Pharmacogenomic dosing of warfarin: ready or not?

Warfarin is a medication with a narrow therapeutic index, nonlinear intrapatient pharmacokinetics, and high interpatient variability in its dose-response relationship. These characteristics create great difficulty in determining an appropriate dose; sub- or supratherapeutic doses can increase the risk of bleeding and venous thromboembolism complications. Algorithms based on nongenetic factors of patient age, gender, body weight, diseases, diet, smoking, and medication traditionally have been used to determine warfarin dose requirements. However, these formulas account for less than 20% of the variability in warfarin response. Following completion of the Human Genome Project, several genetic variants of CYP2C9 and VKORC1 have been identified that account for a greater proportion of the variability in patient response to warfarin than is explained by nongenetic factors. Moreover, algorithms that analyze both patient genetic and nongenetic factors, i.e., pharmacogenomics, in warfarin response account for 55% to 60% of the variability. This raises the prospect of enhancing the ability to predict warfarin dose requirements and, thereby, improving its safety, effectiveness, and therapy efficiency. This review evaluates the impact of combining genetic and nongenetic factors in accounting for the variability in warfarin response and the prospect that pharmacogenomic algorithms will improve warfarin dosing early in therapy, possibly achieving a more rapid attainment of the therapeutic dose, improving safety, and increasing effectiveness. The most comprehensive and widely available pharmacogenomic algorithms for estimating warfarin dose requirements when initiating therapy, www.WarfarinDosing.org, is reviewed.

Carbamazepine dose-concentration relationship in elderly nursing home residents.

PURPOSE: To describe the dose-concentration relationships of carbamazepine (CBZ) in elderly nursing home residents and the effect of sex, age, and type of co-medications. RESULTS: This is a cross-sectional study of elderly (> or = 65 years) nursing home residents across the United States (N=92). Data collection was from 1 June 1998 to 31 December 2000. The mean CBZ dose was 9.2+/-5.4 mg/(kg day(-1)) (+/-Standard Deviation) and serum concentration was 5.9+/-2.2mg/L. The daily dose was significantly lower in the oldest-old age group (> or = 85 years, mean 476.9 mg/day (95% confidence interval CI) 326.5-627.3) as compared to the dose in the young-old (65-74 years, mean 724.4 mg/day (CI) 603.4-845.4) (p=0.016). Adjusted for body weight, doses were similar on a mg/(kg day(-1)) basis. The majority of observed CBZ serum concentrations were at the lower end (67.4%) or below (20.7%) the suggested therapeutic range for younger adult outpatients. CONCLUSIONS: Total daily CBZ doses and patient weight decreased with age. The average dose for elderly nursing home residents was approximately 9 mg/(kg day(-1)). Carbamazepine serum concentrations were lower than those used for younger adults, suggesting that these patients may be more sensitive to CBZ.

Exercise Performance During the First Two Years After Left Ventricular Assist Device Implantation.

Exercise performance of patients with left ventricular assist devices (LVADs) improves after postimplant cardiac rehabilitation (CR). Few studies assess the effectiveness of a CR and its long-term effect of exercise performance. For this purpose, we retrospectively analyzed data from LVAD patients, who underwent a stationary CR twice after pump implantation. Data from exercise training and cardiopulmonary exercise tests (CPETs) were analyzed. Fifteen patients (age: 57 ± 10 years, male 87%) were admitted to the rehabilitation clinic twice 39 ± 18 and 547 ± 197 days after LVAD implantation. An improvement from the beginning to the end of the second CR was observed in bicycle ergometer training (14.0 ± 8.8 vs. 35.7 ± 14.7 W; p < 0.001), in muscular strength (e.g., leg press: 41 ± 10 vs. 53 ± 14 kg; p < 0.001), and in 6 minute walk distance (421 ± 126 m vs. 480 ± 133 m; p = 0.040). Between the first and the second CR, improvement in all the training modules was observed as well as an increase in CPETs peak workload (56 ± 24 vs. 83 ± 26 W; p < 0.001) but not in peak oxygen consumption (12.3 ± 3.2 vs. 12.2 ± 4.0 ml/min/kg; p = 0.906). Thus, over long implant periods, patients showed improvement of their exercise performance in the submaximal load range, but no change in the aerobic capacity was observed.

