Effect of high-dose atorvastatin on renal function in subjects with stroke or transient ischemic attack in the SPARCL trial.

BACKGROUND AND PURPOSE: Higher low-density lipoprotein cholesterol is associated with more rapid chronic kidney disease progression; reduction in cholesterol with statins, in conjunction with statins' pleiotropic effects, such as decreasing inflammation, may be renoprotective. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial assessed the effect of statin treatment on the risk of nonfatal and fatal stroke in subjects with a noncardioembolic stroke or transient ischemic attack, no known coronary heart disease, and low-density lipoprotein cholesterol between 2.6 and 4.9 mmol/L (100-190 mg/dL). METHODS: We explored the effect of randomization to atorvastatin 80 mg/d or placebo on the change in estimated glomerular filtration rate (eGFR; using the 4-component Modification of Diet in Renal Disease Study equation) in SPARCL subjects (n=4731) with (eGFR, <60 mL/min per 1.73 m2; n=3119) and without (eGFR, ≥60 mL/min per 1.73 m2; n=1600) chronic kidney disease overall and by glycemic status at baseline. RESULTS: Mean baseline eGFR was similar between treatment groups (65.5±0.26 versus 65.6±0.26 mL/min per 1.73 m2 atorvastatin versus placebo; 33% versus 34% had chronic kidney disease, respectively; P=0.55). After 60 months, eGFR increased 3.46±0.33 mL/min per 1.73 m2 in those randomized to atorvastatin versus 1.42±0.34 mL/min per 1.73 m2 in those randomized to placebo (P<0.001) independent of baseline renal function. In the subgroup with diabetes mellitus at randomization, eGFR increased 1.12±0.92 mL/min per 1.73 m2 in the atorvastatin group and decreased 1.69±0.92 mL/min per 1.73 m2 in placebo group during a period of 60 months (P=0.016). CONCLUSIONS: This post hoc analysis suggests that atorvastatin treatment may improve renal function in patients with prior stroke or transient ischemic attack with and without chronic kidney disease, and that atorvastatin treatment may prevent eGFR decline in patients with stroke and diabetes mellitus. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00147602.

Abrupt discontinuation compared with a 1-week taper regimen in depressed outpatients treated for 24 weeks with desvenlafaxine 50 mg/d.

The objective of this study was to determine whether the occurrence of discontinuation symptoms was equivalent for abrupt discontinuation versus 1-week taper to desvenlafaxine 25 mg/d after a 24-week treatment with desvenlafaxine 50 mg/d (administered as desvenlafaxine succinate) for major depressive disorder. Adult outpatients with major depressive disorder who completed the 24 weeks of open-label treatment with desvenlafaxine 50 mg/d were randomly assigned to no discontinuation (desvenlafaxine 50 mg/d), taper (desvenlafaxine 25 mg/d), or abrupt discontinuation (placebo) groups for the double-blind (DB) taper phase. The primary end point was Discontinuation-Emergent Signs and Symptoms (DESS) scale total score during the first 2 weeks of the DB phase. The null hypothesis that the absolute difference of greater than 2.5 in DESS scores between taper and abrupt discontinuation groups was tested by calculating the 95% 2-sided confidence interval on the mean difference between the 2 groups. Of the 480 patients enrolled in the open-label phase, 357 (≥1 postrandomization DESS record) were included in the primary analysis. Adjusted mean ± SE DESS scores were 4.1 ± 0.72 for no discontinuation (n = 72), 4.8 ± 0.54 for taper (n = 139), and 5.3 ± 0.52 for abrupt discontinuation (n = 146) groups. The difference in adjusted mean DESS total scores between the abrupt discontinuation and taper groups was 0.50 (95% confidence interval, -0.88 to 1.89) within the prespecified margin (±2.5) for equivalence. The number of patients who discontinued because of adverse events or discontinuation symptoms during the DB period was similar between the taper (2.8%) and abrupt discontinuation (2.1%) groups. These findings indicate that an abrupt discontinuation of desvenlafaxine 50 mg/d produces statistically equivalent DESS scores compared with the 1-week taper using 25 mg/d.

Prediction of major vascular events after stroke: the stroke prevention by aggressive reduction in cholesterol levels trial.

