Geriatrics Abstracts - August 2007

Digoxin Dosing for Heart Failure

The therapeutic range for digoxin in heart failure has recently become lower and narrower, and is associated with reduced mortality; however, methods for dosing have not changed. The authors of this study sought to develop a new method to determine the initial dose of digoxin in patients with heart failure. Over a 6-month period, medical records were screened and reviewed for hospitalized adult patients who had a steady-state digoxin concentration. A multiple linear regression was estimated relating digoxin concentration, digoxin dose, creatinine clearance, and ideal body weight to generate an equation relating the dose of digoxin with these variables and a specific target digoxin concentration of 0.7 ng/mL (0.9 nmol/L). This new method was then compared with two existing methods. The study included 54 patients (mean [SD] age, 68 [15] years, with a mean (SD) creatinine clearance of 50 (25) mL/min (0.8 [0.4] mL/s) and mean (SD) ideal body weight of 62 (11) kg. The authors’ proposed method and the Jusko and Koup method were more accurate than the Jelliffe method in predicting digoxin concentration. Root mean square errors were as follows: for the Jelliffe method (using ideal body weight), 0.810; for the Koup and Jusko method (with heart failure), 0.401; our proposed method, 0.375. The proposed method was then used to create a dosing nomogram.The authors concluded that because the new therapeutic window of digoxin is associated with improved outcomes, more intensive dosage refinement should be considered. To this end, the authors offer new dosing recommendations and a nomogram for determining the initial dose of digoxin in patients with heart failure.

Bauman JL, DiDomenico RJ, Viana M, Finch M. A method of determining the dose of digoxin for heart failure in the modern era. Arch Intern Med 2006;166:2539-2545.

Folic Acid and Age-Related Hearing Loss

Low folate status has been associated with poor hearing. The authors of this study sought to determine whether folic acid supplementation slows age-related hearing loss. They conducted a double-blind, randomized, placebo-controlled trial conducted from September 2000 to December 2004 in 728 older men and women in the Netherlands recruited from municipal and blood bank registries with plasma total homocysteine concentrations 13 µmol/L or greater serum and vitamin B12 concentrations 200 pmol/L or greater at screening, and no middle ear dysfunction, unilateral hearing loss, or pathologic ear conditions unrelated to aging. Subjects were given daily oral folic acid (800 µg) or placebo supplementation for 3 years. They measured 3-year change in hearing thresholds, assessed as the average of the pure-tone air conduction thresholds of both ears of the low (0.5-kHz, 1-kHz, and 2-kHz) and high (4-kHz, 6-kHz, and 8-kHz) frequencies. Findings showed that Initial median hearing thresholds were 11.7 dB (interquartile range, 7.5 to 17.5 dB) for low frequencies and 34.2 dB (interquartile range, 22.5 to 50.0 dB) for high frequencies. Sixteen participants (2%) were lost to follow-up. After 3 years, thresholds of the low frequencies increased by 1.0 dB (95% CI, 0.6 to 1.4 dB) in the folic acid group and by 1.7 dB (CI, 1.3 to 2.1 dB) in the placebo group (difference, –0.7 dB [CI, –1.2 to –0.1 dB]; P = 0.020). Folic acid supplementation did not affect the decline in hearing high frequencies. The limitations were that the strict criterion for participation on the basis of serum homocysteine concentrations limits extrapolation to the general population. Folic acid fortification of food was prohibited in the Netherlands during the study, so baseline folate levels in participants were about half of those found in the U.S. population. The authors concluded that folic acid supplementation slowed the decline in hearing of the speech frequencies associated with aging in a population from a country without folic acid fortification of food. The effect requires confirmation, especially in populations from countries with folic acid fortification programs.

Durga J, Verhoef P, Anteunis LJC, et al. Effects of folic acid supplementation on hearing in older adults. A randomized, controlled trial. Ann Intern Med 2007;146:1-9.

