Frequency of Clinical Monitoring of Serum Concentrations of Digoxin, Potassium, and Creatinine, and Recording of Electrocardiograms in Digoxin-Treated Patients: A Japanese Claims Database Analysis.

Guidelines for cardiovascular drug therapy recommend monitoring serum digoxin concentration (SDC) in patients receiving digoxin treatment, especially those with renal dysfunction and hypokalemia. However, only a few studies have reported the prevalence of SDC monitoring and laboratory testing in clinical practice. Therefore, the aim of this study was to describe the frequency of SDC monitoring and laboratory testing in digoxin users and to assess the association between SDC monitoring and patient characteristics. We used the Japanese insurance claims data covering approximately 1.7 million patients aged 20-74 years between January 1, 2005 and March 31, 2014. All patients who had at least one prescription for digoxin were included. The frequency of SDC and laboratory tests was calculated and the association between patient characteristics and SDC monitoring was assessed using logistic regression analysis. A total of 98867 prescriptions of digoxin were issued to 3458 patients between 2005 and 2014. The annual mean frequencies of monitoring SDC, serum potassium level and serum creatinine level and of recording electrocardiograms was 16.8, 34.8, 38.7, and 24.1%, respectively. Atrial fibrillation, chronic heart failure, renal diseases, and use of oral anticoagulants were associated with SDC monitoring. We found the frequency of SDC monitoring to be relatively low in Japanese clinical practice.

The Assessment of Serum Drug Levels to Diagnose Non-Adherence in Stable Chronic Heart Failure Patients.

BACKGROUND: The aim of our study was to evaluate the prevalence of drug non-adherence in stable chronic heart failure (CHF) patients using serum drug levels (SDL) assessment. METHODS: CHF patients were prospectively enrolled during scheduled outpatient visit. Except standard procedures an unanticipated blood sampling for the SDL assessment was obtained. Analysis was focused on the prescribed heart failure and antihypertensive medication and was performed by liquid chromatography coupled with mass spectrometry. The patient was labelled as non-adherent if at least one of drugs assessed was not found in the serum. In the first half of patients multiple SDL have been evaluated during the follow-up. RESULTS: Eighty one patients were enrolled. The non-adherence was proven in twenty of them (25%). In the subgroup of thirty eight patients with multiple SDL evaluation the non-adherence raised significantly with increasing number of visits assessed together (21% for single visit, 29% for two of three visits assessed together and 34% for all three visits evaluated together, all p < 0.001). CONCLUSION: The non-adherence was proven in significant part of stable CHF patients using SDL assessment. This method seems to be reliable and effective and should be a part of clinical assessment in selected patients with CHF.

Theophylline Population Pharmacokinetics and Dosing in Children Following Congenital Heart Surgery With Cardiopulmonary Bypass.

Children undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) frequently develop acute kidney injury due to renal ischemia. Theophylline, which improves renal perfusion via adenosine receptor inhibition, is a potential targeted therapy. However, children undergoing cardiac surgery and CPB commonly have alterations in drug pharmacokinetics. To help understand optimal aminophylline (salt formulation of theophylline) dosing strategies in this population, a population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM) from 71 children (median age 5 months; 90% range 1 week to 10 years) who underwent cardiac surgery requiring CPB and received aminophylline as part of a previous randomized controlled trial. A 1-compartment model with linear elimination adequately described the pharmacokinetics of theophylline. Weight scaled via allometry was a significant predictor of clearance and volume. In addition, allometric scaled clearance increased with age implemented as a power maturation function. Compared to prior reports in noncardiac children, theophylline clearance was markedly reduced across age. In the final population pharmacokinetic model, optimized empiric dosing regimens were developed via Monte Carlo simulations. Doses 50% to 75% lower than those recommended in noncardiac children were needed to achieve target serum concentrations of 5 to 10 mg/L.

Pharmacokinetic and pharmacodynamic drug-drug interaction assessment between pradigastat and digoxin or warfarin.

