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Biomedical subjects

D Craig Brater

Publications and source records attributed to D Craig Brater.

17 recordsLinked to original sources
PubMed2005

Association between adherence measurements of metoprolol and health care utilization in older patients with heart failure.

OBJECTIVE: Data from electronic dosing monitors and published pharmacokinetic parameters were used to derive medication adherence measures for immediate-release metoprolol and examine their association with health care utilization of outpatients aged 50 years or older with heart failure. METHODS: We used a 1-compartment model and published population pharmacokinetic parameters to estimate mean plasma metoprolol concentrations for patients treated for 6 to 12 months. In the absence of directly measured plasma concentrations, we calculated the intended mean plasma concentration (Cp'(ave)) under the assumption of perfect adherence to the prescribed dose and frequency of administration. Projected mean plasma concentrations (Cp(ave)) were estimated by use of data from recorded dosing times. In addition to taking adherence (percentage of dose taken) and scheduling adherence (percentage of doses taken on schedule), we calculated the deviation from the intended exposure (DeltaCp(ave) = Cp'(ave) - Cp(ave)) and the proportion of intended exposure achieved by the patient (Cp(ave) /Cp'(ave)). We assessed the association between the adherence measures and the numbers of emergency department visits and hospital admissions experienced by the patients. RESULTS: Patients (N = 80) were aged 62 +/- 8 years. Mean DeltaCp(ave) and Cp(ave)/Cp'(ave) were 7.9 ng/mL (SD, 10.7) and 0.6 (SD, 0.3), respectively. Log-linear models adjusted for patient functional status indicated that greater deviation from the intended metoprolol exposure (DeltaCp(ave)) was associated with increased numbers of emergency department visits ( P < .0001) and hospital admissions (P < .0001). A higher proportion of intended exposure (Cp(ave) /Cp'(ave)) corresponded to a reduced number of emergency department visits (P = .0204) and hospital admissions (P = .0093). Taking adherence was univariately associated with both emergency department visits and hospital visits (P < .0001 and P = .0010, respectively). Scheduling adherence was associated with the number of emergency department visits (P = .0181) but not with the number of hospital admissions (P = .1602). Model selection procedures consistently chose the proposed measures over taking adherence and scheduling adherence. CONCLUSION: Deviation from the intended exposure and proportion of intended exposure achieved by the patient are valid adherence measures for immediate-release metoprolol and are associated with health care utilization. The potential utility of these measures for other beta-adrenergic antagonists and perhaps other cardiovascular drugs should be investigated.

Aged↗
PubMed2005

Renal effects of the cyclooxygenase-inhibiting nitric oxide donator AZD3582 compared with rofecoxib and naproxen during normal and low sodium intake.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) and can thereby reduce renal function, especially with respect to solute excretion and renal perfusion. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is a COX-inhibiting nitric oxide donator. Donation of nitric oxide by AZD3582 could preserve blood flow and thereby counteract the deleterious effects of COX inhibition in the gastrointestinal tract and possibly in other organ systems, including the kidney. The aim of this single-dose study was to assess the hypothesis that AZD3582 would not adversely affect renal function compared with NSAIDs. METHODS: In a parallel, randomized, double-blind fashion, a total of 60 healthy subjects (age range, 20-44 years) received 2 single doses of 750 mg AZD3582, 1500 mg AZD3582, 50 mg rofecoxib, 500 mg naproxen, or placebo (n = 12 per group). The first dose was given after a 5-day normal-sodium diet (150 mmol/d), and the second was given after a consecutive 3-day low-sodium diet (10 mmol/d). Urinary sodium excretion during normal sodium intake and glomerular filtration rate (GFR) (assessed by iohexol clearance) during sodium depletion were the primary variables measured. RESULTS: Urinary sodium excretion was reduced in all active treatment groups (maximal reduction of approximately 11 mmol/h during normal sodium intake, P < .05 versus placebo for all groups). GFR was also reduced in all active treatment groups. In sodium-depleted subjects, the mean (SD) maximal reduction in GFR during 0 to 6 hours for 750 mg AZD3582, 1500 mg AZD3582, 50 mg rofecoxib, and 500 mg naproxen was 28.1 mL/min (13.5 mL/min), 33.7 mL/min (23.3 mL/min), 25.2 mL/min (29.2 mL/min), and 41.7 mL/min (30.7 mL/min), respectively, with a statistically significant difference between 500 mg naproxen and placebo. Relative changes in sodium excretion and GFR were similar during normal sodium intake and sodium depletion during active treatment. CONCLUSION: The renal effects of 750 mg and 1500 mg AZD3582 were similar to those of 500 mg naproxen and 50 mg rofecoxib. Thus the potential for nitric oxide donation to create a renal-sparing agent was not found for AZD3582.

