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Home Management of Warfarin Treatment Through a Real-Time Supervised Telemedicine Solution: A Randomized Controlled Trial.
Brasen, CL, Madsen, JS, Parkner, T, Brandslund, I
Telemedicine journal and e-health : the official journal of the American Telemedicine Association. 2019;(2):109-115
Abstract
BACKGROUND Many patients are undergoing oral anticoagulation treatment with vitamin K antagonists, which necessitates measuring international normalized ratio (INR) several times each month. INTRODUCTION Patients can learn to measure their INR at home and choose their own dose for the next period with potential gains in treatment quality and reduced healthcare expenses. This is, however, connected to the potential problem of losing tight external control of the patient treatment. MATERIALS AND METHODS We performed a randomized controlled trial using the telemedicine software CSO/AC together with the INR point-of-care-test CoaguChek XS for 10 months to investigate the use of criteria-driven healthcare interactions. A total of 87 patients were divided into two groups. The patient self-management (PSM) group was surveilled using the criteria INR <1.8, INR >4.5, change in warfarin/week >1.25 mg, missing INR or dosage. The patient self-testing (PST) group was handled as routine care. RESULTS A total of 84 patients were followed for 10 months. No differences were seen in average INR or fraction of INR in therapeutic range (2-3) in the two groups or the start compared with the end. The PST group was handled using 4.2 interactions per month whereas the PSM group used 1.1 interactions per month. No adverse effects of PSM were observed. DISCUSSION Using criteria-driven interactions enabled a considerable reduction in interactions per month. The two groups were comparable in terms of treatment effect and safety. CONCLUSIONS Using criteria to guide PSM interactions maintains good treatment effect while reducing healthcare expenses.
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A Randomized, Placebo-Controlled, Double-Blind Crossover Study to Assess a Unique Phytosterol Ester Formulation in Lowering LDL Cholesterol Utilizing a Novel Virtual Tracking Tool.
Reaver, A, Hewlings, S, Westerman, K, Blander, G, Schmeller, T, Heer, M, Rein, D
Nutrients. 2019;(9)
Abstract
Elevated blood concentration of low-density lipoprotein cholesterol (LDLc) is a primary risk factor for developing cardiovascular disease. Lifestyle interventions including an increase in dietary phytosterols as well as medications have proven effective in lowering LDLc. The primary objective of this randomized, placebo controlled, double blind, crossover study was to determine the impact of a new phytosterol emulsion for dietary supplements (1.5 g/day phytosterol equivalents) on LDLc concentrations. Thirty-two healthy adults were randomly assigned to receive placebo or treatment followed by a washout period, followed by placebo or treatment, each phase lasting one month. Secondary endpoints related to cardiovascular health were also assessed. Study management, including screening, recruitment, monitoring, compliance, and data collection, were done remotely (a siteless clinical trial) utilizing a novel virtual tool. Phytosterol supplementation significantly lowered LDLc concentrations by 10.2% (16.17 mg/dL or 0.419 mmol/L, p = 0.008 by paired t-test, p = 0.014 by Wilcoxon signed rank testing). No secondary biomarkers were found to change significantly. Supplementation with phytosterols in a new dietary supplement formulation efficiently and safely decreases LDLc within one month in a free-living setting.
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Clinically Relevant Drug-Drug Interactions in Primary Care.
Carpenter, M, Berry, H, Pelletier, AL
American family physician. 2019;(9):558-564
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Abstract
Drug interactions are common in the primary care setting and are usually predictable. Identifying the most important and clinically relevant drug interactions in primary care is essential to patient safety. Strategies for reducing the risk of drug-drug interactions include minimizing the number of drugs prescribed, re-evaluating therapy on a regular basis, considering nonpharmacologic options, monitoring for signs and symptoms of toxicity or effectiveness, adjusting dosages of medications when indicated, and adjusting administration times. Inhibition or induction of cytochrome P450 drug metabolizing isoenzymes is the most common mechanism by which clinically important drug interactions occur. The antimicrobials most likely to affect the international normalized ratio significantly in patients receiving warfarin are trimethoprim/sulfamethoxazole, metronidazole, and fluconazole. An empiric warfarin dosage reduction of 30% to 50% upon initiation of amiodarone therapy is recommended. In patients receiving amiodarone, limit dosages of simvastatin to 20 mg per day and lovastatin to 40 mg per day. Beta blockers should be tapered and discontinued several days before clonidine withdrawal to reduce the risk of rebound hypertension. Spironolactone dosages should be limited to 25 mg daily when coadministered with potassium supplements. Avoid prescribing opioid cough medicines for patients receiving benzodiazepines or other central nervous system depressants, including alcohol. Physicians should consider consultation with a clinical pharmacist when clinical circumstances require the use of drugs with interaction potential.
