Antithrombotic Therapy in Patients With Atrial Fibrillation and Acute Coronary Syndrome Treated Medically or With Percutaneous Coronary Intervention or Undergoing Elective Percutaneous Coronary Intervention: Insights From the AUGUSTUS Trial.

BACKGROUND: The safety and efficacy of antithrombotic regimens may differ between patients with atrial fibrillation who have acute coronary syndromes (ACS), treated medically or with percutaneous coronary intervention (PCI), and those undergoing elective PCI. METHODS: Using a 2×2 factorial design, we compared apixaban with vitamin K antagonists and aspirin with placebo in patients with atrial fibrillation who had ACS or were undergoing PCI and were receiving a P2Y12 inhibitor. We explored bleeding, death and hospitalization, as well as death and ischemic events, by antithrombotic strategy in 3 prespecified subgroups: patients with ACS treated medically, patients with ACS treated with PCI, and those undergoing elective PCI. RESULTS: Of 4614 patients enrolled, 1097 (23.9%) had ACS treated medically, 1714 (37.3%) had ACS treated with PCI, and 1784 (38.8%) had elective PCI. Apixaban compared with vitamin K antagonist reduced International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding in patients with ACS treated medically (hazard ratio [HR], 0.44 [95% CI, 0.28-0.68]), patients with ACS treated with PCI (HR, 0.68 [95% CI, 0.52-0.89]), and patients undergoing elective PCI (HR, 0.82 [95% CI, 0.64-1.04]; Pinteraction=0.052) and reduced death or hospitalization in the ACS treated medically (HR, 0.71 [95% CI, 0.54-0.92]), ACS treated with PCI (HR, 0.88 [95% CI, 0.74-1.06]), and elective PCI (HR, 0.87 [95% CI, 0.72-1.04]; Pinteraction=0.345) groups. Compared with vitamin K antagonists, apixaban resulted in a similar effect on death and ischemic events in the ACS treated medically, ACS treated with PCI, and elective PCI groups (Pinteraction=0.356). Aspirin had a higher rate of bleeding than did placebo in patients with ACS treated medically (HR, 1.49 [95% CI, 0.98-2.26]), those with ACS treated with PCI (HR, 2.02 [95% CI, 1.53-2.67]), and those undergoing elective PCI (HR, 1.91 [95% CI, 1.48-2.47]; Pinteraction=0.479). For the same comparison, there was no difference in outcomes among the 3 groups for the composite of death or hospitalization (Pinteraction=0.787) and death and ischemic events (Pinteraction=0.710). CONCLUSIONS: An antithrombotic regimen consisting of apixaban and a P2Y12 inhibitor without aspirin provides superior safety and similar efficacy in patients with atrial fibrillation who have ACS, whether managed medically or with PCI, and those undergoing elective PCI compared with regimens that include vitamin K antagonists, aspirin, or both. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02415400.

Safety and Efficacy Outcomes 3 Years After Switching to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: Results From a Phase 2 Randomized Trial.

BACKGROUND: In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss. STUDY DESIGN: 36-month follow-up of the intention-to-treat population. SETTING & PARTICIPANTS: CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1.73m2). INTERVENTIONS: At 6 to 36 months posttransplantation, patients were randomly assigned to switch to belatacept-based immunosuppression (n=84) or continue CNI-based therapy (n=89). OUTCOMES: Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed. MEASUREMENTS: Treatment exposure-adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy. RESULTS: Serious adverse events occurred in 33 (39%) belatacept-treated patients and 36 (40%) patients in the CNI group. Treatment exposure-adjusted incidence rates for serious infections (belatacept vs CNI, 10.21 vs 9.31 per 100 person-years) and malignancies (3.01 vs 3.41 per 100 person-years) were similar. More patients in the belatacept versus CNI group had any-grade viral infections (14.60 vs 11.00 per 100 person-years). No posttransplantation lymphoproliferative disorder was reported. Belatacept-treated patients had a significantly greater estimated gain in mean eGFR (1.90 vs 0.07mL/min/1.73m2 per year; P for time-by-treatment interaction effect = 0.01). The probability of acute rejection was not significantly different for belatacept (8.38% vs 3.60%; HR, 2.50 [95% CI, 0.65-9.65; P=0.2). HR for the comparison of belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14-7.07; P=0.9). LIMITATIONS: Exploratory post hoc analysis with a small sample size. CONCLUSIONS: Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.

