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The Centre for Evidence-Based Medicine (CEBM) at Oxford University develops, promotes and disseminates better evidence for health care.
Pharmacological and electronic cigarette interventions for smoking cessation in adults: component network meta-analyses.
BACKGROUND: Tobacco smoking is the leading preventable cause of death and disease worldwide. Stopping smoking can reduce this harm and many people would like to stop. There are a number of medicines licenced to help people quit globally, and e-cigarettes are used for this purpose in many countries. Typically treatments work by reducing cravings to smoke, thus aiding initial abstinence and preventing relapse. More information on comparative effects of these treatments is needed to inform treatment decisions and policies. OBJECTIVES: To investigate the comparative benefits, harms and tolerability of different smoking cessation pharmacotherapies and e-cigarettes, when used to help people stop smoking tobacco. SEARCH METHODS: We identified studies from recent updates of Cochrane Reviews investigating our interventions of interest. We updated the searches for each review using the Cochrane Tobacco Addiction Group (TAG) specialised register to 29 April 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster-RCTs and factorial RCTs, which measured smoking cessation at six months or longer, recruited adults who smoked combustible cigarettes at enrolment (excluding pregnant people) and randomised them to approved pharmacotherapies and technologies used for smoking cessation worldwide (varenicline, cytisine, nortriptyline, bupropion, nicotine replacement therapy (NRT) and e-cigarettes) versus no pharmacological intervention, placebo (control) or another approved pharmacotherapy. Studies providing co-interventions (e.g. behavioural support) were eligible if the co-intervention was provided equally to study arms. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods for screening, data extraction and risk of bias (RoB) assessment (using the RoB 1 tool). Primary outcome measures were smoking cessation at six months or longer, and the number of people reporting serious adverse events (SAEs). We also measured withdrawals due to treatment. We used Bayesian component network meta-analyses (cNMA) to examine intervention type, delivery mode, dose, duration, timing in relation to quit day and tapering of nicotine dose, using odds ratios (OR) and 95% credibility intervals (CrIs). We calculated an effect estimate for combination NRT using an additive model. We evaluated the influence of population and study characteristics, provision of behavioural support and control arm rates using meta-regression. We evaluated certainty using GRADE. MAIN RESULTS: Of our 332 eligible RCTs, 319 (835 study arms, 157,179 participants) provided sufficient data to be included in our cNMA. Of these, we judged 51 to be at low risk of bias overall, 104 at high risk and 164 at unclear risk, and 118 reported pharmaceutical or e-cigarette/tobacco industry funding. Removing studies at high risk of bias did not change our interpretation of the results. Benefits We found high-certainty evidence that nicotine e-cigarettes (OR 2.37, 95% CrI 1.73 to 3.24; 16 RCTs, 3828 participants), varenicline (OR 2.33, 95% CrI 2.02 to 2.68; 67 RCTs, 16,430 participants) and cytisine (OR 2.21, 95% CrI 1.66 to 2.97; 7 RCTs, 3848 participants) were associated with higher quit rates than control. In absolute terms, this might lead to an additional eight (95% CrI 4 to 13), eight (95% CrI 6 to 10) and seven additional quitters per 100 (95% CrI 4 to 12), respectively. These interventions appeared to be more effective than the other interventions apart from combination NRT (patch and a fast-acting form of NRT), which had a lower point estimate (calculated additive effect) but overlapping 95% CrIs (OR 1.93, 95% CrI 1.61 to 2.34). There was also high-certainty evidence that nicotine patch alone (OR 1.37, 95% CrI 1.20 to 1.56; 105 RCTs, 37,319 participants), fast-acting NRT alone (OR 1.41, 95% CrI 1.29 to 1.55; 120 RCTs, 31,756 participants) and bupropion (OR 1.43, 95% CrI 1.26 to 1.62; 71 RCTs, 14,759 participants) were more effective than control, resulting in two (95% CrI 1 to 3), three (95% CrI 2 to 3) and three (95% CrI 2 to 4) additional quitters per 100 respectively. Nortriptyline is probably associated with higher quit