Global trial led by St. Michael’s Hospital scientists delivers landmark insights into vein graft failure after heart surgery

Open-heart coronary artery bypass grafting (CABG) remains one of the most commonly performed operations worldwide. In the vast majority of cases, surgeons use saphenous vein grafts (SVGs) taken from the leg. Despite their widespread use, SVGs are prone to failure—with up to 20–30 per cent showing narrowing or blockage within two years. To date, no proven therapies exist to directly prevent this problem.

Cholesterol lowering is known to play a vital role in protecting coronary arteries and reducing major adverse cardiovascular events (MACE). Whether even more intensive cholesterol reduction—beyond statins—could also protect vein grafts has been an open question.

Under the leadership of St. Michael’s Hospital, a site of Unity Health Toronto, investigators launched the NEWTON-CABG CardioLink-5 trial, a first-of-its-kind international study testing the role of the PCSK9 inhibitor evolocumab in patients undergoing CABG. Results, presented on Sept. 1 as a Hotline Late Breaker at the European Society of Cardiology conference in Madrid and published simultaneously in The Lancet, showed that while cholesterol lowering remains essential for long-term heart health, further intensification with evolocumab did not meaningfully reduce early vein graft failure in the short-term.

“It was an honor to co-lead this global trial to better understand why saphenous veins, so commonly used in open-heart surgery worldwide, often fail within the first few years,” said Dr. Subodh Verma, trial primary investigator, study lead author and St. Michael’s Hospital physician-scientist.

“We found that in the short term, adding more intensive cholesterol-lowering drugs beyond statins does not appear to reduce this stubborn risk. However, patients should remember that long-term intensive cholesterol-lowering remains critical for cardiovascular health.”

Importantly, he said, the trial reminds the cardiovascular community of the persistent and recalcitrant nature of vein graft disease, and highlights the urgent need for novel strategies that go beyond cholesterol lowering alone. By ruling out one possible pathway, the trial sharpens the focus for future innovation and reinforces the importance of continued research in this space.

The problem

A saphenous vein graft (SVG) is a common surgical technique, where veins from the leg are used to bypass a blocked artery. SVGs are used in nearly all cases of coronary artery bypass surgery (CABG), which is one of the most common heart procedures performed in the world.

Data suggest that approximately 20-30 per cent of SVGs fail within the first year after bypass surgery, and nearly 50 per cent of SVGs are blocked within 10 years after surgery. SVG failure can have negative consequences for patients, including angina (chest pain), heart attacks and long-term mortality.

The trial

The NEWTON-CABG CardioLink-5 trial is the first multicentre, double-blind, randomized controlled trial to test the effect of the drug Evolocumab (otherwise known as Repatha) against placebo on SVG failure. Between June 2019-Nov 2022, 782 patients were enrolled in the study in four different countries: Canada, Australia, Hungary and the U.S.

Evolocumab is a type of PCKS9 inhibitor drug, which is commonly prescribed and is effective at helping patients lower their cholesterol. It is not clear what impact they have on vein graft failure, the researchers said.

“Intensive cholesterol lowering in high cardiovascular risk patients, including those after coronary bypass surgery, is proven to reduce heart attacks, strokes, and death. It also improves coronary artery blockages by reducing their size and rupture risk. What was unknown is whether this approach also benefits the vein grafts used in bypass procedures,” said Dr. Lawrence Leiter, physician-scientist at St. Michael’s and Study Chair.

Results

The trial found that Evolocumab compared to placebo, both added to statins, greatly reduced cholesterol levels, but it did not reduce the rate of vein graft disease two years after surgery. The study authors say more trials are needed to better understand the role of cholesterol on SVG.

The CardioLink platform

The NEWTON-CABG trial was conducted via the CardioLink platform, a heart and vascular surgery clinical research platform that offers evidence-based translational and clinical insights to support clinical decisions and improve management practices.

Founded in 2015 by Verma and St. Michael’s physician-scientist and study senior author Dr. David Mazer, the platform has grown its network of global investigators and expanded its scope of research.

The completion of the NEWTON-CABG trial is a tremendous accomplishment and a testament to the CardioLink platform and other research supports at St. Michael’s Hospital, said Mazer.

“Co-leading the NEWTON-CABG trial—originated and conducted from St. Michael’s Hospital—has been a challenge and a great privilege for me. This was the largest study ever to address the critical question of cholesterol lowering on vein graft patency after coronary bypass surgery, and it reflects the impact of our CardioLink platform of clinical trials on the global stage,” he said.

“With skillful trial management by the Applied Health Research Centre and the extraordinary dedication and resilience of our study teams, especially during the COVID-19 pandemic, we’ve published a landmark study that will help refine future treatment strategies for bypass patients.”

Dr. Ori Rotstein, Vice President of Research and Innovation at St. Michael’s Hospital, Unity Health Toronto, reiterated these messages.  “Rigorous clinical trials addressing important questions are essential to delivering optimal care to our patients,” he said. “The research performed in the NEWTON-CABG trial via the CardioLink platform will have impact on the care of patients with cardiovascular disease worldwide.”

By: Marlene Leung