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Background pharmacological therapy in the ANTHEM-HF: comparison to contemporary trials of novel heart failure therapies.
Premchand, RK, Sharma, K, Mittal, S, Monteiro, R, Libbus, I, Ardell, JL, Gregory, DD, KenKnight, BH, Amurthur, B, DiCarlo, LA, et al
ESC heart failure. 2019;(5):1052-1056
Abstract
AIMS: Clinical trials of new heart failure (HF) therapies administer guideline-directed medical therapy (GDMT) as background pharmacologic treatment (BPT). In the ANTHEM-HF Pilot Study, addition of autonomic regulation therapy to GDMT significantly improved left ventricular function, New York Heart Association (NYHA) class, 6 min walk distance, and quality of life in patients with HF with reduced ejection fraction (HFrEF). A post hoc analysis was performed to compare BPT in ANTHEM-HF with two other trials of novel HF therapies: the PARADIGM-HF study of sacubitril-valsartan and the SHIFT study of ivadrabine. All three studies evaluated patients with HFrEF, and the recommendations for use of GDMT were similar. A left ventricular ejection fraction ≤40% was required for entry into ANTHEM-HF and PARADIGM-HF and ≤35% for SHIFT. NYHA 2 or 3 symptoms were required for entry into ANTHEM-HF, and patients with predominantly NYHA 2 or 3 symptoms were enrolled in PARADIGM-HF and SHIFT. METHODS AND RESULTS Data on BPT were obtained from peer-reviewed publications and the public domain. Pearson's χ2 test was used to evaluate differences in proportions, and Student's unpaired t-test was used to evaluate differences in mean values. The minimum period of stable GDMT required before randomization was longer in ANTHEM-HF: 3 months vs. 1 month in PARADIGM-HF and SHIFT, respectively. When compared with PARADIGM-HF and SHIFT, more patients in ANTHEM-HF received beta-blockers (100% vs. 93% and 89%, P < 0.04 and P < 0.007) and mineralocorticoid receptor antagonists (75% vs. 55% and 61%, P < 0.002 and P < 0.03). More patients in PARADIGM-HF received an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker than in ANTHEM-HF or SHIFT (100% vs. 85%, P < 0.0001, and 100% vs. 91%, P < 0.001), which was related to PARADIGM's design. When beta-blocker doses in ANTHEM-HF and SHIFT were compared, significantly fewer patients in ANTHEM-HF received doses ≥100% of target (10% vs. 23%, P < 0.02), and fewer patients tended to receive doses ≥50% of target (17% vs. 26%, P = 0.11). When ANTHEM-HF and PARADIGM-HF were compared, more patients in ANTHEM-HF tended to receive doses ≥100% of target (10% vs. 7%, P = 0.36), and fewer patients tended to receive doses ≥50% of target (17% vs. 20%, P = 0.56). CONCLUSIONS Background treatment with GDMT in ANTHEM-HF compared favourably with that in two other contemporary trials of new HF therapies. The minimum period of stable GDMT required before randomization was longer, and GDMT remained unchanged for the study's duration. These findings serve to further support the potential role of autonomic regulation therapy as an adjunct to GDMT for patients with HFrEF.
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Development of a computer-interpretable clinical guideline model for decision support in the differential diagnosis of hyponatremia.
González-Ferrer, A, Valcárcel, MÁ, Cuesta, M, Cháfer, J, Runkle, I
International journal of medical informatics. 2017;:55-64
Abstract
INTRODUCTION Hyponatremia is the most common type of electrolyte imbalance, occurring when serum sodium is below threshold levels, typically 135mmol/L. Electrolyte balance has been identified as one of the most challenging subjects for medical students, but also as one of the most relevant areas to learn about according to physicians and researchers. We present a computer-interpretable guideline (CIG) model that will be used for medical training to learn how to improve the diagnosis of hyponatremia applying an expert consensus document (ECDs). METHODS We used the PROForma set of tools to develop the model, using an iterative process involving two knowledge engineers (a computer science Ph.D. and a preventive medicine specialist) and two expert endocrinologists. We also carried out an initial validation of the model and a qualitative post-analysis from the results of a retrospective study (N=65 patients), comparing the consensus diagnosis of two experts with the output of the tool. RESULTS The model includes over two-hundred "for", "against" and "neutral" arguments that are selectively triggered depending on the input value of more than forty patient-state variables. We share the methodology followed for the development process and the initial validation results, that achieved a high ratio of 61/65 agreements with the consensus diagnosis, having a kappa value of K=0.86 for overall agreement and K=0.80 for first-ranked agreement. CONCLUSION Hospital care professionals involved in the project showed high expectations of using this tool for training, but the process to follow for a successful diagnosis and application is not trivial, as reported in this manuscript. Secondary benefits of using these tools are associated to improving research knowledge and existing clinical practice guidelines (CPGs) or ECDs. Beyond point-of-care clinical decision support, knowledge-based decision support systems are very attractive as a training tool, to help selected professionals to better understand difficult diseases that are underdiagnosed and/or incorrectly managed.
