In a standing-room-only Late Breaking Clinical Trial session at the American Heart Association Scientific Sessions, Marc P. Bonaca, MD, MPH, of the TIMI Study Group at Brigham and Women’s Hospital, shared the results of a substudy that examined patients with peripheral arterial disease (PAD) enrolled in the FOURIER (Further Cardiovascular OUtcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial. The response in these patients to LDL-C lowering with evolocumab and related clinical outcomes were truly impressive. I found the positive results an interesting juxtaposition to the session that I’d attended earlier in the day on barriers to access for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.
FOURIER was a landmark randomized controlled trial of evolocumab versus placebo on top of maximal statin therapy in 27,564 patients with atherosclerotic cardiovascular disease (ASCVD). At baseline, participants were considered to have PAD if they had intermittent claudication plus an ankle brachial index of <0.85, or alternatively if they had undergone a peripheral vascular procedure. With a median follow-up of 2.2 years, patients were followed for the primary composite endpoint of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization. A key secondary composite endpoint was cardiovascular death, MI, or stroke. Major adverse limb events (MALE) were also recorded, defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia.
Among the 3,642 patients with PAD in FOURIER, evolocumab conferred a significant 21% relative reduction for the primary cardiovascular endpoint and 27% relative reduction in the secondary cardiovascular endpoint. There was no significant heterogeneity in treatment effect compared with patients who did not have PAD, and because they had a higher absolute risk for events, the PAD patients exhibited a higher absolute risk reduction of 3.5% (number needed to treat, 29) compared to other patients.
MACE plus MALE
The clinical benefit of evolocumab in PAD patients extended beyond major adverse cardiac events (MACE) to MALE where there was a 42% relative risk reduction. There was even a consistent reduction in MALE in patients without PAD, and the relationship between lower achieved LDL-C and lower risk of limb events extended to LDL-C levels as low as <10 mg/dL. Of note, FOURIER confirmed low LDL-C measurements at this level through the gold standard beta quantification.
The exciting new results substantially add to those previously reported from the FOURIER trial. From a clinical perspective, the new data show that the robust lowering of LDL-C with evolocumab on top of statin therapy to a median LDL-C of 31 mg/dL, and much lower in many patients, reduced MACE with an attractive NNT in patients with symptomatic PAD. Evolocumab produces a large reduction in MALE in both patients with PAD and in those without PAD but at risk for it.
Equally impressive, considering the composite of MACE/MALE in patients with symptomatic PAD and no previous MI or stroke, is that evolocumab produced an absolute risk reduction of 6.3% in just over two years, which translates to a number needed to treat of 16. This number would be expected to drop lower and lower with longer treatment.
With no apparent major harms to offset the observed efficacy of evolocumab, these findings are highly encouraging for clinicians, and the major barrier to use remains cost/access. These data support the safety and efficacy of LDL-C reduction to very low target levels as a core focus of prevention in not only patients with prior MI or stroke, but also symptomatic PAD.