Hypercholesterolemia paradox in relation to mortality in acute coronary syndrome

Background: Hypercholesterolemia is a risk factor for coronary artery disease, yet is associated with lower risk of adverse outcomes in patients with acute coronary syndromes (ACS). Hypothesis: We explored this paradox in 84 429 patients with non-ST-segment elevation ACS in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines registry. Methods: We examined the association between a history of hypercholesterolemia and in-hospital mortality after adjusting for clinical covariates. After excluding patients with previously diagnosedhypercholesterolemia, we repeated the analysis, examining the association between newly diagnosed hypercholesterolemia (inhospital low-density lipoprotein cholesterol [LDL-C] ≥100 mg/dL) and mortality. Results: A history of hypercholesterolemia was associated with lower in-hospital mortality (unadjusted odds ratio [OR]: 0.58; 95% confidence interval [CI]: 0.55, 0.62). This protective association persisted after adjusting for baseline characteristics (OR: 0.71; 95% CI: 0.66, 0.76) and prior statin use (OR: 0.74; 95% CI: 0.68, 0.80). Among 22 711 patients with no history of hypercholesterolemia, 12 809 had a new in-hospital diagnosis of hypercholesterolemia. Unadjusted mortality in these patients was lower than among those with normal LDL levels (OR: 0.58; 95% CI: 0.50, 0.67); however, this difference was not significant after multivariable adjustment (OR: 0.86; 95% CI: 0.73, 1.01). Conclusions: The association of hypercholesterolemia with better outcomes highlights a major challenge in observational analyses. Our results suggest this paradox may result from confounding due to other clinical characteristics, impact of statin treatment, and perhaps most importantly, the fact that previously diagnosed hypercholesterolemia is a marker for patients with more prior medical contact.