Evolocumab reduced LDL-C resulting in fewer CV events for patients with peripheral artery disease.
Marc P. Bonaca, MD
The PSCK9 inhibitor evolocumab (Rapatha) demonstrated pronounced reductions in low-density lipoprotein cholesterol (LDL-C) resulting in fewer cardiovascular (CV) events compared with placebo for patients with peripheral artery disease (PAD), according to a new analysis of the FOURIER presented at the 2017 AHA Meeting.
In the analysis, there were marked reductions in major adverse cardiovascular events (MACE) with robust improvements in absolute risk reduction (ARR) with evolocumab over placebo for patients with PAD. Reductions in LDL-C were also associated with improvement in major adverse limb events (MALE), according to co-author of the analysis, Marc P. Bonaca, MD, who presented the findings during a late-breaking session in the AHA meeting.
"LDL-C reduction to very low levels should be considered in patients with peripheral artery disease, regardless of history of MI or stroke, to reduce the risk of MACE and MALE," said Bonaca, a cardiovascular medicine specialist at Brigham and Women's Hospital (BWH). "Patients with PAD are at heightened risk of MACE and MALE," he added.
The FOURIER trial enrolled 27,564 stable high-risk patients with established CV disease, including a myocardial infarction (MI), symptomatic PAD, or prior stroke. All patients were on high or moderate intensity statin therapy with or without ezetimibe. Those with LDL-C ≥70 mg/dL or non-high-density lipoprotein cholesterol (HDL-C) ≥100 mg/dL were randomized to evolocumab at 140 mg or 420 mg every 2 weeks or placebo.
In the primary analysis of the study, there was a 59% reduction in median levels of LDL-C with evolocumab versus placebo (P <.00001). The median LDL-C level was 30 mg/dL in the treatment arm compared with nearly 86 mg/dL in the placebo group. Additionally, there was a 15% to 20% drop in the risk of CV disease in patients on statin therapy.
Overall, the FOURIER trial enrolled 3642 patients with symptomatic lower extremity PAD. Of these patients, 1505 had not had a prior MI or stroke. At baseline, 69% had intermittent claudication and ABI <0.85 and 57% had peripheral revascularization for a median of 3.7 years. Twenty-six percent of patients had both conditions. Those in the PAD group were 64 years of age, 28% were female, and 69% were on high-dose statins.
For those with PAD, there was a 3.5% ARR for MACE with evolocumab versus placebo. This represented a relative risk reduction (RRR) of 27% favoring the PCSK9 inhibitor. In those with PAD with no prior MI or stroke, evolocumab elicited an RRR of 43%, with an ARR of 4.8%. In those without PAD, the ARR was 1.4% favoring the treatment arm over placebo, a 19% RRR.
For those with PAD, 13.0% experienced a MACE compared with 7.6% for patients with a history of MI and stroke but no PAD. For those with PAD with a history of MI or stroke, 14.9% had a MACE compared with 10.3% for those with PAD but no stroke or MI history.
MALE occurred in 2.4% of those treated with placebo compared with 1.5% in the evolocumab group for those with PAD (HR, 0.63; 95% CI, 0.39-1.03). For those without PAD, MALE was seen for 0.16% of patients in the placebo group and for 0.076% of those in the evolocumab arm (HR, 0.37; 95% CI, 0.16-0.88). For those with PAD and no prior MI or stroke, there was a 1.3% ARR with evolocumab (HR, 0.43; P = .042).
For those with PAD, 10.9% of patients in the evolocumab group had a MACE or MALE compared with 15% with placebo, an ARR of 4.1% (HR, 0.73; P = .0014). For those without PAD, the rate of MALE or MACE was 7.8% and 6.3%, for placebo and evolocumab, respectively (HR, 0.80; P <.001). For those with PAD but no prior MI or stroke, the ARR was 6.3% for MACE or MALE (12.8% vs 6.5%; HR, 0.52; P = .0006).
"As we continue to look deeper into the data from the FOURIER study, we are able to identify subsets of patients that can derive even greater clinical benefit from intensive LDL-C lowering with evolocumab, in addition to what is achieved with statins alone," senior investigator Marc Sabatine, MD, chairman, TIMI Study Group, Lewis Dexter, MD Distinguished Chair in Cardiovascular Medicine, Brigham and Women's Hospital, said in a statement. "These results offer additional ways for clinicians to tailor therapies for their patients to reduce the risk of recurrent cardiovascular events."
Bonaca MP, Nault P, Giugliano RP, et al. LDL Cholesterol Lowering with Evolocumab and Outcomes in Patients with Peripheral Artery Disease: Insights from the FOURIER trial. Presented at: 2017 AHA Annual Meeting; Anaheim, California; November 11-15, 2017.