Adult↗
PubMed2005

Medication and dietary compliance beliefs in heart failure.

Patients with heart failure are required to comply with a medication regimen and dietary sodium restrictions. The objectives of this study were to determine the most frequently perceived benefits of and barriers to compliance with medication and dietary sodium restrictions and evaluate the relevancy of these scale items for testing in tailored intervention studies. Data were collected as part of two studies that evaluated the psychometric properties of two questionnaires. The most frequently identified benefit of medication compliance was decreasing the chance of being hospitalized, and the most commonly reported barrier was disruption of sleep. Patients were knowledgeable about the benefits of compliance with dietary sodium restrictions, and the poor taste of food on the low sodium diet was the most common barrier. Heart failure patients perceive benefits of and barriers to compliance with therapeutic regimens that are likely to be amenable to tailored interventions designed to enhance compliance.

Adult↗
PubMed2004

Health care and medication costs and use among older adults with heart failure.

BACKGROUND: Heart failure disproportionately affects older adults for whom multiple medications are prescribed to prevent exacerbations and hospitalization. To target interventions effectively, it is important to understand the association of medication acquisition with health care utilization and costs. METHODS: We used electronic medical records from an urban public health care system to identify patients aged >/=50 years who had a diagnosis of heart failure. We assessed the association between inappropriate or appropriate medication supplies and hospitalization and costs using multivariable analyses that adjusted for demographic characteristics, prior health care use, health status, and insurance status. RESULTS: Total health care costs for treating 1554 patients with heart failure from 1996 to 2000 were 36.6 million dollars (in 2000 dollars). Less than a third of patients received appropriate medication supplies (between 90% and 110% of the supplies needed) annually. Compared with patients with appropriate supplies, the odds of hospitalization were greater among those with undersupplies (odds ratio [OR] = 3.1; 95% confidence interval [CI]: 2.3 to 4.2; P <0.0001) or oversupplies (OR = 2.0; 95% CI: 1.7 to 2.4; P <0.0001). Total costs were 25% higher for patients with undersupplies (95% CI: 8% to 46%; P = 0.004) and 18% higher for those with oversupplies (95% CI: 7% to 30%; P = 0.0009) than for those with appropriate supplies. CONCLUSION: Among adults with heart failure, inappropriate medication supplies were associated with increased hospitalization and higher costs. Monitoring medication supplies from electronic medical records may be a useful component of programs aiming to improve care while managing costs.

Adrenergic beta-Antagonists↗
PubMed2004

A conceptual framework to study medication adherence in older adults.

