Efficacy and safety of Bacillus clausii (O/C, N/R, SIN, T) probiotic combined with oral rehydration therapy (ORT) and zinc in acute diarrhea in children: a randomized, double-blind, placebo-controlled study in India.

BACKGROUND: Childhood diarrhea remains a major disease burden, particularly in developing countries, and is a leading cause of death in children aged < 5 years, worldwide. Treatment of acute diarrhea now includes probiotics to potentially reduce the duration and severity of the illness. This phase 3, randomized, placebo-controlled, double-blind study assessed the efficacy and safety of four strains (O/C, N/R, SIN, T) of Bacillus clausii probiotic (Enterogermina®) plus oral rehydration therapy (ORT) and zinc, versus placebo plus ORT and zinc, in infants and children in India with acute moderate diarrhea. METHODS: Patients aged 6 months to 5 years with acute moderate diarrhea (WHO 2005 definition) of < 48 h' duration were randomly assigned to receive one mini bottle of either polyantibiotic-resistant B. clausii (oral suspension of 2 billion spores per 5 mL bottle) or matching placebo twice daily (morning and evening) for 5 days. Exclusion criteria included known hypersensitivity to B. clausii or excipients in the study treatment, or to other probiotics. Patients were admitted to hospital from Day 1 and discharged ≥6 h after diarrhea resolution, or a maximum of 5 days. The primary endpoint was duration of acute diarrhea from randomization to recovery. Secondary endpoints included frequency of stools, diapers with stools, or dehydration status. RESULTS: In total, 457 patients were randomized; 454 were treated. Similar proportions of patients showed recovery from diarrhea over the 120 h after randomization (97.0% in the B. clausii group [n = 227]; 98.0% on placebo [n = 227]). Median time to recovery was also similar: 42.83 (95% CI: 40.90-44.90) hours for B. clausii and 42.13 (95% CI: 39.80-43.87) hours for placebo. However, no statistically significant difference was observed between groups (hazard ratio = 0.93 [95% CI: 0.77-1.13]; p = 0.6968); nor were there statistically significant differences between groups for the secondary endpoints. Treatment with B. clausii was well tolerated with incidence of adverse events (9.7%) similar to that for placebo (12.3%). CONCLUSIONS: No significant difference in efficacy between B. clausii and placebo was demonstrated. Sample size may have been inadequate to allow detection of a between-group difference in efficacy, given the mild/moderate severity (only ~ 20% of patients had nausea/vomiting or abdominal pains) and short duration of disease among subjects, the relatively late start of treatment (most were already on Day 2 of their disease episode when study treatment started) and the effectiveness of the standard of care with ORT and zinc in both treatment groups. TRIAL REGISTRATION: CTRI number CTRI/2018/10/016053 . Registered on 17 October 2018. EudraCT number 2016-005165-31 . Registered 14 May 2020 (retrospectively registered).

The SAGE study: Global observational analysis of glycaemic control, hypoglycaemia and diabetes management in T1DM.

AIMS: To describe glycaemic control and diabetes management in adults with type 1 diabetes (T1DM), in a real-life global setting. MATERIALS AND METHODS: Study of Adults' GlycEmia (SAGE) was a multinational, multicentre, single visit, noninterventional, cross-sectional study in adult patients with T1DM. Data were collected at a single visit, analysed according to predefined age groups (26-44, 45-64 and ≥65 years) and reported across different regions. The primary endpoint was the proportion of participants achieving HbA1c  less than 7.0 % in each age group. Secondary endpoints included incidence of hypoglycaemia, severe hypoglycaemia and severe hyperglycaemia leading to diabetic ketoacidosis (DKA) and therapeutic management of T1DM. RESULTS: Of 3903 included participants, 3858 (98.8%) were eligible for the study. Overall, 24.3% (95% confidence interval [CI]: 22.9-25.6) of participants achieved the glycaemic target of HbA1c  less than 7.0 %, with more participants achieving this target in the 26-44 years group (27.6% [95% CI: 25.5-29.8]). Target achievement was highest in Eastern and Western Europe, and lowest in the Middle East. The incidence of hypoglycaemia and of severe hyperglycaemia leading to DKA tended to decrease with age, and varied across regions. Age and regional differences were observed in therapeutic management, including types of device/insulin usage, frequency of insulin dose adjustment and technology usage. CONCLUSIONS: Glycaemic control remains poor in adults with T1DM globally. Several areas of treatment may be optimised to improve outcomes, including supporting patient self-management of insulin therapy, increasing use of technologies such as CGM, and greater provision of healthcare support.

