Association Between Omega-3 Fatty Acid Treatment and Atrial Fibrillation in Cardiovascular Outcome Trials: A Systematic Review and Meta-Analysis.

PURPOSE: Data on the relationship between omega-3 fatty acid (n-3 FA) therapy with atrial fibrillation (AF) have been inconsistent. We investigate the association between n-3 FA and risk for AF by pooling data from available large, cardiovascular outcome trials. METHODS: We performed a systematic search on PubMed and Embase for studies on n-3 FA with AF as an outcome measure. Large (≥ 1000 participants) randomized controlled trials with ≥ 1-year follow-up period were included. The association between n-3 FA and risk of AF or stroke was assessed. Mantel-Haenszel random effects model was used to calculate risk ratios (RR) with 95% confidence intervals (CI). We then performed meta-regression to evaluate effect on AF by dose of n-3 FA therapy. RESULTS: A total of 8 randomized control trials encompassing 83,112 participants were included in the meta-analysis. Of these, five trials assessed a lower dose of n-3 FA (≤ 1 g daily, n = 61,096) while 3 trials assessed a higher dose (> 1 g daily, n = 22,016). In meta-analysis, a significant association was noted between n-3 FA treatment and risk of AF (4.0% vs 3.3%; RR 1.24, 95% CI 1.11-1.38, p = 0.0002). There was a modest but still significant association in the lower dose (n-3 FA ≤ 1 g daily) sub-group (RR 1.12, 95% CI 1.04-1.21, p = 0.004) and stronger association in the higher dose (n-3 FA > 1 g daily) sub-group (RR 1.51, 95% CI 1.26-1.80, p < 0.001; p-interaction between low versus high subgroups = 0.003). There was no increase in stroke risk (RR 1.04, 95% CI 0.90-1.20). Meta-regression demonstrated a significant association between dose of n-3 FA with risk for AF events (log RR 0.103, 95% CI 0.048-0.159, p < 0.001). CONCLUSION: While overall AF event rates were low, n-3 FA treatment is associated with increased risk for AF.

Assessment of Body Weight Changes in Patients with Inflammatory Bowel Diseases Initiating Biologic Therapy: A Prospective Cohort Study.

BACKGROUND: Prior studies have inconsistently suggested that biologic therapy may be associated with weight gain in inflammatory bowel disease patients (IBD). Our aim was to compare weight gain across different biologic therapy classes with distinct mechanisms of action. METHODS: This prospective cohort study recruited patients with moderate to severe IBD initiating outpatient biologic therapy with anti-TNF (infliximab, adalimumab), vedolizumab, or ustekinumab. Weight measurements were performed at weeks 0, 14, 30, and 54. Changes in weight between baseline and each of the follow-up visits were modeled as a continuous variable, and multivariate regression assessed the independent effect of therapeutic class on this outcome. RESULTS: Our study enrolled 269 patients (163 CD, 106 UC) initiating biologic therapy [99 anti-TNF (37%), 122 vedolizumab (45%), 48 ustekinumab (18%)]. From baseline, the weight significantly increased at week 14 with a mean of 0.36 kg (± 3.8 kg, p = 0.004) and continued to increase compared to baseline with 0.96 kg (± 3.9 kg, p < 0.001) and 1.29 kg (± 4.2 kg, p < 0.001) at week 30 and 54, respectively. On univariate and multivariable analysis, no significant differences between any of the biologic therapies for weight gain were seen at any time point (weight gain anti-TNF: 0.31 kg, 1.06 kg, 1.33 kg; VDZ: 0.30 kg, 0.83 kg, 1.10 kg; UST: 0.63 kg, 1.21 kg, 2.31 kg at wk 14, wk 30, and wk 54, respectively). None of the disease activity parameters showed any statistical association with weight gain. CONCLUSION: There was no difference in weight gain among the different biologic therapeutic classes.

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in the treatment of venous thromboembolism.