rates than control (OR 1.35, 95% CrI 1.02 to 1.81; 10 RCTs, 1290 participants; moderate-certainty evidence), resulting in two (CrI 0 to 5) additional quitters per 100. Non-nicotine/placebo e-cigarettes (OR 1.16, 95% CrI 0.74 to 1.80; 8 RCTs, 1094 participants; low-certainty evidence), equating to one additional quitter (95% CrI -2 to 5), had point estimates favouring the intervention over control, but CrIs encompassed the potential for no difference and harm. There was low-certainty evidence that tapering the dose of NRT prior to stopping treatment may improve effectiveness; however, 95% CrIs also incorporated the null (OR 1.14, 95% CrI 1.00 to 1.29; 111 RCTs, 33,156 participants). This might lead to an additional one quitter per 100 (95% CrI 0 to 2). Harms There were insufficient data to include nortriptyline and non-nicotine EC in the final SAE model. Overall rates of SAEs for the remaining treatments were low (average 3%). Low-certainty evidence did not show a clear difference in the number of people reporting SAEs for nicotine e-cigarettes, varenicline, cytisine or NRT when compared to no pharmacotherapy/e-cigarettes or placebo. Bupropion may slightly increase rates of SAEs, although the CrI also incorporated no difference (moderate certainty). In absolute terms bupropion may cause one more person in 100 to experience an SAE (95% CrI 0 to 2). AUTHORS' CONCLUSIONS: The most effective interventions were nicotine e-cigarettes, varenicline and cytisine (all high certainty), as well as combination NRT (additive effect, certainty not rated). There was also high-certainty evidence for the effectiveness of nicotine patch, fast-acting NRT and bupropion. Less certain evidence of benefit was present for nortriptyline (moderate certainty), non-nicotine e-cigarettes and tapering of nicotine dose (both low certainty). There was moderate-certainty evidence that bupropion may slightly increase the frequency of SAEs, although there was also the possibility of no increased risk. There was no clear evidence that any other tested interventions increased SAEs. Overall, SAE data were sparse with very low numbers of SAEs, and so further evidence may change our interpretation and certainty. Future studies should report SAEs to strengthen certainty in this outcome. More head-to-head comparisons of the most effective interventions are needed, as are tests of combinations of these. Future work should unify data from behavioural and pharmacological interventions to inform approaches to combined support for smoking cessation.
Weight management strategies in Middle-Aged Women (MAW): Development and validation of a questionnaire based on the Oxford Food and Activity Behaviors Taxonomy (OxFAB-MAW) in a Portuguese sample
Background: The Oxford Food and Activity Behaviors (OxFAB) taxonomy systematize the cognitive-behavioral strategies adopted by individuals who are attempting to manage their weight. The present study aimed to (1) develop a questionnaire based on the OxFAB taxonomy, specifically adapted for middle-aged women—the OxFAB-MAW—stage of life and sex, which present a high incidence of obesity, (2) assess the psychometric properties of this tool, and (3) evaluate the discriminative power of the OxFAB-MAW (normal weight vs. obesity). Methods: Overall, 1,367 Portuguese middle-aged women between 45 and 65 years (M = 52.3, SD = 5.15) filled in a sociodemographic, health, and menopause-related questionnaire, as well as the OxFAB-MAW. Results: Confirmatory factor analysis demonstrated an acceptable model fit (comparative fit index = 0.928, Tucker–Lewis index = 0.913, root mean square error of approximation = 0.072, and standardized root mean square residual = 0.054). Five domains with one item were grouped into other domains, and the Weight Management Aids domain was also removed. The OxFAB-MAW showed factorial, convergent, discriminant, and external validity, as well as composite reliability. Conclusion: The OxFAB-MAW questionnaire is a valid, reliable, and theory-driven tool for assessing weight management strategies in middle-aged women, being able to discriminate between clinical and non-clinical groups (normal weight vs. obesity) in several domains. This instrument can be used to gather valid and reliable data, useful in both research and clinical settings (especially focused on structuring interventions and preventive obesity programs within this specific life cycle stage).