BACKGROUND: Identifying patients with recent stroke or transient ischemic attack (TIA) at high risk of major vascular events (MVEs; stroke, myocardial infarction, or vascular death) may help optimize the intensity of secondary preventive interventions. We evaluated the relationships between the baseline Framingham Coronary Risk Score (FCRS) and a novel risk prediction model and with the occurrence of MVEs after stroke or TIA in subjects enrolled in the Stroke Prevention by Aggressive Reduction in Cholesterol Level (SPARCL) trial. METHODS: Data from the 4731 subjects enrolled in the SPARCL study were analyzed. Hazard ratios (HRs) from Cox regression models were used to determine the risk of subsequent MVEs based on the FCRS predicting 20% or more 10-year coronary heart disease risk. The novel risk model was derived based on multivariable modeling with backward selection. Model discrimination (c-statistics) was assessed using the areas under the receiver operating characteristic curves. RESULTS: Of 3969 subjects with complete data, 27% had a baseline FCRS of 20% or more. In multivariable analysis, an FCRS of 20% or more was associated with twice the risk of subsequent MVEs (HR = 1.92, 95% confidence interval [CI]: 1.63-2.27). The novel model based on a multivariable analysis included age (HR = 1.37, 95% CI: 1.25-1.51 per 10 years), diabetes (HR = 1.82, 95% CI: 1.51-2.18), male sex (HR = 1.35, 95% CI: 1.12-1.61), and an apolipoprotein (APO)-B/APO-A1 ratio (HR = 1.56, 95% CI: 1.16-2.11). The c-statistic was .58 (95% CI: .55-.60) for the FCRS of 20% or more and .65 (95% CI: .63-.67) for the novel model. CONCLUSIONS: Both a baseline FCRS of 20% or more and a novel predictive model were associated with future MVEs in SPARCL trial subjects. The novel model needs to be validated, and the benefits of using either the FCRS or the novel model in clinical practice needs to be assessed.

Vitamin D levels do not predict cardiovascular events in statin-treated patients with stable coronary disease.

BACKGROUND: This post hoc nested case-control analysis of the TNT study was designed to investigate whether baseline vitamin D level is a significant predictor of cardiovascular risk among statin-treated patients and whether changes in vitamin D after treatment with atorvastatin are associated with improved cardiovascular outcomes. METHODS: A total of 10,001 patients with stable coronary heart disease were randomized to atorvastatin 80 or 10 mg for a median of 4.9 years. This analysis included 1,509 patients (497 with a subsequent cardiovascular event and 1,012 without an event) with vitamin D levels determined at baseline and 1 year. Event rates were analyzed by Cox proportional hazard model by baseline vitamin D levels, with vitamin D as a continuous variable, and with change in vitamin D level as the predictor. RESULTS: Vitamin D deficiency (<15 ng/mL) or insufficiency (15- <30 ng/mL) was present in 108 (7.2%) of 1,509 and 625 (41.4%) of 1,509 of patients, whereas 46 (3.0%) of 1,509 had elevated vitamin D. There was no relationship between baseline vitamin D levels or change in vitamin D levels and cardiovascular events or mortality. Modeling of events with vitamin D as a continuous variable similarly showed no relationship of vitamin D to events. These findings held true after adjustment for seasonal variations in vitamin D and other confounders. CONCLUSION: In statin-treated patients with stable coronary heart disease, vitamin D levels did not predict cardiovascular risk. Changes in plasma concentrations of vitamin D after 1 year of treatment made no contribution to the efficacy of atorvastatin therapy.

Systemic exposure to atorvastatin between Asian and Caucasian subjects: a combined analysis of 22 studies.

The aim of the present study was to determine whether there is a differing pattern of systemic exposure to atorvastatin in Asian versus Caucasian subjects by comparison of data obtained from completed pharmacokinetic studies. Pharmacokinetic data were analyzed from completed single-dose (10-80 mg) studies in Asian and Caucasian subjects. Dose normalized area under the concentration-time curve (AUC) and maximum observed concentration (Cmax) (AUC(dn) and Cmax(dn)) were obtained by dividing each value by the administered dose. Dose-per-bodyweight normalized AUC and Cmax (AUC(dn,wt) and Cmax,(dn,wt)) were obtained by dividing each value by the administered dose per unit bodyweight. Mean difference and 90% confidence intervals for Asian versus Caucasian comparisons were calculated for atorvastatin pharmacokinetic values based on the t statistic and expressed as ratios using Caucasians as the reference. Data were analyzed from 310 Asians and 579 Caucasians from 22 studies. AUC(dn) (Asian = 2.35, Caucasian = 2.06 [ng·hr·mL(-1)]/mg) and Cmax(dn) (Asian = 0.39, Caucasian = 0.40 Cmax(dn,wt)) and the equivalent dose-per-bodyweight normalized values for atorvastatin (AUC(dn,wt): Asian = 157.5, Caucasian = 156.4 [ng·hr·mL(-1)]/[mg·kg(-1)]; Cmax(dn,wt): Asian = 26.2, Caucasian = 30.3 [ng·mL(-1)]/[mg·kg(-1)]) were similar in both ethnic groups. Mean differences and 90% confidence interval for the differences fell within the limits (0.8-1.25) except for Cmax(dn,wt), for which the lower limit was slightly below 80%. No differences were noted in the systemic exposure to atorvastatin between Asian and Caucasian subjects. These data therefore demonstrate that dosing considerations in the current labels for atorvastatin are similar for Asian compared with Caucasian subjects.

