Gloria Cordoba

Definition, reporting, and interpretation of composite outcomes in clinical trials: systematic review

Objective To study how composite outcomes, which have combined several components into a single measure, are defined, reported, and interpreted. Design Systematic review of parallel group randomised clinical trials published in 2008 reporting a binary composite outcome. Two independent observers extracted the data using a standardised data sheet, and two other observers, blinded to the results, selected the most important component. Results Of 40 included trials, 29 (73%) were about cardiovascular topics and 24 (60%) were entirely or partly industry funded. Composite outcomes had a median of three components (range 2–9). Death or cardiovascular death was the most important component in 33 trials (83%). Only one trial provided a good rationale for the choice of components. We judged that the components were not of similar importance in 28 trials (70%); in 20 of these, death was combined with hospital admission. Other major problems were change in the definition of the composite outcome between the abstract, methods, and results sections (13 trials); missing, ambiguous, or uninterpretable data (9 trials); and post hoc construction of composite outcomes (4 trials). Only 24 trials (60%) provided reliable estimates for both the composite and its components, and only six trials (15%) had components of similar, or possibly similar, clinical importance and provided reliable estimates. In 11 of 16 trials with a statistically significant composite, the abstract conclusion falsely implied that the effect applied also to the most important component. Conclusions The use of composite outcomes in trials is problematic. Components are often unreasonably combined, inconsistently defined, and inadequately reported. These problems will leave many readers confused, often with an exaggerated perception of how well interventions work.

Health Alliance for prudent antibiotic prescribing in patients with respiratory tract infections (HAPPY AUDIT) -impact of a non-randomised multifaceted intervention programme

BackgroundExcessive use of antibiotics is worldwide the most important reason for development of antimicrobial resistance. As antibiotic resistance may spread across borders, high prevalence countries may serve as a source of bacterial resistance for countries with a low prevalence. Therefore, bacterial resistance is an important issue with a potential serious impact on all countries. Initiatives have been taken to improve the quality of antibiotic prescribing in primary care, but only few studies have been designed to determine the effectiveness of multifaceted strategies across countries with different practice setting. The aim of this study was to evaluate the impact of a multifaceted intervention targeting general practitioners (GPs) and patients in six countries with different health organization and different prevalence of antibiotic resistance.MethodsGPs from two Nordic countries, two Baltic Countries and two Hispano-American countries registered patients with respiratory tract infections (RTIs) in 2008 and 2009. After first registration they received individual prescriber feedback and they were offered an intervention programme that included training courses, clinical guidelines, posters for waiting rooms, patient brochures and access to point of care tests (Strep A and C-Reactive Protein). Antibiotic prescribing rates were compared before and after the intervention.ResultsA total of 440 GPs registered 47011 consultations; 24436 before the intervention (2008) and 22575 after the intervention (2009). After the intervention, the GPs significantly reduced the percentage of consultations resulting in an antibiotic prescription. In patients with lower RTI the GPs in Lithuania reduced the prescribing rate by 42%, in Russia by 25%, in Spain by 25%, and in Argentina by 9%. In patients with upper RTIs, the corresponding reductions in the antibiotic prescribing rates were in Lithania 20%, in Russia 15%, in Spain 9%, and in Argentina 5%.ConclusionA multifaceted intervention programme targeting GPs and patients and focusing on improving diagnostic procedures in patients with RTIs may lead to a marked reduction in antibiotic prescribing. The pragmatic before-after design used may suffer from some limitations and the reduction in antibiotic prescribing could be influenced by factors not related to the intervention.