Pharmacotherapy for idiopathic pulmonary arterial hypertension during the past 25 years.

OBJECTIVE: To review the current pharmacotherapy for idiopathic pulmonary arterial hypertension (IPAH). METHODS: A search of the primary literature was conducted by using MEDLINE, the National Institutes of Health medical research Web site (www.clinicaltrials.gov), and the United States Food and Drug Administration's Center for Drug Evaluation and Research Web site (www.fda.gov/cder). RESULTS: Until the early 1980s, conventional therapy for IPAH consisted of anticoagulation, diuretics, digitalis extracts, and supplemental oxygen, yet the 5-year mortality rate remained at 66%. Calcium channel blocker therapy was introduced with the hope that it would improve survival in patients with IPAH, but it was found to be effective in only approximately 25% of patients. In 1996, intravenous epoprostenol was the first drug to show long-term benefit on hemodynamics, exercise capacity, and survival. However, administration of epoprostenol requires a permanently indwelling central venous catheter, and tachyphylaxis is common, necessitating continuous dosage escalations. Subsequently, treprostinil, a prostacyclin analog of epoprostenol that can be administered by continuous subcutaneous infusion, was introduced, followed by aerosolized iloprost, a prostacyclin analog for inhalation. An increasing understanding of the multiple pathogeneses of IPAH led to the discovery of another target for drug therapy, and bosentan, an orally administered agent, became the first endothelin-receptor antagonist approved for treatment of IPAH. Most recently, the phosphodiesterase inhibitor, sildenafil, has received approval from the United States Food and Drug Administration for the treatment of IPAH. CONCLUSION: Recently developed pharmacotherapies offer greater effectiveness and safety than traditional agents for the treatment of IPAH.

Safety and efficacy of cardiac rehabilitation for patients with continuous flow left ventricular assist devices.

BACKGROUND: Despite the increasing use of left ventricular assist devices (LVADs) in terminal heart failure, cardiac rehabilitation protocols have not yet been documented in larger LVAD patient cohorts. The aim of this study was to investigate safety and efficacy of exercise training during a rehabilitation programme after post-operative discharge of LVAD patients. METHODS: Rehabilitation data obtained between 2010-2012 from 41 LVAD patients (mean age 54.8 ± 11.6 years; 20% female) were retrospectively analysed. The exercise protocol consisted of strength exercises for lower limbs, bicycle ergometry, walking and gymnastics. The numbers of training sessions, their duration and intensity as well as adverse events were documented. Spiroergometry was performed at least once and twice in a subgroup of 15 patients (at the beginning and end of rehabilitation). RESULTS: Rehabilitation started 48 ± 38 days post LVAD implantation with an average duration of 32 ± 6 days. An increase in exercise capacity was observed. Duration (19 ± 4 vs 14 ± 2 min, p < 0.001) and intensity of bicycle ergometry increased (module number 6.2 ± 2.8 vs 2.0 ± 1.9, p < 0.001) as well as muscular strength all muscle groups trained (e.g. 33.6 ± 15.2 vs 26.6 ± 11.9 kg at the leg press, p = 0.002). Spiroergometry revealed an increase of maximal oxygen consumption (14.5 ± 5.2 vs 11.3 ± 4.1 ml/min/kg, p = 0.007) in the subgroup that underwent two examinations. In the whole population the average increase was lower (12.81 ± 4.35 ml/min/kg). One training-related adverse event (non-sustained ventricular tachycardia) was observed. CONCLUSION: Exercise training for LVAD patient as part of a multidisciplinary rehabilitation programme is effective and safe. This warrants the broad application of exercise training after LVAD implantation.

Pneumococcal polysaccharide revaccination: immunoglobulin g seroconversion, persistence, and safety in frail, chronically ill older subjects.