Anticoagulant plasma concentrations and patient characteristics might affect the benefit-risk balance of therapy. This study assessed the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism treatment (VTE-T) using data from the phase 3 EINSTEIN-DVT and EINSTEIN-PE studies. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and the known correlation between rivaroxaban plasma concentrations and PT dynamics. The composite efficacy outcomes evaluated were recurrent deep-vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent DVT, PE and all-cause death; safety outcomes were major bleeding and the composite of major or non-major clinically relevant (NMCR) bleeding. Exposure-response relationships were evaluated using multivariate logistic and Cox regression for the twice-daily (BID) and once-daily (OD) dosing periods, respectively. Predicted rivaroxaban exposure and CrCl were significantly associated with both efficacy outcomes in the BID period. In the OD period, exposure was significantly associated with recurrent DVT and PE but not recurrent DVT, PE and all-cause death. The statistically significant exposure-efficacy relationships were shallow. Exposure-safety relationships were absent within the investigated exposure range. During both dosing periods, low baseline hemoglobin and prior bleeding were associated with the composite of major or NMCR bleeding. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit-risk could be identified within the investigated exposure range. Therefore, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-T.

Safety and efficacy of herbal medicine for acute intracerebral hemorrhage (CRRICH): a multicentre randomised controlled trial.

OBJECTIVE: To evaluate the safety and efficacy of removing blood stasis (RBS) herbal medicine for the treatment of acute intracerebral haemorrhage (AICH) within a 6-hour time window. STUDY DESIGN: A randomised, multicentre, double-blind, placebo-controlled study performed in 14 hospitals in China. PARTICIPANTS AND INTERVENTIONS: Patients with AICH were randomly assigned to receive a placebo, the ICH-1 (Intracerebral Haemorrhage) formula (eight herbs, including the RBS herbs hirudo and tabanus) or the ICH-2 formula (six herbs without the RBS herbs hirudo and tabanus) within 6 hours of ICH onset. OUTCOMES: The primary safety outcome was the incidence of haematoma enlargement at 24 hours and at 10 days after treatment. The secondary outcome was the incidence of poor prognosis (mortality or modified Rankin Scale score ≥5) assessed at 90 days after symptom onset. RESULTS: A total of 324 subjects were randomised between October 2013 and May 2016: 105 patients received placebo; 108 patients received the ICH-1 formula; and 111 patients received the ICH-2 formula. The incidence of haematoma enlargement at 24 hours was 7.8% in the placebo group, 12.3% in the ICH-1 group and 7.5% in the ICH-2 group; the incidence of haematoma enlargement on day 10 was 1.1% in the placebo group, 1.1% in the ICH-1 group, and 3.1% in the ICH-2 group, with no significant differences among the groups (P>0.05). The mortality rates were 3.8% in the placebo group, 2.8% in the ICH-1 group, and 0.9% in the ICH-2 group; the incidences of poor prognosis were 7.1% in the placebo group, 6.0% in the ICH-1 group and 4.8% in the ICH-2 group at 3 months, with no significant differences among the groups (p>0.05). However, the overall frequency of treatment-emergent adverse events in the ICH-1 group (12.1%) was higher among the three groups (5.8% and 2.8%, respectively, p<0.05). All three cases of serious adverse events were in the ICH-1 group. CONCLUSIONS: Ultra-early administration of ICH-1 formula for AICH patients did not exert significant beneficial effects on clinical outcomes but increased the risk of bleeding, which probably resulted from the inclusion of RBS herbal medicines in ICH-1. TRIALREGISTRATION NUMBER: NCT01918722.

Limited Sampling Strategies Using Linear Regression and the Bayesian Approach for Therapeutic Drug Monitoring of Moxifloxacin in Tuberculosis Patients.

