The nonalcoholic fatty liver disease (NAFLD) fibrosis score, cardiovascular risk stratification and a strategy for secondary prevention with ezetimibe

Abstract

Objective: The nonalcoholic fatty liver disease fibrosis score (NFS) is comprised of unique metabolic risk indicators that may accurately predict residual cardiovascular (CV) risk in patients with established coronary disease and metabolic dysfunction.

Methods: We applied the NFS prospectively to 14,819 post-ACS patients randomized to ezetimibe/simvastatin (E/S) or placebo/simvastatin (P/S), in the IMPROVE-IT trial, using validated NFS cutoffs. The primary endpoint included CV death, myocardial infarction, unstable angina, revascularization or stroke. Outcomes were compared between NFS categories and treatment arms using frequency of events, KM rates and adjusted Cox proportional hazard models. The ability of the NFS to predict recurrent CV events was independently validated in 5395 placebo-treated patients enrolled in the SOLID-TIMI 52 trial.

Results: Among 14,819 patients enrolled in IMPROVE-IT, 14.2% (N = 2106) were high-risk (NFS > 0.67). The high-risk group had a 30% increased risk of recurrent major CV events, compared to the low-risk NFS group (HR 1.30 [1.19-1.43]; p < 0.001). Among high-risk patients, ezetimibe/simvastatin conferred a 3.7% absolute reduction in risk of recurrent CV events, compared to placebo/simvastatin (HR 0.85 [0.74-0.98]), translating to a number-needed-to-treat of 27. Similar benefit was not found in the low-risk group (HR ezetimibe/simvastatin vs. placebo/simvastatin, 1.01 [0.91-1.12]; p-interaction = 0.053). The relationship between NFS category and recurrent CV events was independently validated in patients enrolled in SOLID-TIMI 52 (HR for NFS > 0.67 vs. NFS < -1.455 = 1.55 [1.32-1.81]; p < 0.001).

Conclusion: Stratification of cardiovascular risk by NFS identifies an independent population of patients who are at highest risk of recurrent events, and most likely to benefit from dual lipid-lowering therapy. Clinical trials.gov: NCT00202878.

Keywords: Acute coronary syndrome; Cardiovascular disease; Ezetimibe; Fatty liver; Low-density lipoprotein cholesterol; Metabolic syndrome; NAFLD; Statin.

Conflict of interest statement

Declarations

Competing interests: The authors report no conflicts of interest.

Copyright © 2018 Elsevier B.V. All rights reserved.

Figures

Figure 1

7-year Kaplan-Meier (KM) rates of the primary cardiovascular (CV) endpoint, according to baseline NAFLD Fibrosis Score (NFS) category. The primary CV endpoint was defined as a composite of CV death, non-fatal myocardial infarction (MI), unstable angina, coronary revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) ≥ 30 days post-randomization, or non-fatal stroke. To calculate the adjusted hazard ratio of the primary CV endpoint in the high vs. low NFS groups, multivariate cox proportional hazards regression models were used, adjusted for age, race, hypertension, current smoking, prior percutaneous coronary intervention (PCI), and a history of congestive heart failure (CHF).

Figure 2

Adjusted, 7-year Kaplan-Meier (KM) rates by treatment group and baseline NAFLD Fibrosis score (NFS). Among those with high baseline NFS, ezetimibe significantly reduced primary cardiovascular (CV) events compared to placebo (HR 0.85; 95% CI 0.74–0.98), corresponding to a 3.7% treatment-related absolute risk reduction (ARR) and number needed to treat (NNT) of 27.