Two FOURIER Subgroup Analyses Show Added Benefit of Evolocumab in Those With PAD, Prior MI

ANAHEIM, CA—Patients with PAD and those with a prior MI—especially individuals within 2 years of their event, with more than one MI, and with multivessel disease—may derive particular benefit from treatment with the PCSK9 inhibitor evolocumab (Repatha; Amgen), according to two new analyses of the FOURIER trial.

Due to its high cost (currently $14,300 per year of treatment), the drug has been lambasted by multiple cost-effectiveness analyses and surveys showing that the majority of patients prescribed PCSK9 inhibitors never end up receiving them.

“At the end of the day, not all of our patients with [atherosclerotic cardiovascular disease] can have these expensive medications,” said Lynne Braun, PhD, CNP (Rush University Medical Center, Chicago, IL), who discussed both studies presented in a late-breaking science session today here at the American Heart Association 2017 Scientific Sessions. “I commend these subgroup analyses,” she continued, “because they will help clinicians truly target the use of these PCSK9 inhibitors to the patients who will benefit the most.”

In the FOURIER trial, adding evolocumab to high-intensity statin therapy in patients with stable atherosclerotic cardiovascular disease reduced the risk of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization—the study’s primary endpoint—by 15% when compared with placebo, an absolute difference of 1.5%. That was driven by a reduction in nonfatal events, with no significant reduction in cardiovascular mortality.

Marc Bonaca, MD, MPH (Brigham and Women’s Hospital, Boston, MA), presented the PAD subgroup analysis, which was simultaneously published in Circulation. Of the FOURIER participants, 3,642 had symptomatic lower-extremity PAD, including 1,505 with no history of MI or stroke. Evolocumab reduced the primary endpoint consistently in patients both with and without PAD, but the drop was numerically greater in the PAD patients. In patients with PAD the absolute risk reduction (RR) on evolocumab versus placebo was 3.5%, yielding a number needed to treat (NNT) over 2.5 years of 29. In the no-PAD group, the absolute RR was 1.4%, yielding an NNT over 2.5 years of 72. In patients with PAD and no previous stroke or MI, the absolute RR was even greater at 4.8%, with an NNT of 21. Evolocumab also reduced the risk of major adverse limb events (MALE) in all patients compared with placebo (HR 0.58; 95% CI 0.38-0.88), with consistent effects for those with and without PAD.

LDL cholesterol “reduction to very low levels should be considered in patients with PAD, regardless of history of MI or stroke, to reduce the risk of MACE and MALE,” Bonaca concluded.

MI in FOURIER

In a second presentation, Marc Sabatine, MD, MPH (Brigham and Women’s Hospital), looked at the 22,351 patients with prior MI in FOURIER study based on time from qualifying MI, number of prior MIs at baseline, and the presence of multivessel disease. Those patients within 2 years of their MI seemed to benefit more from evolocumab treatment compared with placebo than patients who were more than 2 years post-MI. The same thing was observed for patients with two or more prior MIs and those with multivessel disease.

Risk of CV Death, MD, or Stroke by MI Subgroup

At least 63% of the FOURIER study population had at least one risk factor—recent MI, two or more MIs, or multivessel disease—Sabatine said, meaning that evolocumab would contribute to a 2% absolute risk reduction over 2 years. Extrapolating that out to 5 years would mean a 5% absolute risk reduction and an NNT of about 20, he reported.

“These readily ascertainable clinical features offer one approach to tailoring therapy,” Sabatine concluded.

Many Unanswered Questions

“These prespecified subgroups are indeed high-risk,” Braun, the discussant, explained during her remarks. “In terms of symptomatic PAD, we know that having a low [ankle-brachial index] increases risk for both all-cause and cardiovascular disease mortality. For individuals with a history of MI, risk of a recurrent MI or fatal coronary heart disease within 5 years is 17% for men and higher for women [at] 21%.”

As such, she said, the results of Bonaca’s presentation are “very exciting,” especially in the cohort of patients with no history of MI or stroke. However, while “hard endpoints [are] what these clinical trials are really all about, . . . as a clinician, I wonder about what my patients are most concerned about,” Braun commented. “And that is: does profound LDL lowering translate to less claudication, improved quality of life, and greater physical activity tolerance? Given that these were prespecified subgroups, I'm hoping that these measurements were made in these subgroups so that we'll learn more about the important clinical outcomes.”

For Sabatine’s analysis, Braun pointed out that while the patients “were treated well with high or moderate intensity statin therapy, . . . the baseline LDL was ok, not great but ok.” The results showing a greater benefit with evolocumab versus placebo in those with a history a more recent event, two or more prior MIs, or multivessel disease “makes absolute sense from what we know about the statin trials,” she said. “Once again, our patients who need it the most and had the highest risk achieved the greater benefits.”

A question Braun said she is left with is: “How does intensive LDL lowering lead to even fewer events in these high-risk subgroups?”

“Could there be greater plaque regression as shown in the GLAGOV trial,” she speculated, “meaning that if there's more disease, is there more atheroma regression and does that then lead to fewer cardiovascular disease events? Or is there something more? Does PCSK9 inhibition impact inflammatory processes leading to greater plaque stabilization?”

Also, she asked, could there be an “independent role” for lowering lipoprotein(a) with evolocumab given that studies have shown that PCSK9 inhibitors have a modest effect on this?

As a parting shot, Braun asked FOURIER investigators why both analyses included “so few women.” Bonaca’s and Sabatine’s study populations were made up only of 28% and 22% women, respectively.

“We know that MIs do occur less frequently in women compared to men, but they do occur at a greater proportion than what was represented in this trial,” she said. “Can we truly discern the benefit achieved with respect to a woman’s risk?”

Finally, it remains to be known whether evolocumab plus statin therapy will show a mortality benefit versus statin therapy alone in longer follow-up. “We need to know the answer to this question, obviously,” Braun concluded.