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Evaluation of Chronic Obstructive Pulmonary Disease (COPD) and reduced ejection fraction heart failure (HFrEF) discharge medication prescribing: Is drug therapy concordant with national guidelines associated with a reduction in 30-day readmissions?
Richardson, A, Tolley, E, Hartmann, J, Reedus, J, Bowlin, B, Finch, C, Sands, CW, Self, T
Respiratory medicine. 2016;:135-140
Abstract
INTRODUCTION Approximately 1 in 5 hospitalized COPD patients are readmitted within 30 days of discharge. CHF coexists in more than 20% of patients with COPD, and is associated with early readmission for COPD. Reducing 30-day hospital readmissions for COPD is of intense current interest. METHODOLOGY A retrospective chart review was performed to identify patients discharged with COPD exacerbation and HFrEF. The primary objective was to evaluate if discharge medication prescribing following guidelines for both COPD and HFrEF correlates with reduced 30-day readmission rates. RESULTS The study included 281 admissions with 39.1% prescribed appropriate discharge medications for both COPD and HFrEF; 30-day readmission rate was 24.5% for these patients compared to 31.1% that were not prescribed appropriate medications (p = 0.24). Beta blockers, ACE inhibitors or ARBS, and aldosterone antagonists were under-prescribed, but this did not significantly associate with increased readmission (p = 0.51, p = 0.23 or 0.99, and p = 0.18, respectively). Those prescribed hydralazine or nitrates were more likely to readmit (both p = 0.01). Diabetes and hyperlipidemia were associated with increased readmission (p = 0.01 and 0.05). CONCLUSIONS This study did not show a significant difference in 30-day readmission rate based on appropriate discharge medications for both COPD and HFrEF. The comorbidities diabetes and hyperlipidemia and prescription of hydralazine or nitrates were significantly associated with increased readmission rate. Larger patient populations may be needed to assess if guideline based discharge medication prescribing is associated with reduced 30-day readmissions for COPD.
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Pharmacokinetics of isoniazid, rifampin, and pyrazinamide in children younger than two years of age with tuberculosis: evidence for implementation of revised World Health Organization recommendations.
Thee, S, Seddon, JA, Donald, PR, Seifart, HI, Werely, CJ, Hesseling, AC, Rosenkranz, B, Roll, S, Magdorf, K, Schaaf, HS
Antimicrobial agents and chemotherapy. 2011;(12):5560-7
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Abstract
The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dosage recommendations for children. No pharmacokinetic studies for these revised dosages are available for children <2 years. The aim of the study was to document the pharmacokinetics of the first-line anti-TB agents in children <2 years of age comparing previous and revised WHO dosages of isoniazid (INH; 5 versus 10 mg/kg/day), rifampin (RMP; 10 versus 15 mg/kg/day), and pyrazinamide (PZA; 25 versus 35 mg/kg/day) and to investigate the effects of clinical covariates, including HIV coinfection, nutritional status, age, gender, and type of tuberculosis (TB), and the effect of NAT2 acetylator status. Serum INH, PZA, and RMP levels were prospectively assessed in 20 children <2 years of age treated for TB following the previous and the revised WHO dosage recommendations. Samples were taken prior to dosing and at 0.5, 1.5, 3, and 5 h following dosing. The maximum drug concentration in serum (C(max)), the time to C(max) (t(max)), and the area under the concentration-time curve (AUC) were calculated. Eleven children had pulmonary and 9 had extrapulmonary TB. Five were HIV infected. The mean C(max) (μg/ml) following the administration of previous/revised dosages were as follows: INH, 3.19/8.11; RMP, 6.36/11.69; PZA, 29.94/47.11. The mean AUC (μg·h/ml) were as follows: INH, 8.09/20.36; RMP, 17.78/36.95; PZA, 118.0/175.2. The mean C(max) and AUC differed significantly between doses. There was no difference in the t(max) values achieved. Children less than 2 years of age achieve target concentrations of first-line anti-TB agents using revised WHO dosage recommendations. Our data provided supportive evidence for the implementation of the revised WHO guidelines for first-line anti-TB therapy in young children.