High-dose atorvastatin and risk of atrial fibrillation in patients with prior stroke or transient ischemic attack: analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.

BACKGROUND: Observational analyses and short-term randomized trials have suggested that statins reduce occurrence or recurrence of atrial fibrillation (AF). We tested the hypothesis that long-term treatment with high-dose atorvastatin reduces occurrence of AF in patients with prior stroke or transient ischemic attack. METHODS: We examined development of new AF in the SPARCL trial that compared atorvastatin 80 mg daily with placebo in 4,731 patients with prior stroke or transient ischemic attack. Patients who had chronic or paroxysmal AF or were taking medications for treatment or prophylaxis of AF at the time of enrollment were excluded. Atrial fibrillation was identified from electrocardiograms submitted to a blinded central electrocardiographic laboratory and from investigators' adverse event reports. RESULTS: Patients were followed up for a median of 4.8 years, corresponding to >20,000 patient-years of observation with a median of 5 electrocardiograms per patient. The primary efficacy measure, the time from randomization to first occurrence of new AF, did not differ between treatment groups. By intention to treat, there were 139 cases of new AF in the atorvastatin group and 122 cases in the placebo group, corresponding to incidence rates of 1.32 and 1.14 cases per 100 patient-years observation (hazard ratio 1.15, 95% CI 0.90-1.46, P = .26). On-treatment analysis yielded similar findings, with incidence rates of 1.26 and 1.01 cases per 100 patient-years observation in the atorvastatin and placebo groups, respectively (hazard ratio 1.25, 95% CI 0.94-1.67, P = .12). CONCLUSION: High-dose atorvastatin does not prevent development of AF in patients with prior stroke or transient ischemic attack.

Lipid treatment assessment project 2: a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals.

BACKGROUND: Information about physicians' adherence to cholesterol management guidelines remains scant. The present survey updates our knowledge of lipid management worldwide. METHODS AND RESULTS: Lipid levels were determined at enrollment in dyslipidemic adult patients on stable lipid-lowering therapy in 9 countries. The primary end point was the success rate, defined as the proportion of patients achieving appropriate low-density lipoprotein cholesterol (LDL-C) goals for their given risk. The mean age of the 9955 evaluable patients was 62+/-12 years; 54% were male. Coronary disease and diabetes mellitus had been diagnosed in 30% and 31%, respectively, and 14% were current smokers. Current treatment consisted of a statin in 75%. The proportion of patients achieving LDL-C goals according to relevant national guidelines ranged from 47% to 84% across countries. In low-, moderate-, and high-risk groups, mean LDL-C was 119, 109, and 91 mg/dL and mean high-density lipoprotein cholesterol was 62, 49, and 50 mg/dL, respectively. The success rate for LDL-C goal achievement was 86% in low-, 74% in moderate-, and 67% in high-risk patients (73% overall). However, among coronary heart disease patients with > or =2 risk factors, only 30% attained the optional LDL-C goal of <70 mg/dL. In the entire cohort, high-density lipoprotein cholesterol was <40 mg/dL in 19%, 40 to 60 mg/dL in 55%, and >60 mg/dL in 26% of patients. CONCLUSIONS: Although there is room for improvement, particularly in very-high-risk patients, these results indicate that lipid-lowering therapy is being applied much more successfully than it was a decade ago.

Relative and cumulative effects of lipid and blood pressure control in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial.

