Noninferiority and Safety of Nadolol vs Propranolol in Infants With Infantile Hemangioma: A Randomized Clinical Trial.

Importance: Propranolol for infantile hemangiomas (IH) has been shown to be effective and relatively safe. However, other less lipophilic ß-blockers, such as nadolol, may be preferable in individuals who experience propranolol unresponsiveness or adverse events. Objective: To document the noninferiority and safety of oral nadolol compared with oral propranolol in infants with IH. Design, Setting, and Participants: This double-blind noninferiority prospective study with a noninferiority margin of 10% compared propranolol with nadolol in infants aged 1 to 6 months with problematic IH. The study was conducted in 2 academic pediatric dermatology centers in Canada between 2016 and 2020. Infants aged 1 to 6 months with a hemangioma greater than 1.5 cm on the face or 3 cm or greater on another body part causing or with potential to cause functional impairment or cosmetic disfigurement. Interventions: Oral propranolol and nadolol in escalating doses up to 2 mg/kg/d. Main Outcomes and Measure: Between-group differences comparing changes in the bulk (size and extent) and color of the IH at week 24 with baseline using a 100-mm visual analog scale. Results: The study included 71 patients. Of these, 36 were treated with propranolol. The mean (SD) age in this group was 3.1 (1.4) months, and 31 individuals (86%) were female. Thirty-five infants were treated with nadolol. The mean (SD) age in this group was 3.2 (1.6) months, and 26 individuals (74%) were female. The difference in IH between groups by t test was 8.8 (95% CI, 2.7-14.9) for size and 17.1 (95% CI, 7.2-30.0) for color in favor of the nadolol group, demonstrating that nadolol was noninferior to propranolol. Similar differences were noted at 52 weeks: 6.0 (95% CI, 1.9-10.1) and 10.1 (95% CI, 2.9-17.4) for size and color improvement, respectively. For each doubling of time unit (week), the coefficient of involution was 2.4 (95% CI, 0.5-4.4) higher with nadolol compared with propranolol. Safety data were similar between the 2 interventions. Conclusions and Relevance: Oral nadolol was noninferior to oral propranolol, indicating it may be an efficacious and safe alternative in cases of propranolol unresponsiveness or adverse events, or when faster involution is required. Trial Registration: ClinicalTrials.gov Identifier: NCT02505971.

Beta-blocker choice and exchangeability in patients with heart failure and chronic obstructive pulmonary disease: an Italian register-based cohort study.

Clinical guidelines suggest that for patients with heart failure and concurrent chronic obstructive pulmonary disease (COPD), metoprolol/bisoprolol/nebivolol should be preferred over carvedilol. However, studies suggest a high proportion of carvedilol usage that remains unexplained. Therefore, we aimed to investigate the predictors of carvedilol choice in patients with heart failure and COPD that were naïve to carvedilol or metoprolol/bisoprolol/nebivolol. Caserta Local Health Unit databases (Italy) were used as data sources. Age, sex, chronic/acute comorbidities, and co-medications were included in a logistic regression model to assess predictors of carvedilol choice. Chronic comorbidities include those defined in the Elixhauser comorbidity index and all hospitalizations within two years prior to the first beta-blocker prescription. Comedications include all redeemed prescriptions within one year prior to the beta-blocker prescription. Kernel density estimations were used to assess the overlap in propensity and preference scores distributions for receiving carvedilol and thereby potential beta-blocker exchangeability. Totally, 10091 patients composed the study population; 2011 were exposed to carvedilol. The overlapping of propensity scores distributions was 57%. Accordingly, the exchangeability was not reached. Atrioventricular block (Odds Ratio, OR 8.20; 95% Confidence Interval, 95% CI 1.30-51.80), cerebrovascular thrombosis (OR 7.06; 95% CI 1.14-43.68), chronic kidney disease (OR 4.32; 95% CI 1.16-16.02), and acute heart failure (OR 1.97; 95% CI 1.28-3.03) hospitalizations were statistically significantly associated with carvedilol choice. Analogously, human insulin (OR 3.00; 95% CI 1.24-7.24), fondaparinux (OR 2.47; 95% CI 1.17-5.21) or strontium ranelate (OR 2.03; 95% CI 1.06-3.90) redeemed prescriptions. In conclusion, this study suggests the absence of beta-blockers exchangeability and a preferential choice of carvedilol in patients with heart failure, COPD and concurrent chronic kidney disease, atrioventricular block, cerebrovascular thrombosis, acute heart failure or redeeming human insulin, fondaparinux or strontium ranelate prescriptions. Therefore, it suggests that choice of prescribing carvedilol over metoprolol/bisoprolol/nebivolol is driven by differences in comorbidities and co-treatments.

