Imputation method adjusted for covariates for nonrespondents in instruments with applications.

In clinical research, measurement instruments (or questionnaires) consisting of a number of items (questions) are often used to assess treatment effect, e.g., quality-of-life assessment, and clinical disease activity index. In many situations, instead of an individual component, it is of interest to provide an assessment of the treatment effect in some overall measures, e.g., subscale or total score. In practice, these types of data often suffer from incompleteness. A common method is to simply ignore all the item nonrespondents from the analysis. Although this method is statistically valid under the assumption of missing completely at random (MCAR), it suffers from decreasing power/efficiency. In this paper, we propose a regression imputation approach adjusted for covariates with item nonrespondents in the instrument. The proposed method provides consistent estimators, which are asymptotically normal. A bootstrap procedure is also proposed to estimate the asymptotic variance of the derived estimators. A simulation study was conducted to study the finite samples performance of the derived estimators. It is also shown that the estimators based on the imputed data set are more efficient than the estimators based on the completers only. The proposed methodology was illustrated through two applications in observational studies.

Combined therapy with cinacalcet and low doses of vitamin D sterols in patients with moderate to severe secondary hyperparathyroidism.

BACKGROUND: Adequate control of all four KDOQI biochemical targets for chronic kidney disease, bone and mineral disorder (CKD-MBD), which include parathyroid hormone (PTH), calcium (Ca), phosphorus (P) and Ca x P, remains difficult and is accomplished in <6% of patients receiving haemodialysis. The objective of the current study was to determine whether treatment with cinacalcet combined with low doses of vitamin D sterols improves control of both PTH and Ca x P among haemodialysis patients with secondary hyperparathyroidism (sHPT). METHODS: This multicentre, open-label study enrolled haemodialysis subjects (N = 444) with moderate to severe sHPT (mean serum biPTH > 160-430 pg/mL) (approximately iPTH 300-800 pg/mL or ng/L). Cinacalcet was titrated sequentially (30-180 mg/day) during an 8-week dose-titration phase to achieve biPTH

A note on sample size calculation based on propensity analysis in nonrandomized trials.

In nonrandomized trials, patients are not randomly assigned to treatment groups with equal probability. Instead, the probability of assignment varies from patient to patient depending on patients baseline covariates. This often results in a non-comparable treatment groups due to treatment imbalance. As a result, the United States Food and Drug Administration (FDA) recommended that the method of propensity score analysis be employed to overcome this problem. In this note, a formula for sample size calculation is developed based on a proposed weighted Mantel-Haenszel test on the strata defined by the propensity score analysis. It was shown that the sample size formula derived by Nam (1998) based on the test statistic proposed by Gart (1985) is a special case of the sample size formula derived in this note.

Cinacalcet hydrochloride (Sensipar) in hemodialysis patients on active vitamin D derivatives with controlled PTH and elevated calcium x phosphate.

Active vitamin D derivatives attenuate the severity of secondary hyperparathyroidism but often increase serum calcium (Ca) and phosphorus (P) as a result of enhanced intestinal absorption. The calcimimetic cinacalcet HCl lowers parathyroid hormone (PTH) and tends to decrease Ca x P. A 16-wk, open-label clinical trial was conducted in adult hemodialysis patients who had controlled PTH (biointact PTH [biPTH] 80 to 160 pg/ml) and elevated Ca x P (> 55 mg2/dl2) and were receiving paricalcitol > 6 microg/wk (or an equipotent dose of an alternative active vitamin D derivative). At the start of the study, active vitamin D derivatives were decreased to a mean equivalent dose of paricalcitol 6 microg/wk, and cinacalcet was titrated from 30 mg/d to a maximum possible dose of 180 mg/d. Of the 72 study patients, 53 (74%) completed 8 wk of dose titration with cinacalcet. In response to cinacalcet, the following mean percentage changes were observed: biPTH, -1.8%; Ca, -9.7% (P < 0.0001), phosphorus, -11.1% (P < 0.0001), and Ca x P, -20.1% (P < 0.0001). At the end of the study, approximate Kidney Disease Outcomes Quality Initiative targets for biPTH (< or = 160 pg/ml) were achieved in 85% (45 of 53) of patients and for Ca x P (< or = 55 mg2/dl2) in 72% (38 of 53) of patients. Concurrent achievement of both targets occurred in 47% (25 of 53) of patients. In this open-label clinical trial, hemodialysis patients who had controlled PTH but elevated Ca x P and were taking moderate- to high-dose active vitamin D derivatives achieved improved control of mineral metabolism with a combination of low-dose active vitamin D derivatives and cinacalcet. The long-term effects of this treatment regimen on clinical outcomes should be tested prospectively.