BACKGROUND AND PURPOSE: The relative contributions of on-treatment low- and high-density lipoprotein cholesterol (LDL-C, HDL-C), triglycerides, and blood pressure (BP) control on the risk of recurrent stroke or major cardiovascular events in patients with stroke is not well defined. METHODS: We randomized 4731 patients with recent stroke or transient ischemic attack and no known coronary heart disease to atorvastatin 80 mg per day or placebo. RESULTS: After 4.9 years, at each level of LDL-C reduction, subjects with HDL-C value above the median or systolic BP below the median had greater reductions in stroke and major cardiovascular events and those with a reduction in triglycerides above the median or diastolic BP below the median showed similar trends. There were no statistical interactions between on-treatment LDL-C, HDL-C, triglycerides, and BP values. In a further exploratory analysis, optimal control was defined as LDL-C <70 mg per deciliter, HDL-C >50 mg per deciliter, triglycerides <150 mg per deciliter, and SBP/DBP <120/80 mm Hg. The risk of stroke decreased with as the level of control increased (hazard ratio [95% confidence interval] 0.98 [0.76 to 1.27], 0.78 [0.61 to 0.99], 0.62 [0.46 to 0.84], and 0.35 [0.13 to 0.96]) for those achieving optimal control of 1, 2, 3, or 4 factors as compared to none, respectively. Results were similar for major cardiovascular events. CONCLUSIONS: We found a cumulative effect of achieving optimal levels of LDL-C, HDL-C, triglycerides, and BP on the risk of recurrent stroke and major cardiovascular events. The protective effect of having a higher HDL-C was maintained at low levels of LDL-C.

Statin treatment and stroke outcome in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.

BACKGROUND AND PURPOSE: Laboratory experiments suggest statins reduce stroke severity and improve outcomes. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial was a placebo-controlled, randomized trial designed to determine whether treatment with atorvastatin reduces strokes in subjects with recent stroke or transient ischemic attack (n=4731). We analyzed SPARCL trial data to determine whether treatment favorably shifts the distribution of severities of ischemic cerebrovascular outcomes. METHODS: Severity was assessed with the National Institutes of Health Stroke Scale, Barthel Index, and modified Rankin Scale score at enrollment (1 to 6 months after the index event) and 90 days poststroke in subjects having a stroke during the trial. RESULTS: Over 4.9 years, strokes occurred in 576 subjects. There were reductions in fatal, severe (modified Rankin Scale score 5 or 4), moderate (modified Rankin Scale score 3 or 2), and mild (modified Rankin Scale score 1 or 0) outcome ischemic strokes and transient ischemic attacks and an increase in the proportion of event-free subjects randomized to atorvastatin (P<0.001 unadjusted and adjusted). Results were similar for all outcome events (ischemic and hemorrhagic, P<0.001 unadjusted and adjusted) with no effect on outcome hemorrhagic stroke severity (P=0.174 unadjusted, P=0.218 adjusted). If the analysis is restricted to those having an outcome ischemic stroke (ie, excluding those having a transient ischemic attack or no event), there was only a trend toward lesser severity with treatment based on the modified Rankin Scale score (P=0.0647) with no difference based on the National Institutes of Health Stroke Scale or Barthel Index. CONCLUSIONS: The present exploratory analysis suggests that the outcome of recurrent ischemic cerebrovascular events might be improved among statin users as compared with nonusers.

Low- and high-density lipoprotein cholesterol goal attainment in dyslipidemic women: The Lipid Treatment Assessment Project (L-TAP) 2.

BACKGROUND: Differences between women and men have been documented for both diagnostic testing and treatment in cardiology. This analysis evaluates whether low-density lipoprotein cholesterol (LDL-C) success rates according to current guidelines and high-density lipoprotein cholesterol (HDL-C) levels differ by gender in the L-TAP 2 population. METHODS: Patients aged > or =20 years with dyslipidemia on stable lipid-lowering therapy were assessed in 9 countries between September 2006 and April 2007. Low-density lipoprotein cholesterol goal attainment by cardiovascular risk level and region and determinants of low HDL-C were compared between genders. RESULTS: Of 9,955 patients (45.3% women) evaluated, women had a significantly lower overall LDL-C success rate than men (71.5% vs 73.7%, P = .014), due entirely to the difference in the high-risk/coronary heart disease (CHD) group (LDL-C goal <100 mg/dL, 62.6% vs 70.6%, P < .0001) Among CHD patients with > or =2 additional risk factors, only 26.7% of women and 31.5% of men (P = .021) attained the optional LDL-C goal of <70 mg/dL. High-density lipoprotein cholesterol was <50 mg/dL in 32.2% of women and <40 mg/dL in 26.8% of men (P < .0001), including 38.2% of women and 29.8% of men in the high risk/CHD group (P < .0001). Predictors of low HDL-C in women included diabetes, smoking, waist circumference, and hypertension. CONCLUSIONS: Cholesterol treatment has improved substantially since the original L-TAP a decade ago, when only 39% of women attained their LDL-C goal. However, high-risk women are undertreated compared to men, and a substantial opportunity remains to reduce their cardiovascular risk.

