The idea that further LDL-lowering helps with this issue after CABG can be put to bed, says Subodh Verma.
MADRID, Spain—Adding evolocumab (Repatha; Amgen) to statin therapy does not lower the risk of saphenous vein graft (SVG) failure among patients who undergo coronary artery bypass surgery, the NEWTON-CABG CardioLink-5 study showed.
Presented earlier this week at the European Society of Cardiology Congress 2025, and published simultaneously in the Lancet, the study is a failed attempt to find a solution to a persistent and difficult surgical problem.
“I would say 90% of procedures that occur involve the use of these [saphenous] veins,” said lead investigator Subodh Verma, MD (St. Michael’s Hospital/Unity Health, Toronto, Canada). “Vein graft failure has remained a recalcitrant problem since the advent [of CABG surgery]. It is a stubborn problem for which we have no solutions. Twenty, 40, and 50% of vein grafts undergo vein graft failure by year two, three, or four, respectively, and when vein grafts fail, they’re associated with poor prognosis.”
SVG is caused by multiple factors, including the technical challenges of surgery, such as poor distal-target-vessel quality and competition from native coronary blood flow. It might also be caused by maladaptive structural changes that result when the vein graft is exposed to the high pressures of the arterial circulation.
The role of LDL cholesterol in SVG failure is not known, said Verma. While some studies have linked higher LDL levels to SVG occlusion and suggested that lower levels could reduce the risk, other studies with statin therapy to lower LDL-cholesterol and reduce SVG risk haven’t panned out. The results of this randomized, controlled trial, however, are pretty clear, said Verma.
“Further cholesterol-lowering with PCSK9 inhibitors is not the solution to this problem,” he said. “I think the LDL hypothesis is put to rest.”
Straightforward Answers
The NEWTON-CABG CardioLink-5 trial, which was done at 23 sites in Canada, the United States, Australia, and Hungary, investigated the role of more intensive lipid-lowering with evolocumab, a PCSK9 inhibitor that is approved for lowering LDL cholesterol and reducing the risk of cardiovascular events in patients with and without established cardiovascular disease.
In total, 782 patients (mean age 66 years; 14% female) were randomized to evolocumab or placebo on top of background statin therapy. Median LDL cholesterol level at baseline was 1.85 mmol/L (72 mg/dL). Nearly all patients were taking aspirin and beta-blockers at baseline, and roughly 40% were taking an ACE inhibitor or ARB. Baseline systolic and diastolic blood pressures were well controlled at 123/74 mm Hg. Nearly all patients received a left internal thoracic artery graft (94%), and a median of three SVGs were used during the procedure, the majority of which were harvested endoscopically (68%).
The primary efficacy endpoint was the vein graft disease rate, defined as the proportion of SVGs with 50% or greater stenosis or total occlusion on coronary CT angiography or clinically indicated coronary angiography 24 months after the index CABG procedure.
Further cholesterol-lowering with PCSK9 inhibitors is not the solution to this problem. Subodh Verma
At 24 months, evolocumab cut LDL-cholesterol levels by more than 52% while there was a 4% reduction in the placebo group. However, the rate of vein graft disease, the study’s primary endpoint, did not differ between treatment arms: 21.7% in the evolocumab group and 19.7% in the placebo arm (P = 0.44). There was no benefit on any of the key secondary endpoints, including the percentage of patients with 100% graft occlusion, nor in any of the prespecified subgroups.
Verma stressed that despite the results, lowering LDL cholesterol remains an important aspect of secondary prevention, even after surgery.
What About Arterial Grafting?
There is evidence that using arterial grafts, particularly the internal thoracic arteries, as well as the radial artery, results in better long-term graft patency than using the SVG. Revascularization guidelines from the US and Europe emphasize grafting the internal thoracic artery to the LAD in patients undergoing CABG surgery and both documents give preference to the radial artery over a saphenous vein conduit for other non-LAD lesions.
Even among patients who receive multiple arterial grafts, however, the saphenous vein is still commonly used, said Verma.
“We are using more and more arterial grafts, but the use of total arterial revascularization, even in centers that do a lot of arterial grafts, will often have two arteries and you need one vein,” he said. “The solution to the global problems of vein graft failure is not to say everybody should do arterial grafting, because there are arterial grafting issues. Radial arteries can only be used on certain types of target vessels, because they are subjected to competitive flow.”
Nonetheless, when appropriate, “the push towards using more arteries needs to be emphasized,” added Verma.
François Mach, MD (Geneva University Hospital, Switzerland), the discussant for the study, stressed that NEWTON-CABG CardioLink-5 is not a negative trial, but one that provides an answer to an important clinical question. He noted that the reduction in LDL cholesterol is on par with what was achieved in the FOURIER trial, the landmark study that showed using evolocumab on top of statin therapy reduced the risk of MACE in patients with established cardiovascular disease.
The 24-month follow-up, which Verma cited as a potential limitation, isn’t a problem for Mach either. In HUYGENS and PACMAN-AMI, for example, 12 months of treatment with evolocumab and alirocumab (Praluent; Sanofi/Regeneron) led to significant changes in the “quality and quantity of atherosclerotic plaques in the coronary arteries,” said Mach. However, both Verma and Mach noted that the response to treatment likely differs between coronary arteries and native veins grafted into the arterial circulation.
“The biology may be different,” said Verma.
One potential area of research for the prevention of SVG could be targeting inflammation or thrombosis. Additionally, it might be worth investigating whether intraoperative or postoperative imaging could be used to help identify technical failures or abnormal flow patterns that could be driving graft occlusion, said Verma. A provocative solution raised by Mach includes avoiding SVGs with xenotransplantation, such as by using arteries from animals in CABG surgeries.