Determinants of Residual Risk in Secondary Prevention Patients Treated With High- Versus Low-Dose Statin Therapy

Abstract

Background— Cardiovascular events occur among statin-treated patients, albeit at lower rates. Risk factors for this “residual risk” have not been studied comprehensively. We aimed to identify determinants of this risk above and beyond lipid-related risk factors. Methods and Results— A total of 9251 coronary patients with low-density lipoprotein cholesterol <130 mg/dL randomized to double-blind atorvastatin 10 or 80 mg/d in the Treating to New Targets (TNT) study had complete on-treatment 1-year lipid data. Median follow-up was 4.9 years. The primary end point was major cardiovascular events (n=729): coronary death, nonfatal myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. Multivariable determinants of increased risk were older age (adjusted hazard ratio [aHR], 1.13 per 1 SD [8.8 years]; 95% confidence interval [CI], 1.04–1.23), increased body mass index (aHR, 1.09; 95% CI, 1.02–1.17 per 4.5 kg/m 2 ), male sex (aHR, 1.33; 95% CI, 1.07–1.65), hypertension (aHR, 1.38; 95% CI, 1.17–1.63), diabetes mellitus (aHR, 1.33; 95% CI, 1.11–1.60), baseline apolipoprotein B (aHR, 1.19; 95% CI, 1.11–1.28 per 19 mg/dL), and blood urea nitrogen (aHR, 1.10; 95% CI, 1.03–1.17 per 4.9 mg/dL), in addition to current smoking, prior cardiovascular disease, and calcium channel blocker use. Determinants of decreased risk were high-dose statin (aHR, 0.82; 95% CI, 0.70–0.94), aspirin use (aHR, 0.67; 95% CI, 0.56–0.81), and baseline apolipoprotein A-I (aHR, 0.91; 95% CI, 0.84–0.99 per 25 mg/dL). On-treatment 1-year lipids or apolipoproteins were not additionally associated with risk in multivariable models. Known baseline variables performed moderately well in discriminating future cases from noncases (Harrell c index=0.679). Conclusions— Determinants of residual risk in statin-treated secondary prevention patients included lipid-related and nonlipid factors such as baseline apolipoproteins, increased body mass index, smoking, hypertension, and diabetes mellitus. A multifaceted prevention approach should be underscored to address this risk. Clinical Trial Registration— URL: http://clinicaltrials.gov . Unique identifier: NCT00327691.

Dyslipidemia and Diabetes: Reciprocal Impact of Impaired Lipid Metabolism and Beta-Cell Dysfunction on Micro- and Macrovascular Complications

“…There are similar results from other important clinical studies such as the Pravastatin or Atorvastatin Evaluation and Infection TherapyThrombolysis In Myocardial Infarction study (PROVE IT-TIMI), the Incremental Decrease in End Points Through Aggressive Lipid Lowering study (IDEAL), and the Treating to New Targets study (TNT). The studies revealed that a residual CVD risk was existent even after treatment with statins, with 22.4% of patients in the PROVE IT-TIMI study, 12.0% in the IDEAL trial, and 8.7% in the TNT study [12,13]. Despite a significant reduction of LDL-C levels through the treatment with statins, a considerable residual CVD risk remains in T2D patients.…”

“…However, several studies suggest that abnormalities in HDL cholesterol constitute a CVD risk factor epidemiologically independent of the LDL profile in T2D patients [13]. Normally, HDL particles possess several antiatherogenic properties independent of the wellknown reverse cholesterol transport from the arterial wall to the liver excretion [33].…”

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

“…Nevertheless, some patients cannot tolerate recommended statin doses1; a high proportion of patients do not achieve adequate reduction of low‐density lipoprotein cholesterol (LDL‐C), despite high‐intensity statin therapy2; and even patients who achieve guideline recommended reductions may have high residual ASCVD risk 3. Consequently, alternative therapies designed to lower LDL‐C and improve outcomes are needed.…”

Epidemiology: Disease Associations and Modulators of HDL-Related Biomarkers

“…Mendelian randomization studies have not supported a causal effect of HDL-C in the atherosclerotic disease process (Voight et al 2012;Holmes et al 2014). Moreover, statin trials have shown that HDL-C is predictive among patients treated with statin even at low LDL levels (Barter et al 2007), whereas it is not predictive among patients taking placebo (Ridker et al 2010;Mora et al 2012). Further research is needed to clarify the role of HDL-C as a risk factor.…”

“…Recently, NMR methods have enabled high-throughput determination of HDL particle concentration. Plasma levels of large particles and low particle number are consistently associated with low CHD prevalence (Mora et al 2012). …”