Evaluating the impact of a Risk Evaluation and Mitigation Strategy with tolvaptan to monitor liver safety in patients with autosomal dominant polycystic kidney disease.

Background: On approval of JYNARQUE (tolvaptan) for use in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk for rapid progression, the US Food and Drug Administration required a Risk Evaluation and Mitigation Strategy (REMS) from the sponsor, which includes collection of post marketing liver safety data. Methods: This is a retrospective interim analysis of the ongoing REMS. The period evaluated was from REMS implementation (14 May 2018) at tolvaptan commercialization to the analysis cutoff date (23 February 2021). Patients were previously tolvaptan-naïve and initiated tolvaptan in the post marketing setting. Reports of possible severe drug-induced liver injury (DILI) were evaluated for severity based on the evidence obtained (e.g. liver enzyme levels, symptoms, diagnostic tests and event outcomes). The incidence of DILI was compared between the REMS and tolvaptan clinical trials in ADPKD. Results: Among 6711 REMS patients, 60 (0.9%) cases of possible severe DILI were reported, 4 of which were confirmed as serious and potentially fatal by the sponsor. One of these four patients met Hy's law criteria. In all four patients, liver enzymes normalized after tolvaptan discontinuation. The duration of tolvaptan exposure in the REMS is currently shorter than in completed clinical trials, but within this limitation, the incidence of possible severe DILI was lower in the REMS than in clinical trials (incidence rate ratio 0.587; P = .000411). Conclusions: In interim data on >6000 tolvaptan REMS patients, <1% experienced possible severe DILI. Monthly monitoring, as described in the tolvaptan prescribing information, enables the prompt detection of liver enzyme abnormalities and appropriate drug discontinuation.

The effects of adenosine A(1) receptor antagonism in patients with acute decompensated heart failure and worsening renal function: the REACH UP study.

BACKGROUND: Worsening renal function (WRF) portends a poor prognosis, and recent deterioration in creatinine might identify patients with elevated intrarenal adenosine in whom adenosine A(1) antagonism may improve renal hemodynamics and function. The purpose of this pilot study was to assess whether rolofylline, an adenosine A(1) antagonist (A(1)RA), would facilitate diuresis while maintaining renal function in patients with acutely decompensated heart failure (ADHF) and recent WRF. METHODS AND RESULTS: Seventy-six patients with ADHF, volume overload, and recent renal deterioration received rolofylline (30 mg, n = 36) or placebo (n = 40) for 3 days. Rolofylline did not demonstrate a beneficial effect on the primary end points of worsening heart failure or renal function after admission or death or readmission within 30 days. Similar proportions of patients receiving rolofylline (33%) and placebo (30%) were treatment failures within 30 days. However, persistent renal impairment (through Day 14) tended to be less common with rolofylline (6%) than placebo (18%). At Day 14, 11 patients receiving placebo and 13 patients receiving rolofylline had a decrease in creatinine > or = 0.3 mg/dL. There were fewer heart failure readmissions with rolofylline (n = 2) than with placebo (n = 7) through Day 60. CONCLUSIONS: The Placebo-Controlled Study of the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (ie, REACH UP) study did not demonstrate any clear benefit of rolofylline in patients with ADHF and worsening renal function. However, beneficial trends raise the possibility that A(1)RAs might prevent renal dysfunction in these high risk patients. To test this hypothesis, further larger studies need to evaluate the effects of adenosine A(1) antagonists in patients with progressive renal dysfunction in the face of active heart failure therapy.

Racial/ethnic disparity in kidney transplantation outcomes: influence of donor and recipient characteristics.