Prescribing style and variation in antibiotic prescriptions for sore throat: cross-sectional study across six countries

BackgroundVariation in prescription of antibiotics in primary care can indicate poor clinical practice that contributes to the increase of resistant strains. General Practitioners (GPs), as a professional group, are expected to have a fairly homogeneous prescribing style. In this paper, we describe variation in prescribing style within and across groups of GPs from six countries.MethodsCross-sectional study with the inclusion of 457 GPs and 6394 sore throat patients. We describe variation in prescribing antibiotics for sore throat patients across six countries and assess whether variation in “prescribing style” – understood as a subjective tendency to prescribe – has an important effect on variation in prescription of antibiotics by using the concept of prescribing style as a latent variable in a multivariable model. We report variation as a Median Odds Ratio (MOR) which is the transformation of the random effect variance onto an odds ratio; Thus, MOR = 1 means similar odds or strict homogeneity between GPs’ prescribing style, while a MOR higher than 1 denotes heterogeneity in prescribing style.ResultsIn all countries some GPs always prescribed antibiotics to all their patients, while other GPs never did. After adjusting for patient and GP characteristics, prescribing style in the group of GPs from Russia was about three times more heterogeneous than the prescribing style in the group of GPs from Denmark – Median Odds Ratio (6.8, 95% CI 3.1;8.8) and (2.6, 95% CI 2.2;4.4) respectively.ConclusionPrescribing style is an important source of variation in prescription of antibiotics within and across countries, even after adjusting for patient and GP characteristics. Interventions aimed at influencing the prescribing style of GPs must encompass context-specific actions at the policy-making level alongside GP-targeted interventions to enable GPs to react more objectively to the external demands that are in place when making the decision of prescribing antibiotics or not.

Point of care susceptibility testing in primary care - does it lead to a more appropriate prescription of antibiotics in patients with uncomplicated urinary tract infections? Protocol for a randomized controlled trial

BackgroundUrinary tract infection (UTI) is a common infection in primary care and is the second leading reason for prescription of antibiotics in Denmark. The diagnosis is often based on symptoms and urine dip-stick, which has limited validity, causing the risk of unnecessary antibiotic prescription. Additionally, with increasing antibiotic resistance, the risk of choosing an antibiotic to which an infecting pathogen is resistant is rising. Combined point-of-care-tests (POCT) for urine culture and susceptibility testing have been developed and validated for primary care, and performing such a test in all patients with suspected UTI in primary care seems rational in order to reduce the use of inappropriate antibiotics. However, the clinical effect of the culture and susceptibility test has not yet been investigated. This study aims to investigate whether POCT urine culture and susceptibility testing decreases the inappropriate use of antibiotics and leads to faster patient recovery.Methods/designRandomized controlled open label trial of two diagnostic approaches. 750 patients with symptoms of uncomplicated UTI, consecutively contacting their general practitioner (GP), randomized to either POCT urine culture and susceptibility testing and targeted treatment or POCT urine culture without susceptibility testing and empirical treatment. Treatment is started when the POCT is read. The two groups are compared with regard to appropriate choice of antibiotics, clinical remission, and microbiological cure rates.DiscussionThe results of this study may provide important evidence to recommend POCT culture and susceptibility testing in all patients with suspected uncomplicated UTI. This could become an additional strategy to fight antibiotic resistance.Trial registrationClinicalTrials.gov NCT02323087.

Predictors for antibiotic prescribing in patients with exacerbations of COPD in general practice

Background: The aim of this study was to describe the antibiotic prescribing rate in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD), to analyse predictors for antibiotic prescribing and to explore the influence of the use C-reactive protein (CRP) rapid test. Methods: A cross-sectional study was carried out in January and February 2008 in primary care. General practitioners (GPs) from six countries (Denmark, Sweden, Lithuania, Russia, Spain and Argentina) registered all patients with AECOPD during a 3-week period. A multilevel logistic regression model was estimated using two hierarchical levels, (i) patients and (ii) physicians, and was used to analyse the association between antibiotic prescribing and potential predictors for antibiotic use: patients’ age and gender, duration and symptoms and signs of exacerbations (fever, cough, dyspnoea, sputum volume and purulence) and the results of the CRP test. Results: A total of 617 GPs registered 1233 patients with AECOPD. A total of 970 patients (79%) were prescribed antibiotics, varying from 49% (Denmark) to 93% (Russia). The presence of purulent sputum was the strongest predictor for antibiotic treatment (odds ratio [OR] 8.7; 95% confidence interval [CI] 5.9–12.8). CRP determination was carried out mainly in Denmark and Sweden and its use was the strongest protective factor for antibiotic therapy (OR 0.3; 95% CI 0.2-0.6). GPs that used CRP testing weighted purulent sputum lower than GPs who did not use CRP testing. CRP values had a strong influence on the antibiotic prescribing rate. Conclusions: Antibiotic treatment for AECOPD is very high. This study shows that GPs performing CRP rapid tests prescribe fewer antibiotics than those who do not.