Validity of Performance and Outcome Measures for Heart Failure.

Background Numerous quality metrics for heart failure (HF) care now exist based on process and outcome. What remains unclear, however, is if the correct quality metrics are being emphasized. To determine the validity of certain measures, we compared correlations between measures and reliability over time. Measures assessed include guideline-recommended ß-blocker (BB), any BB, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker, mineralocorticoid receptor antagonist, and hydralazine/isosorbide dinitrate (in blacks) use among candidates, 30-day mortality, 1-year mortality, and 30-day readmission. Methods and Results This was an observational cohort analysis using chart review and electronic resources for 55 735 patients from 102 Veterans Affairs medical centers hospitalized with HF from 2008 to 2013. Assessments of convergent validity and reliability were performed. Significant correlations were found between in-hospital rates of ACE inhibitor use and the following measures: BB use, 30-day mortality, and 1-year mortality. Guideline-recommended BB use was also significantly correlated with mineralocorticoid receptor antagonists, 30-day mortality, and 1-year mortality. There was no correlation between 30-day readmission rates and any therapy or mortality. Measure reliability over time was seen for guideline-recommended BBs ( r=0.57), mineralocorticoid receptor antagonists ( r=0.50), 30-day mortality ( r=0.29), and 1-year mortality ( r=0.31). ACE inhibitor and readmission rates were not reliable measures over time. Conclusions BB use, ACE inhibitor use, mortality, and mineralocorticoid receptor antagonist use are valid measures of HF quality. Thirty-day readmission rate did not seem to be a valid measure of HF quality of care. If the goal is to identify high-quality HF care, the emphasis on decreasing readmission rates might be better directed towards improving usage of the recommended therapies.

Beta-blockers in patients with advanced liver disease: Has the dust settled?

Nonselective beta-blockers (NSBBs) have been the backbone for the treatment of portal hypertension in cirrhosis for the last 3 decades. A publication in 2010 of a prospective observational study suggested that NSBBs could increase mortality in patients with refractory ascites. This opened a controversy about the safety and efficacy of NSBBs in patients with advanced liver disease and led to the publication of a large corpus of observational data assessing the safety of NSBBs in patients with advanced cirrhosis. In this article, we briefly review the clinical pharmacology of NSBBs, the pathophysiological basis for the underlying benefits and harms of NSBBs in advanced cirrhosis, and the evidence in favor and against the use of NSBBs in specific scenarios. Finally, we summarize the current recommendations and propose areas of opportunity for future research. Liver Transplantation 23 1058-1069 2017 AASLD.

Application of a colorimetric technique in quality control for printed pediatric orodispersible drug delivery systems containing propranolol hydrochloride.

The feasibility of a colorimetric technique was investigated in CIELAB color space as an analytical quality control method for content uniformity of printed orodispersible pediatric delivery systems. Inkjet printing was utilized to fabricate orodispersibe film formulations containing propranolol hydrochloride in a colored ink base using three different edible substrates. A thin sweetener coating layer of saccharin was successfully included in the final dosage forms for palatability purposes using a casting knife. Optical microscopy, scanning electron microscopy and scanning white light interferometry analyses were conducted to study the effect of printing on the surface morphology and topography of the substrates. Differential scanning calorimetry and attenuated total reflectance infrared spectroscopy were used to study the solid state properties and possible interactions between the drug and the excipients. The inkjet printing technique deposited precise and uniform escalating doses (0.08-3.16mg) of the active pharmaceutical ingredient onto the substrates (R(2)≥0.9934). A disintegration test with clear end-point detection confirmed that all the substrates meet the requirements of the Ph. Eur. to disintegrate within 180s. The colorimetric technique proved to be a reliable method to distinguish the small color differences between formulations containing an escalating dose of propranolol hydrochloride.

