The independent association of mortality with LDL-C management, and number and types of atherosclerotic cardiovascular disease events: a large nationwide real-world cohort study

Background The 2019 ESC/EAS Guidelines recommend LDL-C goal of <55 mg/dL and also reducing the starting cholesterol level by ≥50% in patients with atherosclerotic cardiovascular disease (ASCVD). Despite advances in prevention, patients with ASCVD remain at high risk for recurrent events and incur substantial healthcare costs. The cumulative clinical and economic impact of recurrent ASCVD events and the importance of lipid control in real-world practice is not well quantified . Methods We performed a retrospective, event-based cohort study using a nationwide payer-provider health plan in Israel database, covering 2.8 million members (one quarter of the population). Very high-risk adults aged 40–79 years with a first ASCVD event (myocardial infarction [MI], ischemic stroke [IS], peripheral arterial disease [PAD], carotid endarterectomy, or multi-bed disease) between 2006–2022 and ≥12 months prior continuous enrollment were included and followed through 2023. Time-dependent Cox models assessed associations between cumulative number/type of events, last LDL-C level (most recent measurement within each ASCVD event), and risk of all-cause mortality, after adjusting for demographics, comorbidities, socioeconomic status (SES), and index year. Sensitivity analyses included retrospective analyses excluding the last year of life or using a fixed index date (1 January 2014). Results We included 25,285 patients (mean age 66.5 years; 74% male); 44% with diabetes, and 58% ever-smokers. Compared with first MI, adjusted hazard rate (aHR) for mortality was higher for PAD (aHR =2.03 (95% CI: [1.82, 2.26])), and multi-bed disease (aHR =3.71 [3.34, 4.13]). Recurrent MI (aHR=1.68 [1.47, 1.91] for 2MI; aHR= 2.23 [1.80, 2.76] for >=3MI) and recurrent IS (aHR=1.28 [1.18, 1.38] for 1IS; aHR =3.68 [3.22, 4.20] for >=2IS) were associated with progressive increases in mortality. Poor lipid control was also strongly associated with higher mortality risk (Figure 1). When compared to LDL-C level of 70–<100 mg/dL, LDL-C of <55 mg/dL and 55-<70 mg/dL were associated with lower mortality risk (aHR= 0.60 [0.54, 0.65] for <55 mg/dL; aHR =0.67 [0.61, 0.73] for 70–<100 mg/dL). Low SES, diabetes, hypertension, smoking, and older age were all statistically significantly and independently associated with increased mortality risk (all p<0.01 (Table 1)). Findings were robust in all sensitivity analyses. Conclusions In a large nationwide cohort, recurrent ASCVD events and multi-bed disease were associated with markedly higher mortality compared to patients experiencing single ASCVD events. LDL-C is an important modifiable factor and LDL-C at goal was associated with lower risk of mortality. These data highlight the need for earlier, more intensive, and sustained prevention- particularly aggressive LDL-C lowering and comprehensive risk factor management—in patients with established ASCVD, especially in patients with recurrent events or with polyvascular disease.