A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Ambroxol Hard-Boiled Lozenges in Patients with Acute Pharyngitis.

INTRODUCTION: The aim of this study was to evaluate the efficacy and safety of a new hard-boiled lozenge formulation containing ambroxol 20 mg versus placebo for the relief of sore throat in patients with acute pharyngitis. METHODS: This was a phase 3, randomized, double-blind, placebo-controlled, parallel-group multicenter trial conducted between June and September 2018 in South Africa. Patients with a diagnosis of acute pharyngitis, onset ≤ 72 h, and sore throat pain of at least moderate intensity were randomized to receive either ambroxol 20 mg or placebo hard-boiled lozenges. The primary efficacy endpoint was the normalized time-weighted sum of pain intensity differences (SPID) from baseline over 3 h following administration of the first lozenge (SPIDnorm,0-3h). Secondary efficacy endpoints included SPID 24 h after the first lozenge intake (SPIDnorm,0-24h) and patient assessment of efficacy at 3 and 24 h after the first lozenge. RESULTS: Of 422 patients from 11 centers, 390 were randomized to one of the two treatment groups (n = 196, ambroxol; n = 194, placebo) and 388 were analyzed (modified intention-to-treat). The mean ± standard deviation SPIDnorm,0-3h values were -0.386 (0.259) and -0.366 (0.243) in the ambroxol and placebo groups, respectively, and the adjusted mean ± standard error SPIDnorm0-3h difference between ambroxol and placebo was -0.020 (0.025) (p = 0.443). Comparable results between treatment groups were also found for SPIDnorm,0-24h and patient assessment of efficacy at 3 and 24 h after the first lozenge. The incidence of treatment-emergent adverse events (TEAEs) was similar between treatment groups (11.7% for ambroxol versus 9.3% for placebo). CONCLUSION: Although marked pain relief was observed over the first 3 h of treatment, superiority of ambroxol 20 mg hard-boiled lozenges versus placebo was not demonstrated in this study. TRIAL REGISTRATION: NCT03583658. FUNDING: Sanofi-Aventis Group.

Patient-reported outcomes in relapsing forms of MS: Real-world, global treatment experience with teriflunomide from the Teri-PRO study.

BACKGROUND: Patient-reported outcomes (PROs) provide clinicians with further understanding of the impact of treatment on patients' daily lives. In addition, real-world studies, which employ broader inclusion criteria than randomized trials, may help to inform prescribing decisions when selecting a disease-modifying therapy (DMT) to treat relapsing forms of MS (RMS). We sought to use PROs to determine patient treatment satisfaction and other treatment outcomes, and report safety and tolerability associated with teriflunomide, in the global, phase 4 Teri-PRO study (NCT01895335). METHODS: Patients with RMS (N = 1000) received teriflunomide for 48 weeks per local labeling. The primary endpoint was Global Satisfaction with teriflunomide treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM, V1.4). Secondary endpoints included TSQM scores at Week (W)48 vs baseline in patients switching to teriflunomide from other DMTs ('switchers'), additional PROs, and safety. RESULTS: Mean TSQM Global Satisfaction score at W48 was high (68.2). Switchers reported significant improvements across all four TSQM domains at W48 vs baseline (all p < 0.0001). Adverse events were consistent with teriflunomide clinical trials. CONCLUSION: Patients reported high treatment satisfaction with teriflunomide, with switchers also reporting improved treatment satisfaction vs baseline. High treatment satisfaction in patients with RMS may lead to improved adherence, and hence treatment outcomes.

Insulin regimens and glycemic control in different parts of Europe over 4years after starting insulin in people with type 2 diabetes: Data from the CREDIT non-interventional study.