OBJECTIVE: The purpose of this study was to evaluate the basis for the racial/ethnic disparity in kidney allograft survival. METHODS: We conducted a retrospective study of 2130 patients who underwent kidney transplantation between January 1995 and December 2003. Patient and graft survivals were compared using Kaplan-Meier analysis. RESULTS: Black recipients were more likely than white recipients to have hepatitis C infection (24.6% vs 7.1%), current tobacco use (21.2% vs 13.1%), previous alcohol use (22.6% vs 9.7%), and past illicit drug use (13.6% vs 3.9%). Current employment was less common among blacks. Additionally, black recipients were more likely to have a prior kidney transplant (16.7% vs 11.0%) and to have a cadaver kidney donor (74% vs 56.5%). The 5-year allograft survival rate was 72% for whites and 59% for blacks (p < .01). Previous kidney transplantation, cadaveric donor, donor age, recipient employment status, and recipient tobacco use were associated with allograft survival in a Cox proportional hazard model. CONCLUSIONS: Graft survival rate in black kidney transplant recipients is significantly lower than whites, and this disparity can be partially explained by the low rate of live donors and a higher previous transplantation rate in blacks.

Cigarette smoking and incident chronic kidney disease: a systematic review.

BACKGROUND: Several studies have examined the role of cigarette smoking in the development of renal disease in human populations. However, there have been no systematic reviews on the evidence linking smoking with incident renal disease. METHODS: We performed an evidence-based evaluation of peer-reviewed research published during 1966-2005, from a search of five databases, including Ovid MEDLINE and EMBASE. RESULTS: Of the 28 studies that were reviewed, 11 were excluded from the final analysis due to poor methodological quality (n = 6), no reported risk estimate for the association between smoking and kidney disease (n = 3), inability to find a Japanese translator (n = 1), and duplicate cohort (n = 1). Seventeen studies were included in the final analysis; seven studies found an overall significant association between smoking and incident chronic kidney disease, and three studies found a significantly increased risk of chronic kidney disease in current smokers that was gender and/or dose related. An increased risk of developing chronic kidney disease among smokers was significantly associated with male gender (relative risk 2.4, 95% confidence interval 1.2-4.5), >20 cigarettes smoked/day (odds ratio 1.51, 95% confidence interval 1.06-2.15, and relative risk 2.3, 95% confidence interval 1.2-4.3), and smoking >40 years (odds ratio 1.45, 95% confidence interval 1.00-2.09). A pooled estimate of the relative risk (meta-analysis) was deemed inappropriate due to the heterogeneity in methodologies utilized by the different studies. CONCLUSIONS: This comprehensive review reveals overall evidence for current cigarette smoking as a risk factor for incident chronic kidney disease. Further investigation is needed to more carefully examine the strength of the association between cigarette smoking and incident kidney disease.

Survival benefit of recombinant human erythropoietin administration prior to onset of end-stage renal disease: variations across surrogates for quality of care and time.

BACKGROUND: Recombinant human erythropoietin (rHuEPO) is recommended pre-dialysis to correct the anemia of chronic kidney disease. This study evaluated the impact of pre-dialysis rHuEPO on mortality in incident end-stage renal disease (ESRD) patients with varying levels of pre-ESRD care. METHODS: The study included 15,807 individuals whose exposure to rHuEPO was determined from HCFA 2728 forms. RESULTS: Median follow-up after starting dialysis was 32.8 months. Pre-ESRD rHuEPO use occurred in only 3,994 (25.3%) subjects and was more common in individuals with insurance, currently employed, started on outpatient dialysis, and initiated on peritoneal dialysis. During the study, 8,608 (54.5%) patients died. The risk of death was lower for rHuEPO-treated patients versus non-treated (relative risk 0.87, 95% CI 0.82-0.92). The survival benefit with rHuEPO was greatest early after dialysis initiation (relative risk at 1 vs. 7 years post-dialysis 0.73, 95% CI 0.66-0.80 vs. 0.87, 95% CI 0.82-0.92, respectively), did not vary across several surrogates for quality of care, and was greatest in those with the highest achieved hematocrit pre-ESRD. CONCLUSION: Pre-dialysis rHuEPO confers a survival benefit that depends on achieved hematocrit and diminishes post-dialysis, but is independent of several surrogates for quality of care except for insurance status pre-ESRD.