Atorvastatin reduces the risk of cardiovascular events in patients with carotid atherosclerosis: a secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.

BACKGROUND AND PURPOSE: The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial found that treatment with atorvastatin 80 mg per day reduced the risk of stroke and cardiovascular events in patients with a recent transient ischemic attack (TIA) or stroke. We hypothesized this benefit would be greatest in the subgroup of patients with carotid stenosis. METHODS: The SPARCL trial randomized patients with TIA or stroke within 1 to 6 months without known coronary heart disease (CHD) and low-density lipoprotein cholesterol 100 to 190 mg/dL to treatment with atorvastatin 80 mg per day or placebo. Investigators identified subjects as having carotid stenosis not requiring revascularization at the time of randomization. Of the total SPARCL population, 1007 were documented as having carotid stenosis at baseline, 3271 did not, and the status of 453 was unknown. RESULTS: We found no heterogeneity in the treatment effect for the SPARCL primary (fatal and nonfatal stroke) and secondary end points between the group with and without carotid stenosis. The group with carotid artery stenosis had greater benefit when all cerebro- and cardiovascular events were combined. In the group with carotid artery stenosis, treatment with atorvastatin was associated with a 33% reduction in the risk of any stroke (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.47, 0.94; P=0.02), and a 43% reduction in risk of major coronary events (HR 0.57, 95% CI 0.32, 1.00; P=0.05). Later carotid revascularization was reduced by 56% (HR 0.44, 95% CI 0.24, 0.79; P=0.006) in the group randomized to atorvastatin. CONCLUSIONS: Consistent with the overall results of the SPARCL intention to treat population, intense lipid lowering with atorvastatin reduced the risk of cerebro- and cardiovascular events in patients with and without carotid stenosis. The carotid stenosis group may have greater benefit.

Relative effects of statin therapy on stroke and cardiovascular events in men and women: secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study.

BACKGROUND AND PURPOSE: In SPARCL, treatment with atorvastatin 80 mg daily reduced stroke risk in patients with recent stroke or TIA and no known coronary heart disease by 16% versus placebo over 4.9 years of follow-up. The purpose of this secondary analysis was to determine whether men and women similarly benefited from randomization to statin treatment. METHODS: The effect of sex on treatment-related reductions in stroke and other cardiovascular outcomes were analyzed with Cox regression modeling testing for sex by treatment interactions. RESULTS: Women (n=1908) constituted 40% of the SPARCL study population. At baseline, men (n=2823) were younger (62.0+/-0.21 versus 63.9+/-0.27 years), had lower systolic BPs (138.1+/-0.35 versus 139.5+/-0.47 mm Hg), higher diastolic BPs (82.2+/-0.20 versus 81.0+/-0.25 mm Hg), more frequently had a history of smoking (73% versus 38%), and had lower total cholesterol (207.0+/-0.54 versus 218.9+/-0.67 mg/dL) and LDL-C levels (132+/-0.45 versus 134+/-0.57 mg/dL) than women. Use of antithrombotics and antihypertensives were similar. After prespecified adjustment for region, entry event, time since event, and age, there were no sex by treatment interactions for the combined risk of nonfatal and fatal stroke (treatment Hazard Ratio, HR=0.84, 95% CI 0.68, 1.02 in men versus HR=0.84, 95% CI 0.63, 1.11 in women; treatment x sex interaction P=0.99), major cardiac events (HR=0.61, 95% CI 0.42, 0.87 in men versus HR=0.76, 95% CI 0.48, 1.21 in women; P=0.45), major cardiovascular events (HR=0.78, 95% CI 0.65, 0.93 in men versus HR=0.84, 95% CI 0.65, 1.07 in women; P=0.63), revascularization procedures (HR=0.50, 95% CI 0.37, 0.67 in men versus HR=0.76, 95% CI 0.46, 1.24 in women; P=0.17), or any CHD event (HR=0.54, 95% CI 0.41, 0.72 in men versus 0.67 95% CI 0.46, 0.98 in women; P=0.40). CONCLUSIONS: Stroke and other cardiovascular events are similarly reduced with atorvastatin 80 mg/d in men and women with recent stroke or TIA.

Gender, body weight, disease activity, and previous radiotherapy influence the response to pegvisomant.