AIMS: A number of insulin regimens are used in type 2 diabetes. This analysis aims to better understand the evolution of insulin therapy in different regions of Europe. METHODS: Data from people starting any insulin were collected in eastern Europe (EEur: Croatia, Russia, Ukraine), northern Europe (NEur: Finland, Germany, UK) and southern Europe (SEur: France, Italy, Portugal, Spain). Retrospective data on starting insulin and prospective follow-up data were extracted from clinical records. RESULTS: At 4years, 1699 (76.0%) of 2236 eligible people had data. EEur participants were mostly female, younger and had shorter diabetes duration on starting insulin, yet had highest baseline HbA1c and more micro-/macrovascular disease. A majority (60%-64%) in all regions started on basal insulin alone, declining to 30%-38% at 4years, with most switching to basal+mealtime insulin regimen (24%-40%). Higher baseline (28%) and 4-year use (34%) of premix insulin was observed in NEur. Change in HbA1c (SD) ranged from -1.2 (2.1)% (-13 [23]mmol/mol) in NEur to -2.4 (2.0)% (-26 [22]mmol/mol) in EEur. Weight change ranged from +1.9 (8.3) kg in NEur to +3.2 (7.0) kg in SEur. Overall documented hypoglycemia ranged from 0.3 (1.3) to 1.3 (4.4) events/person/6-months (NEur vs. EEur, respectively) and was stable with time. Severe hypoglycemia rates remained low. CONCLUSION: When starting insulin, HbA1c and prevalence of complications were higher in EEur. Regional differences exist in choice of insulin regimens in Europe. However, people starting insulin improved and sustained their glycemic control regardless of regional differences or insulin regimens used.

Regional Lack of Consistency in the Management of Atrial Fibrillation (from the RECORD-AF Trial).

American and European society guidelines for atrial fibrillation management mostly agree on the utilization of rate and rhythm control strategies and the indications for oral anticoagulant (OAC) use. However, the level of adherence to guidelines in clinical practice may vary by region. In this study, data analysis from The Registry on Cardiac rhythm disorders assessing the control of Atrial Fibrillation (RECORD-AF) registry, an international registry in patients with newly diagnosed atrial fibrillation of <1 year, shows that differences in practice exist between 3 regions, namely Western Europe, Eastern Europe, and North America. Data analyzed included major cardiovascular outcomes at 12 months, choice of rhythm versus rate control strategy and the use of OAC according to CHADS2 score between regions, and the cost incurred according to management strategy. In conclusion, there is preference for rhythm control strategy in Europe compared to North America without a significant impact on major cardiovascular outcomes; there is significant discrepancy in the use of OAC in Eastern Europe compared to the 2 other regions; and rate control was found to be more costly in all regions.

Atrial Fibrillation Management Strategies in Routine Clinical Practice: Insights from the International RealiseAF Survey.

BACKGROUND: Atrial fibrillation (AF) can be managed with rhythm- or rate-control strategies. There are few data from routine clinical practice on the frequency with which each strategy is used and their correlates in terms of patients' clinical characteristics, AF control, and symptom burden. METHODS: RealiseAF was an international, cross-sectional, observational survey of 11,198 patients with AF. The aim of this analysis was to describe patient profiles and symptoms according to the AF management strategy used. A multivariate logistic regression identified factors associated with AF management strategy at the end of the visit. RESULTS: Among 10,497 eligible patients, 53.7% used a rate-control strategy, compared with 34.5% who used a rhythm-control strategy. In 11.8% of patients, no clear strategy was stated. The proportion of patients with AF-related symptoms (EHRA Class > = II) was 78.1% (n = 4396/5630) for those using a rate-control strategy vs. 67.8% for those using a rhythm-control strategy (p<0.001). Multivariate logistic regression analysis revealed that age <75 years or the paroxysmal or persistent form of AF favored the choice of a rhythm-control strategy. A change in strategy was infrequent, even in patients with European Heart Rhythm Association (EHRA) Class > = II. CONCLUSIONS: In the RealiseAF routine clinical practice survey, rate control was more commonly used than rhythm control, and a change in strategy was uncommon, even in symptomatic patients. In almost 12% of patients, no clear strategy was stated. Physician awareness regarding optimal management strategies for AF may be improved.