[Update on therapy of chronic heart failure. Innovations and studies from last year]. / Update zur Therapie der chronischen Herzinsuffizienz. Neue Erkenntnisse und Studien des letzten Jahres.

Chronic heart failure is one of the most common chronic diseases worldwide with increasing prevalence and incidence. Due to the high morbidity and mortality a standardized and evidence-based therapy is crucial. The present review article gives an overview about the innovations in 2014 based on the current guidelines of the European Society of Cardiology. First, improvements in established medication regimens regarding beta blockers and mineralocorticoid receptor antagonists as well as treatment options for heart rate reduction will be explained. Second, new pharmacological developments, such as angiotensin receptor neprilysin inhibition will be discussed. Finally, new insights into common comorbidities of patients with chronic heart failure, such as atrial fibrillation and hyperkalemia will be presented.

Neuroenhancement - perspectives of Swiss psychiatrists and general practitioners.

QUESTIONS UNDER STUDY: Although the ethical and health implications of neuroenhancement have been intensely discussed over the past years, little is known about the experiences and attitudes of physicians confronted with requests for neuroenhancing substances. The aim of this study was to explore general practitioners' and psychiatrists' familiarity with such requests and their willingness to prescribe these products. METHOD: A nation-wide cross-sectional survey among general practitioners and psychiatrists in Switzerland was conducted. A questionnaire was developed, pre-tested and sent out to a pre-defined sample of 1,600 Swiss practising physicians in the fields of psychiatry and general practice/internal medicine in the German-speaking and French-speaking part of Switzerland. RESULTS: A total of 393 questionnaires were returned (response rate: 24.7%). 80.2% of study participants were encountered requests for neuroenhancing products in their own practice, mostly not exceeding 1-2 times a year. A total of 41.1% were undecided when asked if they categorically against neuroenhancement, 49% would decide on a case-by-case basis, and 9.6% would decide according to patients' wishes. CONCLUSIONS: Swiss psychiatrists and general practitioners are confronted with requests for neuroenhancement, albeit not very frequently. Most participants embrace a pragmatic position towards neuroenhancement, although there is also a considerable degree of uncertainty about the appropriateness of a categorical refusal. A minority would follow a consumer model that leaves the decision about the use of neuroenhancers to the client, even though this conflicts with legal requirements regarding drug prescriptions.

ß-blocker withdrawal among patients presenting for surgery from home.

OBJECTIVE: This study sought to measure the prevalence of perioperative ß-blocker noncompliance by patients who were prescribed long-term ß-blocker therapy and presented for surgery from home. The effect of patient noncompliance on the presenting heart rate on the day of surgery also was examined. DESIGN: Prospective observational study with outcome data obtained from reviews of medical records. SETTING: The preoperative clinic and operating rooms of a Veterans Administration hospital. PARTICIPANTS: Patients on long-term ß-blocker therapy who presented from home for surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic and comorbidity data and data on self-reported compliance to ß-blocker therapy, vital signs on the initial day of surgery, and recent ambulatory vital signs were collected. Ten of 50 subjects (20%; 95% confidence interval, 9-31) reported not taking their ß-blocker on the day of surgery. These self-reported nonadherers exhibited a higher presenting heart rate on the day of surgery than adherent subjects (median, 78 v 65 beats/min; p = 0.02 by Wilcoxon rank-sum test). The difference-in-difference analysis in heart rate between baseline primary care and the day of surgery also was statistically significant between compliant and noncompliant subjects (-7 v + 12.5 beats/min; p < 0.00001). CONCLUSIONS: Patient self-report and physiologic data documented a failure to take ß-blockers and possible ß-blocker withdrawal in 20% of patients who presented for surgery from home. If these findings are confirmed in larger studies, improved patient understanding of and compliance with medication instructions during preoperative visits should be a focus of future quality improvement initiatives.