CONTEXT/OBJECTIVE: To effectively normalize IGF-I in patients with acromegaly, various covariates may affect dosing and plasma concentrations of pegvisomant. We assessed whether sex, age, weight, and previous radiotherapy influence dosing of pegvisomant in patients with active disease. DESIGN: Data from 69 men and 49 women participating in multicenter, open-label trials of pegvisomant were retrospectively evaluated using multiple regression techniques. Sixty-nine subjects (39 men, 30 women) had undergone external beam pituitary radiotherapy. Serum IGF-I was at least 30% above age-related upper limit of normal in all patients at study entry. After a loading dose of pegvisomant (80 mg), patients were commenced on 10 mg/d. Pegvisomant dose was adjusted by 5 mg every eighth week until serum IGF-I was normalized. RESULTS: At baseline, men had significantly higher mean serum IGF-I levels than women despite similar GH levels. After treatment with pegvisomant, IGF-I levels were similar in men and women. A significant correlation between baseline GH, IGF-I, body weight, and the dose of pegvisomant required to normalize serum IGF-I was observed (all P < 0.001). Women required an average of 0.04 mg/kg more pegvisomant than men and a mean weight-corrected dose of 19.2 mg/d to normalize serum IGF-I [14.5 mg/d (men); P < 0.001]. Patients treated with radiotherapy required less pegvisomant to normalize serum IGF-I despite similar baseline GH/IGF-I levels (15.2 vs. 18.5 mg/d for no previous radiotherapy; P = 0.002). CONCLUSIONS: Sex, body weight, previous radiotherapy, and baseline GH/IGF-I influence the dose of pegvisomant required to normalize serum IGF-I in patients with active acromegaly.

The effect of conjugated estrogens/bazedoxifene therapy on body weight of postmenopausal women: pooled analysis of five randomized, placebo-controlled trials.

OBJECTIVE: This post hoc analysis compared body weight, body mass index (BMI), and BMI category changes in postmenopausal women treated with conjugated estrogens/bazedoxifene (CE/BZA) versus placebo in the Selective Estrogens, Menopause, and Response to Therapy (SMART) trials. METHODS: Data were pooled from five randomized, double-blind, placebo- and active-controlled studies in postmenopausal women aged 40 to 75 years with a uterus given CE 0.45 mg/BZA 20 mg (n = 1,607), CE 0.625 mg/BZA 20 mg (n = 1,598), or placebo (n = 1,256) for at least 12 weeks and up to 2 years. Changes from baseline in body weight, BMI (kg/m(2)), and World Health Organization BMI category (underweight <18.5; normal 18.5 to <25; overweight 25 to <30; obese ≥30) during treatment were evaluated. RESULTS: Mean body weight increased less than 0.9 kg and mean BMI increased less than 0.4 kg/m(2) in all treatment groups at all time points. There were no statistically significant between-group differences, except for significantly greater increases in weight (P = 0.015) and BMI (P = 0.014) with placebo versus CE 0.625 mg/BZA 20 mg at month 12. Approximately, 10% of women in the CE/BZA groups and 11% in the placebo group had increases in body weight greater than 7% of baseline. The majority of BMI changes were within ±7%, and there were no statistically significant between-group differences in BMI category distributions during treatment. CONCLUSIONS: Significant increases in body weight or BMI were not observed in postmenopausal women receiving CE 0.45 mg/BZA 20 mg or CE 0.625 mg/BZA 20 mg for up to 2 years in the Selective Estrogens, Menopause, and Response to Therapy trials.

Relation Between Change in Renal Function and Cardiovascular Outcomes in Atorvastatin-Treated Patients (from the Treating to New Targets [TNT] Study).

Statins may have nephroprotective as well as cardioprotective effects in patients with cardiovascular disease. In the Treating to New Targets (TNT) study (NCT00327691), patients with coronary heart disease (CHD) were randomized to atorvastatin 10 or 80 mg/day and followed for 4.9 years. The relation between intrastudy change in estimated glomerular filtration rate (eGFR) from baseline and the risk of major cardiovascular events (MCVEs, defined as CHD death, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke) was assessed among 9,500 patients stratified by renal function: improving (change in eGFR more than +2 ml/min/1.73 m(2)), stable (-2 to +2 ml/min/1.73 m(2)), and worsening (less than -2 ml/min/1.73 m(2)). Compared with patients with worsening renal function (1,479 patients, 15.6%), the rate of MCVEs was 28% lower in patients with stable renal function (2,241 patients, 23.6%) (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.60 to 0.87; p = 0.0005) and 64% lower in patients with improving renal function (5,780 patients, 60.8%; HR 0.36; 95% CI 0.30 to 0.43; p <0.0001). For each 1 ml/min/1.73 m(2) increase in eGFR, the absolute reduction in the rate of MCVEs was 2.7% (HR 0.973; 95% CI 0.967 to 0.980; p <0.0001). An absolute MCVE rate reduction per 1 ml/min/1.73 m(2) increase in eGFR of 2.0% was reported with atorvastatin 10 mg and 3.3% with atorvastatin 80 mg. In conclusion, intrastudy stabilization or increase in eGFR in atorvastatin-treated patients with CHD from the TNT study was associated with a reduced rate of MCVEs. Statin-treated CHD patients with progressive renal impairment are at high risk for future cardiovascular events.