Safety and efficacy of ezetimibe added on to rosuvastatin 5 or 10 mg versus up-titration of rosuvastatin in patients with hypercholesterolemia (the ACTE Study).

The present multicenter, 6-week, randomized, double-blind, parallel-group, clinical trial evaluated the safety and efficacy of ezetimibe (10 mg) added to stable rosuvastatin therapy versus up-titration of rosuvastatin from 5 to 10 mg or from 10 to 20 mg. The study population included 440 subjects at moderately high/high risk of coronary heart disease with low-density lipoprotein (LDL) cholesterol levels higher than the National Cholesterol Education Program Adult Treatment Panel III recommendations (<100 mg/dl for moderately high/high-risk subjects without atherosclerotic vascular disease or <70 mg/dl for high-risk subjects with atherosclerotic vascular disease). Pooled data demonstrated that ezetimibe added to stable rosuvastatin 5 mg or 10 mg reduced LDL cholesterol by 21%. In contrast, doubling rosuvastatin to 10 mg or 20 mg reduced LDL cholesterol by 5.7% (between-group difference of 15.2%, p <0.001). Individually, ezetimibe plus rosuvastatin 5 mg reduced LDL cholesterol more than did rosuvastatin 10 mg (12.3% difference, p <0.001), and ezetimibe plus rosuvastatin 10 mg reduced LDL cholesterol more than did rosuvastatin 20 mg (17.5% difference, p <0.001). Compared to rosuvastatin up-titration, ezetimibe add-on achieved significantly greater attainment of LDL cholesterol levels of <70 or <100 mg/dl (59.4% vs 30.9%, p <0.001), and <70 mg/dl in all subjects (43.8% vs 17.5%, p <0.001); produced significantly greater reductions in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B (p <0.001); and resulted in similar effects on other lipid parameters. Adverse experiences were generally comparable among the groups. In conclusion, compared to up-titration doubling of the rosuvastatin dose, ezetimibe 10 mg added to stable rosuvastatin 5 mg or 10 mg produced greater improvements in many lipid parameters and achieved greater attainment of the National Cholesterol Education Program Adult Treatment Panel III recommended LDL cholesterol targets in subjects with elevated LDL cholesterol and at moderately high/high coronary heart disease risk.

The comparative efficacy of ezetimibe added to atorvastatin 10 mg versus uptitration to atorvastatin 40 mg in subgroups of patients aged 65 to 74 years or greater than or equal to 75 years.

BACKGROUND: Coronary heart disease (CHD) risk increases with age; yet lipid-lowering therapies are significantly under-utilized in patients > 65 years. The objective was to evaluate the safety and efficacy of lipid-lowering therapies in older patients treated with atorvastatin 10 mg + ezetimibe 10 mg (EZ/Atorva) vs. increasing the atorvastatin dose to 40 mg. METHODS: Patients ≥ 65 years with atherosclerotic vascular disease (LDL-C ≥ 1.81 mmol/L) or at high risk for coronary heart disease (LDL-C ≥ 2.59 mmol/L) were randomized to EZ/Atorva for 12 wk vs. uptitration to atorvastatin 20 mg for 6 wk followed by atorvastatin 40 mg for 6 wk. The percent change in LDL-C and other lipid parameters and percent patients achieving prespecified LDL-C levels were assessed after 12 wk. RESULTS: EZ/Atorva produced greater reductions in most lipid parameters vs. uptitration of atorvastatin in patients ≥ 75 years (n = 228), generally consistent with patients 65-74 years (n = 812). More patients achieved LDL-C targets with combination therapy vs. monotherapy in both age groups at 6 wk and in patients ≥ 75 years at 12 wk. At 12 wk, more patients ≥ 75 years achieved LDL-C targets with monotherapy vs. combination therapy. EZ/Atorva produced more favorable improvements in most lipids vs. doubling or quadrupling the atorvastatin dose in patients ≥ 75 years, generally consistent with the findings in patients 65-74 years. CONCLUSIONS: Our results extended previous findings demonstrating that ezetimibe added to a statin provided a generally well-tolerated therapeutic option for improving the lipid profile in patients 65 to 74 years and ≥ 75 years of age.