BACKGROUND: Adults aged > or =50 years often have multiple chronic diseases requiring multiple medications. However, even drugs with well-documented benefits are often not taken as prescribed, for a variety of reasons. OBJECTIVE: The objective of this article was to provide background information about medication adherence and its measurement, the development of the conceptual model for use in adherence research, and supportive intervention strategies such as pharmaceutical care by pharmacists to improve chronic medication use in older adults. METHODS: English-language literature published from 1990 to 2000 was searched on MEDLINE, International Pharmaceutical Abstracts, and AARP Ageline using the terms aged, heart failure, CHF, adherence, chronic heart failure, compliance, and related terms. The authors used their personal files and libraries to obtain seminal literature and textbooks published before 1990. RESULTS: Although the cognitive processes needed to manage and take medications decline with aging, the number of prescription and nonprescription medications consumed increases. Other factors such as vision, hearing, health literacy, disability, and social and financial resources may all complicate the ability of older adults to adhere to the pharmacologic prescription. CONCLUSIONS: Many factors are associated with medication adherence and related health outcomes in older adults. Therefore, strategies to improve adherence will need to be multidimensional, including improvements in pharmacy services that consider age-related factors (eg, declining cognitive and physical functions) as well as a variety of environmental and social factors.

Aged↗
PubMed2004

Methodology of an ongoing, randomized, controlled trial to improve drug use for elderly patients with chronic heart failure.

BACKGROUND: Medications can improve the functioning and health-related quality of life of patients with chronic heart failure (CHF) and reduce morbidity, mortality, and costs of treatment. However, patients may not adhere to therapy. Patients with complex medication regimens and low health literacy are at risk for nonadherence. OBJECTIVE: The primary goal of this project is to develop and assess a multilevel pharmacy-based program to improve patient medication adherence and health outcomes for elderly CHF patients with low health literacy. METHODS: In this 4-year, controlled trial, patients aged 50 years with a diagnosis of CHF who are being treated at Wishard Health Services (Indianapolis, Indiana) are randomly assigned to pharmacist intervention or usual care. Intervention patients receive 9 months of pharmacist support and 3 months of postintervention follow-up. The intervention involves a pharmacist providing verbal and written education, icon-based labeling of medication containers, and therapeutic monitoring. The pharmacist identifies patients' barriers to appropriate drug use, coaches them on overcoming these barriers, and coordinates medication use issues with their primary care providers. Daily updates of relevant monitoring data are delivered via an electronic medical record system and stored in a personal computer system designed to support pharmacist monitoring and facilitate documentation of interventions. To measure medication adherence objectively, electronic monitoring lids are used on all CHF medications for patients in both study groups. Other assessments include self-reported medication adherence, results of echocardiography (eg, ejection fraction), brain natriuretic peptide concentrations, and health-related quality of life. Health services utilization, refill adherence, and cost data derive from electronic medical records. After completion of this study, the data can be used to assess the effectiveness and cost-effectiveness of our intervention. RESULTS: One hundred twenty-two patients have been assigned to receive the intervention and 192 to receive usual care. CONCLUSIONS: Our study aims to improve patients' knowledge and self-management of their medication and to improve medication monitoring in a multilevel pharmacy-based intervention. By doing so, we intend that the intervention will improve the health outcomes of elderly patients with CHF.

Aged↗
PubMed2004

Furosemide responsiveness, non-adherence and resistance during the chronic treatment of heart failure: a longitudinal study.

BACKGROUND AND METHODS: Loop diuretic therapy is an essential part of chronic systolic heart failure (CH)F management, yet response to treatment can be variable. We analysed diuretic responsiveness in 39 stable patients with CHF in the community over 2 years. We measured serum ACE as a marker of adherence to ACE inhibitor therapy and urinary furosemide as a marker of diuretic adherence and action. Patients' clinical outcome was stable and not hospitalized (Group 0); alive but hospitalized (Group 1); or dead during follow up (Group 2). RESULTS: Prescribed furosemide dose was variable (range 20-370 mg generally once daily) and progressive dose increments were common. Failed furosemide adherence (defined as < 10% of a dose excreted in 24 h urine where normal average excretion = 50% of an oral dose) during static prescribed dosing was infrequent relative to all days of therapy; yet was equally common across all outcome groups. Furosemide non-adherence appeared to be independent of non-adherence with ACE inhibitor (as marked by serum ACE activity > 20 U l(-1)) treatment. Furosemide responsiveness (mm of sodium excreted per mg furosemide in urine) showed no relationship to prescribed dose and paradoxically tended to rise in patients with higher basal aldosterone concentrations. Furosemide responsiveness fell by outcome class despite increased dose. Within-patient responsiveness remained relatively constant although highly variable between individuals. CONCLUSIONS: Furosemide responsiveness varied greatly between individuals but was constant within an individual. Non-adherence with furosemide was less common among those who died and appeared to occur at different time points from non-adherence with ACE inhibitor treatment, which was slightly more common in all outcome groups. Patients who died were prescribed higher furosemide doses and had greater furosemide excretion yet had similar sodium excretion. The main factor in response to chronic furosemide therapy was intrarenal diuretic resistance. Gross non-adherence was less important.

