Focused atorvastatin therapy in managed-care patients with coronary heart disease and CKD.

BACKGROUND: This post hoc analysis of the Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) Study investigates the effect of focused atorvastatin therapy versus usual care on cardiovascular outcomes in patients with coronary heart disease (CHD) with and without chronic kidney disease (CKD). STUDY DESIGN: Prospective randomized open-label; median follow-up, 54.3 months. SETTING & PARTICIPANTS: Managed care or Veterans Affairs facilities; 2,442 patients with CHD with dyslipidemia; mean age, 61.6 years. INTERVENTION: Focused atorvastatin therapy to a low-density lipoprotein cholesterol goal of less than 80 mg/dL or maximum dose of 80 mg/d versus usual care as deemed appropriate by patients' regular physicians. PREDICTOR: Baseline estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease Study equation of less than 60 mL/min/1.73 m(2) (patients with CKD) and 60 mL/min/1.73 m(2) or greater (patients without CKD). OUTCOMES & MEASUREMENTS: The primary end point was time to first cardiovascular event. Change from baseline eGFR was assessed in 1,768 patients with follow-up renal data. RESULTS: At baseline, 579 patients (23.7%) had CKD: 31.6% of these patients experienced a primary cardiovascular event during the study versus 23.6% of patients without CKD (hazard ratio [HR], 1.41; 95% confidence interval [CI], 1.18 to 1.68; P < 0.001). Compared with usual care, atorvastatin therapy reduced the relative risk of a primary outcome by 28% in patients with CKD (HR, 0.72; 95% CI, 0.54 to 0.97; P = 0.02) and 11% in patients without CKD (HR, 0.89; 95% CI, 0.74 to 1.07; P = 0.3) (P for treatment by CKD interaction = 0.2). There was no decrease in eGFR in atorvastatin-treated patients during the course of the study. LIMITATIONS: Follow-up of atorvastatin patients was restricted to every 6 months; interim data were unavailable for usual-care patients. CONCLUSIONS: Patients with CHD and CKD are at increased risk of cardiovascular events. Compared with usual care, focused atorvastatin treatment decreased cardiovascular risk for established patients in real-world settings, with no significant difference in treatment effects observed between patients with and without CKD.

Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands.

Macrocyclic chelators and their metal complexes have widespread applications in the biomedical sciences, including radiopharmaceutical chemistry. The use of copper radionuclides in radiopharmaceuticals is increasing. Macrocyclic chelators have been found to have enhanced in vivo stability over acyclic chelators such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA). The currently used chelators of choice for labeling copper radionuclides to biological molecules are analogues of TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid); however, recent reports have demonstrated evidence of in vivo instability of the radio-Cu(II)-TETA complexes. A new class of structurally reinforced macrocycles, the "cross-bridged" cyclam derivatives, form highly stable complexes with Cu(II) that are resistant to dissociation in strong acid. Here, we evaluate a series of (64)Cu(II) cross-bridged macrocyclic complexes for biological stability and in vivo behavior. The ligands evaluated include the parent ligand, 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (1), and three 4,11-di-pendant arm derivatives: 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (2); 4,11-bis(N,N-diethyl-amidomethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (3); and 4,11-bis(amidoethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (4). Copper-64 formed complexes with ligands 1-4 in high radiochemical yields. The (64)Cu-2 complex was neutral, while (64)Cu complexes of 1, 3, and 4 were positively charged. All complexes showed no decomposition in rat serum out to 24 h. Biodistribution experiments in Sprague-Dawley rats indicated that (64)Cu-1, -3, and -4 were taken up by the liver and kidney and cleared slowly over 24 h, whereas (64)Cu-2 cleared rapidly from all tissues. The rapid clearance of the (64)Cu-2 complex from the blood and liver, as well as liver metabolism experiments in rats, suggests that it is highly stable in vivo. A bifunctional chelator of 2 is a significant candidate for labeling copper radionuclides to biological molecules for diagnostic imaging and targeted radiotherapy.