General Practitioners’ Views on the Acceptability and Applicability of Using Quality Indicators as an Intervention to Reduce Unnecessary Prescription of Antibiotics in Four South American Countries

As part of the quality improvement program “Health Alliance for Prudent Prescribing, Yield And Use of anti-microbial Drugs In the Treatment of respiratory tract infections” (HAPPY AUDIT) South America, we planned to implement an intervention based on the use of quality indicators as a means to influence General Practitioners’ (GPs) prescribing decision. Knowledge on the acceptability and applicability of an intervention is crucial to decide whether the intervention is suitable and will achieve the expected outcomes. This study explores GPs’ views about the acceptability and applicability of using quality indicators as an intervention to influence their prescribing decision in patients with suspected Respiratory Tract Infections (RTIs) across four countries in South-America. In March 2015, GPs that were participating in HAPPY AUDIT South America were invited to participate in focus groups. A discussion guide covering the domains acceptability and applicability was used. Data was analyzed through systematic text condensation with an inductive approach. 171 GPs were invited and 48% participated. Acceptability ranged from totally acceptable to slightly acceptable. This spectrum of GPs views on acceptability was influenced by themes concerning applicability. In conclusion, there is a positive attitude towards the use of quality indicators. Nonetheless, applicability challenges have to be taken into consideration and solved if we are to achieve a large effect with the implementation of this intervention.

Antibiotic prescriptions for suspected respiratory tract infection in primary care in South America

Objectives To describe and compare antibiotic prescribing patterns for primary care patients with respiratory tract infections (RTIs) in four South American countries. Methods This was a prospective observational study. General practitioners (GPs) from Argentina, Bolivia, Paraguay and Uruguay registered data about all consultations of patients with suspected RTIs in the winter of 2014 (June–August). Variation in antibiotic prescriptions was assessed using a two-level hierarchical logistic model. Results Participating GPs (n = 171) registered 11 446 patients with suspected RTI; 3701 (33%) of these received an antibiotic prescription. There was a wide variation across countries in the use and selection of antibiotics. For example, 94% of patients with acute bronchitis were prescribed antibiotics in Bolivia, while in Uruguay only 21% received antibiotics. Amoxicillin was the most commonly prescribed antibiotic across countries, but prescription rates varied between 45% in Bolivia and 69% in Uruguay. Compared with the overall mean prescribing rate, and after adjusting for clinical presentation and demographics, prescribing of antibiotics varied by a factor of 6, the OR ranging from 0.37 (95% CI = 0.21–0.65) in Uruguay to 2.58 (95% CI = 1.66–4) in Bolivia. Conclusions The large variation in use and selection of antibiotics across countries is not explained by different patient populations. It could be explained by diagnostic uncertainty and contextual characteristics beyond clinical practice. Reducing uncertainty and country variation requires greater support from the healthcare systems by providing GPs with evidence-based guidelines and tools to apply them.