OBJECTIVES: To determine the 1-month postpneumococcal polysaccharide-revaccination immunoglobulin G (IgG) antibody response, its persistence at 1 year, and tolerability of revaccination in frail, chronically ill older nursing facility residents. DESIGN: Prospective study conducted between December 1998 and July 2000. SETTING: Six skilled nursing facilities in the Minneapolis-St. Paul, Minnesota, metropolitan area. PARTICIPANTS: Sixty-seven subjects aged 65 and older having received primary vaccination with pneumococcal polysaccharide vaccine (PPV) at least 5 years before enrollment. INTERVENTION: Revaccination with one dose of 23-valent PPV. MEASUREMENTS: Adverse events and concentrations of seven individual pneumococcal polysaccharide type-specific IgG antibodies (against serotypes 4, 6B, 9V, 14, 18C, 19F, 23F) and their aggregate before and 1 and 12 months after revaccination. RESULTS: A significant increase in all individual and aggregate median antibody concentrations over baseline was observed 1 month after revaccination. However, after 1 year, the increase remained significant only for serotypes 6B and 18C and the aggregate parameter. One month after revaccination, the mean increase in antibody concentration over baseline was significantly greater than 1.4-fold for six of the seven serotypes and the aggregate. However, the increase was not significantly greater than 1.4 at 1 year for any of the serotypes or the aggregate. Minor, self-limited localized adverse reactions and systemic reactions occurred in 11.3% of the subjects. CONCLUSIONS: In frail, chronically ill older nursing facility residents, revaccination with 23-valent PPV at least 5 years after primary vaccination (whether primary vaccination occurred before or after age 65) is associated with a significant, albeit brief, immunological response for most of the serotypes tested. Revaccination was well tolerated.

Gastrointestinal disease control after histamine2-receptor antagonist dose modification for renal impairment in frail chronically ill elderly patients.

OBJECTIVES: To determine whether histamine2-receptor antagonist (H2RA) dose modified for renal impairment affects gastrointestinal (GI) disease control. DESIGN: Concurrent medical record review. SETTING: One hundred forty-six nursing facilities throughout the United States. PARTICIPANTS: Three hundred thirty-six patients aged 65 and older receiving H2RAs for GI disorders. INTERVENTION: H2RA dose modified for renal impairment or no dose change. MEASUREMENTS: Disease control (no H2RA dose increase for 6 months or longer, additional GI medication, hospitalizations, emergency room visits, and unscheduled physician visits for GI symptoms) was evaluated using chart review at 3, 6, 9, and 12 months in nursing home patients aged 65 and older with H2RA dose modified for decreased creatinine clearance (ClCr) according to manufacturer. RESULTS: Three hundred thirty-six patients, mean age +/- standard deviation 85.9 +/- 7.9, with mean ClCr of 33.6 +/- 10.4 mL/min, were recommended to receive lower H2RA doses based upon estimated renal function. Patients were analyzed in two groups: H2RA dose reduced (Group 1) and dose reduction not adopted or implemented (Group 2). There was no difference in baseline characteristics (age, weight, ClCr, or starting H2RA dose and indication) between the two groups. One hundred ninety-eight patients in Group 1 were taking 195.5 +/- 71.0 mg per day of nizatidine or equivalent, compared with 183.7 +/- 66.6 mg for 138 patients in Group 2. For patients with 90 days of follow-up, the mean H2RA dose in Group 1 was 100.2 +/- 44.3 mg, compared with 187.8 +/- 69.9 for Group 2 (P <.0001) The mean decrease in daily dose for Groups 1 and 2 after 365 days were 98.9 +/- 72.9 mg and 22.2 +/- 68.2 mg, respectively (P <.0001). Except for more physician visits in Group 2, disease control was similar for all groups. Major and minor GI bleeding events were similar across both groups and over time. The 12-month mortality rate was 12.1% and 21.7% for Groups 1 and 2, respectively. This difference was statistically significant (P =.02). CONCLUSION: The findings suggest that the dose of H2RAs may be decreased based upon renal function in frail elderly patients without compromising GI disease control.

Strategies for optimizing antiepileptic drug therapy in elderly people.

