Effects of PCSK9i on MACE and death as a function of baseline eGFR in patients with recent ACS
Effect of alirocumab on major adverse cardiovascular events according to renal function in patients with a recent acute coronary syndrome: prespecified analysis from the ODYSSEY OUTCOMES randomized clinical trial
Introduction and methods
Chronic kidney disease (CKD) patients are at high risk to develop a major adverse cardiovascular event (MACE) [1-3]. Statin therapy decreases risk for CV events in patients with moderate-to-severe CKD , but not in the ones in need of dialysis [4-6]. Updated US guidelines on the management of blood cholesterol consider patients with stage 3 or 4 CKD at very high risk and recommend high-intensity or maximum-tolerated statin treatment, and addition of ezetimibe or an PCSK9 inhibitor if LDL-c concentrations remain above 70 mg/mL [3,7].
The PSCK9i alirocumab reduced CV events in acute coronary syndrome (ACS) patients , and safely decreased LDL c levels in patients with CKD . However, the efficacy and safety in patients with ACS and CKD receiving alirocumab has not been investigated. This subanalysis of the ODYSSEY OUTCOME trial determined whether the effects of alirocumab, in addition to intensive or maximum-tolerated statin therapy, on MACE and death are influenced by renal function.
The ODYSSEY OUTCOME trial was a randomized, double-blind, placebo-controlled comparison of alirocumab and placebo. A total of 18,924 patients with ACS 1 to 12 months before randomization were randomly assigned (1:1) to receive alirocumab 75 mg or placebo subcutaneously every 2 weeks. Inclusion criteria were: persistent dyslipidemia (LDL-c ≥70 mg/dL), or ≥100 mg/dL non-HDL-c, or ApoB ≥80 mg/dL despite treatment with atorvastatin (40-80 mg daily) or rosuvastatin (20-40 mg daily), or maximum-tolerated dose of one of these statins. Patients with an eGFR <30 mL/min/1.73 m² were excluded. Primary outcome was a composite of MACE, including death due to coronary heart disease, non-fatal MI, ischemic stroke, or hospitalization due to unstable angina. Secondary outcome was all-cause mortality. Median follow-up was 2.8 (IQR 2.3-3.4) years. This subanalysis evaluated the effect of alirocumab on MACE and death across estimated glomerulus filtration rate (eGFR) levels. Baseline eGFR was obtained at the first visit and calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. The groups were subdivided into eGFR <60 mL/min/1.73m² (n=2122), eGFR 60 to <90 mL/min/1.73m² (n=9326), and eGFR ≥90 mL/min/1.73m² (n=7470).
- Baseline LDL-c was 92±31 mg/mL in both treatment groups. In the group treated with alirocumab, LDL-c concentration decreased irrespective of kidney function. In the eGFR <60 mL/min/1.73m² group LDL-c was reduced to 40±30 mg/dL, in the eGFR 60 to <90 mL/min/1.73m² group to 38±30 mg/dL, and in the eGFR ≥90 mL/min/1.73m² group to 38±28 mg/dL at 4 months. Corresponding values at 36 months were 52±36, 56±40, and 60±42 mg/dL, respectively.
- Annualized incidence rates for MACE and death increased progressively with decreasing eGFR, starting at eGFR values <80 mL/min/1.73m². Incidence rates for MACE and death were lower in the alirocumab group compared to the placebo group across all eGFR subgroups. There were no significant interactions of assigned treatment and eGFR on incidence rates for MACE and death (P=0.14 and P=0.59, respectively).
- There was a significant reduction in the incidence per 100 patient-years at risk of MACE in patients receiving alirocumab with an eGFR between 60-<90 mL/min/1.73m² (HR=0.83, 95% CI:0.73-0.95, P=0.006) and ≥ 90 mL/min/1.73m² (HR=0.78, 95% CI:0.67-0.92, P=0.0026) compared with patients on placebo in the respective eGFR groups. No significant differences in treatment effects of alirocumab on incident MACE were observed between the alirocumab and placebo groups with eGFR levels of <60 mL/min/1.73m² (HR=0.97, 95% CI: 0.81-1.18, P=0.78, [P-interaction=0.21]).
- No significant differences in treatment effects of alirocumab on all-cause death were observed between the baseline eGFR groups (P-interaction=0.83).
- Alirocumab had no effect on eGFR over the duration of follow-up. No differences in percentages of patients with a reduction in eGFR from baseline of ≥30% were found between treatment groups.
- Patients in the alirocumab group, irrespective of eGFR subgroup, reported a higher incidence of local injection-site reaction. Rates of other adverse events were similar in both treatment groups across all eGFR groups.
Treatment with alirocumab, compared to placebo, led to a significant reduction in MACE in patients with recent ACS with eGFR levels ≥60 mL/min/1.73m². No significant differences in incidence rates in MACE between treatment groups were found in patients with eGFR <60 mL/min/1.73m². There were no significant interactions of treatment (alirocumab or placebo) and eGFR on incidence rates of MACE or all-cause death.