Emerging Cardiovascular Disease Biomarkers and Incident Diabetes Mellitus Risk in Statin-Treated Patients With Coronary Artery Disease (from the Treating to New Targets [TNT] Study).

Whether biomarkers associated with cardiovascular disease risk also predict incident diabetes mellitus (DM) is unknown. Our objective was to determine if a panel of 18 biomarkers previously associated with risk of cardiovascular disease also predicts incident DM in statin-treated patients with coronary artery disease (CAD). The Treating to New Targets (TNT) study is a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of coronary heart disease events. Fasting plasma levels of standard lipids and of 18 emerging CAD risk biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in a random sample of 1,424 TNT patients. After exclusion of patients with DM at baseline (n = 253), 101 patients developed DM during the median follow-up of 4.9 years. Patients with incident DM had lower levels of total and high-molecular weight adiponectin, lipoprotein-associated phospholipase A2 (Lp-PLA2), soluble receptor of advanced glycation end products, and vitamin D compared with patients without incident DM. In contrast, insulin, soluble CD40 ligand, and soluble intercellular adhesion molecule-1 levels were higher in patients with incident DM compared with those without. Plasma levels of C-reactive protein, cystatin C, lipoprotein(a), monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, neopterin, N-terminal fragment of pro-B-type natriuretic peptide, osteopontin, and soluble vascular cell adhesion molecule-1 were comparable in patients with and without incident DM. After multivariate adjustment, total and high-molecular weight adiponectin as well as Lp-PLA2 were negatively associated with incident DM. Results of this study suggest that plasma lipids and some emerging CAD risk biomarkers, such as adiponectin and Lp-PLA2, may be useful for predicting incident DM in statin-treated patients with stable CAD.

Limited efficacy of growth hormone (GH) during transition of GH-deficient patients from adolescence to adulthood: a phase III multicenter, double-blind, randomized two-year trial.

CONTEXT: Treatment of GH-deficient adolescents in transition to adulthood remains challenging. OBJECTIVE: The objective was to assess the safety and efficacy of GH in GH-deficient adolescents in transition. PATIENTS: Fifty-eight GH-deficient adolescents (mean age, 15.8 +/- 1.8 yr; 33 males) at near completion of their linear growth participated in the study. INTERVENTION: Baseline studies were done while subjects were on GH. Subjects were retested (insulin-induced hypoglycemia) 4 wk after GH discontinuation and reclassified as persistently GH-deficient or controls (n = 18). GH-deficient subjects were randomized to GH (n = 25, approximately 20 microg/kg.d) or placebo (n = 15). SETTING: The multicenter study was conducted over a 2-yr period. MAIN OUTCOMES: Changes in body composition, bone mineral density (BMD), quality of life (QOL), cardiovascular and metabolic markers were measured. RESULTS: All groups had normal measures of lipid and carbohydrate metabolism, body composition, BMD, cardiac function, muscle strength, and QOL at baseline and after 2 yr. IGF-I concentrations decreased in all, but less so in the GH-group (P = 0.013). There was a greater increase in lean body mass (lesser adiposity) in the GH group than placebo at 12 months, but not at 24 months. CONCLUSIONS: 1) GH-deficient patients properly treated in childhood can have normal BMD, body composition, cardiac function, muscle strength, carbohydrate and lipid metabolism, and QOL when reaching adult height; and 2) continuation of GH therapy for 2 yr did not change these measures as compared to placebo-treated or control subjects. GH-deficient adolescents in good metabolic status at the time of epiphyseal fusion may safely discontinue GH for at least 2 yr. Follow-up is needed to determine whether GH therapy is eventually warranted in subjects treated with GH during childhood.

Incidence and Timing of Taper/Posttherapy-Emergent Adverse Events Following Discontinuation of Desvenlafaxine 50 mg/d in Patients With Major Depressive Disorder.