Four-year evolution of insulin regimens, glycaemic control, hypoglycaemia and body weight after starting insulin therapy in type 2 diabetes across three continents.

AIMS: It is of interest to understand how insulin therapy currently evolves in clinical practice, in the years after starting insulin in people with type 2 diabetes. We aimed to describe this evolution prospectively over 4 years, to assist health care planning. METHODS: People who had started any insulin were identified from 12 countries on three continents. Baseline, then yearly follow-up, data were extracted from clinical records over 4 years. RESULTS: Of the 2999 eligible people, 2272 were followed over 4 years. When starting insulin, mean (SD) duration of diabetes was 10.6 (7.8) years, HbA1c 9.5 (2.0)% (80 [22]mmol/mol) and BMI 29.3 (6.3)kg/m(2). Initial insulin therapy was basal 52%, premix 23%, mealtime+basal 14%, mealtime 8% and other 3%; at 4 years, 30%, 25%, 33%, 2% and 5%, respectively, with 5% not on insulin. Insulin dose was 20.2U/day at the start and 45.8U/day at year 4. There were 1258 people (55%) on their original regimen at 4 years, and this percentage differed according to baseline insulin regimen. HbA1c change was -2.0 (2.2)% (-22 [24]mmol/mol) and was similar by final insulin regimen. Hypoglycaemia prevalence was <20% in years 1-4. Body weight change was mostly in year 1, and was very variable, mean +2.7 (7.5)kg at year 4. CONCLUSION: Different insulin regimens were started in people with differing characteristics, and they evolved differently; insulin dose, hypoglycaemia and body weight change were diverse and largely independent of regimen.

Use of antithrombotics in atrial fibrillation in Africa, Europe, Asia and South America: insights from the International RealiseAF Survey.

BACKGROUND: The implementation of international guidelines for antithrombotic use in atrial fibrillation (AF) in routine practice is not well known, particularly, in some parts of the world, such as the Middle East and Africa. AIM: To describe and analyse the use of antithrombotics in patients with AF in routine practice. METHODS: The RealiseAF international cross-sectional survey enrolled 10,523 patients (with at least one documented AF episode in the preceding 12 months) from 831 sites. Participating physicians were randomly selected from physician list forms. RESULTS: Mean age was 66.6 ± 12.2 years. In 47.4% of the patients with a CHADS2 score ≥ 2, oral anticoagulants were not prescribed. Patients who had a CHADS2 score ≥ 2, permanent or persistent AF, valvular heart disease, a stroke leading to hospitalization in the previous year or treatment by a cardiologist (rather than an internist) were most likely to receive oral anticoagulants. Patients aged ≥ 75 years and those with coronary heart disease; major bleeding leading to hospitalization in the previous year or a rhythm control strategy was least likely to receive oral anticoagulants. Appropriate antithrombotic treatment was prescribed in 66.7% of the patients with a CHADS2 score ≥ 2 in the Middle East/Africa, 55.3% in Europe, 43.9% in Latin America and 31.7% in Asia. CONCLUSION: There is substantial deviation from international guidelines in antithrombotic use for AF in routine clinical practice, with overuse and underuse of antithrombotics in about 50% of the cases and important geographical differences. These findings emphasize the need for improved medical education worldwide and a better understanding of geographical disparities in the implementation of guidelines.

Clinical characteristics, management, and control of permanent vs. nonpermanent atrial fibrillation: insights from the RealiseAF survey.