Administration, Oral↗
PubMed2004

Randomized trial of AT-1015 for treatment of intermittent claudication. A novel 5-hydroxytryptamine antagonist with no evidence of efficacy.

AT-1015 is a novel selective 5-HT2A serotonin receptor antagonist that is known to impair platelet aggregation and vasoconstriction. Serotonin has been hypothesized to contribute to claudication symptoms in individuals with peripheral arterial disease (PAD) via microvascular vasoconstrictor and thrombotic effects. AT-1015 was thus evaluated in 439 patients with claudication who were randomized in a double-blind, placebo-controlled trial comparing 10 mg, 20 mg, and 40 mg BID versus placebo for 24 weeks. Treadmill walking performance was assessed by peak walking time (PWT) and pain-free walking time (PFWT). Quality of life (QoL) was measured by the Walking Impairment Questionnaire (WIQ) and the Health Status Survey SF-36. Limb hemodynamics was assessed with the ankle-brachial index (ABI). The 40 mg arm was terminated prematurely by recommendation of the Data Safety Monitoring Committee due to an excess number of non-fatal myocardial infarctions. At study conclusion, there were no statistically significant differences in the mean change of PWT, PFWT, ABI and QoL between the 10 mg and 20 mg BID treatment groups compared with placebo. The proportion of patients who experienced an adverse event (AE) was similar across all treatment groups. Antimuscarinic and gastrointestinal AEs were more common in the AT-1015 treatment groups. Two deaths occurred: one in the placebo group and the other in the AT-1015 20 mg group. Although a prolongation of the QTc interval was observed in all groups, this was not clinically significant (QTc > 500 ms). Mean supine pulse rates were significantly increased in all AT-1015 treatment groups, consistent with predicted antimuscarinic effects. Population pharmacokinetic analysis fit a one-compartment model with first-order absorption and elimination. These data indicate that selective serotonin receptor blockade does not improve exercise tolerance or quality of life in individuals with claudication.

Aged↗
PubMed2003

Loop diuretics: from the Na-K-2Cl transporter to clinical use.

The diuretic response to loop diuretics in various disease states has consistently been found to be subnormal. One of the key determinants of the degree of diuretic response is the functional integrity of the sodium-potassium-chloride transporter in the loop of Henle. Studies in animal models suggest that expression/activity of the transporter may be affected by factors such as altered natural splicing events of NKCC2 (the gene encoding for the renal transporter), renal prostanoids, vasopressin, and other autacoids. We have reviewed the pharmacokinetics and pharmacodynamics of loop diuretics in health and in edematous disorders for which they are used. On the basis of evidence reviewed in this paper, we propose that altered expression or activity of the sodium-potassium-chloride transporter in the loop of Henle, in conjunction with events occurring in other segments of the nephron, possibly accounts for the altered diuretic response to these agents. Thus the modulators of this altered expression/activity could serve as important therapeutic targets for alternative diuretic regimens in these conditions.

Animals↗
PubMed2003

Association between adherence to diuretic therapy and health care utilization in patients with heart failure.