OBJECTIVE: The purpose of this post hoc analysis was to evaluate the incidence and timing of taper/posttherapy-emergent adverse events (TPAEs) following discontinuation of long-term treatment with desvenlafaxine (administered as desvenlafaxine succinate). METHOD: This was a phase 4, randomized, double-blind, placebo-controlled study conducted at 38 research centers within the United States between March 2010 and February 2011. Adult outpatients with major depressive disorder (MDD; DSM-IV-TR criteria) who completed 24 weeks of open-label treatment with desvenlafaxine 50 mg/d were randomly assigned to 1 of 3 groups for the double-blind taper phase: desvenlafaxine 50 mg/d for 4 weeks (no discontinuation), desvenlafaxine 25 mg/d for 1 week followed by placebo for 3 weeks (taper), or placebo for 4 weeks (abrupt discontinuation). The primary endpoint, Discontinuation-Emergent Signs and Symptoms Scale (DESS) score over the first 2 weeks of the taper phase, was described previously. Secondary assessments included incidence and timing of TPAEs (any adverse event that started or increased in severity during the double-blind phase) and the percentage of patients who could not continue the taper phase due to discontinuation symptoms. The Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16) assessed MDD status. RESULTS: A total of 480 patients enrolled in the open-label phase; the full analysis set included 357 patients (taper, n = 139; abrupt discontinuation, n = 146; no discontinuation, n = 72). TPAEs occurred in all groups through week 4. The incidence of any TPAE was lower for taper versus abrupt discontinuation at week 1 (P < .001), similar at week 2, and lower for taper versus abrupt discontinuation at weeks 3 and 4 (P ≤ .034). The most common TPAEs (incidence ≥ 3%) in the taper group were nausea and headache (3% each) at week 1 and dizziness (5%) and headache (4%) at week 2. The most common TPAEs in the abrupt discontinuation group were dizziness (8%), headache (8%), nausea (4%), irritability (3%), and diarrhea (3%) at week 1 and headache (3%) at weeks 2 and 3. The most common TPAE in the no discontinuation group was nausea (6%) at week 2. CONCLUSION: The overall incidence of any TPAE was lower in the taper versus abrupt discontinuation groups. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01056289.

Pharmacokinetics and pharmacodynamics of extended-release glipizide GITS compared with immediate-release glipizide in patients with type II diabetes mellitus.

This study was designed to compare the pharmacokinetic and short-term pharmacodynamic profile of extended-release glipizide GITS (Glucotrol XL) given in a dosage of 20 mg once daily with that of immediate-release glipizide (Glucotrol) 10mg twice daily in patients with type II diabetes mellitus. In an open-label, randomized, two-way crossover study, each glipizide formulation was administered for 5 days. Serial blood samples were drawn at baseline and on the 5th day of each treatment phase for measurement of glipizide, glucose, insulin, and C-peptide concentrations. At steady state, the mean Cmax after immediate-release glipizide was significantly greater than after glipizide GITS, and the tmax was considerably shorter. Although the mean Cmin with glipizide GITS was about 80% higher than with immediate-release glipizide, the mean AUC0-24 was significantly lower. Despite the lower plasma concentrations with glipizide GITS in this short-term study, the two formulations had similar effects on serum concentrations of glucose, insulin, and C-peptide. The absence of a pronounced peak plasma concentration with the GITS formulation might confer advantages in terms of maintaining clinical effectiveness and reducing the potential to cause adverse effects.

Remission status after long-term sertraline treatment of pediatric obsessive-compulsive disorder.

BACKGROUND: Despite its high chronicity, few studies have evaluated the effectiveness of long-term treatment for pediatric obsessive-compulsive disorder (OCD). The goal of the current analysis is to evaluate remission among children and adolescents with OCD treated with sertraline for 12 months. METHODS: Children (6-12 years old, n = 72) and adolescents (13-18 years old, n = 65) with Diagnostic and Statistical Manual of Mental Disorders (third edition, revised) OCD, who had completed a 12-week, double-blind, placebo-controlled sertraline study, were administered open-label sertraline 50-200 mg for 52 weeks. Full remission was defined by a Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) score of 8 or less, and partial remission was defined as a CY-BOCS score of 15 or less. RESULTS: Using an last observation carried forward analysis, 47% of patients achieved a full remission, and an additional 25% achieved a partial remission. Among study completers, full remission was achieved by 55% of patients and partial remission by 31%. Two thirds of patients with severe OCD at baseline (CY-BOCS of 26 or greater) achieved full or partial remission. Children were more likely to achieve a full remission than adolescents. CONCLUSION: Sertraline is effective in the treatment of childhood and adolescent OCD, with initial acute response converting to remission and improved functional status in a substantial proportion of patients. More research is needed to develop pharmacologic and psychotherapeutic strategies that facilitate the achievement of full remission in the remaining patients suffering from this chronic and disabling illness.