Tablet splitting: Product quality assessment of metoprolol succinate extended release tablets.

Metoprolol succinate extended release tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval. Despite the flexibility that controlled release pellets may offer, segregation is one of the challenges that commonly occur during tableting for such drug delivery system. Since all commercial metoprolol succinate extended release tablets are scored, they are deemed suitable for splitting. The present study was aimed at utilizing an innovative technology to determine the dose uniformity for split tablets. Four marketed drug products consisting of innovator and generics were evaluated for effect of splitting on weight, assay and content uniformity. Novel analytical tool such as near infrared (NIR) chemical imaging was used to visualize the distribution of metoprolol succinate and functional excipients on the surfaces of the marketed tablets. The non-homogeneous distribution of directly compressed metoprolol succinate beads on the surface of the tablets as well as the split intersection explained the large variation in the split tablets' weight and content uniformity results. The obtained results indicated the usefulness of NIR chemical imaging to determine the need for content uniformity studies for certain split tablets.

Determination of water quality standards for chemical mixtures: extension of a methodology developed for herbicides to a group of insecticides and a group of pharmaceuticals.

Monitoring surveys throughout America and Europe have demonstrated the widespread presence of organic synthetic substances such as pesticides and pharmaceuticals in surface water. To avoid deleterious effects on the aquatic system, many countries determine water quality criteria for pesticides. For each substance, the comparison of the concentration measured in water with its criterion gives an indication of the pressure this substance put on the aquatic system. However, in the environment, aquatic organisms are not only exposed to single pesticides but typically to mixtures of these substances. It is therefore of particular importance to take mixtures into account when defining water quality criteria, which is rarely done yet. We recently developed a method to define consistent and comparable water quality criteria for mixtures of herbicides having a similar mode of action. These criteria are calculated based on species sensitivity curves; the method assumes that these curves are parallel for substances having similar mode of action. The aim of this study was to apply our method to six organophosphates (insecticides) and to three ß-blockers (pharmaceuticals), other groups of compounds commonly detected in surface water. We found some evidence that the developed methodology gives consistent results for these groups too. The hypothesis of parallelism was accepted in 2/3 (ß-blockers) and 2/6 of the cases (organophosphates) for both species sensitivity curves based on effect concentrations 50% and on no-observed effect concentrations. The use of water quality criteria for mixture is illustrated by two case studies, which show the importance of taking mixtures into account in water quality legislation.

Guideline adherence for pharmacotherapy of chronic systolic heart failure in general practice: a closer look on evidence-based therapy.

BACKGROUND: There is robust evidence for effective pharmacotherapy of chronic (systolic) heart failure (CHF) which has led to the creation of guidelines, but many surveys evaluating CHF treatment show an under-utilisation of relevant drugs, while setting and patient population appear to be crucial for adequate appraisal of treatment patterns. AIMS: To evaluate the guideline adherence (GA) of general practitioners (GPs) in a well-defined patient population with CHF in primary care (PC). METHODS: A cross-sectional analysis was performed with the data of 167 patients enrolled in 37 GP practices (Germany) with documented left ventricular systolic dysfunction (LVEF: 33.3 +/- 6.9%). GA was assessed as usual (prescribing "yes" or "no"), through evaluation of target dosing, while adjusting for potential clinical contraindications, and through a modified Guideline Adherence Indicator-3 (mGAI-3), which assesses three relevant groups of substances according to New York Heart Association (NYHA) functional class: ACE-Inhibitors (ACE-I) or angiotensin receptor blockers (ARB), beta-blockers (BB) and aldosterone-antagonists (AA). RESULTS: Prescription rates for ACE-I/ARB, BB or both were 80%, 75% and 62%, respectively. The proportion of target doses reached for ACE-I was 16%, for BB only 8%. When adjusted for potential (mainly relative) contraindications (COPD, heart rate <60/min, hypotension, hyperkalaemia and renal dysfunction), the percentage of target doses reached increased to 49% for ACE-I/ARBs and 46% for BB. Application of the mGAI-3 showed moderate to perfect GA for usual assessment, proportion of target dose reached and adjusted in 83%, 16% and 55% of the patients, respectively. CONCLUSION: In the context of this patient and doctor setting, life-saving treatment was provided above average when assessed by usual criteria. The application of additional criteria showed further room for improvement. Future interventions aiming at optimisation should be tailored to the needs of doctors and patients likewise.