Effects of the renin inhibitor MK-8141 (ACT-077825) in patients with hypertension.

The renin inhibitor MK-8141 (ACT-077825) demonstrates substantial immunoreactive active renin (ir-AR) increase (sevenfold) without a persistent plasma renin activity (PRA) decrease. The present study assessed the antihypertensive efficacy of MK-8141 in hypertensive patients. In this double-blind, placebo- and active comparator-controlled study, 195 patients with hypertension (trough sitting diastolic blood pressure ≥92 to <105 mm Hg, trough sitting systolic blood pressure <170 mm Hg, and 24-hour mean diastolic blood pressure [DBP] ≥80 mm Hg) were randomized to one of four treatments (stratified by race, black versus others): MK-8141 250 mg, MK-8141 500 mg, enalapril 20 mg, or placebo. Blood pressure was measured at trough and as 24-hour ambulatory blood pressure monitoring. The primary end point was change from baseline in 24-hour mean ambulatory DBP measured after 4 weeks. At week 4, the change from baseline in 24-hour mean (95% CI) ambulatory DBP compared with placebo was -1.6 mm Hg (-4.2, 1.1), -1.1 mm Hg (-3.9, 1.6), and -4.9 (-7.5, -2.2) for MK-8141 250 mg, MK-8141 500 mg, and enalapril 20 mg, respectively. Only mean ambulatory DBP-lowering with enalapril 20 mg was statistically significant. Enalapril, but not MK-8141, also significantly lowered 24-hour mean ambulatory systolic blood pressure (SBP) compared with placebo (-6.7 mm Hg [-10.5, -2.8]). Neither enalapril nor MK-8141 significantly lowered trough DBP and SBP compared with placebo. MK-8141 was generally well tolerated. In patients with hypertension, MK-8141 (ACT-077825) did not produce significant blood pressure-lowering efficacy despite a demonstrated effect of the drug on ir-AR, in the absence of durable PRA suppression.

Lipid lowering for secondary prevention of cardiovascular disease in older adults.

A perceived lack of evidence for benefit and safety concerns may lead to underprescription of HMG-CoA reductase inhibitors (statins) in older adults. This article reviews clinical data regarding the effect of lipid-lowering therapies on cardiovascular outcomes in older adults with a focus on secondary prevention and safety considerations in this population. A literature search of the PubMed database (January 1984 to April 2009) was performed using search terms that included: 'aged' (MeSH heading), 'elderly', 'anticholesteremic agents', 'antilipemic agents', 'hydroxymethylglutaryl-CoA reductase inhibitors', 'cardiovascular diseases', 'randomized controlled trial', 'meta-analysis' and 'drug safety'. Results from large, randomized, controlled trials show that statin therapy lowers both all-cause and coronary heart disease mortality and reduces myocardial infarction, stroke and the need for revascularization in individuals aged ≥65 years who have a history of coronary heart disease. Given the high rate of recurrent cardiovascular events in older adults, there is substantial potential for statin treatment to provide benefits in this population. When older patients are prescribed statins, attention should be given to potential drug interactions, age-related changes in drug pharmacokinetics, adverse effects such as myopathy and risks arising from co-morbid conditions. Additional studies on the benefits and risks of lipid-lowering therapy in individuals aged ≥70 years who have no history of cardiovascular disease, and particularly in those aged ≥80 years, are needed. Other available lipid-modifying drugs - bile acid sequestrants (bile acid binding protein modulators), ezetimibe, niacin and fibrates (fibric acid derivatives) - may be required in patients who are statin-intolerant or have mixed dyslipidaemia, or in whom standard doses of statins may not be sufficient to achieve low-density lipoprotein cholesterol goals.

