NOBLE at 5 Years: New Data Favor CABG for Left Main Disease
The paper adds fodder for the controversy dogging EXCEL, and the guidelines for revascularization in left main CAD.
Dropped into the middle of the uproar around EXCEL, fuller 5-year data from the NOBLE trial confirm what was seen in a preliminary report released in 2016: PCI carries a higher risk of major adverse cardiac or cerebrovascular events compared with CABG in patients with unprotected left main coronary disease, with a similar risk of mortality.
The previous preliminary report was based on a limited number of patients who had reached 5 years of follow-up, investigator Niels Holm, MD (Aarhus University Hospital, Denmark), explained to TCTMD. Now, with data collected over 98% of the total follow-up time of the trial, the findings are more robust.
“We have now reached the predefined number of events for the trial to be conclusive,” Holm said. “That the trial is conclusive is of paramount importance in terms of scientific credibility and robustness of the numbers and the main conclusions.”
The safety and efficacy of PCI relative to CABG in patients with left main CAD is a hot topic at the moment amid ongoing controversy over the results of the other major clinical trial in this space, EXCEL, which had been initially presented alongside NOBLE in 2016.
As reported by TCTMD, a BBC Newsnight broadcast roiled the waters earlier this month, alleging that critical data were concealed in the public reporting of EXCEL. The European Association for Cardio-Thoracic Surgery (EACTS), after reviewing data that had been leaked to BBC journalists, reacted by withdrawing support for the left main “chapter” of the 2018 Clinical Guidelines for Myocardial Revascularization, jointly written with the European Society of Cardiology (ESC).
Several days later, EXCEL investigators released a 3,500-word response to the BBC exposé, in turn triggering a rebuttal from David Taggart, MD, PhD (University of Oxford, England), the surgeon who first raised concerns about the trial at the 2019 EACTS meeting in October. In the weeks that followed, EACTS has called for an independent investigation of the data, the American Association for Thoracic Surgery (AATS) has issued a statement supporting calls for all data to be made publicly available, and the ESC has said that while it stands by current guidelines, it will work with surgical colleagues to review any new data that come to light.
How these updated NOBLE findings—published online December 23, 2019, ahead of print in the Lancet—will factor into the dispute remains to be seen, but Holm called for measured consideration of all available data moving forward.
“Both [NOBLE and EXCEL] inform the treatment that we do today and I think the most important thing now is to have a really thorough and scientific and clinically relevant discussion—in particular in the guideline committees—to evaluate this, free of the heated debate that we have seen here the past 2 months and in particular the past 2 weeks,” Holm said. “So, I definitely hope that we can now have an informed debate. It should not be rushed. We need a thorough discussion of the findings in these two trials and also compared with the older trials of left main revascularization.”
Repeat Revascularization, Nonprocedural MI Higher With PCI
PCI has been pitted against CABG in patients with left main CAD in several trials, with PRECOMBAT and SYNTAX indicating no difference in mortality between the revascularization modalities. Of note, however, 5-year data from EXCEL indicated an elevated risk of mortality after PCI versus CABG (13.0% vs 9.9%). The NOBLE investigators point out that none of those trials were powered to assess differences in mortality.
NOBLE compared PCI—primarily with the umirolimus-eluting Biomatrix Flex stent (Biosensors)—and CABG in 1,201 patients with unprotected left main disease at 36 hospitals in nine countries in northern Europe. The results reported in 2016 were based on a median follow-up of 3.1 years; this new paper brings the median follow-up to 4.9 years.
As seen in the preliminary data, the rate of MACCE (all-cause mortality, nonprocedural MI, repeat revascularization, or stroke) was higher after PCI versus CABG (28.4% vs 19.0%; HR 1.58; 95% CI 1.24-2.01). That difference did not establish that PCI was noninferior to CABG, and, in fact, CABG was superior (P = 0.0002).
The higher MACCE rate after PCI was driven by nonprocedural MI (7.6% vs 2.7%; HR 2.99; 95% CI 1.66-5.39) and repeat revascularization (17.1% vs 10.2%; HR 1.73; 95% CI 1.25-2.40). There were no significant differences in all-cause mortality (9.4% vs 8.7%; HR 1.08; 95% CI 0.74-1.59) or stroke (4% vs 2%; HR 1.75; 95% CI 0.86-3.55).
