Addition of the PCSK9 inhibitor evolocumab to statin therapy after cardiac bypass surgery did not improve 24-month graft patency in the NEWTON-CABG CardioLink-5 trial.

Subodh Verma, MD, cardiac surgeon at St. Michael’s Hospital at the University of Toronto, Toronto, Canada, and lead investigator of the NEWTON-CABG trial, highlighted vein graft failure after coronary artery bypass graft surgery (CABG) as “one of the most persistent clinical problems in cardiac surgery today.”

“This is the largest clinical trial to address vein graft failure in the modern era on top of excellent standard of care,” he said.

“Vein grafts continue to fail at very high rates despite improvements in surgical techniques and standard of care. Our results show that further cholesterol-lowering is not the solution to this problem, and research into understanding the biological underpinnings of vein graft failure is urgently needed,” he added.

Verma presented the results at the recent European Society of Cardiology (ESC) Congress 2025. The results were also published online simultaneously in The Lancet. 

Lack of Benefit With Low-Density Lipoprotein-Lowering

CABG is the most commonly performed surgical revascularization procedure. About 1 million procedures are performed each year worldwide, with the vast majority using vein grafts, according to Verma. 

“But vein graft failure has remained a recalcitrant problem since the advent of CABG for which we have no solutions, with 1 in 5 vein grafts failing by 2 years after surgery, and this is associated with poor prognosis,” he explained. “Still, in 2025, despite advances in surgical techniques and background therapies, and despite optimal blood pressure control and use of statins, graft failure remains a stubborn problem.”

Researchers have made numerous attempts to understand whether the biology of vein graft failure is similar to the biology that affects the coronary arteries, he noted. 

“We know that cholesterol plays a key role in atherosclerotic plaque development and progression, but is it also a critical component of vein graft failure? This is the question the NEWTON-CABG trial addressed,” he said. 

In the trial, Verma and colleagues evaluated a strategy of adding a PCSK9 inhibitor to the standard of care. 

“PCSK9 inhibitors are very effective in reducing LDL [low-density lipoprotein] cholesterol and ischemic cardiovascular events in patients who have cardiovascular disease. But the question is whether further intensified LDL-lowering on top of moderate- to high-intensity statins will prevent the development of vein graft disease,” Verma said.

The investigator-initiated trial enrolled 782 patients at 23 sites in Canada, the US, Australia, and Hungary. All underwent CABG with at least two saphenous vein grafts and were on moderate- or high-intensity statins. The researchers randomly assigned patients within 21 days of CABG to subcutaneous evolocumab 140 mg or placebo every 2 weeks. 

The primary endpoint was the rate of vein graft disease at 24 months, defined as the proportion of vein grafts with at least 50% occlusion on coronary CT angiography or clinically indicated invasive angiography.

At baseline, median LDL cholesterol was 1.85 mmol/L. Treatment with evolocumab reduced LDL cholesterol by an average of 48.4% when adjusted for placebo at 24 months (-52.4% vs -4.0%).

But this decrease in LDL cholesterol was not associated with a reduction in the rate of vein graft disease, which occurred in 21.7% of grafts in the evolocumab group and 19.7% of those in the placebo group at 24 months (P = .44). 

Limitations of the NEWTON-CABG trial included a high rate of missing final vein graft patency data, which researchers attributed to difficulties caused by the COVID-19 pandemic.

But the authors noted that the baseline characteristics of patients with missing data were similar to those included in the efficacy analyses. Sensitivity analyses using different approaches to account for missing data were also consistent with the primary results, suggesting that missing data likely did not introduce bias. 

In addition, logistical constraints during the pandemic precluded performance of baseline imaging, so early vein graft failure due to technical issues, which are likely unresponsive to LDL modulation, cannot be excluded and might have diluted the treatment effect. However, these failures were presumed to be evenly distributed between the two study groups. 

‘Putting the LDL Hypothesis to Rest’

Verma noted vein graft failure may be related to several different mechanisms. Some believe traditional risk factors such as cholesterol, smoking, and blood pressure would be dominant due to the occurrence of atherosclerosis, whereas others believe atherosclerosis is not the issue.

“We are taking a vein graft from an environment of low pressure and putting it into a high-pressure arterial circuit. Because of arterialization, this leads to neointimal hyperplasia, which is a different process altogether than atherosclerosis,” he explained.

Other possible explanations for vein graft failure could be related to surgical techniques, vessel size, and standard of care, he added.

“I think that because blood pressures were well controlled and all patients were on moderate- to high-intensity statins, these results have put the LDL hypothesis to rest, and probably also the blood pressure hypothesis,” Verma said. 

He suggested inflammation and thrombosis as other potential mechanisms to target. 

“We also need intraoperative imaging, or imaging right after the procedure, to make sure that technical failure rates are minimized, or different biological flow patterns are recognized that could be the driver of this problem,” Verma said.

“This is a very important trial that has answered a critical question. It shows clearly that further lowering LDL cholesterol with a very potent drug after CABG will not decrease the failure of saphenous vein grafts after CABG,” Francois Mach, MD, of Geneva University Hospitals, Geneva, Switzerland, said.

Mach suggested new drugs targeting inflammation may be a promising strategy worth investigating. 

In response to a suggestion that use of arterial grafts rather than vein grafts may be a better approach, Verma said, “Yes, we are using more and more arterial grafts in appropriate patients, but this also has issues. For example, radial arteries can only be used on certain types of target vessels because they are subjected to competitive flow.” 

This study was funded by Amgen Canada. Verma reported receiving speaking honoraria/consulting fees from Abbott, Amarin Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly and Company, HLS Therapeutics, Janssen Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio Pharmaceuticals, Inc., and TIMI.