Abstract
The log linear association between on-treatment LDL-C levels and ASCVD events is amplified in higher risk patient subgroups of statin versus placebo trials. Update previous systematic review to evaluate how the log linear association influences the magnitude of cardiovascular risk reduction from intensifying LDL-C lowering therapy. MEDLINE/PubMED, Clinical trials.gov, and author files were searched from 1/1/2005 through 10/30/2019 for subgroup analyses of cardiovascular outcomes trials of moderate versus high intensity statin, ezetimibe, and PCSK9 mAbs with an ASCVD endpoint (nonfatal myocardial infarction or stroke, cardiovascular death). Annualized ASCVD event rates were used to extrapolate 5-year ASCVD risk for each treatment group reported in subgroup analyses, which were grouped into a priori risk groups according to annualized placebo/control rates of ≥4%, 3-3.9%, or <3% ASCVD risk. Data were pooled using a random-effects model. Weighted least-squares regression was used to fit linear and log-linear models. Systematic review identified 96 treatment subgroups from 2 trials of moderate versus high intensity statin, 2 trials of a PCSK9 mAb versus placebo, and 1 trial of ezetimibe versus placebo. A log linear association between on-treatment LDL-C and ASCVD risk represents the association between on-treatment LDL-C levels and ASCVD event rates, especially in higher risk subgroups. Greater relative and absolute cardiovascular risk reductions from LDL-C lowering were observed when baseline LDL-C was >100 mg/dl and in extremely high risk ASCVD patient groups. Greater cardiovascular and mortality risk reduction benefits from intensifying LDL-C lowering therapy may be expected in those with LDL-C ≥100 mg/dl, or in extremely high risk patient groups. When baseline LDL-C <100 mg/dl, the log linear association between LDL-C and event rates suggests that treatment options other than further LDL-C lowering should also be considered for optimal risk reduction.
Highlights
Current guidelines recommend intensifying low density lipoprotein cholesterol (LDL-C) lowering therapy when LDL-C remains above certain thresholds, or to achieve LDL-C goals [1, 2]
When baseline LDL-C
Amplification of the log linear association between LDL-C levels and cardiovascular event rate occurs in higher risk patient subgroups in the statin versus placebo randomized trials and appears to be linear in lower risk patient group (Fig 1A) [6]
Summary
Current guidelines recommend intensifying low density lipoprotein cholesterol (LDL-C) lowering therapy when LDL-C remains above certain thresholds, or to achieve LDL-C goals [1, 2]. Amplification of the log linear association between LDL-C levels and cardiovascular event rate occurs in higher risk patient subgroups in the statin versus placebo randomized trials and appears to be linear in lower risk patient group (Fig 1A) [6]. Evidence of a log linear association between LDL-C level and cardiovascular events for ezetimibe and PCSK9 mAb trials comes from a meta-analysis of statin, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibiting monoclonal antibody (mAb) cardiovascular outcomes trials [7]. Amplification of the log linear association in higher risk patient groups was found in a recent pooled analysis of Phase 3a efficacy trials of alirocumab, a PCSK9 mAb. An amplification of the log linear relationship between baseline LDL-C level and cardiovascular event rates was observed in very high risk patient groups with diabetes, chronic kidney disease or polyvascular disease (S1 Fig) [8]. The log linear association between on-treatment LDL-C levels and ASCVD events is amplified in higher risk patient subgroups of statin versus placebo trials
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