BACKGROUND: Atrial fibrillation can be categorized into nonpermanent and permanent atrial fibrillation. There is less information on permanent than on nonpermanent atrial fibrillation patients. This analysis aimed to describe the characteristics and current management, including the proportion of patients with successful atrial fibrillation control, of these atrial fibrillation subsets in a large, geographically diverse contemporary sample. METHODS AND RESULTS: Data from RealiseAF, an international, observational, cross-sectional survey of 10,491 patients with atrial fibrillation, were used to characterize permanent atrial fibrillation (N = 4869) and nonpermanent atrial fibrillation (N = 5622) patients. Permanent atrial fibrillation patients were older, had a longer time since atrial fibrillation diagnosis, a higher symptom burden, and were more likely to be physically inactive. They also had a higher mean (SD) CHADS2 score (2.2 [1.3] vs. 1.7 [1.3], p<0.001), and a higher frequency of CHADS2 score ≥2 (67.3% vs. 53.0%, p<0.001) and comorbidities, most notably heart failure. Physicians indicated using a rate-control strategy in 84.2% of permanent atrial fibrillation patients (vs. 27.5% in nonpermanent atrial fibrillation). Only 50.2% (N = 2262/4508) of permanent atrial fibrillation patients were controlled. These patients had a longer time since atrial fibrillation diagnosis, a lower symptom burden, less obesity and physical inactivity, less severe heart failure, and fewer hospitalizations for acute heart failure than uncontrolled permanent atrial fibrillation patients, but with more arrhythmic events. The most frequent causes of hospitalization in the last 12 months were acute heart failure and stroke. CONCLUSION: Permanent atrial fibrillation is a high-risk subset of atrial fibrillation, representing half of all atrial fibrillation patients, yet rate control is only achieved in around half. Since control is associated with lower symptom burden and heart failure, adequate rate control is an important target for improving the management of permanent atrial fibrillation patients.

Heart failure in patients with atrial fibrillation is associated with a high symptom and hospitalization burden: the RealiseAF survey.

BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) often coexist; the consequences of such coexistence are unclear. HYPOTHESIS: HF in patients with AF is associated with poor outcomes. METHODS: This post hoc analysis of RealiseAF, a survey of AF patients, compared symptoms, hospitalizations, management, and AF control in patients with vs without HF. A total of 10,523 AF patients were analyzed according to presence/absence of HF. RESULTS: History of HF was present in 45.8%, and in more patients with permanent vs persistent, paroxysmal, or first-episode AF (55.6%, 44.3%, 32.9%, and 29.8%, respectively; P < 0.0001). Patients with vs those without history of HF, and patients with HF and reduced ejection fraction (HF-REF) vs those with HF and a preserved ejection fraction (HF-PEF), had more frequent cardiovascular (CV) risk factors and more severe symptoms. Presence vs absence of HF, and HF-REF vs HF-PEF, were associated with lower rates of AF control (54.6% vs 62.8% and 49.3% vs 60.3%, respectively; both P < 0.0001). The rate-control strategy was used more frequently in HF patients, particularly those with HF-REF, than the rhythm-control strategy. CV hospitalizations occurred more frequently in patients with HF than those without (41.8% vs 17.5%; P < 0.001) and more frequently in patients with HF-REF than in those with HF-PEF (51.6% vs 35.6%; P < 0.0001). CONCLUSIONS: AF patients with HF, particularly HF-REF, experience heavy symptom and hospitalization burdens, and have relatively low rates of AF control. Further studies are needed to identify ways to improve the management and treatment outcomes of this very high-risk patient population.

Inappropriate use of antiarrhythmic drugs in paroxysmal and persistent atrial fibrillation in a large contemporary international survey: insights from RealiseAF.

AIMS: International atrial fibrillation (AF) guidelines have defined optimal drugs for patients with various underlying diseases, but the extent to which real-life practice complies with these guidelines is unknown. This study aimed to evaluate the appropriate use of antiarrhythmic drugs (AADs) in patients with paroxysmal and persistent AF from the RealiseAF survey, according to the 2006 American College of Cardiology/American Heart Association/European Society of Cardiology AF guidelines. METHODS AND RESULTS: RealiseAF was an international cross-sectional, observational survey of 10 523 eligible patients from 26 countries on 4 continents, with ≥1 AF episode documented by standard electrocardiogram or by Holter monitoring in the last 12 months. Participating physicians were randomly selected during 2009-10 from lists of office-based or hospital-based cardiologists and internists. Overall, 4947 patients with paroxysmal (n = 2606) or persistent AF (n = 2341) were included; mean (standard deviation) age was 64.7 (12.4) and 66.0 (11.8) years, respectively. Class Ic drugs were prescribed in 589 patients (11.9%); however, in 20.0% of these patients, the indication was not consistent with published guidelines. Similarly, for the 219 patients prescribed sotalol (4.4%), 16.0% received treatment for an indication that deviated from the published guidelines. Amiodarone was prescribed as first-line therapy in 1268 patients (25.6%), but 49.9% of these did not have heart failure or hypertension with significant left ventricular hypertrophy. CONCLUSION: The use of AADs for persistent or paroxysmal AF in this large contemporary international survey showed some deviations from international guidelines. The highest discordance came with the use of amiodarone in first line. Clearly, there is a large discrepancy between published guidelines and current practice.