Background: The COVID-19 pandemic has highlighted health disparities affecting ethnic minority communities. There is growing concern about the lack of diversity in clinical trials. This study aimed to assess the representation of ethnic groups in UK-based COVID-19 randomised controlled trials (RCTs). Methods: A systematic review and meta-analysis were undertaken. A search strategy was developed for MEDLINE (Ovid) and Google Scholar (1st January 2020–4th May 2022). Prospective COVID-19 RCTs for vaccines or therapeutics that reported UK data separately with a minimum of 50 participants were eligible. Search results were independently screened, and data extracted into proforma. Percentage of ethnic groups at all trial stages was mapped against Office of National Statistics (ONS) statistics. Post hoc DerSimonian-Laird random-effects meta-analysis of percentages and a meta-regression assessing recruitment over time were conducted. Due to the nature of the review question, risk of bias was not assessed. Data analysis was conducted in Stata v17.0. A protocol was registered (PROSPERO CRD42021244185). Results: In total, 5319 articles were identified; 30 studies were included, with 118,912 participants. Enrolment to trials was the only stage consistently reported (17 trials). Meta-analysis showed significant heterogeneity across studies, in relation to census-expected proportions at study enrolment. All ethnic groups, apart from Other (1.7% [95% CI 1.1–2.8%] vs ONS 1%) were represented to a lesser extent than ONS statistics, most marked in Black (1% [0.6–1.5%] vs 3.3%) and Asian (5.8% [4.4–7.6%] vs 7.5%) groups, but also apparent in White (84.8% [81.6–87.5%] vs 86%) and Mixed 1.6% [1.2–2.1%] vs 2.2%) groups. Meta-regression showed recruitment of Black participants increased over time (p = 0.009). Conclusions: Asian, Black and Mixed ethnic groups are under-represented or incorrectly classified in UK COVID-19 RCTs. Reporting by ethnicity lacks consistency and transparency. Under-representation in clinical trials occurs at multiple levels and requires complex solutions, which should be considered throughout trial conduct. These findings may not apply outside of the UK setting.
Use of Cognitive and Behavioral Strategies During a Weight Loss Program: A Secondary Analysis of the Doctor Referral of Overweight People to Low-Energy Total Diet Replacement Treatment (DROPLET) Trial
Background: Achieving a sustained energy deficit is essential for weight loss, but the cognitive and behavioral strategies that support this goal are unclear. Objective: The goal of this study was to investigate the number and type of cognitive and behavioral strategies used by participants who were enrolled in a 1-year weight loss trial and to explore associations between strategies and magnitude of weight loss at 3 months and 1 year. Design: The study is a secondary post-hoc exploratory analysis of data collected as part of the Doctor Referral of Overweight People to Low-Energy total diet replacement Treatment (DROPLET), a randomized controlled trial conducted in general practices in England, United Kingdom, between January 2016 and August 2017. Participants/setting: This study involved 164 participants from both intervention and control groups of the DROPLET trial who completed the Oxford Food and Behaviours (OxFAB) questionnaire to assess the use of 115 strategies grouped into 21 domains used to manage their weight. Interventions: Participants were randomized to either a behavioral weight loss program involving 8 weeks total diet replacement (TDR) and 4 weeks of food reintroduction or a program delivered by a medical practice nurse over a 3-month period (usual care [UC]). Main outcome measures: Weight was objectively measured at baseline, 3 months, and 1 year. Cognitive and behavioral strategies used to support weight loss were assessed using the OxFAB questionnaire at 3 months. Statistical analysis performed: Exploratory factor analysis was used to generate data-driven patterns of strategy use, and a linear mixed-effects model was used to examine associations between use of these patterns and weight change. Results: No evidence was found of a difference in the number of strategies (mean difference, 2.41; 95% confidence interval [CI], −0.83, 5.65) or the number of domains used (mean difference, −0.23; 95% CI, −0.69, 0.23) between the TDR group and the UC group. The number of strategies was not associated with weight loss at either 3 months (−0.02 kg; 95% CI, −0.11, 0.06) or 1 year (−0.05 kg; 95% CI, −0.14, 0.02). Similarly, the number of domains used was not associated with weight loss at 3 months (−0.02 kg; 95% CI, −0.53, 0.49) or 1 year (−0.07 kg; 95% CI, −0.60, 0.46). Factor analysis identified four coherent patterns of strategy use, identified as Physical Activity, Motivation, Planned Eating, and Food Purchasing patterns. Greater use of strategies in the Food Purchasing (−2.6 kg; 95% CI, −4.42, −0.71) and Planned Eating patterns (−3.20 kg; 95% CI, −4.94, −1.46) was associated with greater weight loss at 1 year. Conclusions: The number of cognitive and behavioral strategies or domains used does not appear to influence weight loss, but the types of strategy appear of greater importance. Supporting people to adopt strategies linked to planned eating and food purchasing may aid long-term weight loss.