Therapeutic drug monitoring (TDM) of moxifloxacin is recommended to improve the response to tuberculosis treatment and reduce acquired drug resistance. Limited sampling strategies (LSSs) are able to reduce the burden of TDM by using a small number of appropriately timed samples to estimate the parameter of interest, the area under the concentration-time curve. This study aimed to develop LSSs for moxifloxacin alone (MFX) and together with rifampin (MFX+RIF) in tuberculosis (TB) patients. Population pharmacokinetic (popPK) models were developed for MFX (n = 77) and MFX+RIF (n = 24). In addition, LSSs using Bayesian approach and multiple linear regression were developed. Jackknife analysis was used for internal validation of the popPK models and multiple linear regression LSSs. Clinically feasible LSSs (one to three samples, 6-h timespan postdose, and 1-h interval) were tested. Moxifloxacin exposure was slightly underestimated in the one-compartment models of MFX (mean -5.1%, standard error [SE] 0.8%) and MFX+RIF (mean -10%, SE 2.5%). The Bayesian LSSs for MFX and MFX+RIF (both 0 and 6 h) slightly underestimated drug exposure (MFX mean -4.8%, SE 1.3%; MFX+RIF mean -5.5%, SE 3.1%). The multiple linear regression LSS for MFX (0 and 4 h) and MFX+RIF (1 and 6 h), showed mean overestimations of 0.2% (SE 1.3%) and 0.9% (SE 2.1%), respectively. LSSs were successfully developed using the Bayesian approach (MFX and MFX+RIF; 0 and 6 h) and multiple linear regression (MFX, 0 and 4 h; MFX+RIF, 1 and 6 h). These LSSs can be implemented in clinical practice to facilitate TDM of moxifloxacin in TB patients.

Using an Integrated Care Pathway for Late-Life Schizophrenia Improves Monitoring of Adverse Effects of Antipsychotics and Reduces Antipsychotic Polypharmacy.

OBJECTIVE: Antipsychotic use in older patients is associated with many adverse effects, including tardive dyskinesia and extrapyramidal symptoms, which, in turn, increase the risk of falling. Antipsychotics are also associated with metabolic syndrome and cognitive impairment in older patients. Integrated care pathways (ICPs) are designed to manage specific conditions using standardized assessments and measurement-based interventions. This study aims to compare the use of recommended tools to monitor for adverse effects associated with antipsychotics in older patients managed within an ICP and those managed under usual care conditions-i.e., treatment as usual (TAU). METHODS: We reviewed and compared the health records of 100 older patients enrolled in an ICP for late-life schizophrenia with those of 100 older patients treated with antipsychotics under TAU conditions. RESULTS: Monitoring rates were significantly higher in the ICP group than in the TAU group for all assessments: extrapyramidal symptoms (94% versus 5%), metabolic disturbances (91% versus 25%), fall risk (82% versus 35%), and cognitive impairment (72% versus 28%). Rates of antipsychotic polypharmacy were also six times higher in the TAU group. CONCLUSION: Older patients with schizophrenia treated with antipsychotics within an ICP experience higher rates of monitoring and less psychotropic polypharmacy than older patients treated with antipsychotics under TAU conditions. These findings suggest that an ICP can improve the quality of antipsychotic pharmacotherapy in older patients and thus possibly its effectiveness. This needs to be confirmed by a randomized controlled trial.

Use of flecainide in combination antiarrhythmic therapy in patients with arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Antiarrhythmic therapy is commonly used for suppression of arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) in conjunction with implantable cardioverter-defibrillators and catheter ablation. The efficacy of combination flecainide and sotalol/metoprolol therapy for patients refractory to single agents and/or catheter ablation has not been well established. OBJECTIVE: The purpose of this study was to describe our experience with the addition of flecainide in combination with sotalol/metoprolol for treatment of arrhythmias in patients with ARVC. METHODS: We reviewed all patients within our genetic arrhythmia program with a definite diagnosis of ARVC (45 patients) and identified 8 patients treated with a combination of flecainide with sotalol/metoprolol after failure of single-agent therapy and/or catheter ablation. These patients were monitored with at least yearly clinic visits and device interrogations focused on the detection of major ventricular arrhythmias. RESULTS: Of the 8 patients reviewed, 6 demonstrated excellent arrhythmia control after initiation of combination therapy with flecainide and sotalol/metoprolol. These patients have been arrhythmia-free for an average of 35.5 months. Two patients have demonstrated recurrent arrhythmias despite combination therapy and have undergone repeat epicardial and endocardial ablation. Recurrence was noted to occur within 2 months of therapy. Patients were diverse with regard to the severity of disease as well as in the presence of genetic mutations. CONCLUSION: The addition of flecainide in combination with sotalol/metoprolol may be an effective antiarrhythmic strategy for the control of ventricular arrhythmias in patients with ARVC refractory to single-agent therapy and/or catheter ablation.