The elderly take more antiepileptic drugs (AEDs) than all other adults. This extensive use directly correlates with an increased prevalence of epilepsy in a growing population of older people, as well as other neuropsychiatric conditions such as neuropathic pain and behavioral disorders associated with dementia and for which AEDs are administered. The agents account for nearly 10% of all adverse drug reactions in the elderly and are the fourth leading cause of adverse drug reactions in nursing home residents. Numerous factors associated with advanced age contribute to the high frequency of untoward drug effects in this population; however, strategies are available to ensure optimal outcomes.

Valproic acid doses, concentrations, and clearances in elderly nursing home residents.

VPA daily dose and total VPA concentrations for 146 elderly (> or =65 years) nursing home residents collected from June 1998 to December 2000 in homes located throughout the United States are presented. Average age was 78.5+/-8.0 years old. The mean VPA daily dose was 16.2+/-11.2mg/kg and mean total VPA concentration was 48.5+/-24.8 mg/L. The majority (56.2%) of the VPA residents are being maintained at total VPA levels <50mg/L. Mean daily dose (19.4+/-11.4, 16.3+/-12.1, and 11.3+/-7.6 mg/kg/day; p=0.003) and total VPA concentration (56.4+/-25.8, 47.7+/-22.6, and 38.7+/-23.1mg/kg/day; p=0.003) decreased by age groups (65-74, 75-84, and > or =85 years). Daily dose and total VPA concentration were not different in residents receiving inhibitory or inducing co-medications, between men and women, or by albumin level. Total VPA clearance was similar between men and women, among age groups, or according to inducing or inhibiting co-medications.

Phenytoin use in elderly nursing home residents.

BACKGROUND: Phenytoin (PHT) dosing regimens are often determined based on experience in those aged <65 years rather than in those aged >or=65 years. OBJECTIVE: The goal of this study was to determine the impact of sex, age, receipt of concomitant inhibitors or inducers of PHT metabolism, and albumin levels on doses and total serum concentrations of PHT in elderly nursing home residents. METHODS: Consulting pharmacists to nursing homes located throughout the United States collected data from June 1998 to December 2000. The mean daily dose per person and mean total serum PHT concentration were tested for statistical differences by sex, age group (6-74, 75-84, and >or=85 years), coadministration of PHT inhibitors or inducers, and albumin levels. RESULTS: Data were collected from 387 residents (259 women, 128 men) of 112 nursing homes in 19 states who received PHT and for whom PHT concentrations were available. The mean (SD) age of the study population was 79.4 (7.8) years; women constituted 67.0% of the study population. The mean (SD) total daily dose and total PHT concentration were 4.9 (1.8) mg/kg and 11.7 (6.4) mg/L, respectively. In general, women received higher mean (SD) daily doses of PHT compared with men (5.1 [1.8] vs 4.6 [1.6] mg/kg, respectively; P=0.017) to achieve similar total serum concentrations (11.6 [6.4] and 12.0 [6.6] mg/L). PHT doses and serum concentrations were similar between age groups. There were no differences in daily doses (mg/kg or mg/d) or total serum concentrations of PHT based on concomitant use of inhibitors or inducers of PHT metabolism or on albumin levels, CONCLUSIONS: In this study in elderly nursing home residents, women received higher doses of PHT than men to achieve similar total serum PHT concentrations. There were no differences in doses or total serum PHT concentrations by age group, use of concomitant inducers or inhibitors of PHT metabolism, or albumin levels.

Efficacy of oral extended-release oxybutynin in cognitively impaired older nursing home residents with urge urinary incontinence: a randomized placebo-controlled trial.