Pradigastat, a novel diacylglycerol acyltransferase-1 inhibitor, was evaluated for both pharmacokinetic (PK) and pharmacodynamic (PD) drug-drug interactions when co-administered with digoxin or warfarin in healthy subjects. This open-label study included two parallel subject cohorts each with three sequential treatment periods. Forty subjects were enrolled in the study with 20 subjects allocated to each cohort. PK and PD (PT/INR for warfarin only) samples were collected in each period. The statistical analysis results showed that the 90% CIs of the geometric mean ratios of digoxin, R-warfarin, and S-warfarin PK parameters (AUC and Cmax) were all within 0.80-1.25 interval. The 90% CIs of the geometric mean ratios of pradigastat PK parameters (AUC and Cmax) were within 0.80-1.25 interval when co-administered with warfarin; while co-administration with digoxin slightly reduced pradigastat exposure (∼15%). The results also showed that 90% CIs of the geometric mean ratios of warfarin PD parameters (AUC(PT), PTmax, AUC(INR), and INRmax) were within 0.80-1.25 interval. Pradigastat and digoxin or warfarin had no relevant clinical PK or PD drug-drug interactions. Administration of pradigastat and warfarin or pradigastat and digoxin as a mono or combined treatment appears to be safe and tolerated.

Assessment of the appropriateness of serum digoxin concentration measurement in a medical group setting.

BACKGROUND: Recent quality initiatives require that the routine annual therapeutic drug-monitoring (TDM) parameters for the high-risk medication digoxin include a measure of renal function and a serum potassium level but not a serum digoxin concentration (SDC) measurement. Several studies have shown that the majority of the SDCs obtained in hospital settings provide little clinically actionable information. OBJECTIVE: To evaluate the appropriateness and utility of SDCs ordered in a medical group practice setting by categorizing the reason the SDC was ordered and identifying action taken in response to the result. METHODS: The descriptive study was conducted as a retrospective, electronic medical record (EMR) review of 90 primary care patients with continuous prescriptions for digoxin current on their medication profile with no gaps in therapy for at least 2 years prior to an SDC result entered into the EMR between January 1, 2009, and September 30, 2009. The reason the SDC was ordered was abstracted independently by 2 reviewers, who then assigned it to 1 of 8 predefined indication categories based on previously published criteria and practice guidelines. A third reviewer resolved inter-reviewer discrepancy (n = 1). RESULTS: A total of 90 patients with at least 1 SDC met inclusion criteria. Routine monitoring was the most frequent SDC order indication category with 35 patients (38.9%), 17 (48.6%) of whom did not have the recommended monitoring measures of potassium or renal function drawn concurrently. Patients were included in other categories as follows: confirmation of signs/symptoms of toxicity 30 (33.3%); assessment of factors altering pharmacokinetics 5 (5.6%); assessment of dosage change 5 (5.6%); assessment of drug interaction 3 (3.3%); assessment of clinical response 3 (3.3%); assessment of adherence 1 (1.1%); and other 2 (2.2%). Across all categories, a total of 19 (21.1%) of SDC results were outside the therapeutic range of 0.5 nanograms (ng) per mL and 2.0 ng per mL, 18 of which were below 0.5 ng per mL, with none of the subtherapeutic levels leading to a change in digoxin therapy. Only 1 patient (1.1%) had therapy changed in response to an elevated abnormal SDC result of 2.1 ng per mL and was in the routine monitoring category. CONCLUSIONS: The majority of SDC results obtained in our medical group setting did not lead to clinical action, such as dose adjustment or drug discontinuation. SDCs were commonly measured as part of routine monitoring, which is considered an inappropriate indication, and often without being accompanied by better markers for digoxin toxicity such as serum potassium levels and measures of renal function as recommended by drug-monitoring quality initiatives. Provider education is needed regarding the most indicative digoxin TDM parameters to obtain in order to satisfy quality initiatives.