Therapeutic drug monitoring of the ß-lactam antibiotics: what is the evidence and which patients should we be using it for?

Traditional antibiotic dosing was not designed for today's escalating antibiotic resistance, lack of novel antibiotics and growing complexity in patient populations. Dosing that ensures optimal antibiotic exposures should be considered essential to increase the likelihood of effective patient treatment. Given the variability in these exposures across different patients, a 'one-dose-fits-all' approach is increasingly problematic. Therapeutic drug monitoring (TDM) of the ß-lactams, the most widely used antibiotic class, is underutilized in certain populations. Clinical experience with ß-lactam TDM remains relatively scarce. Patients most likely to benefit from such an intervention include the critically ill, the obese, the elderly and those with cystic fibrosis. Most centres actively performing ß-lactam TDM target a minimum 100% of the time during the dosing interval that the free (unbound) concentration of antibiotic exceeds the MIC of the pathogen (100% fT>MIC), which is higher than a traditional target supported by in vitro data. Ideally, isolated pathogens should undergo MIC testing along with TDM on a regular basis, allowing clinicians to address the triad of bug, drug and patient ('mug') in equal measure.

ABR obtained from time-efficient train stimuli for cisplatin ototoxicity monitoring.

BACKGROUND: Nonbehavioral methods for identifying cisplatin ototoxicity are important for testing patients with cancer who become too tired or sick to provide a reliable response. The auditory brainstem response (ABR) is a nonbehavioral test that is sensitive to ototoxicity but can be time consuming to implement over a range of frequencies and/or levels. To address this issue, trains of stimuli were developed that offer reliable ABR testing over a range of tone-burst frequencies and levels at a time savings of 77% relative to tone-burst stimuli presented individually. The clinical accuracy of this new method has yet to be determined on a clinical population. PURPOSE: This project was designed to determine the test performance of a time-effective ABR methodology aimed at identifying hearing shifts from cisplatin among veterans. A secondary goal was to determine whether improved test performance could be achieved by including our previously developed ototoxicity risk assessment model in the ABR prediction algorithm. RESEARCH DESIGN: A set of discriminant functions were derived using logistic regression to model the risk for cisplatin-induced hearing change. Independent variables were one of several ABR metrics alone and combined with an ototoxicity risk assessment model that includes pre-exposure hearing and cisplatin dose. Receiver operating characteristic curve analysis was used to evaluate the test performance of these discriminant functions. STUDY SAMPLE: Twenty-two male veterans treated with cisplatin for various cancers provided data from a total of 71 monitoring appointments. DATA COLLECTION AND ANALYSIS: Data were collected prospectively from one ear of each participant as designated below. Hearing shift was determined for frequencies within an octave of each patient's high-frequency hearing limit, tested in 1/6th-octave steps. ABRs were monitored using a set of two intensity trains from the highest two multiple frequency tone-burst center frequencies (up to 11.3 kHz) that yielded a robust response at baseline. Each intensity train was presented at 65-105 dB peSPL in 10 dB steps. Scorable ABRs were generally limited to the highest two intensities; therefore, analyses concern those levels. RESULTS: The ABR measurement failure was high, up to 52% for some frequencies and levels. Furthermore, the ABR was not frequently obtained at levels below 85 dB peSPL, consistent with previous studies that suggest a stimulus level of greater than 80 dB peSPL is required to obtain a reliable response to trained stimuli. Using multivariate metrics that included the dose-ototoxicity model, the most accurate scoring function was change in amplitude at lowest half-octave frequency obtained at 105 dB (change in wave V amplitude at frequency 2/105). However, absence of wave V at a monitor patient visit of the ABR response at levels 105 or 95 dB peSPL was deemed the preferred scoring function, because it had lower measurement failure and was within one standard error of the most accurate function. CONCLUSIONS: Because of the large number of responses that could not be measured at baseline, this technique as implemented holds limited value as an ototoxicity-monitoring method.

