COMMENTARY

EXCEL and NOBLE: Bias Confirmation for Left Main PCI or CABG?

Michael J. Mack, MD; Sanjit S. Jolly, MD, MSc

Disclosures

November 14, 2016

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Michael J. Mack, MD: Good afternoon. My name is Mike Mack. I am a cardiac surgeon at Baylor Scott & White Health in Dallas.

Sanjit S. Jolly, MD, MSc: I am Sanjit Jolly, an interventional cardiologist at McMaster University.

Dr Mack: We had some exciting, late-breaking clinical trials presented here at Transcatheter Cardiovascular Therapeutics (TCT) 2016. We are going to discuss EXCEL and NOBLE, two trials on coronary artery bypass graft (CABG) versus percutaneous coronary intervention (PCI) for patients with left main disease. Both were significantly sized trials with long-awaited results, but treatment of left main disease may not be as clear as we had hoped. Sanjit, would you tell us about the results of EXCEL?

EXCEL Trial

Dr Jolly: EXCEL[1] was a randomized trial of nearly 2000 patients who received PCI versus CABG for left main disease. At a follow-up of 3 years, the hard primary outcome of cardiovascular death, myocardial infarction (MI), and stroke was similar between treatments. PCI patients had lower rates of MI within 30 days than patients who underwent CABG. Revascularization of the target vessel was higher with PCI. That is no surprise, because with a bypass or with arterial revascularization, you are going to have less revascularization.

The important point is that unlike many PCI trials, the definition of MI in EXCEL—CK-MB 10 times the greater limit of normal—was the same for both PCI and CABG. For most PCI trials, people would say that that is ridiculous, that those are huge enzyme releases. The authors really wanted to make the definition the same for both so as not to bias one over the other. Obviously some people would argue with that.

NOBLE Trial

Dr Mack: The other trial that was presented was the Danish NOBLE trial,[2] which evaluated 1200 patients. It was an "all-comer" study, which is one of the differentiations between the two trials and perhaps one of the explanations as to why we have different outcomes. The EXCEL trial included patients in the lower two tertiles of the SYNTAX score (< 33). Also different from EXCEL was the endpoint of death, stroke, nonprocedural MI (which means that anything that happened in the first 30 days was not counted), and repeat revascularization. They found that the inferiority boundary was not met for PCI versus CABG at a median follow-up of 3.1 years and that CABG may be superior to PCI for this primary endpoint.

There have been a lot of discussions as to why results were different between the two trials, some of which I have listed. Rather than gaining clarity, we may have further confusion. Can you tell me, Sanjit, how you would interpret these trials? How would you explain the difference and what the other differentiating factors are in terms of interpretation?

Why Were the Results Different?

Dr Jolly: PCI and stent technology have gotten better. We are now seeing rates of stent thrombosis of < 1%. Rates of stent thrombosis in EXCEL were very low and acute graft occlusion was about 5%. With stent versus main graft, stent thrombosis is very rare. But when you go back to the early meta-analysis data of CABG versus medical therapy, where do you see the benefit? You really see it at the 5- to 10-year phase. In NOBLE, we had outcomes out to 5 years, and they actually increased the primary outcome or the time to follow-up so that they could get more events because of increased power. With EXCEL, we only have 3 years of data. As an interventional cardiologist who likes doing PCI and enjoys doing left main PCI, I want to see the 5-year data.

Dr Mack: That is fair. I would say that there is not a clear winner or loser in either trial. But there is more information for the practicing clinician. I still think it comes down to multidisciplinary team decision-making about what is best for an individual patient. Can you talk about how you make a decision for a particular patient and how this information helps or does not help inform you for that?

Choosing Between PCI and CABG

Dr Jolly: That is an excellent point. At our institution, we have a heart-team approach. We discuss these cases with the cardiovascular surgeons with whom we have a good relationship. The surgeon may say, "This patient is 84 years old, has renal insufficiency, and has had a prior stroke. I think he would be better served with PCI." As an interventionalist, I may say, "This patient has a chronic total occlusion that is very calcified, and multiple vessels would require rotablation. The SYNTAX score is high so I think he would do better with bypass surgery."

Dr Mack: One of the differentiating factors we have talked about is the SYNTAX score. There may have been more bifurcation disease in the EXCEL trial and there may have been more concomitant coronary disease other than left main in NOBLE because of the score. This may help explain why the outcomes were different. I certainly agree that patient-related factors such as age, frailty, degree of debility, chronic renal insufficiency, etc., should be used to decide whether a patient should have surgery. When deciding the candidacy for PCI, I think it comes down to anatomic factors and amount of disease. What do you think?

Dr Jolly: That is very accurate. We also want to have shared decision-making with the patient and discuss the relative risks and benefits. Some patients say, "I do not want bypass surgery under any circumstances." Others say, "I would much prefer bypass. I do not want to come back for repeated procedures." That is valuable to know.

Will Practice Change?

Dr Mack: Do you think this is going to change clinical practice?

Dr Jolly: Anytime a large-scale trial comes out and supports what you are already doing, you will do more of it. People who are referring to bypass surgery will look at NOBLE and say, "That is the right thing to do." People who are doing left main PCI fairly frequently will look at EXCEL and say, "You know what, I am doing the right thing." I think it will magnify people's practice because they will find supportive evidence. Will we see a paradigm shift? I do not think so. Not yet.

Dr Mack: We have two very robust trials. Our level of evidence is definitely increasing in terms of this disease. Do you think this is sufficient evidence and that the guidelines should be changed?

Dr Jolly: That is an excellent question. The guideline committee will have some debate on their hands for what is the best approach. With results that are divergent—although EXCEL was a larger trial—they may decide to hold off and wait for further longer-term data from the trials.

Dr Mack: The other part of this is, it is very difficult to enroll patients in these types of trials, and they are very expensive trials to do. I do not think we are going to see other major trials in this arena for the foreseeable future. Like you said, we are going to be dependent upon further analyses and sub-analyses of this very robust dataset in order to help inform clinical decision-making.

Dr Jolly: You are absolutely right. It is hard to raise funding for these sorts of trials and it is hard to consent patients for PCI versus CABG trial given the differences. Patients often want the less invasive therapy.

Dr Mack: I could not agree more. As usual, we sit on different sides of the clinical arena, but we have pretty universal agreement.We hope you found this session from TCT 2016 informative.

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