Assessment of digoxin antibody use in patients with elevated serum digoxin following chronic or acute exposure.

OBJECTIVE: To evaluate the use of antidotal therapy in patients with an elevated digitalis concentration following chronic or acute exposure. DESIGN AND SETTING: Retrospective review of patient records over 2 years in 20 city hospitals in France. PATIENTS: Overall 838 patients with an elevated serum digitalis concentration (digoxin > 1.95ng /ml or digitoxin > 23ng /ml) were included in the study. Of these, 67 (8%) had received antidotal therapy with Fab fragments. MEASUREMENTS AND RESULTS: The relationships between previously reported prognostic criteria and use of antidotal therapy were investigated. We identified five independent factors that were associated with the use of antidotal therapy: acute overdose (OR 15.74), Fab fragment availability in the hospital (11.06), serum potassium (1.81), and heart rate (0.96). Mortality was significantly lower in Fab-treated (6%, 4/67) than untreated patients (15%, 117/770). CONCLUSIONS: Antidotal therapy is underused in patients with an elevated digitalis concentration especially in patients with chronic digitalis exposure. These patients in our series presented a higher mortality rate than patients with acute poisoning. Although they were older and tended to have a history of cardiac disease, they did not differ from patients with acute poisoning with regard to the main severity criteria and prognostic factors. The use of identical criteria for antidotal treatment after acute and chronic poisoning should help optimize outcomes. Fab fragment availability is insufficient in France but ranks only second after type of poisoning (acute or chronic) in the multivariate association with Fab treatment.

Low high-density lipoprotein cholesterol: an important consideration in coronary heart disease risk assessment.

PURPOSE OF REVIEW: One aim is to summarize evidence from observational studies and clinical trials evaluating the inverse relationship between high-density lipoprotein and coronary heart disease. Other aims are to explore the mechanisms underlying the reported cardioprotective effects of high-density lipoprotein and to evaluate therapeutic modalities to increase high-density lipoprotein levels and functionality. RECENT FINDINGS: In addition to reverse cholesterol transport, recent data suggest that high-density lipoprotein possesses antioxidant, anti-inflammatory and fibrinolytic properties and the inverse relationship between high-density lipoprotein cholesterol and coronary heart disease is most evident with associated elevations in low-density lipoprotein cholesterol and triglyceride. Recent data suggest, however, that even after low-density lipoprotein cholesterol is sufficiently reduced, residual coronary heart disease risk persists with low high-density lipoprotein cholesterol. The excess death rate reported with the high-density lipoprotein cholesterol raising drug torcetrapib appears to have been the result of an off-target effect of the drug, rather than an effect attributable to cholesteryl ester transfer protein inhibition. SUMMARY: Low high-density lipoprotein cholesterol remains an important consideration in coronary heart disease risk assessment, however several issues remain unresolved. They include the extent to which low high-density lipoprotein cholesterol in the absence of other risk factors augments risk, the relationship between high-density lipoprotein functionality and levels of high-density lipoprotein cholesterol and whether and to what extent improving these parameters independently offsets coronary heart disease risk.

Digoxin prescribing for heart failure in elderly residents of long-term care facilities.

