Earlier this year, the phase III, randomized trial FOURIER (n=27,564) unveiled a new treatment option – evolocumab, an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9), for hypercholesterolemic patients to reduce their cardiovascular risk.1 As previously reported, the trial showed a significant 15% risk reduction in the primary endpoint – a composite of cardiovascular death, myocardial infarction (MI), stroke, and hospitalization for unstable angina or coronary revascularization.1 In the recent American Heart Association (AHA) 2017 Scientific Sessions, two subgroup analyses of FOURIER further demonstrated that patients with peripheral artery disease (PAD) or a history of heart attacks may benefit the most from PCSK9 inhibitors.2,3
In these subgroup analyses, 8,402 patients had their most recent MI happened within 2 years, 5,285 patients had ≥2 prior MIs, and another 5,618 patients had residual multivessel coronary artery disease (CAD).2 Higher background risks of cardiovascular events or death were demonstrated in the latter two subgroups (104% higher for ≥2 prior MIs; 47% higher for residual multivessel CAD; p<0.001), yet both the relative and absolute risk reductions of major adverse cardiovascular event (MACE) with evolocumab as compared to placebo were greater in these groups (Table 1).2 On the other hand, patients with PAD in FOURIER (n=3,642) also showed a higher background risk, and the risk reductions with evolocumab in these patients were higher (Table 1).3
“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,” said Dr. Marc Sabatine, the lead investigator of FOURIER.4
Of note, Dr. Marc P Bonaca, the lead author of the PAD subgroup analysis, pinpointed the risk reduction in patients with symptomatic PAD but no prior MI or stroke, which will usually be treated with high-intensity statin. “Among 60% of patients in the analysis who were already on high-intensity statins when they entered the study, there was still a significant reduction in major adverse limb events.”5
The analyses undoubtedly assist clinicians to identify patients who will benefit the most from evolocumab. “With these simple, readily identifiable features, you identify patients who are at higher baseline risk, and their relative risk reduction is also higher [when given PCSK9 inhibitors on top of statins],” mentioned Dr. Marc Sabatine, the lead investigator of FOURIER. “They offer one approach to tailoring therapy for our patients,” Dr. Sabatine believed.5
1. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722.
2. Sabatine MS, de Ferrari GM, Giugliano RP, et al. Clinical Benefit of Evolocumab in Patients with a History of MI: An Analysis From FOURIER. AHA 2017 Scientific Sessions; Anaheim, CA; November 13, 2017. Session LBS.02.
3. Bonaca MP, Nauly P, Guigliano RP, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: Insights from the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk). Circulation. 2017 [Epub ahead of print].
4. New Analyses Presented At AHA 2017 Show Repatha (evolocumab) Significantly Reduced Cardiovascular Events In Patients With Peripheral Artery Disease And In Patients With A History Of Heart Attacks. Amgen News Releases. 2017 (Accessed December 27, 2017, at http://www.amgen.com/media/news-releases/2017/11/new-analyses-presented-at-aha-2017-show-repatha-evolocumab-significantly-reduced-cardiovascular-events-in-patients-with-peripheral-artery-disease-and-in-patients-with-a-history-of-heart-attacks/).
5. FOURIER: Aim PCSK9 Inhibitors at Highest of High-CV-Risk Patients? Medscape, 2017. (Accessed December 23, 2017, at https://www.medscape.com/viewarticle/889017).