Epoetin alfa use in patients with ESRD: an analysis of recent US prescribing patterns and hemoglobin outcomes.

BACKGROUND: It is unknown to what degree physicians adjust erythropoietin doses to achieve hemoglobin levels (11.0 to 12.0 g/dL [110 to 120 g/L]) recommended by the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) for patients with end-stage renal disease receiving hemodialysis. Our objective is to examine epoetin alfa prescribing patterns for achieving the target hemoglobin level range in this population. METHODS: Monthly hemoglobin levels and epoetin alfa doses from 2 large databases were retrospectively analyzed. One data set comprised 31,267 patients from the Fresenius Medical Care-North America (FMC-NA) database, and the other comprised 128,761 patients based on claims for Medicare services. RESULTS: Longitudinal evaluation of the FMC-NA data set showed that hemoglobin levels in patients administered epoetin alfa cycled in and out of the NKF-K/DOQI hemoglobin target range, and doses were decreased in 98.8% of patients with persistent hemoglobin levels greater than 12.0 g/dL (> 120 g/L). Hemoglobin levels in patients from the Medicare data set that initially were outside the target range migrated into the range with epoetin alfa dose titration. FMC-NA patients with a 3-month average hemoglobin level less than 11.0 g/dL (< 110 g/L) were administered significantly greater epoetin alfa doses than those with average hemoglobin levels greater than 12.0 g/dL (> 120 g/L; 21,838 versus 13,503 U/wk; P < 0.0001). Less than 0.4% of patients administered epoetin alfa were persistently anemic (hemoglobin < 11.0 g/dL [< 110 g/L]) and were administered persistently high doses (> 30,000 U/wk), but failed to respond with a 0.5-g/dL or greater (> or = 5-g/L) increase in hemoglobin levels. CONCLUSION: In these analyses, few hemodialysis patients experienced persistent anemia while being administered high epoetin alfa doses. Physicians appeared to appropriately adjust doses to achieve hemoglobin levels recommended by the NKF-K/DOQI guidelines.

Glimepiride pharmacokinetics in obese versus non-obese diabetic patients.

BACKGROUND: Type 2 diabetes is a global concern, accounting for the vast majority of cases of diabetes. Type 2 diabetes is associated with insulin deficiency and insulin resistance and, increasingly, with patients who are overweight or obese. Glimepiride is a popular choice of oral antidiabetic agent for patients with Type 2 diabetes since it increases both insulin secretion and insulin sensitivity and, unlike some other oral agents, is associated with weight neutrality or even weight loss. OBJECTIVE: To assess the pharmacokinetic characteristics of glimepiride and its metabolites in normal-weight and morbidly obese patients with type 2 diabetes to determine whether the pharmacokinetics of glimepiride are altered by obesity. METHODS: Normal-weight (n = 14) and morbidly obese (n = 14) men and women (in a 1:1 ratio) with type 2 diabetes received a single oral dose of glimepiride 8 mg following an overnight fast. Serum concentrations of glimepiride and its metabolites, cyclohexyl hydroxymethyl derivative (MI) and carboxyl derivative (MII), and urinary concentrations of these metabolites were measured. RESULTS: There was no significant difference between the 2 patient groups for glimepiride in terms of mean peak concentration (C(max)) (p = 0.0807), time to reach C(max) (t(max)) (p = 0.9916), AUC(0-24) (p = 0.2609), AUC(0- infinity ) (p = 0.1275), or terminal half-life (p = 0.3076). Mean t(max) values and relative total clearances for the 2 groups were also equivalent. Some differences were noted with respect to the pharmacokinetics of metabolites between the groups. In particular, over a 24-hour period, the morbidly obese group excreted statistically significantly greater amounts of MI (p = 0.0430) and MII (p = 0.0051) compared with the normal-weight group. However, none of the differences was considered clinically significant since these metabolites do not have meaningful pharmacologic activity. CONCLUSIONS: Overall, the results presented here indicate that no intrinsic difference is observed in the oral clearance of glimepiride in obese patients compared with non-obese patients. Given that the dosage is titrated to achieve optimal fasting glucose levels, no special dose consideration is required for the use of glimepiride in the treatment of obese patients with type 2 diabetes.