LDL treatment-years: a new paradigm for cardiovascular risk reduction

Abstract Background The relationship between the reduction of low-density lipoprotein cholesterol (LDL-C) and cardiovascular (CV) risk is well established; however, the optimal threshold for improving CV outcomes remains unclear. This threshold is especially critical in very-high risk patients, for whom guidelines recommend LDL-C reduction of more than 50% from baseline and an LDL-C goal of 55 mg/dL. The concept of LDL treatment-years, defined as the LDL reduction (mg/dL) multiplied by the duration of treatment (years), may be a more precise target. Purpose This study aims to identify the LDL treatment-years necessary to achieve a reduction in major adverse cardiovascular events (MACE) in randomized controlled trials (RCTs) investigating LDL-lowering interventions with primary outcome of MACE. Methods We conducted a systematic search of Embase and PubMed for RCTs reporting MACE following LDL-lowering interventions, excluding non-human, pediatric, phase I, and non-cardiovascular-focused studies. Data extraction included participant numbers, risk reduction metrics, and a random-effects meta-analysis estimated hazard ratios (HR) with 95% CIs. Linear, segmented, and piecewise regression analyses described the relationship of LDL treatment-years to HR and identified LDL treatment-year thresholds for significant MACE reduction, guided by the Akaike Information Criterion for model selection. Results A total of 32 RCTs (22 positive, 11 negative) were included with 305,907 participants (Figure 1). The mean LDL treatment-year exposure across all trials was 109.7 (range -6.8 to 244.5). The mean HR for MACE was 0.90 (median: 0.81, SD: 0.12). Mean treatment exposure was 135.6 LDL treatment-years for positive trials and 57.8 for negative trials. A simple linear regression line with y-intercept forced to one describes the expected relationship of HR to LDL treatment-years for positive trials (y = -0.001575X+1) and negative trials (y = -0.001248X+1). The segmented regression model identified a breakpoint at 79.5 LDL treatment-years as the threshold exposure at which MACE significantly declines. Conclusions This analysis of 32 RCTs identifies a threshold of 79.5 mg/dl LDL treatment-years required to reduce MACE. This threshold explains the failure of negative trials, the success of positive trials, and the time to benefit. This threshold questions the logic of stepwise care in LDL-C lowering after acute coronary syndrome (ACS). The first year following ACS is a high-risk period for recurrent events, necessitating a more aggressive and timely treatment algorithm. Slow titration of statins and eventually adding on ezetimibe will delay achievement of the LDL treatment-years threshold at the cost of an increase in MACE. Early, more aggressive treatment with PCSK9 inhibitors post-ACS could achieve this threshold in a timelier fashion. A static LDL-C target fails to recognize the true amount and duration of LDL-C lowering required to benefit the individual patient.Figure 1