STUDY OBJECTIVE: To determine the relationship between adherence to diuretic therapy and health care utilization. DESIGN: Prospective, observational study. SETTING: University-affiliated medical center. PATIENTS: Forty-two patients with heart failure. INTERVENTION: Electronic monitoring of adherence to diuretic therapy (percentage of diuretic prescription container openings) and to scheduling (percentage of container openings within a specific time). MEASUREMENTS AND MAIN RESULTS: All patients were prescribed a diuretic, most commonly furosemide (88%). Patients varied widely in adherence to therapy (mu = 72% +/- 30%) and to scheduling (mu = 43% +/- 30%). Education was a predictor of drug-taking adherence (p=0.0062) but not of scheduling adherence. Log-linear models revealed that poor scheduling adherence was associated with increased cardiovascular-related hospitalizations (chi2 11.63, p=0.0006) and predicted more heart failure-related hospitalizations (chi2 4.04, p=0.0444). In contrast, neither measure was significantly associated with cardiovascular- or heart failure-related emergency department visits. We found a moderate correlation between scheduling adherence and taking adherence (r = 0.6513). CONCLUSION: Patients taking a greater proportion of diuretic agents on schedule may decrease the risk of cardiovascular- and heart failure-related hospitalizations. If these findings are confirmed by a larger study, interventions to improve adherence and patient health outcomes should consider the timing of doses as well as the number of daily doses of a diuretic.

Diuretics↗
PubMed2002

BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy.

BACKGROUND: Adenosine may adversely affect renal function via its effects on renal arterioles and tubuloglomerular feedback, but effects of adenosine blockade in humans receiving furosemide and ACE inhibitors is unknown. METHODS AND RESULTS: This was a randomized, double-blind, ascending-dose, crossover study evaluating 3 doses of BG9719 in 63 patients with congestive heart failure. Patients received placebo or 1 of 3 doses of BG9719 on 1 day and the same medication plus furosemide on a separate day. Renal function and electrolyte and water excretion were assessed. BG9719 alone caused an increase in urine output and sodium excretion (P<0.05). Although administration of furosemide alone caused a large diuresis, addition of BG9719 to furosemide increased diuresis, which was significant at the 0.75-microg/mL concentration. BG9719 alone improved glomerular filtration rate (GFR) at the 2 lower doses. Furosemide alone caused a decline in GFR. When BG9719 was added to furosemide, however, creatinine clearance remained at baseline at the 2 lower doses. CONCLUSIONS: In patients with congestive heart failure on standard therapy, including ACE inhibitors, BG9719 increased both urine output and GFR. In these same patients, furosemide increased urine output at the expense of decreased GFR. When BG9719 was given in addition to furosemide, urine volume additionally increased and there was no deterioration in GFR. A1 adenosine antagonism might preserve renal function while simultaneously promoting natriuresis during treatment for heart failure.

Aged↗
PubMed2002

Renal effects of cyclooxygyenase-2-selective inhibitors.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used. These agents are associated with adverse renal effects caused by the reduction in synthesis of renal prostaglandins through inhibition of cyclooxygenase (COX). Both isoforms of COX, COX-1 and COX-2, are expressed in the kidney in constitutive and inducible forms. It is assumed therefore that the COX-2-selective inhibitors, rofecoxib and celecoxib, would have an effect on renal function similar to that of nonselective NSAIDs. Several studies have evaluated this issue, although they have different study models and some have design flaws that limit their interpretation. Therefore, conclusions should be based on the pattern of observed effects rather than on individual data. These studies suggest that both celecoxib and rofecoxib can cause sodium retention and decrease glomerular filtration rate (GFR) to a similar extent as nonselective NSAIDs in patients at risk for adverse renal effects. Consequently, the same precautions regarding renal risk that are followed for nonselective NSAIDs should be used when selective COX-2 inhibitors are administered.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

Anti-inflammatory agents and renal function.