Beyond first-line HIV treatment regimens: the current state of antiretroviral regimens, viral load monitoring, and resistance testing in resource-limited settings.

PURPOSE OF REVIEW: With the availability of antiretroviral drugs in resource-limited settings, there is a rapid scale-up of antiretroviral therapy in developing countries. RECENT FINDINGS: The review focuses on the issues faced while patients are on first-line antiretroviral therapy in the absence of viral load monitoring, and the availability and progress of the second-line antiretroviral drugs and the salvage regimens in resource-limited settings. SUMMARY: There is an urgent need for low-cost, low-tech viral load monitoring in resource-limited settings. Fixed-dose combination of antiretrovirals for first-line and second-line therapy will result in better effectiveness. There is a need for newer antiretroviral drugs in resource-limited settings.

Evaluation of vitamin B12 monitoring in a veteran population on long-term, high-dose metformin therapy.

BACKGROUND: Metformin can result in vitamin B(12) deficiency, potentially leading to complications such as neuropathy. Annual monitoring of vitamin B(12) has been suggested; however, it is unknown whether current practice reflects this recommendation. OBJECTIVE: To identify vitamin B(12) monitoring patterns in patients on long-term, high-dose metformin. Secondary objective was to determine the frequency of new vitamin B(12) deficiency, anemia, and neuropathy documented after initiation of high-dose metformin. METHODS: Electronic medical records of veterans treated at the Veterans Affairs Maryland Healthcare System with high-dose metformin (≥2000 mg/day) as of November 1, 2010, were reviewed. Data regarding metformin treatment, vitamin B(12) measurements, and documentation of vitamin B(12) deficiency, cyanocobalamin supplementation, anemia, and neuropathy were collected. Subjects treated with metformin for less than 1 year or those with documented peripheral neuropathy, megaloblastic anemia, vitamin B(12) deficiency, or a condition associated with vitamin B(12) malabsorption prior to metformin initiation were excluded. RESULTS: Subjects (N = 235) had a mean metformin dose of 2050 mg/day and mean duration of treatment of 5.2 years. Sixty percent did not have vitamin B(12) measured. Of subjects receiving metformin for 10 years or more, nearly half (46%) never had vitamin B(12) measured. New documentation of vitamin B(12) deficiency or cyanocobalamin supplementation was found in 5.5% of the population, and anemia was found in 12%. Of the 14% with new neuropathy, 42% did not have vitamin B(12) measured. CONCLUSIONS: Vitamin B(12) was not routinely monitored in patients on high-dose metformin, even in those at highest risk (≥10 years of therapy), or in those with potential manifestations of vitamin B(12) deficiency (neuropathy). Cases of vitamin B(12) deficiency and resulting anemia or neuropathy may be undiagnosed and untreated because of lack of monitoring. Prospective studies examining the effect of increased vitamin B(12) monitoring on identification and treatment of vitamin B(12) deficiency in patients on metformin are warranted.

Frequency of laboratory measurement and hyperkalaemia in hospitalised patients using serum potassium concentration increasing drugs.