Pharmacotherapy Adherence and Long-Term Mortality After Acute MI

The extent to which drug adherence may affect survival remains unclear, in part because mortality differences may be attributable to "healthy adherer" behavioral attributes more so than to pharmacological benefits. The authors conducted a study to explore the relationship between drug adherence and mortality in survivors of acute myocardial infarction (AMI) in a population-based, observational, longitudinal study of 31,455 elderly AMI survivors between 1999 and 2003 in Ontario. All patients filled a prescription for statins, beta-blockers, or calcium channel blockers, with the latter drug considered a control given the absence of clinical trial–proven survival benefits. Patient adherence was subdivided a priori into 3 categories—high (proportion of days covered, 80%), intermediate (proportion of days covered, 40%-79%), and low (proportion of days covered, <40%)—and compared with long-term mortality (median of 2.4 years of follow-up) using multivariable survival models (and propensity analyses) adjusted for sociodemographic factors, illness severity, comorbidities, and concomitant use of evidence-based therapies. Results showed that among statin users, compared with their high-adherence counterparts, the risk of mortality was greatest for low adherers (deaths in 261/1071 (24%) vs 2310/14 345 (16%); adjusted hazard ratio, 1.25; 95% confidence interval, 1.09-1.42; P = .001) and was intermediary for intermediate adherers (deaths in 472/2407 (20%); adjusted hazard ratio, 1.12; 95% confidence interval, 1.01-1.25; P = .03). A similar but less pronounced dose-response–type adherence-mortality association was observed for beta-blockers. Mortality was not associated with adherence to calcium channel blockers. Moreover, sensitivity analyses demonstrated no relationships between drug adherence and cancer-related admissions, outcomes for which biological plausibility do not exist. The authors concluded that the long-term survival advantages associated with improved drug adherence after AMI appear to be class-specific, suggesting that adherence outcome benefits are mediated by drug effects and do not merely reflect an epiphenomenon of "healthy adherer" behavioral attributes.

Rasmussen JN, Chong A, Alter DA. Relationship between adherence to evidence-based pharmacotherapy and long-term mortality after acute myocardial infarction. JAMA 2007;297:177-186.

Vitamin E and Cognitive Function in Women

Oxidative stress may play a key role in the development of cognitive impairment. Long-term supplementation with vitamin E, a strong antioxidant, may provide cognitive benefits. The Women's Health Study is a randomized, double-blind, placebo-controlled trial of vitamin E supplementation (600 IU [alpha-tocopherol acetate], on alternate days) begun between 1992 and 1995 among 39 876 healthy U.S. women. From 1998, 6377 women 65 years or older participated in a cognitive substudy. Three cognitive assessments of general cognition, verbal memory, and category fluency were administered by telephone at 2-year intervals. The primary outcome was a global composite score averaging performance on all tests. Repeated measures analyses were conducted to examine mean performance and mean differences in cognitive change, and logistic regression was used to estimate relative risks of substantial decline. Results showed there were no differences in global score between the vitamin E and placebo groups at the first assessment (5.6 years after randomization: mean difference, –0.01; 95% confidence interval [CI], –0.04 to 0.03) or at the last assessment (9.6 years of treatment: mean difference, 0.00; 95% CI, –0.04 to 0.04). Mean cognitive change over time was also similar in the vitamin E group compared with the placebo group for the global score (mean difference in change, 0.02; 95% CI, –0.01 to 0.05; P = .16). The relative risk of substantial decline in the global score in the vitamin E group compared with the placebo group was 0.92 (95% CI, 0.77 to 1.10). The authors concluded that long-term use of vitamin E supplements did not provide cognitive benefits among generally healthy older women.

Kang JH, Cook N, Manson J, Buring JE, Grodstein F. A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med 2006;166:2462-2468.

Anemia Status, Hemoglobin Concentration, and Mortality

Anemia is viewed as a negative prognostic factor in the elderly population; its independent impact on survival is unclear. In this study, baseline hemoglobin quintiles and anemia, as defined by the World Health Organization criteria, were assessed in relation to mortality in the Cardiovascular Health Study, a prospective cohort study with 11.2 years of follow-up of 5888 community-dwelling men and women age 65 years or older, enrolled in 1989-1990 or 1992-1993 in four U.S. communities. Results showed that a total of 1205 participants were in the lowest hemoglobin quintile (< 13.7 g/dL for men; < 12.6 g/dL for women), and 498 (8.5%) were anemic (< 13 g/dL for men; <12 g/dL for women). A reverse J-shaped relationship with mortality was observed; age-, sex-, and race-adjusted hazard ratios (95% confidence interval [CI]) in the first and fifth quintiles, compared with the fourth quintile, were 1.42 (95% CI, 1.25-1.62) and 1.24 (95% CI, 1.09-1.42). After multivariate adjustment, these hazard ratios were 1.33 (95% CI, 1.15-1.54) and 1.17 (95% CI, 1.01-1.36). The demographic- and fully-adjusted hazard ratios of anemia for mortality were 1.57 (95% CI, 1.38-1.78) and 1.38 (95% CI, 1.19-1.54). Adjustment for causes and consequences of anemia (renal function, inflammation, or frailty) did not reduce associations. The authors concluded that lower and higher hemoglobin concentrations and anemia by World Health Organization criteria were independently associated with increased mortality. The WHO criteria did not identify risk as well as a lower hemoglobin value. Additional study is needed on the clinically valid definition for and causes of anemia in the elderly, and on the increased mortality at the extremes of hemoglobin concentrations.

Zakai NA, Katz R, Hirsch C, et al. A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort. Arch Intern Med 2005;165:2214-2220.