The purpose of this review is to provide an overview of the effect of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-specific-2 inhibitors (coxibs) on renal function. Both COX isoforms (COX-1 and COX-2) constitutively are expressed in the adult mammalian kidney and contribute to the biosynthesis of prostaglandins (PGs). Inhibition of COX activity in the kidney by NSAIDs has relatively mild consequences in healthy individuals, but can lead to serious adverse events in patients whose renal function is PG dependent. Most studies have reported transient decreases in sodium excretion upon initiation of therapy with either traditional NSAIDs or coxibs. In patients whose renal function is dependent on prostanoids, both nonselective NSAIDs and coxibs can affect the glomerular filtration rate. Changes in renal function may result in hypertension and edema. Several studies have compared the effects of traditional NSAIDs, celecoxib, and rofecoxib on blood pressure and incidence of edema, but the results have not been consistent, as the trials used different clinical models and study designs. No trials to date have been performed with rigorous study designs that allow meaningful drug comparisons at comparably effective doses. In consequence, patients who are at risk for adverse renal events should be monitored with the same caution when receiving coxibs as when receiving treatment with nonselective NSAIDs. They include patients with congestive heart failure or renal or hepatic disease, as well as those of advanced age receiving therapy with diuretics or angiotensin-converting enzyme (ACE) inhibitors.

Acute Kidney Injury↗
PubMed2001

Effects of albumin/furosemide mixtures on responses to furosemide in hypoalbuminemic patients.

Hypoalbuminemic patients often have sufficient fluid accumulation to mandate diuretic therapy but are often resistant to diuresis. Studies have suggested that hypoalbuminemia itself impairs delivery of effective amounts of diuretic agent into the urine, the site of action. Therefore, administration of mixtures of albumin and loop diuretics may enhance responses. Thirteen patients with biopsy-proven cirrhosis and ascites (age, 51.2 +/- 8.1 yr; Child-Pugh score, 8.5 +/- 1.0; serum albumin concentration, 3.0 +/- 0.6 g/dl) were studied in this randomized crossover study. Sodium balance was maintained throughout the study with a metabolic diet. All patients received spironolactone, but administration of all other diuretic agents was discontinued. Each patient received all of the following four treatments intravenously: (1) 40 mg of furosemide, (2) 25 g of albumin, (3) 40 mg of furosemide and 25 g of albumin premixed ex vivo, and (4) 40 mg of furosemide and 25 g of albumin infused simultaneously into different arms. Responses were assessed by measuring urinary sodium excretion and relating the urinary furosemide excretion rate to the sodium excretion rate. Additionally, the pharmacokinetics of furosemide were assessed. Furosemide pharmacokinetics were similar for all treatment arms. Albumin alone had negligible diuretic effects. Neither albumin regimen increased the response to furosemide. Moreover, the relationship between the urinary furosemide excretion rate and the sodium excretion rate was unaffected by albumin. In conclusion, albumin failed to enhance the diuretic effects of furosemide in cirrhotic patients with ascites. Therefore, the coadministration of albumin and furosemide for the treatment of cirrhosis, and likely other hypoalbuminemic conditions, should not be used clinically.

Adult↗
PubMed2000

Urinary protein binding does not affect response to furosemide in patients with nephrotic syndrome.

Response to loop diuretics in patients with nephrotic syndrome (NS) is subnormal. Studies in animal models of NS have suggested that binding of diuretic to urinary albumin is one of the mechanisms that may be operative in this diuretic resistance. To explore this hypothesis, 12 patients with NS were studied to determine whether displacement from urinary protein binding with sulfisoxazole would restore response to 120 mg of furosemide. The study was stopped after treating seven patients because it was clear that sulfizoxazole had no effect. Sodium excretion (mean +/- SD) from furosemide alone was 239 +/- 90 versus 240 +/- 115 mEq/8 h with sulfisoxazole. Sulfisoxazole had modest effects on serum pharmacokinetics of furosemide but had no effect on either the time course of furosemide urinary excretion or overall amount excreted: 49 +/- 15 mg versus 54 +/- 12 mg for furosemide alone and furosemide plus sulfisoxazole, respectively. It is concluded that urinary protein binding of loop diuretics is not a major mechanism for the diuretic resistance of NS. In turn, strategies aimed at displacing such binding are unlikely to be clinically helpful.

Adult↗