Sample preparation on polymeric solid phase extraction sorbents for liquid chromatographic-tandem mass spectrometric analysis of human whole blood--a study on a number of beta-agonists and beta-antagonists.

Alternative strategies for sample preparation of human blood samples were evaluated including protein precipitation (PP) and solid phase extraction (SPE) on Waters Oasis polymeric columns. Gradient chromatography within 15 min was performed on a Hypersil Polar-RP column combined with a Sciex API 2000 triple quadrupol instrument equipped with an electro-spray interface. Beta-agonists and beta-antagonists available on the Swedish market were included in the study. A combination of zinc sulphate and ethanol was found effective for PP. A clear supernatant was achieved that either could be injected directly on the LC-MS-MS system for analysis or transferred to a SPE column for further extraction and analyte concentration. Retention on the hydrophilic-lipophilic balanced sorbent HLB as well as the mixed mode cationic MCX and anionic MAX sorbents were investigated. On HBL the relative lipophilicity of the target analytes was investigated. At a high pH when the amino alcohols are deprotonised the more non-polar analytes (e.g., carvediol, betaxolol, bisoprolol and propranolol) were well retained on the sorbent and for the majority methanol content higher than 50% in water (v/v) was needed for elution. Some analytes though, with additional weak acidic functionalities (fenoterol, salbutamol, sotalol, and terbutaline) were poorly retained. On MAX the retention of these weak acids was improved when loaded under basic conditions but under neutral conditions analyte recoveries was comparable with HLB. On MCX all the analytes were well retained allowing a wash step of 100% methanol at neutral and low pH. By applying the supernatant from PP in combination with an additional portion of aqueous formic acid (2%) the analytes could be loaded and retained. High extraction recoveries were found for most analytes but for a few, significant losses were seen during PP (e.g., formoterol) and/or evaporation (e.g., fenoterol, formoterol, labetalol and terbutaline). The effectiveness of the sample preparation was evaluated by ESI ion-suppression studies by post column infusion of the target analyte. An ethanol zinc sulphate aq mixture was found to be more effective than acetonitrile, methanol or ethanol for PP of human whole blood samples. Beside suppression by salts in the front peak, only limited suppression from other artefacts such as more lipophilic compounds was found late in the chromatograms. Some tendency though to concentrate more lipophilic artefacts on the Oasis sorbents was seen. These findings show that the Oasis MCX sorbent is well suited for sample preparation of beta-agonists and beta-antagonists from human whole blood if the objective is to cover a great number of the analytes in the same assay.

Impact of a standardized titration protocol with carvedilol in heart failure: safety, tolerability, and efficacy-a report from the GESICA registry.

Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) studied whether a standardized protocol for the initiation and titration of the beta-blocker carvedilol in a multicenter, open-label program would optimize beta-blocker use in heart failure (HF) patients. The program included: (1) the carvedilol initiation and titration period, and (2) long-term follow-up at 6 and 12 months. Of 1299 patients in the registry, 504 were excluded due to current therapy; of the remaining 795 eligible patients, 293 were excluded due to contraindications. Of the included patients with follow-up data (n = 316), 93.3% tolerated carvedilol initiation and 47.7% of the patients reached the target dose of 50 mg/day for a mean dose of 39 mg/day. Rates were comparable in the elderly (n = 83), of which 53% achieved a target dose for a mean dose of 43.08 mg/day. This protocol improved therapy rates and achieved target doses quickly (average of 4 visits). Concomitant medications did not have to be adjusted and there were low withdrawal rates (10%) and hospital admissions (7.2%) for HF. Patients were able to maintain carvedilol therapy at 6 and 12 months. These results indicate that a standardized titration protocol, as used in GESICA, for the initiation and titration of beta-blockers is well tolerated and may improve beta-blocker use in carefully selected heart failure patients.

Importance of in-hospital initiation of evidence-based medical therapies for heart failure-a review.