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Optimal Sampling Strategies for Therapeutic Drug Monitoring of First-Line Tuberculosis Drugs in Patients with Tuberculosis.
Saktiawati, AMI, Harkema, M, Setyawan, A, Subronto, YW, Sumardi, , Stienstra, Y, Aarnoutse, RE, Magis-Escurra, C, Kosterink, JGW, van der Werf, TS, et al
Clinical pharmacokinetics. 2019;(11):1445-1454
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Abstract
BACKGROUND The 24-h area under the concentration-time curve (AUC24)/minimal inhibitory concentration ratio is the best predictive pharmacokinetic/pharmacodynamic (PK/PD) parameter of the efficacy of first-line anti-tuberculosis (TB) drugs. An optimal sampling strategy (OSS) is useful for accurately estimating AUC24; however, OSS has not been developed in the fed state or in the early phase of treatment for first-line anti-TB drugs. METHODS An OSS for the prediction of AUC24 of isoniazid, rifampicin, ethambutol and pyrazinamide was developed for TB patients starting treatment. A prospective, randomized, crossover trial was performed during the first 3 days of treatment in which first-line anti-TB drugs were administered either intravenously or in fasting or fed conditions. The PK data were used to develop OSS with best subset selection multiple linear regression. The OSS was internally validated using a jackknife analysis and externally validated with other patients from different ethnicities and in a steady state of treatment. RESULTS OSS using time points of 2, 4 and 8 h post-dose performed best. Bias was < 5% and imprecision was < 15% for all drugs except ethambutol in the fed condition. External validation showed that OSS2-4-8 cannot be used for rifampicin in steady state conditions. CONCLUSION OSS at 2, 4 and 8 h post-dose enabled an accurate and precise prediction of AUC24 values of first-line anti-TB drugs in this population. TRIAL REGISTRATION ClinicalTrials.gov (NCT02121314).
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Oral anticoagulant monitoring: Are we on the right track?
Onundarson, PT, Flygenring, B
International journal of laboratory hematology. 2019;:40-48
Abstract
Vitamin K antagonists (VKAs) cannot be administered without regular monitoring in order to assure their efficacy and safety. Indeed, if well managed, the VKAs appear to be no less efficacious or safe than the newer direct oral anticoagulants (DOACs). Although it is claimed that no regular monitoring of the DOACs is needed, their levels are increasingly being measured under a variety of circumstances, for example, prior to surgery, in suspected overdose, to confirm effective reversal, in patients with malabsorption and to assess patient compliance. Although no therapeutic range has been identified for the DOACs, it has been demonstrated for dabigatran and edoxaban that their antithrombotic effect increases gradually with increasing concentrations and that the risk of major bleeding also gradually increases. Furthermore, it has been determined that almost all dabigatran-related thrombotic events occur in patients with the lowest quartile concentration of the drug. This suggests that to assure an ideal effect of DOACs in all patients taking them, some form of regular monitoring and dose tailoring should be performed. For the vitamin K antagonists, the best outcome is obtained using formal algorithms and centralized management. Furthermore, data suggest that replacing the standard prothrombin time as a monitoring test may increase the stability of VKA anticoagulation with consequent reduction in thromboembolism without an increase in bleeding. Thus, it is likely that the outcome of all current oral anticoagulants can be improved in the coming years by improving monitoring and tailoring their effect.