Safety and efficacy of ezetimibe/simvastatin combination versus atorvastatin alone in adults ≥65 years of age with hypercholesterolemia and with or at moderately high/high risk for coronary heart disease (the VYTELD study).

Higher than 80% of coronary heart disease-related mortality occurs in patients ≥65 years of age. Guidelines recommend low-density lipoprotein (LDL) cholesterol targets for these at-risk patients; however, few clinical studies have evaluated lipid-lowering strategies specifically in older adults. This multicenter, 12-week, randomized, double-blind, parallel-group trial evaluated the efficacy and safety of the usual starting dose of ezetimibe/simvastatin (10/20 mg) versus atorvastatin 10 or 20 mg and the next higher dose of ezetimibe/simvastatin (10/40 mg) versus atorvastatin 40 mg in 1,289 hypercholesterolemic patients ≥65 years of age with or without cardiovascular disease. Patients randomized to ezetimibe/simvastatin had greater percent decreases in LDL cholesterol (-54.2% for 10/20 mg vs -39.5% and -46.6% for atorvastatin 10 and 20 mg, respectively; -59.1% for 10/40 mg vs -50.8% for atorvastatin 40 mg; p <0.001 for all comparisons) and the number attaining LDL cholesterol <70 mg/dl (51.3% for 10/20 mg, 68.2% for 10/40 mg) and <100 mg/dl (83.6% for 10/20 mg; 90.3% for 10/40 mg) was significantly larger compared to those receiving atorvastatin for all prespecified dose comparisons (p <0.05 to <0.001). A significantly larger percentage of high-risk patients achieved LDL cholesterol <70 mg/dl on ezetimibe/simvastatin 10/20 mg (54.3%) versus atorvastatin 10 mg (10.9%, p <0.001) or 20 mg (28.9%, p <0.001) and ezetimibe/simvastatin 10/40 mg (69.2%) versus atorvastatin 40 mg (38.2%, p <0.001), and a significantly larger percentage of intermediate-risk patients achieved LDL cholesterol <100 mg/dl on ezetimibe/simvastatin 10/20 mg (82.1%) versus atorvastatin 10 mg (59.3%, p <0.05). Improvements in non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and lipoprotein ratios were significantly greater with ezetimibe/simvastatin than atorvastatin for all comparisons (p <0.01 to <0.001). High-density lipoprotein cholesterol and triglyceride results were variable. All treatments were generally well tolerated. In conclusion, ezetimibe/simvastatin provided significantly greater improvements in key lipid parameters and higher attainment of LDL cholesterol targets than atorvastatin, with comparable tolerability.

Safety and efficacy of ezetimibe added to atorvastatin versus up titration of atorvastatin to 40 mg in Patients > or = 65 years of age (from the ZETia in the ELDerly [ZETELD] study).