PURPOSE: Although, drug-drug interactions (DDIs) between potassium-increasing drugs (PIDs) are known risk factors for developing hyperkalaemia, not much is known about their risk and management strategies during hospitalisation. This study examines the frequency of serum potassium measurements and hyperkalaemia in hospitalised patients, based on the use of one or more PIDs, and the determinants thereof. METHODS: Adult patients hospitalised in the University Medical Centre Utrecht between 2006 and 2008 were included in this cross-sectional study. The frequency of serum potassium measurements and of hyperkalaemia were compared between patients using only one PID at a time (monotherapy group) and patients using two or more PIDs concomitantly (interaction group). The determinants studied were renal failure, diabetes mellitus, use of diuretics, type of DDI, start of the PIDs within the hospital versus continued home medication and medical speciality. RESULTS: Serum potassium was measured more frequently in the interaction group than in the monotherapy group [67 vs. 56%; relative risk (RR) 1.19, 95% confidence interval (CI) 1.14-1.24] and the risk of hyperkalaemia was also increased in the interaction group (9.9 vs. 5.9%, RR 1.7, 95% CI 1.3-2.1). The combination of potassium-sparing diuretics plus a potassium supplement, start of the PID within the hospital and hospitalisation in non-internal medicine departments was associated with higher relative risk estimates for hyperkalaemia. CONCLUSIONS: Among our patient cohort, even when physicians received a direct pop-up to monitor serum potassium levels when prescribing two PIDs concomitantly, serum potassium levels were not measured in 33% of patients, and 10% of patients developed hyperkalaemia. Improved management strategies and/or clinical decision-support systems are needed to decrease the frequency of hyperkalaemia following DDIs.

Monitoring adverse events of the vaccination campaign against influenza A (H1N1) in the Netherlands.

BACKGROUND: In November 2009, a vaccination campaign against Influenza A (H1N1) was started in the Netherlands. The accelerated registration procedure of the vaccines used in this campaign and the use of these vaccines on a large scale indicated a need for real-time safety monitoring. OBJECTIVE: To describe the processing, analysing and performing of signal detection by the Netherlands Pharmacovigilance Centre (Lareb) on reports of adverse events following immunization (AEFI) with respect to the two pandemic influenza vaccines, Focetria® and Pandemrix®, used in the Netherlands. The secondary aim is to provide a summary of the results of the safety monitoring of both vaccines. STUDY DESIGN: Description of the process of collecting information and analysis of the safety monitoring of the pandemic vaccines during the vaccination campaign against H1N1 in the Netherlands. An observational study on adverse events following immunization (AEFIs) associated with vaccines used in this campaign was conducted. RESULTS: The use of a dedicated web form with predefined AEFIs enabled an efficient way of processing and analysing the reports, resulting in a close to real-time monitoring of the safety of the vaccines. From 1 November 2009 until 1 March 2010, 7534 reports concerning one or more AEFIs possibly related to the administration of both vaccines were received. 2788 of the reports related to Focetria® and 4746 of the reports related to Pandemrix®. The total time between receiving the reports and completion was longer for the serious reports (average 2.8 days) compared with the non-serious reports (average 0.8 days). The profile of the reported adverse events is comparable with the information provided in the Summary of Product Characteristics (SPC). Differences in reported AEFIs between both vaccines may be caused by bias and confounding due to the different populations for which these vaccines have been used. No signals of possible batch-related problems were detected for either vaccine. CONCLUSIONS: The method applied allowed for real-time monitoring for AEFIs during the mass vaccination campaign. The use of web-based forms, preferably with information on venue and used batch numbers, enabled an efficient monitoring of possible batch-related problems. No major safety issues occurred with respect to the type of reported AEFIs, or with the batches of either vaccine.

Endoscopic sedation and monitoring practice in Germany: results from the first nationwide survey.

BACKGROUND AND AIMS: The use of sedation (e. g., of short-acting propofol) for gastrointestinal endoscopy has shown an upward trend in the United States and Europe over the last decade. This survey aimed at providing nationwide data on the current practice of endoscopic sedation and monitoring in Germany. METHODS: A 21-item survey regarding current practices of endoscopy, sedation and monitoring in gastrointestinal endoscopy was sent to 3 802 members of the German Society of Digestive and Metabolic Diseases (DGVS). RESULTS: A total of 1 061 / 3 802 (28%) questionnaires were returned. The respondents performed an average of 28 esophagogastro-duodenoscopies (EGDs) and 25 colonoscopies per week. Endoscopic procedures were staged in a hospital setting (60%) more often than in private practices (40%). The majority of the EGDs (74%) and colonoscopies (87%) were carried out under sedation, however, this fact may be influenced by a recall bias. The most frequently used agents for sedation were midazolam in 82% and propofol in 74% of the cases. The most common sedation regimens applied were propofol plus benzodiazepines (38%) and benzodiazepines with an opioid (35%). Patients were routinely monitored by pulse oximetry (97%), automated blood pressure readings (29%) and/or electrocardiography (13%). Supplemental oxygen was routinely administered in 34% of them. Endoscopists' satisfaction with sedation was greater among those using propofol than in the group applying benzodiazepines (visual analogue scale, 8.8 +/- 0.9 vs. 8.2 +/- 1.3, p < 0.0001). CONCLUSION: Besides the common administration of short-acting benzodiazepines, sedation with propofol is also gaining ground in Germany; it is applied mainly in low doses (up to 150 mg). German endoscopists are highly satisfied with these sedation regimens, with propofol significantly leading the score. Patient monitoring predominantly follows currently prevailing guidelines.