OBJECTIVES: To determine the efficacy of oral extended-release oxybutynin for urge urinary incontinence in older female nursing home residents with mild to severe cognitive impairment. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Twelve skilled nursing homes. PARTICIPANTS: Fifty women aged 65 and older with urge incontinence and cognitive impairment. INTERVENTION: Four-week treatment with daily oral extended-release oxybutynin 5 mg or placebo. MEASUREMENTS: Urinary incontinence episodes, urinary frequency, and total dryness assessed hourly over two 8-hour days (8 AM TO 4 PM), and evening and night nursing staff ratings of urinary symptoms. RESULTS: Of the participants, 96% (n = 25) on oxybutynin and 92% (n = 22) on placebo completed the trial. Compared with baseline, both groups achieved a significant median decrease in mean urinary incontinence episodes and urinary frequency at 4 weeks (P = .01-.05). There were no significant between-group differences in any urological outcome. In the exploratory analysis, there were no significant differences from baseline or placebo in any urological outcome with oxybutynin in participants with mild to moderate cognitive impairment and/or adequate mobility compared with participants with more severe cognitive and physical impairment. Staff ratings found that more participants had improvement in urinary symptoms from baseline with oxybutynin than placebo but significant only for delaying evening voiding (P = .02). CONCLUSION: Extended-release oxybutynin 5 mg per day for 4 weeks in older cognitively impaired female nursing home residents did not significantly reduce urinary incontinence and urinary frequency or achieve dryness. Participants with mild to moderate cognitive and/or physical impairment were no more likely to benefit from oxybutynin than more severely impaired individuals in an exploratory analysis but further research in a larger population and perhaps using a larger dose is needed.

Improving geriatric transitional care through inter-professional care teams.

OBJECTIVES: The aim of this study was to examine the impact of the use of an inter-professional care team on patient length of stay and payer charges in a geriatric transitional care unit. METHODS: An analysis of de-identified administrative records for transitional care patients for the 12-month period (2003-2004) cared for by the inter-professional team (n = 163) and cared for by traditional single provider care model (n = 176) was carried out. We conducted logistic regression on length of stay and charges controlling for patient demographics and acuity levels. RESULTS: The inter-professional care team patients had significantly shorter lengths of stay, fewer patient days and lower total charges. Patient diagnosis and acuity were similar across groups. CONCLUSION: This study provides empirical evidence of the impact of an inter-professional care model in providing cost-effective transitional care in a nursing home setting. Evidence of shorter lengths of stay, shorter patient days and lower charges suggests benefit in the development and financing of inter-professional care teams for transitional care services.

Randomized, placebo-controlled trial of the cognitive effect, safety, and tolerability of oral extended-release oxybutynin in cognitively impaired nursing home residents with urge urinary incontinence.

OBJECTIVES: Determine the cognitive effect, safety, and tolerability of oral extended-release oxybutynin in cognitively impaired older nursing home residents with urge urinary incontinence. DESIGN: Randomized, double-blinded, placebo-controlled trial. SETTING: Twelve skilled nursing homes. PARTICIPANTS: Fifty women aged 65 and older with urge incontinence and cognitive impairment. INTERVENTION: Four-week treatment with once-daily oral extended-release oxybutynin 5 mg or placebo. MEASUREMENTS: Withdrawal rates and delirium or change in cognition from baseline at 1, 3, 7, 14, 21, and 28 days after starting treatment using the Confusion Assessment Method (CAM), Mini-Mental State Examination (MMSE), and Severe Impairment Battery (SIB). The Brief Agitation Rating Scale, adverse events, falls incidence, and serum anticholinergic activity change with treatment were also assessed. RESULTS: Participants' mean age +/-standard deviation was 88.6+/-6.2, and MMSE baseline score was 14.5+/-4.3. Ninety-six percent of subjects receiving oxybutynin (n=26) and 92% receiving placebo (n=24) completed treatment (P=.50). The differences in mean change in CAM score from baseline to all time points were equivalent between the oxybutynin and placebo groups. Delirium did not occur in either group. One participant receiving oxybutynin was withdrawn because of urinary retention, which resolved without treatment. Mild adverse events occurred in 38.5% of participants receiving oxybutynin and 37.5% receiving placebo (P=.94). CONCLUSION: Short-term treatment using oral extended-release oxybutynin 5 mg once daily was safe and well tolerated, with no delirium, in older female nursing home participants with mild to severe dementia. Future research should investigate different dosages and long-term treatment.