Heart Institute, Ontario, Canada, suggested some factors that may have contributed to the mortality difference seen in EXCEL that was not seen in NOBLE.
"NOBLE's 9% death rate at 5 years is at the bottom range of what has been generally seen after treatment for left main coronary stenosis; Yusuf et al. published a landmark meta-analysis on this in 1994," he said in an email exchange. This aligns with the NOBLE trial patients being relatively low risk — and lower risk than the EXCEL cohort — with "coronary lesions that were generally limited in scope."
Also, and "much to the credit of the EXCEL investigators," the EXCEL trial was "the first major trial comparing PCI to CABG where excellent adjunct, (i.e., guideline-directed medical therapy) was equally administered to both the surgery and the stenting groups. In previous trials, including SYNTAX, surgery patients uniformly received less optimal adjunct medical therapy," said Ruel.
The equal care given to PCI and CABG patients "may have helped uncover the overall survival benefit with surgery, reflected in EXCEL by a 38% excess odds of death with PCI over CABG," Ruel said.
Ruel was involved in the early planning of EXCEL but was not an active investigator and took no part in the interpretation or presentation of the findings.
About the provision of optimal medical therapy (OMT), Boden suggested otherwise. "If OMT was given equally to both groups, there should be no mortality differences as a function of revascularization type, he said. He's currently involved in the planning of a trial that will compare revascularization (either CABG or PCI) with OMT alone in lower-risk patients with left main disease.
The updated NOBLE findings don't change much for Gregg Stone, MD, Icahn School of Medicine at Mount Sinai, New York City, who is an EXCEL principal investigator and a prominent public voice in the controversy surrounding that trial.
Stone has reported financial relationships with a number of industry entities, including several stent makers.
He notes that the trade-offs are familiar: higher rates of nonprocedural MI and repeat revascularization with PCI but shorter hospital stay and fewer major bleeds and transfusions.
"In the discussion, the NOBLE investigators provide a thoughtful interpretation, that despite the higher MACCE endpoint with PCI than CABG, the similar mortality rate, generally higher stroke rate with CABG (in most studies), and more favorable early course with PCI warrant considering PCI for left main disease in detailed heart team discussions with the patient on the benefits and risks associated with the two treatments to ensure they are able to provide sufficiently informed consent," Stone told theheart.org | Medscape Cardiology in emailed comments.
"This latter message, in my opinion, represents the major take-home message from all trials of PCI vs CABG, [this being that we have] two therapies which are very different, each having strengths and drawbacks," said Stone.
"For some patients on the basis of coronary anatomy and comorbidities, medical judgment will clearly dictate PCI or CABG as the best treatment, whereas for many others both may be considered depending on the short-term and long-term goals and preferences of the patient," he concluded.
Christiansen said the EXCEL controversy did not influence the way in which they presented their new findings or timing of the publication.
As to whether the Class 1A recommendation for PCI in left main disease should be changed as has been advocated by the EACTS, Christiansen suggested, "we await a planned meta-analysis of the major randomized left main trials. As many patients did well after PCI, it may also be of interest if we are using the right tools to identify patients suitable for either PCI or CABG."
Asked to succinctly summarize the message for clinicians who perhaps are not following all the ins and outs of the ongoing discussion about revascularization of left main stenosis, Christiansen said this: "There seems to be no mortality difference comparing PCI and CABG, at least in Europe, and in patients without complex disease outside the left main. Procedural events are higher after CABG and late events are higher after PCI."
He added that individuals with diabetes and three-vessel disease should likely opt for CABG, while those that can have PCI performed by an experienced left main interventionalist (and this includes training in intravascular imaging), and with an assurance of adequate stent expansion, can be offered PCI after a careful discussion of the pros and cons of each option.
Added Ruel: "NOBLE is an interesting trial, but it was performed in 'niche' patients, who were likely selected to be anatomically and physiologically (low incidence of diabetes) favorable to a stent type that, really, is no longer used. Therefore, NOBLE's latest publication is very unlikely to contribute much or resolve the issues recently raised around the EXCEL trial," he said.
"I would add that the threefold myocardial infarction risk with PCI over CABG observed in NOBLE patients adds externally supportive data to the widespread assertion, including from the recent BBC report, that the EXCEL trial was presented to the world and interpreted by its authors in an incomplete way, and by leaving important parts of the story out."
Christiansen reports grant support from Biosensors, which also provided an unrestricted institutional research grant to support this investigator-initiated trial. Stone has reported financial relationships with a number of industry entities, including several stent makers. Boden and Ruel reported no relevant conflicts of interest.
Lancet. Published online December 23, 2019. Abstract
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Cite this: NOBLE at 5 Years Supports CABG Over PCI in Left Main Disease - Medscape - Jan 02, 2020.