Baseline laboratory monitoring of cardiovascular medications in elderly health maintenance organization enrollees.

OBJECTIVES: To identify correlates of laboratory monitoring errors in elderly health maintenance organization (HMO) members at the initiation of therapy with cardiovascular medications. DESIGN: Cross-sectional study in 10 HMOs. SETTING: United States. PARTICIPANTS: From a 2 million-member sample, individuals aged 65 and older who received one of seven cardiovascular medications (angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), amiodarone, digoxin, diuretics, potassium supplements, and statins) and did not have recommended baseline monitoring performed during the 180 days before or 14 days after the index dispensing. MEASUREMENTS: The proportion of members receiving each drug for whom recommended laboratory monitoring was not performed. Laboratory monitoring error rates stratified by sex, age group, chronic disease score, and HMO site were examined, and logistic regression was used to identify predictors of laboratory monitoring errors. RESULTS: Error rates varied by medication class, ranging from 23% of patients receiving potassium supplementation without serum potassium and serum creatinine monitoring to 58% of patients receiving amiodarone who did not have recommended monitoring for thyroid and liver function. Highest error rates occurred in the youngest elderly for ACE inhibitors, ARBs, digoxin, diuretics, and potassium supplements, although in patients receiving amiodarone and statins, errors were most frequent in the oldest elderly. Errors occurred more frequently in patients with less comorbidity. CONCLUSION: Laboratory monitoring errors occurred frequently in elderly HMO members at the initiation of therapy with cardiovascular medications. Further study must examine the association between these errors and adverse outcomes.

Development of population pharmacokinetic models and optimal sampling times for ibuprofen tablet and suspension formulations in children with cystic fibrosis.

High-dose ibuprofen therapy has demonstrated to slow deterioration in pulmonary function in children with cystic fibrosis with mild lung disease. Therapeutic drug monitoring has been recommended to maintain peak concentrations within the range of 50 to 100 mg/L to ensure efficacy. Current methods for dosage individualization are based on dose proportionality using visual inspection of the peak concentration; however, because of interpatient variability in the absorption of the various formulations this method may result in incorrect assessments of the peak concentration achieved. Maximum a posteriori Bayesian analysis (MAP-B) has proven to be a useful and precise method of individualizing the dose of aminoglycosides but requires a description of the structural model. In this study we performed parametric population modeling analysis on plasma concentrations of ibuprofen after single doses of 20 to 30-mg/kg tablet or suspension in children with cystic fibrosis. Patients evaluated in this study were part of a single dose pharmacokinetic study that has been published previously. A one-compartment model with first order absorption and a lag time best described the data. The pharmacokinetic parameters differed significantly depending on the formulation administered. D-optimal sampling times for the suspension and tablet formulations are 0, 0.25 to 0.5, 1, and 3 to 4 hours and 0, 0.25 to 0.5, 1 to 1.5, and 5 hours respectively. Use of MAP-B analysis performed with the 4 d-optimal sampling strategy resulted in accurate and precise estimates of the pharmacokinetic parameters when compared with maximum likelihood analysis using the complete plasma concentrations data set. Further studies are needed to evaluate the performance of these models and the impact on patient outcomes.