BACKGROUND: Digoxin is often used in long-term care (LTC) residents with heart failure despite a high risk of toxicity associated with increased age, comorbidities and polypharmacy. This toxicity may occur at serum digoxin concentrations that are as low as 1.54 nmol/L. OBJECTIVES: To determine the prevalence of digoxin use, estimate the proportion at risk of toxicity and identify correlates of digoxin use in LTC residents with heart failure. METHODS: Cross-sectional survey in eight LTC facilities that lodge a total of 1223 residents. RESULTS: The prevalence of heart failure was 20%. Digoxin was prescribed for 32% of residents with heart failure and was associated with arrhythmia (primarily atrial fibrillation), anticoagulant and diuretic use, and higher serum thyroid-stimulating hormone. Digoxin doses higher than those that achieve the recommended therapeutic peak body stores of 6 microg/kg and 10 microg/kg were prescribed to 80% and 33% of residents with heart failure, respectively. Serum digoxin concentrations were greater than 1.5 nmol/L in 30% of patients. Comorbidities and concurrently prescribed medications that increase the risk of digoxin toxicity were prescribed to 26% of the patients. CONCLUSIONS: Approximately one-third of LTC residents with heart failure received digoxin. Atrial fibrillation was the most important determinant of use. At least 26% of these residents were exposed to an increased risk of digoxin toxicity. Studies are required to determine safe and effective digoxin dosing regimens for frail elderly heart failure patients. Clinicians should exercise caution when using digoxin in LTC residents.

Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18.

OBJECTIVES: This study was designed to evaluate B-type natriuretic peptide (BNP) for risk assessment and clinical decision making over a range of cut points, alone and with cardiac troponin I (cTnI), in patients with non-ST-elevation acute coronary syndromes (ACS). BACKGROUND: B-type natriuretic peptide holds promise for risk stratification. Additional evidence regarding optimal decision limits, use in combination with troponin, and use in targeting therapy is needed before acceptance into clinical use for ACS. METHODS: We evaluated BNP at baseline in 1,676 patients with non-ST-elevation ACS randomized to early invasive versus conservative management. RESULTS: Patients with elevated BNP (>80 pg/ml; n = 320) were at higher risk of death at seven days (2.5% vs. 0.7%, p = 0.006) and six months (8.4% vs. 1.8%, p < 0.0001). The association between BNP and mortality at six months (adjusted odds ratio [OR] 3.3; 95% confidence interval [CI] 1.7 to 6.3) was independent of important clinical predictors, including cTnI and congestive heart failure (CHF). Patients with elevated BNP had a fivefold higher risk of developing new CHF by 30 days (5.9% vs. 1.0%, p < 0.0001). B-type natriuretic peptide added prognostic information to cTnI, discriminating patients at higher mortality risk among those with negative (OR 6.9; 95% CI 1.9 to 25.8) and positive (OR 4.1; 95% CI 1.9 to 9.0) baseline cTnI results. No difference was observed in the effect of invasive versus conservative management when stratified by baseline levels of BNP (p(interaction) > or = 0.6). CONCLUSIONS: Elevated BNP (>80 pg/ml) at presentation identifies patients with non-ST-elevation ACS who are at higher risk of death and CHF and adds incremental information to cTnI. Additional work is needed to identify therapies that may reduce the risk associated with increased BNP.

B-type natriuretic peptide and its clinical utility in patients with heart failure.

The implementation of entirely new clinical laboratory tests such as BNP assays is much more difficult today than it ever has been in the past. Medicare and Medicaid have been operating for many years on fixed reimbursements based on Diagnosis Related Groups (DRGs). Many third-party payers now have capitated contracts, i.e., a fixed reimbursement per member per month, regardless of the number of tests ordered and performed. Laboratories are now cost centers and not sources of revenue, thus the limited amount of income from fee-for-service reimbursements may not sufficient to cover the expenses for performing all testing. Therefore, in order to justify BNP testing, laboratory directors and hospital administrators must be able to demonstrate that implementation of BNP testing results in a savings for the hospital as a whole, even if the laboratory has a negative cost balance. If BNP testing can lead to a reduction or elimination of other tests, or if it improves the efficiency and accuracy of CHF diagnosis so that the number of inappropriate admissions is reduced, the test may be justified. Table 2 lists some specific areas where BNP might impact the other clinical areas. Outcome studies should be performed to determine if any of these changes in clinical practices can be justified.

Some adaptive monte carlo methods for Bayesian inference.