Background: The pharmacological profiles and mechanisms of antidepressants are varied. However, there are common reasons why they might help people to stop smoking tobacco: nicotine withdrawal can produce short-term low mood that antidepressants may relieve; and some antidepressants may have a specific effect on neural pathways or receptors that underlie nicotine addiction. Objectives: To assess the evidence for the efficacy, harms, and tolerability of medications with antidepressant properties in assisting long-term tobacco smoking cessation in people who smoke cigarettes. Search methods: We searched the Cochrane Tobacco Addiction Group Specialised Register, most recently on 29 April 2022. Selection criteria: We included randomised controlled trials (RCTs) in people who smoked, comparing antidepressant medications with placebo or no pharmacological treatment, an alternative pharmacotherapy, or the same medication used differently. We excluded trials with fewer than six months of follow-up from efficacy analyses. We included trials with any follow-up length for our analyses of harms. Data collection and analysis: We extracted data and assessed risk of bias using standard Cochrane methods. Our primary outcome measure was smoking cessation after at least six months' follow-up. We used the most rigorous definition of abstinence available in each trial, and biochemically validated rates if available. Our secondary outcomes were harms and tolerance outcomes, including adverse events (AEs), serious adverse events (SAEs), psychiatric AEs, seizures, overdoses, suicide attempts, death by suicide, all-cause mortality, and trial dropouts due to treatment. We carried out meta-analyses where appropriate. Main results: We included a total of 124 studies (48,832 participants) in this review, with 10 new studies added to this update version. Most studies recruited adults from the community or from smoking cessation clinics; four studies focused on adolescents (with participants between 12 and 21 years old). We judged 34 studies to be at high risk of bias; however, restricting analyses only to studies at low or unclear risk of bias did not change clinical interpretation of the results. There was high-certainty evidence that bupropion increased smoking cessation rates when compared to placebo or no pharmacological treatment (RR 1.60, 95% CI 1.49 to 1.72; I2 = 16%; 50 studies, 18,577 participants). There was moderate-certainty evidence that a combination of bupropion and varenicline may have resulted in superior quit rates to varenicline alone (RR 1.21, 95% CI 0.95 to 1.55; I2 = 15%; 3 studies, 1057 participants). However, there was insufficient evidence to establish whether a combination of bupropion and nicotine replacement therapy (NRT) resulted in superior quit rates to NRT alone (RR 1.17, 95% CI 0.95 to 1.44; I2 = 43%; 15 studies, 4117 participants; low-certainty evidence). There was moderate-certainty evidence that participants taking bupropion were more likely to report SAEs than those taking placebo or no pharmacological treatment. However, results were imprecise and the CI also encompassed no difference (RR 1.16, 95% CI 0.90 to 1.48; I2 = 0%; 23 studies, 10,958 participants). Results were also imprecise when comparing SAEs between people randomised to a combination of bupropion and NRT versus NRT alone (RR 1.52, 95% CI 0.26 to 8.89; I2 = 0%; 4 studies, 657 participants) and randomised to bupropion plus varenicline versus varenicline alone (RR 1.23, 95% CI 0.63 to 2.42; I2 = 0%; 5 studies, 1268 participants). In both cases, we judged evidence to be of low certainty. There was high-certainty evidence that bupropion resulted in more trial dropouts due to AEs than placebo or no pharmacological treatment (RR 1.44, 95% CI 1.27 to 1.65; I2 = 2%; 25 studies, 12,346 participants). However, there was insufficient evidence that bupropion combined with NRT versus NRT alone (RR 1.67, 95% CI 0.95 to 2.92; I2 = 0%; 3 studies, 737 participants) or bupropion combined with varenicline versus varenicline alone (RR 0.80, 95% CI 0.45 to 1.45; I2 = 0%; 4 studies, 1230 participants) had an impact on the number of dropouts due to treatment. In both cases, imprecision was substantial (we judged the evidence to be of low certainty for both comparisons). Bupropion resulted in inferior smoking cessation rates to varenicline (RR 0.73, 95% CI 0.67 to 0.80; I2 = 0%; 9 studies, 7564 participants), and to combination NRT (RR 0.74, 95% CI 0.55 to 0.98; I2 = 0%; 2 studies; 720 participants). However, there was no clear evidence of a difference in efficacy between bupropion and single-form NRT (RR 1.03, 95% CI 0.93 to 1.13; I2 = 0%; 10 studies, 7613 participants). We also found evidence that nortriptyline aided smoking cessation when compared with placebo (RR 2.03, 95% CI 1.48 to 2.78; I2 = 16%; 6 studies, 975 participants), and some evidence that bupropion resulted in superior quit rates to nortriptyline (RR 1.30, 95% CI 0.93 to 1.82; I2 = 0%; 3 studies, 417 participants), although this result was subject to imprecision. Findings were sparse and inconsistent as to whether antidepressants, primarily bupropion and nortriptyline, had a particular benefit for people with current or previous depression. Authors' conclusions: There is high-certainty evidence that bupropion can aid long-term smoking cessation. However, bupropion may increase SAEs (moderate-certainty evidence when compared to placebo/no pharmacological treatment). There is high-certainty evidence that people taking bupropion are more likely to discontinue treatment compared with people receiving placebo or no pharmacological treatment. Nortriptyline also appears to have a beneficial effect on smoking quit rates relative to placebo, although bupropion may be more effective. Evidence also suggests that bupropion may be as successful as single-form NRT in helping people to quit smoking, but less effective than combination NRT and varenicline. In most cases, a paucity of data made it difficult to draw conclusions regarding harms and tolerability. Further studies investigating the efficacy of bupropion versus placebo are unlikely to change our interpretation of the effect, providing no clear justification for pursuing bupropion for smoking cessation over other licensed smoking cessation treatments; namely, NRT and varenicline. However, it is important that future studies of antidepressants for smoking cessation measure and report on harms and tolerability.
Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation
Background: Nicotine replacement therapy (NRT) aims to replace nicotine from cigarettes. This helps to reduce cravings and withdrawal symptoms, and ease the transition from cigarette smoking to complete abstinence. Although there is high-certainty evidence that NRT is effective for achieving long-term smoking abstinence, it is unclear whether different forms, doses, durations of treatment or timing of use impacts its effects. Objectives: To determine the effectiveness and safety of different forms, deliveries, doses, durations and schedules of NRT, for achieving long-term smoking cessation. Search methods: We searched the Cochrane Tobacco Addiction Group trials register for papers mentioning NRT in the title, abstract or keywords, most recently in April 2022. Selection criteria: We included randomised trials in people motivated to quit, comparing one type of NRT use with another. We excluded studies that did not assess cessation as an outcome, with follow-up of fewer than six months, and with additional intervention components not matched between arms. Separate reviews cover studies comparing NRT to control, or to other pharmacotherapies. Data collection and analysis: We followed standard Cochrane methods. We measured smoking abstinence after at least six months, using the most rigorous definition available. We extracted data on cardiac adverse events (AEs), serious adverse events (SAEs) and study withdrawals due to treatment. Main results: We identified 68 completed studies with 43,327 participants, five of which are new to this update. Most completed studies recruited adults either from the community or from healthcare clinics. We judged 28 of the 68 studies to be at high risk of bias. Restricting the analysis only to those studies at low or unclear risk of bias did not significantly alter results for any comparisons apart from the preloading comparison, which tested the effect of using NRT prior to quit day whilst still smoking. There is high-certainty evidence that combination NRT (fast-acting form plus patch) results in higher long-term quit rates than single form (risk ratio (RR) 1.27, 95% confidence interval (CI) 1.17 to 1.37; I2 = 12%; 16 studies, 12,169 participants). Moderate-certainty evidence, limited by imprecision, indicates that 42/44 mg patches are as effective as 21/22 mg (24-hour) patches (RR 1.09, 95% CI 0.93 to 1.29; I2 = 38%; 5 studies, 1655 participants), and that 21 mg patches are more effective than 14 mg (24-hour) patches (RR 1.48, 95% CI 1.06 to 2.08; 1 study, 537 participants). Moderate-certainty evidence, again limited by imprecision, also suggests a benefit of 25 mg over 15 mg (16-hour) patches, but the lower limit of the CI encompassed no difference (RR 1.19, 95% CI 1.00 to 1.41; I2 = 0%; 3 studies, 3446 participants). Nine studies tested the effect of using NRT prior to quit day (preloading) in comparison to using it from quit day onward. There was moderate-certainty evidence, limited by risk of bias, of a favourable effect of preloading on abstinence (RR 1.25, 95% CI 1.08 to 1.44; I2 = 0%; 9 studies, 4395 participants). High-certainty evidence from eight studies suggests that using either a form of fast-acting NRT or a nicotine patch results in similar long-term quit rates (RR 0.90, 95% CI 0.77 to 1.05; I2 = 0%; 8 studies, 3319 participants). We found no clear evidence of an effect of duration of nicotine patch use (low-certainty evidence); duration of combination NRT use (low- and very low-certainty evidence); or fast-acting NRT type (very low-certainty evidence). Cardiac AEs, SAEs and withdrawals due to treatment were all measured variably and infrequently across studies, resulting in low- or very low-certainty evidence for all comparisons. Most comparisons found no clear evidence of an effect on these outcomes, and rates were low overall. More withdrawals due to treatment were reported in people using nasal spray compared to patches in one study (RR 3.47, 95% CI 1.15 to 10.46; 1 study, 922 participants; very low-certainty evidence) and in people using 42/44 mg patches in comparison to 21/22 mg patches across two studies (RR 4.99, 95% CI 1.60 to 15.50; I2 = 0%; 2 studies, 544 participants; low-certainty evidence). Authors' conclusions: There is high-certainty evidence that using combination NRT versus single-form NRT and 4 mg versus 2 mg nicotine gum can result in an increase in the chances of successfully stopping smoking. Due to imprecision, evidence was of moderate certainty for patch dose comparisons. There is some indication that the lower-dose nicotine patches and gum may be less effective than higher-dose products. Using a fast-acting form of NRT, such as gum or lozenge, resulted in similar quit rates to nicotine patches. There is moderate-certainty evidence that using NRT before quitting may improve quit rates versus using it from quit date only; however, further research is needed to ensure the robustness of this finding. Evidence for the comparative safety and tolerability of different types of NRT use is limited. New studies should ensure that AEs, SAEs and withdrawals due to treatment are reported.
