Risk Categorization Using New American College of Cardiology/American Heart Association Guidelines for Cholesterol Management and Its Relation to Alirocumab Treatment Following Acute Coronary Syndromes

Abstract

Background: The 2018 US cholesterol management guidelines recommend additional lipid-lowering therapies for secondary prevention in patients with low-density lipoprotein cholesterol ≥70 mg/dL or non-high-density lipoprotein cholesterol ≥100 mg/dL despite maximum tolerated statin therapy. Such patients are considered at very high risk (VHR) based on a history of >1 major atherosclerotic cardiovascular disease (ASCVD) event or a single ASCVD event and multiple high-risk conditions. We investigated the association of US guideline-defined risk categories with the occurrence of ischemic events after acute coronary syndrome and reduction of those events by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

Methods: In the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), patients with recent acute coronary syndrome and residual dyslipidemia despite optimal statin therapy were randomly assigned to alirocumab or placebo. The primary trial outcome (major adverse cardiovascular events, ie, coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) was examined according to American College of Cardiology/American Heart Association risk category.

Results: Of 18 924 participants followed for a median of 2.8 years, 11 935 (63.1%) were classified as VHR: 4450 (37.3%) had multiple prior ASCVD events and 7485 (62.7%) had 1 major ASCVD event and multiple high-risk conditions. Major adverse cardiovascular events occurred in 14.4% of placebo-treated patients at VHR versus 5.6% of those not at VHR. In the VHR category, major adverse cardiovascular events occurred in 20.4% with multiple prior ASCVD events versus 10.7% with 1 ASCVD event and multiple high-risk conditions. Alirocumab was associated with consistent relative risk reductions in both risk categories (hazard ratio=0.84 for VHR; hazard ratio=0.86 for not VHR; Pinteraction=0.820) and by stratification within the VHR group (hazard ratio=0.86 for multiple prior ASCVD events; hazard ratio=0.82 for 1 major ASCVD event and multiple high-risk conditions; Pinteraction=0.672). The absolute risk reduction for major adverse cardiovascular events with alirocumab was numerically greater (but not statistically different) in the VHR group versus those not at VHR (2.1% versus 0.8%; Pinteraction=0.095) and among patients at VHR with multiple prior ASCVD events versus a single prior ASCVD event (2.4% versus 1.8%; Pinteraction=0.661).

Conclusions: The US guideline criteria identify patients with recent acute coronary syndrome and dyslipidemia who are at VHR for recurrent ischemic events and who may derive a larger absolute benefit from treatment with alirocumab.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402.

Keywords: acute coronary syndrome; alirocumab; dyslipidemias; guideline.

Figures

Figure 1.

Impact of alirocumab treatment on temporal changes in achieved LDL-C values. Very high-risk categorization (A) and substratification of very high-risk patients (B). ASCVD indicates major atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; RF, risk factor; and VHR, very high risk.

Figure 2.

Occurrence of recurrent ischemic events by alirocumab treatment by very-high-risk categorization and by substratification of very-high-risk patients. The frequency of MACE (A) and all-cause death (B). MACE indicates major adverse cardiovascular event; and VHR, very high risk.

Figure 3.

Risk reductions associated by treatment, and very-high-risk categorization, substratification of very-high-risk patients, and baseline LDL-C for very-high-risk and non–very-high-risk patients. MACE (A) and all-cause death (B). An LDL-C value of 100 mg/dL equates to 2.6 mmol/L. ACS indicates acute coronary syndrome; ARR, absolute risk reduction; ASCVD, major atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiovascular event; RF, risk factor; RRR, relative risk reduction; and VHR, very high risk.

Figure 4.

Total nonfatal MACE events and death by very high-risk categorization and treatment assignment to 4 years.A, Treatment group rates represent the expected number of events per 100 patients for total nonfatal MACE and all-cause death events based on mean cumulative function estimates at 4 years; the total number of events observed are in parentheses. Treatment HRs and associated CIs and high-risk categorization by treatment assignment interaction P value are from marginal Cox regression models. B, Accrual of events per 100 patients. The expected number of nonfatal MACE and all-cause death events per 100 patients in the placebo and alirocumab groups at 4 years were 29.9 and 25.1, respectively, for patients classified as very high risk and 9.9 and 8.3, respectively, for patients classified as not very high risk. HR indicates hazard ratio; and MACE, major adverse cardiovascular event.