Few clinical studies have focused on the efficacy of lipid-lowering therapies in patients > or = 65 years of age. The percentage of change from baseline in low-density lipoprotein (LDL) cholesterol and the percentage of patients achieving prespecified LDL cholesterol levels after 12 weeks of ezetimibe 10 mg plus atorvastatin versus up titration of atorvastatin were assessed in subjects > or = 65 years old with hyperlipidemia and at high risk of coronary heart disease. After stabilization of atorvastatin 10-mg therapy, 1,053 patients, > or = 65 years old, at high risk of coronary heart disease, with and without atherosclerotic vascular disease and a LDL cholesterol level that was not <70 or <100 mg/dl, respectively, were randomized to receive ezetimibe added to atorvastatin 10 mg for 12 weeks versus up titration to atorvastatin 20 mg for 6 weeks followed by up titration to atorvastatin 40 mg for an additional 6 weeks. Ezetimibe added to atorvastatin 10 mg resulted in significantly greater changes at week 6 in LDL cholesterol (p <0.001), significantly more patients with atherosclerotic vascular disease achieving a LDL cholesterol level of <70 mg/dl (p <0.001), and significantly more patients without atherosclerotic vascular disease achieving a LDL cholesterol level of <100 mg/dl (p <0.001) at weeks 6 and 12 compared to atorvastatin 20 mg or atorvastatin 40 mg. In addition, ezetimibe plus atorvastatin 10 mg resulted in significantly greater changes at week 6 in total cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, apolipoprotein B (all p <0.001), and HDL cholesterol (p = 0.021) compared with atorvastatin 20 mg and significantly greater changes at week 12 in LDL cholesterol, non-HDL cholesterol, apolipoprotein A-I (p = 0.001), total cholesterol, apolipoprotein B (p <0.030), and HDL cholesterol (p <0.001) compared with atorvastatin 40 mg. Both treatments were generally well tolerated, with comparable safety profiles. In conclusion, adding ezetimibe to atorvastatin 10 mg produced significantly greater favorable changes in most lipids at 6 and 12 weeks and significantly greater attainment of prespecified LDL cholesterol levels than doubling or quadrupling the atorvastatin dose in patients > or =65 years old at high risk for coronary heart disease.

Urinary cotinine as an objective measure of cigarette smoking in chronic kidney disease.

BACKGROUND: Smoking is a modifiable behaviour that may hasten the progression of chronic kidney disease (CKD). Cotinine, a nicotine metabolite, is measurable in body fluids, including urine, and can be utilized as an objective measure of smoking exposure. Its use has not been examined in the CKD population. METHODS: In this cross-sectional study, we evaluated use of 24-h urinary cotinine excretion (Ucot) as a quantitative index of smoking exposure in a CKD population. Methods of comparison included self-report and expired air carbon monoxide (eCO) as standard measures of smoking exposure. Assessments of kidney function included estimated glomerular filtration rate (eGFR) and 24-h urinary protein (Uprot) excretion. RESULTS: Sixty-one patients were enrolled, of whom 12 were excluded for incomplete urine collections. Of the remaining, 77% were active current smokers (mean cigarettes smoked: 12+/-7 per day). The mean eGFR was 47+/-25 ml/min/1.73 m2 with no significant differences among non-smokers. The mean eCO and Ucot were significantly higher in smokers vs non-smokers (12.5+/-6.9 ppm and 1.3+/-1.1 ppm and 1685.87+/-922.77 microg/d and 134.18+/-445.03 microg/d, respectively, P<0.001 for both). Ucot was weakly correlated with eGFR (R=0.40, P=0.005), but not with Uprot (R=0.09, P=0.54). In multivariate analyses, daily cigarette consumption and eCO were the only significant predictors of Ucot (P<0.05 for both). CONCLUSION: In this CKD cohort, Ucot is correlated with commonly used measures of smoking exposure and is minimally influenced by underlying renal function, demonstrating its potential utility in clinical trials examining change in smoking behaviour and effects on renal injury.

Center effects in anemia management of dialysis patients.

This study set out to determine whether there is a center effect on anemia management in hemodialysis patients. The US Renal Data System and Medicare standard analysis files were analyzed. Between-center variation and within-facility correlations in hematocrit values were examined in two separate data sets (years 2000 and 2001) and compared with simulated samples that were composed of random values that assumed no center effect. Mixed-effect models were used to adjust for multiple factors and quantify the within-facility correlation in hematocrit values. Expected hematocrit values were compared in patients who underwent dialysis at poor and superior performing facilities with fixed characteristics including epoetin alpha dosing. There was a wider center variation in hematocrit for the actual versus simulated data and a coefficient of variation of 4.1% for the former versus 1.7% for the latter, in both years. The within-facility correlation for hematocrit was 0.053 (95% confidence interval 0.050 to 0.056; P < 0.001) in 2000 with similar values in 2001 but no within-facility correlation in the simulated data. The impact of these findings was demonstrated with a difference in expected hematocrit for a patient who was treated with fixed-dosage epoetin alpha in the poorest versus best performing units (mean difference in expected hematocrit 3.06; 95% confidence interval 3.03 to 3.09; P < 0.001). Key attributes of a center effect on anemia management in hemodialysis have been identified. The presence of a center effect suggests that there are facility-specific processes that influence performance in dialysis anemia management and are independent of commonly titrated inputs, such as dosing of erythropoietic agents.

