A Randomized Study of Extended Dosing Regimens for Initiation of Epoetin Alfa Treatment for Anemia of Chronic Kidney Disease

Background and objectives: Although epoetin alfa is commonly initiated weekly (QW) in anemic chronic kidney disease (CKD) patients, recent evidence indicates that it can be initiated every 2 wk (Q2W) and used in maintenance therapy every 4 wk (Q4W). This study examined the feasibility of initiating epoetin alfa Q4W in anemic CKD patients not receiving dialysis.Design, setting, participants, & measurements: This open-label study randomized subjects (1:2:2:2) to treatment with epoetin alfa 10,000 IU QW, 20,000 IU Q2W, 20,000 IU Q4W, or 40,000 IU Q4W for 16 wk. Subjects were ≥18 yr, had hemoglobin <11 g/dl, a glomerular filtration rate of 15 to 90 ml/min per 1.73 m², and had not received erythropoietic therapy within 8 wk. The primary analysis was a noninferiority comparison of the 40,000 IU Q4W to the 20,000 IU Q2W group in the per-protocol population with respect to hemoglobin change from baseline to the end of study.Results: Of 262 subjects randomized, 229 comprised the per-protocol population. Mean hemoglobin change from baseline for the 40,000 IU Q4W group (1.24 g/dl) was not inferior to the 20,000 IU Q2W group (1.11 g/dl) with the lower limit of 95% CI, −0.21 g/dl. In the QW, 20,000 IU Q2W, 20,000 IU Q4W, and 40,000 IU Q4W groups, 90%, 87%, 75%, and 86% of subjects, respectively, achieved a hemoglobin increase ≥1 g/dl. Serious adverse events were similar across all groups.Conclusions: Epoetin alfa can be initiated Q4W in anemic CKD subjects.Epoetin alfa, the first commercially available erythropoietic-stimulating agent (ESA), was initially administered three times per week to patients with chronic kidney disease (CKD) and anemia. Today physicians commonly initiate the drug weekly. This may be inconvenient for patients with chronic anemia. In clinical practice, extended dosing regimens may offer advantages for patients and healthcare practitioners in terms of flexibility, improved compliance, and reduced costs (1). To allow for longer dosing intervals, newer ESAs have been developed with longer serum half-lives. There is now increasing evidence that epoetin alfa, despite its relatively short serum half-life, can be administered at extended dosing intervals. Epoetin alfa regimens of up to every 4 wk (Q4W) have been shown to be effective in maintaining hemoglobin (Hb) concentrations ≥11 g/dl in patients with CKD (2–4). Recently, a study demonstrated that epoetin alfa could be effectively initiated every 2 wk (Q2W) (5). The primary objective of this study was to explore the feasibility of initiating therapy with epoetin alfa at dosing intervals of up to Q4W in subjects with anemia of CKD not receiving dialysis.     

Ondine's Curse: hemodynamic response to diaphragm pacing (electrophrenic respiration)

The hemodynamic response to diaphragm pacing was studied in eight patients with Ondine's Curse. It was shown that such pacing could lower the pulmonary artery pressure while correction of hypoxemia alone could not. It was demonstrated that on pacing, calculated pulmonary arteriolar resistance decreased and there was normalization of arterial blood gases. The mechanism for these changes was improved alveolar ventilation.     

Undetected dementia in community-dwelling older people: the Canadian Study of Health and Aging

OBJECTIVE: To estimate the frequency and correlates of undetected dementia in community-dwelling older people. DESIGN: Secondary analysis of data from the Canadian Study of Health and Aging (CSHA) prevalence survey of dementia. SETTING: All 10 provinces of Canada excluding Indian reserves and military units. PARTICIPANTS: A total of 252 community-dwelling older adults diagnosed with dementia in the CSHA survey. MAIN OUTCOME MEASURE: Undetected dementia, defined as occurring in persons who meet standard diagnostic criteria for dementia but who report never having seen a doctor for memory problems. RESULTS: Of the 252 subjects, 64% had undetected dementia. Subjects with mild functional impairment were significantly more likely to have undetected dementia (odds ratio = 2.4, 95% confidence interval 1.2, 5.0). Older subjects and those with mild cognitive impairment showed a trend toward undetected dementia, although the results did not achieve statistical significance. Educational level, number of comorbid conditions, and degree of social support were not significantly associated with undetected dementia. CONCLUSIONS: A large number of older persons are living in the community with undetected dementia. These older people may be at significant risk for delirium, motor vehicle accidents, medication errors, and financial difficulties. As preventive strategies are developed and new cognitive enhancing therapies emerge, we need to reexamine our current guidelines about screening for cognitive impairment in older adults.     

N-dimethylisopropyl propranolol. Effects on myocardial oxygen demands.

N-Dimethylisopropyl propranolol (DMP) is a quaternary derivative which lacks significant beta-adrenergic blocking and local anesthetic effects. It has been reported, nonetheless, to be effective in treating experimental arrhythmias and in limiting the extent of ST-segment elevations following experimental coronary occlusion. The present study examined the effects of DMP on the hemodynamics and myocardial oxygen demands of anesthetized dogs. After a single dose of 3 mg/kg, heart rate fell from 146 +/- 8 to 124 +/- 6 beats/min (P less than 0.0025), and aortic systolic pressure fell from 151 +/- 11 to 141 +/- 9 mm Hg (0.05 less than P less than 0.10), resulting in a 16.8% reduction in the tension-time index. Stroke volume was reduced by 10% despite a 54% increase in left ventricular end-diastolic pressure, suggesting a negative inotropic effect. This was supported by a decrease in maximum extrapolated contractile element velocity from 9.10 +/- 1.05 to 6.61 +/- 65 units/sec (P less than 0.0025). Myocardial oxygen consumption was reduced from 12.0 +/- 1.4 to 9.9 +/- 1.5 ml/min/100 g tissue (P less than 0.05). Myocardial oxygen extraction was unchanged, indicating that the decrease in oxygen consumption resulted from a reduction in myocardial oxygen demand. When heart rate and systolic pressure were artificially restored to control levels, after the administration of DMP, myocardial oxygen consumption remained significantly below the control level. DMP, therefore, appeared to reduce myocardial oxygen demands primarily by its negative inotropic effect. This drug may have application in the treatment of ischemic heart disease.