Evolocumab Benefits High-Risk Patients With Established Cardiovascular and Chronic Kidney Disease

October 31, 2018 — Amgen announced a new Repatha cardiovascular outcomes study (FOURIER) analysis evaluating the effects of Repatha (evolocumab) in patients with established cardiovascular disease by kidney function. In line with previous FOURIER subgroup analyses, these results further demonstrate Repatha's efficacy in reducing not only low-density lipoprotein cholesterol (LDL-C) levels, but also the relative risk for major cardiovascular events such as heart attack and stroke, in high-risk patients including those with mild-to-moderate chronic kidney disease (CKD).^1-4 In these patients (N=4,443), absolute reductions tended to be greater in the risk for the composite secondary endpoint which included cardiovascular death, heart attack or stroke. Adverse events were similar across patients regardless of CKD stage and consistent with the Repatha known safety profile.

The results were presented at the American Society of Nephrology's (ASN) annual Kidney Week, Oct. 23-28 in San Diego.

"Patients with chronic kidney disease are considered a high-risk population due to increased rates of cardiovascular events associated with impaired kidney function," said Robert P. Giugliano, M.D., S.M., Brigham and Women's Hospital, Harvard Medical School and lead investigator. "The results of this analysis demonstrate evolocumab is a safe and effective approach for the reduction of LDL-C and cardiovascular risk in patients with established cardiovascular disease and mild-to-moderate kidney impairment on background lipid-lowering therapies, who require additional treatment options."

Analysis of the FOURIER subgroup of patients with CKD showed treatment with Repatha resulted in consistent and robust reductions in LDL-C levels across all patients independent of kidney function (58.7 percent LDL-C reduction in patients with stage 3 CKD versus 58.2 percent LDL-C reduction in those with preserved kidney function).⁵

Treatment with Repatha was also associated with significant reductions in the risk for the composite of cardiovascular death, heart attack or stroke across patient subgroups regardless of CKD stage. Patients with more advanced CKD tended to have greater reductions in the absolute risk for cardiovascular events (2.5 percent reduction in absolute risk in patients with ≥ stage 3 CKD compared to 1.7 percent absolute risk reduction in patients with preserved kidney function at year three).⁵

Early-stage CKD, which is often associated with comorbidities such as diabetes, high blood pressure and heart disease, affects an estimated 10 percent of Americans.^6,7 CKD is an independent risk factor for the development of cardiovascular disease, with the frequency and risk foradverse outcomes increasing with worsening kidney function.^7-9

FOURIER (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk), a multinational Phase 3 randomized, double-blind, placebo-controlled trial, is designed to evaluate whether treatment with Repatha in combination with statin therapy compared to placebo plus statin therapy reduces cardiovascular events. The primary endpoint is the time to cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary endpoint is the time to cardiovascular death, myocardial infarction or stroke.

Eligible patients with high cholesterol (LDL-C ≥70 mg/dL or non-high-density lipoprotein cholesterol [non-HDL-C] ≥100 mg/dL) and clinically evident atherosclerotic cardiovascular disease at more than 1,300 study locations around the world were randomized to receive Repatha subcutaneous 140 mg every two weeks or 420 mg monthly plus effective statin dose; or placebo subcutaneous every two weeks or monthly plus effective statin dose. Optimized statin therapy was defined as at least atorvastatin 20 mg or equivalent daily with a recommendation for at least atorvastatin 40 mg or equivalent daily where approved. The study was event-driven and continued until at least 1,630 patients experienced a key secondary endpoint.

For more information: www.amgen.com

References

1. Bonaca, M.P., 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 137, 338-350 (2018).

2. Sabatine, M.S., et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol 5, 941-950 (2017).

3. Sabatine, M.S., et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med376, 1713-1722 (2017).

4. Sabatine, M.S., et al. Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease: An Analysis from FOURIER. Circulation (2018).

5. Charytan, D.M. & Sabatine, M.S. Towards Better Medication Usage in Patients with CKD.  Presented at: American Society of Nephrology Annual Conference (San Diego, CA, 2018).

6. CDC, Chronic Kidney Disease Surveillance System—United States. http://www.cdc.gov/ckd. Accessed: October 25, 2018.

7. Subbiah, A.K., Chhabra, Y.K. & Mahajan, S. Cardiovascular disease in patients with chronic kidney disease: a neglected subgroup. Heart Asia 8, 56-61 (2016).

8. Pinkau, T., Hilgers, K.F., Veelken, R. & Mann, J.F. How does minor renal dysfunction influence cardiovascular risk and the management of cardiovascular disease? J Am Soc Nephrol 15, 517-523 (2004).

9. Jellinger, P.S., et al. American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease. Endocr Pract 23, 1-87 (2017).