Dr Lawrence A Leiter

I'm Dr Lawrence Leiter, Endocrinologist and Professor of Medicine at the University of Toronto.

Dr Subodh Verma

And I'm Subodh Verma, I'm a Professor of Surgery at the University of Toronto and a Cardiac Surgeon at St. Michael's Hospital. I was the Principal Investigator of the NEWTON-CABG trial and my friend and colleague, Professor Lawrence Leiter was the Trial Chairman, and the two of us today are going to tell you about the trial that is being presented as a hotline, late-breaking clinical trial at the ESC 2025.

So why don't we get started and ask Dr Leiter to tell us why we went down this road.

What is the reasoning behind the NEWTON-CABG CardioLink-5 study?

Dr Lawrence A Leiter

So at this point we have 30 years of trials showing that cholesterol lowering with various medications will reduce events, especially in patients with prior ASCVD, including patients post coronary artery bypass surgery. So we know in the post-CABG patients, cholesterol lowering will reduce risk of subsequent cardiac events, reduce risk of stroke, reduce risk of cardiovascular mortality. What we haven't yet known is whether cholesterol lowering will also improve the venous graft patency.

We know again that cholesterol lowering is good for arteries, and we have a lot of evidence that cholesterol lowering will reduce the size of plaque and reduce the likelihood of the plaque rupturing in arteries, therefore leading to event reduction. But the whole question is to whether improves venous graft patency was an unknown.

What was the study design and patient population?

Dr Subodh Verma

NEWTON-CABG CardioLink-5 was a global, international trial. It was a randomised, double blind, placebo-controlled trial asking the question of whether intensive LDL cholesterol lowering with evolocumab versus placebo would have effects to reduce vein graft attrition or vein graft disease rates in people who've had bypass surgery.

So as you've just heard from Professor Leiter, bypass surgery is very commonly done. We have a recalcitrant problem where vein grafts fail. They fail at very high rates and we have currently no solutions to address that clinical problem. So we thought, is intensive LDL cholesterol lowering so important in arteries? Would it be important in veins as well? And that's why we embarked on this clinical trial.

The trial was done in four countries: Australia, United States, Canada, and Hungary. It looked at just short of 800 patients randomised to the two arms as I've described to you. What was unique here is that we enrolled people within 21 days of having bypass surgery, and in fact the median time from surgery to randomisation was about 12 or 13 days.

What were the key findings?

So what we found in the trial was over two years the primary outcome was vein graft disease rate. And what we defined that was veins that were more than 50% stenosed or completely occluded at two years, as evaluated by a CCTA or a traditional coronary angiography.

And we found first and foremost that the actual placebo event rate for vein graft failure remains exceedingly high. In fact, 20% of individuals in the placebo group had the primary event where the vein grafts were either 50% occluded or completely 100% blocked. And this was not affected by evolocumab over the two year period.

The secondary endpoints, exploratory endpoints, including a hierarchical win ratio, all of this was consistent with a neutral result in that evolocumab did not have the effect in the short term, two years, to further change the outcome of vein graft stenosis.

Now I'll let my colleague Professor Leiter tell you about how evolocumab affected LDL cholesterol, and then what does this really mean for the totality of the evidence?

Dr Lawrence A Leiter

So importantly, we did not have an LDL entry criteria and the standard of care in the study was extremely good. And the baseline LDL level was around 1.85, so much lower than in other trials. Evolocumab, as expected, lowered LDL by an additional 60%. But because we started off with a relatively low LDL level, the absolute reduction in LDL was less than what was seen in other trials.

How should these findings impact clinical practice?

Dr Subodh Verma

So I would say that first and foremost, there are very limited, good, high-quality data of this size in contemporary bypass surgery. And we know that bypass surgery continues to be done throughout the world – about a million of these cases are done each year, and in the majority of cases veins are used.

So the first message here is that vein grafts continue to pose a persistent and recalcitrant problem clinically for which LDL cholesterol lowering, beyond statins, beyond an LDL of 1.85 to begin with, on top of moderate to high intensity statins in the short term, does not seem to be the dominant biological mechanism.

The second message here would be that patients and providers should remind themselves that these are short-term outcomes and the long-term benefits of LDL cholesterol lowering for atherosclerotic events remain irrefutable and unequivocal, and therefore this should not in any way subtract from their enthusiasm to intensify LDL to further reduce long-term ischemic events.

But I'd be very keen to hear what Professor Leiter has to say, you know, as well with respect to what this means in the totality of evidence.

Dr Lawrence A Leiter

Yeah, so I think a major message is that the results of our trials should not change clinical practise. We have evidence for many trials, including the FOURIER trial with evolocumab, the largest completed outcome trial with a lipid lowering agent that showed dramatic benefits in multiple high-risk patient populations, including those post CABG.

And the patients with the lowest achieved LDL levels had the lowest event rates, and that was seen in the original 2.2 year randomised phase. And the benefit even increased with the additional five years of follow up.

So by all means, people should continue to treat post-CABG patients to get their LDL as low as they can, they should lower it as soon as possible, and we also know the longer the better. It's a mechanistic study and as Professor Verma says, the implication is that we need to look elsewhere to try to see what can improve vein graft patency.

Dr Subodh Verma

And these data are available now, published simultaneously in The Lancet. So for those of you who are interested, you know, you can learn more about it at thelancet.com.

What further research is needed in this area?

Yeah, so I think that's a really important question and that is that for decades now we have been trying to find solutions for this problem. 20 to 30% of vein graphs fail by two years, and that is despite good blood pressure control, and in addition to moderate and high intensity statins, in addition to improvements in technique over the last sort of 20 or 30 years, surgical technique has improved, quality of care has improved.

Despite all of these things, Haemoglobin A1C and diabetes management has improved. We find that these so-called traditional risk factors and system wide changes have made no impact to the very high rates of vein graft failure. And therefore, it really begs the question that we need to go back to the drawing board and think about what is driving this process. Is it technical errors? Is it thrombosis? Is it arterialisation of the vein grafts? Is it poor distal flow? Is it a changing demographic of the type of people being referred for bypass surgery?

But I think we have exhausted the lipid hypotheses in the short term in a very definitive fashion in this trial. And I think we're sending a message that we have to think about other rheological, hemodynamic and other types of novel strategies. Inflammation may be one of them that could potentially be driving improved outcomes here. Or we have to just step away from using vein grafts as often as we do and try to use more arterial conduits for constructing bypass surgery.