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Pharmacokinetic Drug Interactions Between Amlodipine, Valsartan, and Rosuvastatin in Healthy Volunteers.
Seong, SJ, Ohk, B, Kang, WY, Gwon, MR, Kim, BK, Cho, S, Yang, DH, Lee, HW, Yoon, YR
Advances in therapy. 2019;(7):1642-1656
Abstract
INTRODUCTION Amlodipine, valsartan, and rosuvastatin are among the medications widely coadministered for the treatment of hyperlipidemia accompanied by hypertension. The aim of this study was to investigate the possible pharmacokinetic drug-drug interactions between amlodipine, valsartan, and rosuvastatin in healthy Korean male volunteers. METHODS In this phase 1, open-label, multiple-dose, two-part, two-period, fixed-sequence study, the enrolled subjects were randomized into two parts (A and B). In part A (n = 32), each subject received one fixed-dose combination (FDC) tablet of amlodipine/valsartan 10 mg/160 mg alone for 10 consecutive days in period I, and the same FDC for 10 days with concomitant 7-day administration of 20 mg rosuvastatin in period II. In part B (n = 25), each subject received rosuvastatin alone for 7 days in period I, and the FDC for 10 days with concomitant 7-day administration of rosuvastatin in period II. In both parts, there was a 12-day washout between periods. Serial blood samples were collected for up to 72 h for amlodipine and rosuvastatin, and for up to 48 h for valsartan after the last dose of each period. The plasma concentrations of amlodipine, valsartan, and rosuvastatin were determined by using liquid chromatography-tandem mass spectrometry. RESULTS Fifty-seven subjects were enrolled; 30 and 25 subjects completed part A and part B, respectively. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration at steady state (Cmax,ss) and the area under the plasma concentration-time curve over the dosing interval at steady state (AUCτ,ss) were 0.9389 (0.9029-0.9763) and 0.9316 (0.8970-0.9675) for amlodipine, 0.7698 (0.6503-0.9114) and 0.7888 (0.6943-0.8962) for valsartan, and 0.9737 (0.8312-1.1407) and 0.9596 (0.8826-1.0433) for rosuvastatin, respectively. Of the 57 subjects enrolled in this study, 10 subjects experienced 13 adverse events (AEs); no severe or serious AEs were reported. CONCLUSION When amlodipine, valsartan, and rosuvastatin were coadministered to healthy volunteers, the pharmacokinetic exposure to valsartan was decreased, but no change in exposure to amlodipine and rosuvastatin occurred. All treatments were well tolerated. CLINICAL TRIAL REGISTRATION https://cris.nih.go.kr CRIS KCT0001660. FUNDING KyungDong Pharmaceutical Corp. Ltd., Seoul, Republic of Korea.
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Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn's Disease Compared With Reactive Monitoring.
Assa, A, Matar, M, Turner, D, Broide, E, Weiss, B, Ledder, O, Guz-Mark, A, Rinawi, F, Cohen, S, Topf-Olivestone, C, et al
Gastroenterology. 2019;(4):985-996.e2
Abstract
BACKGROUND & AIMS Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD). METHODS We performed a nonblinded, randomized controlled trial of 78 children with CD (6-18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n = 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n = 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 μg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72). RESULTS The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P = .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 μg/g compared with 5 patients in the reactive monitoring group (12%) (P = .003). By week 72 of treatment, 33 patients in the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patients in the reactive monitoring group (60%) (P = .001). CONCLUSIONS In a randomized controlled trial of pediatric patients with CD, we found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462.
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Use of (1→3)-β-d-glucan for diagnosis and management of invasive mycoses in HIV-infected patients.