Monte Carlo methods, in particular Markov chain Monte Carlo methods, have become increasingly important as a tool for practical Bayesian inference in recent years. A wide range of algorithms is available, and choosing an algorithm that will work well on a specific problem is challenging. It is therefore important to explore the possibility of developing adaptive strategies that choose and adjust the algorithm to a particular context based on information obtained during sampling as well as information provided with the problem. This paper outlines some of the issues in developing adaptive methods and presents some preliminary results.

High-performance liquid chromatography-ionspray mass spectrometry for the specific determination of digoxin and some related cardiac glycosides in human plasma.

An original method based upon high-performance liquid chromatography coupled to ionspray mass spectrometry (HPLC-ISP-MS) has been developed for the identification and quantification in plasma of several cardiac glycosides, namely digoxin, digitoxin, lanatoside C and acetyldigitoxin. After single-step liquid-liquid extraction by chloroform-2-propanol (95:5, v/v) at pH 9.5 using oleandrin as an internal standard, solutes are separated on a 4 microm NovaPak C18 (Waters) column (150x2.0 mm, I.D.), using a gradient of acetonitrile-2 mM NH4COOH, pH 3 buffer (flow-rate 200 microl/min, post-column split 1:3). Detection is done by a Perkin-Elmer Sciex API-100 mass analyzer equipped with an ISP interface. In most instances the major ion observed is not [M+H]+ as expected, but [M+NH4]+. The mean retention times (min) are: lanatoside C, 5.74; digoxin, 6.00; digitoxin, 8.08, oleandrin, 8.30, acetyldigitoxin, 8.66 and 9.01 (isomers alpha and beta, respectively). The lower limits of detection in single ion monitoring mode range from 0.15 ng/ml (alpha- and beta-acetyldigitoxin) to 0.60 ng/ml (lanatoside C), making the method less sensitive than radioimmunoassay, whereas it is much more specific.

Assessment of the immunoreactivity of digoxin metabolites and the cross-reactivity with digoxin-like immunoreactive factors in the Roche-TDM ONLINE digoxin assay.

Immunoassays for digoxin measurement have long had the problem of low specificity. Antisera used in these assays may not only measure digoxin and the active metabolites but also cross-react with the noncardioactive metabolites and digoxin-like immunoreactive factors (DLIFs). In this study, we describe the analytical performance of the newly introduced Roche-TDM ONLINE digoxin assay on the COBAS FARA II centrifugal analyzer. The assay possessed linearity up to 5.0 ng/ml, sensitivity of 0.19 ng/ml, average recovery of 100.4%, and day-to-day variability of < 6%. The assay demonstrated no cross-reactivity with DLIFs or spironolactone and its metabolites and negligible reactivity with the digoxin noncardioactive metabolites. In addition, the immunoreactivity of the digoxin active metabolites reflected their cardioactivity. We conclude that the Roche-TDM ONLINE digoxin assay is highly specific and precise and suitable for the therapeutic monitoring of this drug.

Assessment of the pharmacokinetic interaction between zileuton and digoxin in humans.

The effects of coadministration of zileuton on the pharmacokinetic profile of digoxin were investigated in a double-blind placebo-controlled crossover study in 12 healthy male volunteers. During each study phase, the subjects received zileuton 600mg every 6 hours (regimen A) or placebo (regimen B) for 13 days. In addition, all subjects received concomitant digoxin 0.25 mg/day on study days 1 to 11 during both study phases. The study results provide no evidence of any significant overall effect of zileuton on digoxin plasma concentration-time profiles. Although the mean time to reach the maximum plasma concentration for digoxin was significantly shorter after concomitant administration of digoxin and zileuton than after concomitant administration of digoxin and placebo (0.95 vs 1.43 hours), there were no significant differences between the 2 regimens in the values for maximum plasma concentration, area under the plasma concentration-time curve from 0 to 24 hours, elimination half-life, oral clearance, and apparent volume of distribution associated with the terminal phase. Therefore, it is concluded that digoxin and zileuton may be coadministered without risk of clinically relevant effects on the pharmacokinetic profile of digoxin.