Evolocumab Reduces MACE in Patients With and Without Multivessel CAD: FOURIER

Lowering LDL-cholesterol levels with the PCSK9 inhibitor evolocumab (Repatha; Amgen) significantly cuts the risk of major adverse cardiovascular events in patients with and without multivessel coronary artery disease, a new analysis of FOURIER and its open-label extension study confirms.

Overall, the magnitude of effect with evolocumab was nearly twice as large in those who had multivessel disease, with the benefit emerging early and growing larger over time in this higher-risk subgroup. In those without multivessel disease, the treatment effect was seen after roughly 1 year, and did become larger during extended follow-up.

“For those who had multivessel disease, we already had a good sense from FOURIER that they enjoyed a big benefit, and this study ends up clarifying that point,” lead investigator Marc Sabatine, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. “In those first 3 years of the open-label extension study, where the curves were still diverging for both the primary and the secondary endpoint, there was close to 40% reduction in risk. That fits with what we know that the benefit for lipid lowering just continues to grow over time.”

While the benefit was not quite as large in those without multivessel CAD, the reduction in risk was clinically significant, said Sabatine.

“It really supports the idea that intensive lipid lowering is good for patients both with and without multivessel disease once one looks over an appropriate time horizon,” he said.

Patients Followed for 7 Years and More

In a previous subgroup analysis, the FOURIER investigators showed there was a 30% reduction in the risk of cardiovascular death, MI, or stroke in patients with multivessel disease but only a borderline 11% reduction in those with lesser atherosclerotic burden. As Sabatine noted, follow-up was a little over 2 years, which investigators speculated was too short to see a meaningful reduction in events in the lower-risk group without multivessel disease.

“We know from imaging data that intensive lipid lowering, particularly when you get the LDL cholesterol under 60 to 70 mg/dL, which we did in FOURIER—the median was about 30 mg/dL or so—that you start to regress the plaque,” said Sabatine. “The individuals who didn't have any plaque to start with, we thought they would benefit. They wouldn't develop plaque and that would lead to clinical benefit over many years.”

The new study, which was published this week in the Journal of the American College of Cardiology, included patients in FOURIER and FOURIER-OLE, the open-label extension study that included those initially randomized to evolocumab continued on treatment as well as placebo-treated patients who switched to evolocumab. At the start of FOURIER, 6,007 (25%) had multivessel disease and 17,649 had CAD without multivessel disease. The median follow-up of FOURIER was 2.2 years, but the 5,887 patients who entered FOURIER-OLE were followed for an additional 5.0 years. The median and maximum follow-up for the present analysis were 7.1 and 8.6 years, respectively.

It underscores the imperative that aggressive control of risk factors in those with multivessel disease can yield benefit quickly and of large magnitude. Marc Sabatine

Even in this extended follow-up, patients with and without multivessel disease treated with evolocumab had a lower risk of MACE when compared with those initially receiving placebo, which is part of the legacy effect of being initially randomized to active LDL cholesterol-lowering therapy. The magnitude of effect, however, was larger in those with multivessel CAD.

Overall, initial allocation to evolocumab versus initial randomization to placebo significantly reduced the risk of the primary MACE endpoint (cardiovascular death, MI, stroke, coronary revascularization for unstable angina) by 23% in those with multivessel disease and by 11% in those without multivessel disease (P < 0.0001 and P = 0.003, respectively). Similarly, the magnitude of benefit with the secondary endpoint of cardiovascular death, MI, or stroke was larger in those with multivessel disease: 31% versus 15% reductions, respectively (P < 0.0001 and P = 0.001).

Among those with multivessel disease at baseline, the clinical event curves diverged early between patients treated with evolocumab and those initially given placebo. In those without multivessel disease, the benefit accrued more slowly. For example, the reduction in the primary and secondary endpoint among those without multivessel disease initially treated with evolocumab was less than 10% in the first year. In contrast, the risk reduction ranged from 18% to 29% in those with multivessel disease. Beyond 1 year, however, there were 16% to 21% relative reductions in risk of the primary and secondary endpoint in evolocumab-treated patients without multivessel disease, which was still less than the treatment effect seen in the patients with multivessel CAD. 

For cardiovascular mortality, no benefit was observed in those without multivessel CAD during the entire follow-up, but a benefit in patients with multivessel disease emerged beyond 3 years. At 8 years of follow-up, evolocumab-treated patients had a 25% lower risk compared with those initially given placebo (P = 0.046).

Aggressive Risk Factor Control

To TCTMD, Sabatine pointed out that the definition of multivessel disease used in FOURIER differed from what’s in interventional studies. Multivessel disease was defined as a 40% or greater stenosis in two or more large coronary arteries.

“We deliberately selected a relatively mild definition because we were not looking for critical or severe disease that was hemodynamically significant,” he said “We wanted to know that they had multivessel atherosclerosis. We wanted it to be enough that it was a real amount of atherosclerosis.”

Sabatine said there is an indication for patients with a history of atherosclerotic cardiovascular disease, just like those in FOURIER, to reduce LDL cholesterol at least to less than 70 mg/dL as per the US guidelines or to a target of less than 55 mg/dL as recommended in the European guidelines. In fact, a 2022 expert consensus statement from the American College of Cardiology/American Heart Association recommends LDL-cholesterol levels of less than 55 mg/dL based on data from FOURIER and ODYSSEY Outcomes, the large, randomized trial that tested alirocumab (Praluent; Sanofi/Regeneron).

“There's definitely that mandate for all these individuals,” he said. “For those with multivessel disease, I think there's a strong imperative to start as soon as possible. I think it underscores the imperative that aggressive control of risk factors in those with multivessel disease can yield benefit quickly and of large magnitude. Even in those without multivessel disease, you can say that in the long term there will be significant benefit by preventing plaques from forming and thereby preventing these events from coming.”

In an editorial, Vijay Nambi, MD, PhD, and Layla Abushamat, MD (both from Baylor College of Medicine, Houston, TX), say the new analysis is important as it shows that achieving a very low LDL-cholesterol level can reduce the risk of atherosclerotic cardiovascular disease in the setting of lesser cardiovascular burden (ie, those without multivessel CAD).

Nambi and Abushamat say that a cost-effectiveness analysis would be critical to further understanding how to manage such stable patients, particularly those without multivessel disease. Drugs beyond statins will be needed for the majority of patients to get LDL levels down to these aggressive targets, but research, including this study, suggests there is a long-term benefit to treatment, even in those with a lesser burden of disease.