Clinical accuracy of point-of-care urine culture in general practice

Abstract Objective: To assess the clinical accuracy (sensitivity (SEN), specificity (SPE), positive predictive value and negative predictive value) of two point-of-care (POC) urine culture tests for the identification of urinary tract infection (UTI) in general practice. Design: Prospective diagnostic accuracy study comparing two index tests (Flexicult™ SSI-Urinary Kit or ID Flexicult™) with a reference standard (urine culture performed in the microbiological department). Setting: General practice in the Copenhagen area patients. Adult female patients consulting their general practitioner with suspected uncomplicated, symptomatic UTI. Main outcome measures: (1) Overall accuracy of POC urine culture in general practice. (2) Individual accuracy of each of the two POC tests in this study. (3) Accuracy of POC urine culture in general practice with enterococci excluded, since enterococci are known to multiply in boric acid used for transportation for the reference standard. (4) Accuracy based on expert reading of photographs of POC urine cultures performed in general practice. Standard culture performed in the microbiological department was used as reference standard for all four measures. Results: Twenty general practices recruited 341 patients with suspected uncomplicated UTI. The overall agreement between index test and reference was 0.76 (CI: 0.71–0.80), SEN 0.88 (CI: 0.83–0.92) and SPE 0.55 (CI: 0.46–0.64). The two POC tests produced similar results individually. Overall agreement with enterococci excluded was 0.82 (0.77–0.86) and agreement between expert readings of photographs and reference results was 0.81 (CI: 0.76–0.85). Conclusions: POC culture used in general practice has high SEN but low SPE. Low SPE could be due to both misinterpretation in general practice and an imperfect reference standard. Registration number: ClinicalTrials.gov NCT02323087.

Development and validation of a condition-specific diary to measure severity, bothersomeness and impact on daily activities for patients with acute urinary tract infection in primary care

BackgroundUrinary tract infection (UTI) is a common condition in primary care. Patient-reported outcome measures (PROMs) are crucial in the evaluation of interventions to improve diagnosis, treatment and prognosis of UTI. The aim of this study was to identify an existing condition-specific PROM to measure symptom severity, bothersomeness and impact on daily activities for adult patients with suspected urinary tract infection in primary care; or, in the absence of such a PROM, to test items identified from existing PROMs for coverage and relevance in single and group interviews and to psychometrically validate the resulting PROM.MethodsThe literature was searched for existing PROMs covering the three domains. Items from the identified PROMs were tested in single and group interviews. The resulting symptom diary was psychometrically validated using the partial credit Rasch model for polytomous items in a cohort of 451 women participating in two studies regarding UTI.ResultsNo existing PROM fulfilled the inclusion criteria. Content validation resulted in one domain concerning symptom severity (18 items), one concerning bothersomeness (18 items), and one concerning impact on daily activities (7 items). Psychometrical validation resulted in four dimensions in each of the first two domains and one dimension in the third domain.ConclusionsDomains were not unidimensional, which meant that we identified dimensions of patient-experienced UTI that differed substantially from those previously found. We recommend that future studies on UTI, in which PROMs are to be used, should ensure high content validity of their outcome measures and unidimensionality of the included dimensions.

Decreasing Inappropriate Use of Antibiotics in Primary Care in Four Countries in South America—Cluster Randomized Controlled Trial

High antibiotic prescribing and antimicrobial resistance in patients attending primary care have been reported in South America. Very few interventions targeting general practitioners (GPs) to decrease inappropriate antibiotic prescribing have been investigated in this region. This study assessed the effectiveness of online feedback on reducing antibiotic prescribing in patients with suspected respiratory tract infections (RTIs) attending primary care. The aim was to reduce antibiotic prescribing in patients with acute bronchitis and acute otitis media. Both are RTIs for which antibiotics have a very limited effect. A cluster randomized two-arm control trial was implemented. Healthcare centres from Bolivia, Argentina, Paraguay and Uruguay participating in the quality improvement program HAPPY AUDIT were randomly allocated to either intervention or control group. During ten consecutive weeks, GPs in the intervention group received evidence-based online feedback on the management of suspected RTIs. In patients with acute bronchitis, the intervention reduced the antibiotic prescribing rate from 71.6% to 56% (control group from 61.2% to 52%). In patients with acute otitis media, the intervention reduced the antibiotic prescribing from 94.8% to 86.2% (no change in the control group). In all RTIs, the intervention reduced antibiotic prescribing rate from 37.4% to 28.1% (control group from 29% to 27.2%). Online evidence-based feedback is effective for reducing antibiotic prescribing in patients with RTIs attending primary care in South America.