ANAHEIM, CALIF. (FRONTLINE MEDICAL NEWS) – Patients with symptomatic peripheral artery disease or a high-risk history of MI got the biggest bang for the buck from aggressive LDL cholesterol lowering with evolocumab in two new prespecified subgroup analyses from the landmark FOURIER trial presented at the American Heart Association scientific sessions.

“At the end of the day, not all of our patients with ASCVD [atherosclerotic cardiovascular disease] can have these expensive medications. These subgroup analyses will help clinicians to target use of PCSK9 inhibitors to the patients who will benefit the most,” Lynne T. Braun, PhD , commented in her role as discussant of the two secondary analyses, presented back to back in a late-breaking science session. Dr. Braun is a professor in the department of internal medicine at Rush University, Chicago.

The FOURIER trial included 27,564 high-risk patients with prior MI, stroke, and/or symptomatic peripheral arterial disease (PAD) who had an LDL cholesterol level of 70 mg/dL or more on high- or moderate-intensity statin therapy. They were randomized in double-blind fashion to add-on subcutaneous evolocumab (Repatha) at either 140 mg every 2 weeks or 420 mg/month or to placebo, for a median of 2.5 years of follow-up. The evolocumab group experienced a 59% reduction in LDL cholesterol, compared with the controls on background statin therapy plus placebo, down to a mean LDL cholesterol level of just 30 mg/dL.

As previously reported, the risk of the primary composite endpoint – comprising cardiovascular death, MI, stroke, unstable angina, or coronary revascularization – was reduced by 15% in the evolocumab group at 3 years. The secondary endpoint of cardiovascular death, MI, or stroke was reduced by 20%, from 9.9% to 7.9% ( N Engl J Med. 2017;376:1713-22 ).

Evolocumab tamed PAD

At the AHA scientific sessions, Marc P. Bonaca, MD , presented a secondary analysis restricted to the 3,642 FOURIER participants with symptomatic PAD. The goal was to answer two unresolved questions: Does LDL cholesterol lowering beyond what’s achievable with a statin further reduce PAD patients’ cardiovascular risk? And does it reduce their risk of major adverse leg events (MALE), defined as a composite of acute limb ischemia, major amputation, and urgent revascularization?

The answer to both questions turned out to be a resounding yes.

The rate of the composite endpoint comprising cardiovascular death, MI, or stroke was 13% over 3 years in PAD patients randomized to placebo, which was 81% greater than the 7.6% rate in placebo-treated participants with a baseline history of stroke or MI but no PAD, in an analysis adjusted for demographics, cardiovascular risk factors, kidney function, body mass index, and prior revascularization.

The event rate was even higher in patients with PAD plus a history of MI or stroke, at 14.9%. Evolocumab reduced that risk by 27%, compared with placebo in patients with PAD, for an absolute risk reduction of 3.5% and a number-needed-to-treat (NNT) of 29 for 2.5 years.

The benefit of evolocumab was even more pronounced in the subgroup of 1,505 patients with baseline PAD but no prior MI or stroke: a 43% relative risk reduction, from 10.3% to 5.5%, for an absolute risk reduction of 4.8% and a NNT of 21.

A linear relationship was seen between the MALE rate during follow-up and LDL cholesterol level after 1 month of therapy, down to an LDL cholesterol level of less than 10 mg/dL. The clinically relevant composite endpoint of MACE (major adverse cardiovascular events – a composite of cardiovascular death, MI, and stroke) or MALE in patients with baseline PAD but no history of MI or stroke occurred in 12.8% of controls and 6.5% of the evolocumab group. This translated to a 48% relative risk reduction, a 6.3% absolute risk reduction, and a NNT of 16. The event curves in the evolocumab and control arms separated quite early, within the first 90 days of treatment.

The take home message: “LDL reduction to very low levels should be considered in patients with PAD, regardless of their history of MI or stroke, to reduce the risk of MACE [major adverse cardiovascular event] and MALE,” declared Dr. Bonaca of Brigham and Women’s Hospital and Harvard Medical School, both in Boston.

Spotting the patients with a history of MI who’re at highest risk

Marc S. Sabatine, MD, presented the subanalysis involving the 22,351 FOURIER patients with a prior MI. He and his coinvestigators identified three high-risk features within this group: an MI within the past 2 years, a history of two or more MIs, and residual multivessel CAD. Each of these three features was individually associated with a 34%-90% increased risk of MACE during follow-up. All told, 63% of FOURIER participants with prior MI had one or more of the high-risk features.

The hypothesis was that patients with these readily ascertainable clinical features placing them at higher cardiovascular risk would obtain greater benefit from evolocumab. This indeed proved to be the case.

The use of evolocumab in patients with at least one of the three high-risk features was associated with a 22% relative risk reduction and an absolute 2.5% risk reduction, compared with placebo. The event curves diverged at about 6 months, and the gap between them steadily widened during follow-up. Extrapolating from this pattern, it’s likely that evolocumab would achieve an absolute 5% risk reduction in MACE, compared with placebo over 5 years, with an NNT of 20, according to Dr. Sabatine, professor of medicine at Harvard Medical School and chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group.

Lingering questions

Dr. Braun was particularly impressed that the absolute risk reduction in MACE was even larger in patients with baseline PAD but no history of stroke or MI than in PAD patients with such a history. She added that, while she recognizes the value of selecting objectively assessable hard clinical MACE as the primary endpoint in FOURIER, her own patients care even more about other outcomes.

“What my patients with PAD care most about is whether profound LDL lowering translates to less claudication, improved quality of life, and greater physical activity tolerance. These were prespecified secondary outcomes in FOURIER, and I look forward to future reports addressing those issues,” she said.

Another unanswered question involves the mechanism by which intensive LDL cholesterol lowering results in fewer MACE and MALE events in high-risk subgroups. The possibilities include the plaque regression that was documented in the GLAGOV trial , an anti-inflammatory plaque-stabilizing effect being exerted through PCSK9 inhibition, or perhaps the PCSK9 inhibitors’ ability to moderately lower lipoprotein(a) cholesterol levels.

Simultaneous with Dr. Bonaca’s presentation at the AHA, the FOURIER PAD analysis was published online in Circulation (2017 Nov 13; doi: 10.1161/CIRCULATIONAHA.117.032235) .

The FOURIER trial was sponsored by Amgen. Dr. Bonaca and Dr. Sabatine reported receiving research grants from and serving as consultants to Amgen and other companies.


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