An in-depth review of the evidence linking dietary salt intake and progression of chronic kidney disease.

BACKGROUND: Dietary salt has been debated for decades as having a potentially deleterious influence on human health. OBJECTIVES: To determine the quality of research and the relationship between dietary salt and markers for progression of kidney disease. METHODS: Data sources included 7 electronic databases comprehensively searched for literature published between January 1, 1966, and August 31, 2004, and a manual search of bibliographies of relevant papers, and consultation with experts in the field. Differences between the paired reviewers were reconciled through consensus or by a content expert. RESULTS: Sixteen studies met the inclusion-exclusion criteria and were identified for review; however, the study methodologies were extremely heterogeneous. Conclusions commonly cited in the studies include: variations in salt consumption are directly correlated with albuminuria, and an increase in salt consumption is associated with an acute increase in glomerular filtration rate, while a reduction in salt consumption may slow the rate of renal function loss. CONCLUSIONS: The available published information, while highly variable in methods and quality, suggests that variations in dietary salt consumption directly influence albuminuria, with increasing salt intake associated with worsening albuminuria; however, results are inadequate and conflicting on the effects of dietary salt consumption on renal function, especially over a prolonged time. There was no evidence of a detrimental effect of reduced salt intake. On the other hand, there is consistent experimental evidence to link increased salt exposure with kidney tissue injury. On the basis of these data, we believe that dietary salt restriction should be considered in patients with chronic kidney disease.

Racial variations in erythropoietic response to epoetin alfa in chronic kidney disease and the impact of smoking.

BACKGROUND: Of the known risk factors for chronic kidney disease (CKD), race represents one that is non-modifiable, while smoking is another that is modifiable. Moreover, smoking tends to increase red blood cell mass, which is frequently diminished in CKD. No studies have examined the interplay of race with smoking on anaemia management in patients with CKD. METHODS: We examined the effects of smoking on anaemia management in CKD and its variation across race in a previously conducted study of CKD patients (n = 1312) initiated on weekly epoetin alfa and followed for 16 weeks. Smoking status was classified as current vs non-smoker. Race was classified as African-American vs non-African-American. Changes in estimated glomerular filtration rate, urinary albumin excretion, and erythropoietic response to weekly epoetin alfa were examined. RESULTS: Overall, African-Americans had lower baseline Hb than non-African-Americans. African-American non-smokers did not mount an erythropoetic response comparable to other non-smokers by final Hb (mean 11.29 g/dl vs 11.64 g/dl, P<0.001) or week 16 Hb (mean 11.61 g/dl vs 11.86 g/dl, P = 0.02). However, African-American smokers had a more significant erythropoietic response than their non-smoking counterparts and were comparable to their smoking non-African-American counterparts. There was no effect of smoking on renal function or urinary protein excretion over the course of the study. CONCLUSION: African-American non-smokers exhibit a diminished response to standard epoetin alfa dosing than non-smokers in other races. However, African-American smokers with CKD exhibit a response to epoetin alfa comparable to patients of other races. These findings may have implications for African-Americans who have CKD-related anaemia.

Does dietary salt increase the risk for progression of kidney disease?

Due to the inconsistent observations and suboptimal quality of the study designs, there is insufficient clinical evidence to suggest that increased salt intake may adversely modify the rate of progression of kidney disease. However, there is experimental evidence to suggest a link between increased salt exposure and kidney tissue injury. Further clinical trials are needed to evaluate the relationship between dietary salt and risk for progression of chronic kidney disease.