Focusing on mortality, Holm et al note that the rate after CABG was slightly lower in NOBLE than in EXCEL (8.7% vs 9.9%) but that the rate after PCI was higher in EXCEL (13.0% vs 9.4%). Rates of nonprocedural MI and repeat revascularization were generally similar in the two trials. “These findings indicate that the quality of PCI in NOBLE was at least similar to that of EXCEL and the difference in primary outcome is likely to relate to definitions of endpoints,” the authors write, in part to address suggestions from 2016 that the quality of PCI may have been superior in EXCEL.
Moreover, they point out that “neither trial was powered for assessing mortality and a future meta-analysis of all four trials [including PRECOMBAT and SYNTAX] is likely to confirm that mortality is similar for PCI and CABG in revascularization of left main coronary artery stenosis.”
‘A Little Bit for Everyone’
Commenting for TCTMD, interventional cardiologist Robert Yeh, MD (Beth Israel Deaconess Medical Center, Boston, MA), said by email these updated results from NOBLE “are important, and really supportive of the common view that the primary difference in outcomes between CABG and PCI has to do with the development of new disease for which CABG may be protective but PCI, as a focal treatment, may not be. The findings related to higher rates of spontaneous MI after PCI are very consistent with EXCEL and other studies, and frankly, aligned with what most practicing cardiologists believed going in.”
He called the lack of a mortality difference “very reassuring,” while acknowledging that the comparison was underpowered. “I’m very much looking forward to a more updated mortality patient-level meta-analysis that includes all the major trials. That is the big question mark that is hanging over my mind in thinking about offering left main PCI,” Yeh said. “The spontaneous MI trade-off with a much less invasive procedure is the type of question that is a centerpiece of shared decision-making, but it becomes a very different conversation if there is a mortality trade-off.”
As for the role of PCI in left main disease, Yeh said “the biggest group of left main PCI patients in our practice are the surgical turndowns due to frailty or comorbidity. That clearly won’t change.
“For those patients who have complex anatomy and are surgical candidates, I think CABG should be the default,” he continued. “For those patients with not-so-complex disease, in experienced hands I think PCI can be in the conversation, particularly for patients who have strong reasons for wanting to avoid an open-heart procedure. This has been our practice for some time, and I think the emerging data continue to support that. The data don’t support making PCI a default or first approach without the patient having a conversation with surgeons.”
Holm had a similar message. “PCI was clearly inferior to CABG for the primary endpoint of MACCE, but as mortality was similar it may still be justified to do PCI in selected patients,” he said. “Most important is that patients are selected according to their complexity and concomitant diseases that also influence the outcome, such as diabetes and the presence of multivessel disease. It’s of the utmost importance to inform the patient and to have a thorough discussion with the patient about the pros and cons of both treatment options.”
PCI clearly carries greater risks of spontaneous MI and repeat revascularization, he noted, whereas CABG comes with higher risks of reoperation for bleeding, blood transfusion, and sternum infection, as well as a longer initial hospital stay.
This may be particularly true in light of the debate over the definitions of MI used in EXCEL, and the fact that one of the prespecified definitions was not reported. NOBLE, of note, excluded periprocedural MIs in the definition used in the trial.
“Inclusion of periprocedural myocardial infarction in primary composite endpoints was recommended by the Academic Research Consortium and in the universal definition of myocardial infarction, and the EXCEL investigators showed that large periprocedural myonecrosis was associated with increased 3-year mortality,” the NOBLE investigators write. “This finding might have implications for standard clinical evaluation after revascularization. However, inclusion of periprocedural myocardial infarction in a composite endpoint that also includes death is controversial, because the added events in long-term follow-up will then include patients that did not die from a periprocedural myocardial infarction.”
“People upset with EXCEL’s topline conclusion and the handling of periprocedural MI can point to this one as demonstrating a clear win for CABG on the major endpoints,” Yeh said. “Those who thought the mortality issues in EXCEL were a red herring can point to the lack of any difference here. I would anticipate some ‘I told you sos’ from both sides.”
TCTMD Managing Editor Shelley Wood contributed to this story.
Holm NR, Mäkikallio T, Lindsay MM, et al. Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised, non-inferiority NOBLE trial. Lancet. 2019;Epub ahead of print.
- NOBLE was funded by the participating centers and by Biosensors, which provided an unrestricted institutional research grant.
- Holm reports having received institutional research grants from Biosensors, Abbott, Reva Medical, Medis Medical Imaging, and Boston Scientific, and speaker fees from Terumo, Abbott, Reva Medical, and Medis Medical Imaging.
- Yeh reports having investigator-initiated research grants and serving on scientific advisory boards for Abbott Vascular, Boston Scientific, and Medtronic.