Symptoms, functional status and quality of life in patients with controlled and uncontrolled atrial fibrillation: data from the RealiseAF cross-sectional international registry.

BACKGROUND: Rate control and rhythm control are accepted management strategies for atrial fibrillation (AF). OBJECTIVE: RealiseAF aimed to describe the success of either strategy and the impact of control on symptomatic status of patients with AF. METHODS: This international, observational, cross-sectional survey of patients with any history of AF in the previous year, recorded AF characteristics, management and frequency of control (defined as sinus rhythm or AF with resting heart rate ≤80 bpm). RESULTS: Overall, 9665 patients were evaluable for AF control, with 59.0% controlled (sinus rhythm 26.5%, AF ≤80 bpm 32.5%) and 41.0% uncontrolled. Symptom prevalence in the previous week was lower in controlled than uncontrolled AF (55.7% vs 68.4%; p<0.001) and similar for patients in sinus rhythm versus AF ≤80 bpm (54.8% vs 56.4%; p=0.23). At the visit, AF-related functional impairment (EHRA class >I) was seen in 67.4% of patients with controlled AF and 82.1% of patients with uncontrolled AF (p<0.001). Quality-of-life (QoL, measured using EQ-5D) was better for patients with controlled versus uncontrolled AF using the Visual Analogue Scale (mean (SD) score 67.1 (18.4) vs 63.2 (18.9); p<0.001), single index utility score (median 0.78 vs 0.73; p<0.001), or five dimensions of well-being (all p<0.001). Irrespective of AF control, cardiovascular events had led to hospitalisation in the past year in 28.1%. CONCLUSION: AF control is not optimal. Control appears to be associated with fewer symptoms and better QoL, but even patients with controlled AF have frequent symptoms, functional impairment, altered QoL and cardiovascular events. New treatments are needed to improve control and minimise the functional and QoL burden of AF.

Does abdominal obesity have a similar impact on cardiovascular disease and diabetes? A study of 91,246 ambulant patients in 27 European countries.

AIMS: Differences in cardiovascular risk factors across Europe provide an opportunity to examine the impact of adiposity on the frequency of diabetes and cardiovascular disease (CVD). METHODS AND RESULTS: The International Day for Evaluation of Abdominal obesity (IDEA) study evaluated the prevalence of abdominal obesity, elevated body mass index (BMI), and other cardiometabolic risk factors among primary care patients. Abdominal obesity predicted increased diabetes risk, despite socio-economic, demographic, and risk factor differences. Cardiovascular disease was at least two-fold more frequent in Eastern Europe vs. Northwest Europe (P < 0.0001) and 2.5-fold more vs. Southern Europe (P < 0.0001). Waist circumference (WC) predicted increased (P < 0.0001) age- and BMI-adjusted risks of CVD and diabetes. In women, odds ratios (95% confidence intervals) for CVD per 1 SD increase in WC were: Northwest Europe 1.28 (1.18-1.40); Southern Europe 1.26 (1.16-1.37); and Eastern Europe 1.10 (1.03-1.18). Values for diabetes were 1.72 (1.58-1.88), 1.45 (1.35-1.56), and 1.59 (1.46-1.73), with similar findings in men. CONCLUSION: Abdominal obesity impacted similarly on the frequency of diabetes across Europe, despite regional differences in cardiovascular risk factors and CVD rates. Increasing abdominal obesity may offset future declines in CVD, even where CVD rates are lower.