Patients who have had heart failure (HF) face very high risks of hospitalization and mortality. Despite the compelling scientific evidence that angiotensin-converting enzyme inhibitors, aldosterone antagonists, and beta blockers decrease rates of hospitalization and mortality in patients who have had HF, these life-prolonging therapies continue to be underused. Many studies in a variety of clinical settings have documented that important numbers of patients who have had HF are not receiving treatment with these evidence-based therapies, which are recommended by national guidelines, when guided by conventional care. This HF treatment gap results from a variety of complex issues, including lack of systems and disease management programs. This gap in beta-blocker therapy may be due in part to persisting perceptions, despite recent evidence to the contrary, that it should be delayed until patients who developed HF have been stable for 2 to 4 weeks after hospital discharge and that its initiation results in a substantial risk of worsening HF. Conversely, recent clinical trial evidence has substantiated that beta blockers can be safely initiated for patients with HF in the hospital and that there are early benefits, including decreased risks of mortality and hospitalization for worsening HF. It has become increasingly evident that in-hospital initiation of evidence-based cardiovascular therapies and patient education have a positive effect on long-term patient compliance and clinical outcomes. Adopting in-hospital initiation of these therapies as the standard of care (in the absence of contraindications or intolerance) in patients who have HF and stabilized systolic dysfunction could substantially improve treatment rates, decrease the risk of future hospitalizations, and prolong life in the large number of patients who are hospitalized each year for HF.

Impact of contemporary guideline compliance on risk stratification models for acute coronary syndromes in The Registry of Acute Coronary Syndromes.

We compared the predictive value of the Rush score with the Thrombolysis In Myocardial Infarction (TIMI) risk score in unselected patients with an acute coronary syndrome and evaluated the effect of compliance with established guidelines on the accuracy of these models. The Registry of Acute Coronary Syndromes is a retrospective registry of 3,754 consecutive patients (38% women; mean age 67 years) who presented with acute coronary syndrome to the emergency department between April 1, 1999, and December 31, 2000, at 9 hospitals. The primary end point was death, myocardial infarction, or urgent revascularization during hospitalization. Rush classification was based on quartiles of predicted risk of cardiac complication (<2% for class I vs >15% for class IV). The TIMI score was implemented as published. Compliance with guidelines for acute coronary syndrome was assessed with a 4-point scale based on the aggregate use of aspirin, beta blockers, heparin, and glycoprotein IIb/IIIa inhibitors. Fifteen percent of patients met the primary end point. The primary end point rates for TIMI scores 0/1, 2, 3, 4, 5, and 6/7 were 11%, 14%, 13%, 11%, 14%, and 12%, respectively (p = NS). The primary end point rates for Rush classes I, II, III, and IV were 6%, 8%, 9%, and 17%, respectively (p <0.001). After controlling for compliance with established guidelines, the odds ratio of an event increased by 46% for each unit increase in Rush score (p <0.001). After adjusting for the Rush score, the odds ratio decreased by 54% for each unit increase in compliance (p <0.001). Thus, compliance with current American College of Cardiology/American Heart Association guidelines significantly improves prognosis, regardless of the risk score. The use of established risk scores may overestimate event rates in unselected populations.

Combination of direct and indirect evidence in mixed treatment comparisons.

Mixed treatment comparison (MTC) meta-analysis is a generalization of standard pairwise meta-analysis for A vs B trials, to data structures that include, for example, A vs B, B vs C, and A vs C trials. There are two roles for MTC: one is to strengthen inference concerning the relative efficacy of two treatments, by including both 'direct' and 'indirect' comparisons. The other is to facilitate simultaneous inference regarding all treatments, in order for example to select the best treatment. In this paper, we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS. These are multivariate random effects models that allow for variation in true treatment effects across trials. We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models. We also compare models with fixed (unconstrained) baseline study effects with models with random baselines drawn from a common distribution. These models are applied to an illustrative data set and posterior parameter distributions are compared. We discuss model critique and model selection, illustrating the role of Bayesian deviance analysis, and node-based model criticism. The assumptions underlying the MTC models and their parameterization are also discussed.