Farhour, Z, Mehraj, V, Chen, J, Ramendra, R, Lu, H, Routy, JP
Mycoses. 2018;(10):718-722
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Abstract
People living with HIV (PLHIV) are highly vulnerable to invasive fungal infections (IFIs) due to their immune dysfunction. Diagnosis and treatment of IFIs remain challenging due to the requirement of deep tissue sampling to visualise and culture fungi before initiating treatment. Such techniques are less practical in resource-limited settings due to their cost and requirement of relatively invasive procedures. Hence, identification of surrogate markers for the early diagnosis and therapeutic monitoring of IFIs is required. Recent studies have shown that (1→3)-β-d-glucan (BDG), a major fungal cell wall antigen, represents a promising soluble marker for the presumptive diagnosis and therapeutic monitoring of IFIs in HIV-infected patients. Herein, we review findings on the merits of BDG assays in the diagnosis of IFIs and monitoring of antifungal therapies for PLHIV. Conversely to other types of immunocompromised patients, HIV infection is associated with gut damage and subsequent bacterial and fungal translocation leading to elevated BDG plasma levels.
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Real-Life Use of Neurohormonal Antagonists and Loop Diuretics in Chronic Heart Failure: Analysis of Serial Biomarker Measurements and Clinical Outcome.
Brankovic, M, Akkerhuis, KM, van Boven, N, Manintveld, O, Germans, T, Brugts, J, Caliskan, K, Umans, V, Constantinescu, A, Kardys, I
Clinical pharmacology and therapeutics. 2018;(2):346-355
Abstract
We determined the temporal effects of neurohormonal antagonists and loop diuretics on serially assessed (3-monthly) cardiorenal biomarkers, functional status, and clinical outcomes in 250 patients with chronic heart failure (CHF) with reduced ejection fraction. In blood, we measured NT-proBNP, troponin T, C-reactive protein, creatinine, cystatin C; in urine, N-acetyl-beta-d-glucosaminidase and kidney-injury-molecule-1. Angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) were inversely associated with cardiac impairment, inflammation, and renal tubular damage, but not with glomerular dysfunction. Diuretics were associated with worse biomarker profiles and with a hazard ratio for adverse clinical outcome of 1.12 (95% confidence interval: 1.03-1.22) per 40 mg higher doses. ACE-inhibitors/ARBs were more frequently downtitrated and diuretics more frequently uptitrated in patients who experienced endpoints than in those who did not. In conclusion, a decrease or withholding of ACE-inhibitors/ARBs solely based on glomerular function is not justified because of the beneficial effects on the heart, inflammation, and renal tubules. Higher and increased diuretic doses mark progression towards endstage CHF.
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Quality of life in children participating in a non-selective INR self-monitoring VKA-education programme.
Amedro, P, Bajolle, F, Bertet, H, Cheurfi, R, Lasne, D, Nogue, E, Auquier, P, Picot, MC, Bonnet, D
Archives of cardiovascular diseases. 2018;(3):180-188
Abstract
BACKGROUND The quality of life (QoL) of children receiving vitamin K antagonist (VKA) treatment has been scarcely studied. AIM: To assess QoL of children, and its evolution, throughout our non-selective international normalized ratio (INR) self-monitoring education programme. METHODS Children and parents completed QoL questionnaires (Qualin, PedsQL) during education sessions. Scores were compared with those from controls. RESULTS A total of 111 children (mean±standard deviation age 8.7±5.4 years) were included over a 3-year period. Indications for VKA treatment were congenital heart diseases (valve replacement [42.3%], total cavopulmonary connection [29.7%]), myocardiopathy (11.7%), coronary aneurysm (7.2%), venous/intracardiac thrombosis (4.5%), pulmonary artery hypertension (1.8%), arrhythmia (0.9%) and extra-cardiac disease (1.8%). Eighty children, 105 mothers and 74 fathers completed the QoL questionnaires. QoL was good among children aged 1-4 years and moderately impaired in those aged between 5 and 18 years. There was no significant relationship between self-reported QoL and patient's sex, type of VKA, number of group sessions attended, disease duration or time of diagnosis (prenatal or postnatal). QoL scores were significantly lower among children with congenital heart diseases compared with other diseases. There were few differences in QoL between children under transient VKA treatment and those treated for life. Parental proxy QoL scoring correlated well with but was significantly lower than child self-assessments. QoL reported by mothers increased throughout the education programme, independently of any improvement of the health condition. CONCLUSIONS This QoL study provides original data from a large cohort of children and their parents participating in a formalized INR self-monitoring education programme for VKA treatment.