The person-based development and realist evaluation of a pre-consultation form for GP consultations [version 2; peer review: 2 approved].
BackgroundUse of telephone, video and e-consultations is increasing. These can make consultations more transactional, potentially missing patients' concerns. This study aimed to develop a complex intervention to address patients' concerns more comprehensively in general practice and test the feasibility of this in a cluster-randomised framework.The complex intervention used two technologies: a patient-completed pre-consultation form used at consultation opening and a doctor-provided summary report provided at consultation closure. This paper reports on the development and realist evaluation of the pre-consultation questionnaire.MethodsA person-based approach was used to develop the pre-consultation form. An online questionnaire system was designed to allow patient self-completion of a form which could be shared with GPs. This was tested with 45 patients in three rounds, with iterative adjustments made based on feedback after each round.Subsequently, an intervention incorporating the pre-consultation form with the summary report was then tested in a cluster-randomised framework with 30 patients per practice in six practices: four randomised to intervention, and two to control. An embedded realist evaluation was carried out. The main feasibility study results are reported elsewhere.ResultsIntervention Development: 15 patients were recruited per practice. Twelve patients, six GPs and three administrators were interviewed and 32 changes were made iteratively in three rounds. Recruitment rates (proportion of patients responding to the text) increased from 15% in round one to 50% in round three.Realist evaluation: The pre-consultation form was most useful for people comfortable with technology and with hidden concerns or anxiety about the consultation. It resulted in more issues being discussed and support provided, more effective use of time and greater patient satisfaction.ConclusionsThe person-based approach was successful. The pre-consultation form uncovers more depth and improves satisfaction in certain consultations and patients. Technological improvements are required before this could be rolled out more widely.
Penicillin allergy status and its effect on antibiotic prescribing, patient outcomes and antimicrobial resistance (ALABAMA): protocol for a multicentre, parallel-arm, open-label, randomised pragmatic trial
INTRODUCTION: Incorrect penicillin allergy records are recognised as an important barrier to the safe treatment of infection and affect an estimated 2.7 million people in England. Penicillin allergy records are associated with worse health outcome and antimicrobial resistance. The ALlergy AntiBiotics And Microbial resistAnce (ALABAMA) trial aims to determine if an intervention package, centred around a penicillin allergy assessment pathway (PAAP) initiated in primary care, is safe and effective in improving patient health outcomes and antibiotic prescribing. METHODS AND ANALYSIS: The ALABAMA trial is a multicentre, parallel-arm, open-label, randomised pragmatic trial with a nested pilot study. Adults (≥18 years) with a penicillin allergy record and who have received antibiotics in the previous 24 months will be eligible for participation. Between 1592 and 2090 participants will be recruited from participating National Health Service general practices in England. Participants will be randomised to either usual care or intervention to undergo a pre-emptive PAAP using a 1:1 allocation ratio. The primary outcome measure is the percentage of treatment response failures within 28 days of an index prescription. 2090 and 1592 participants are estimated to provide 90% and 80% power, respectively, to detect a clinically important absolute difference of 7.9% in primary outcome at 1 year between groups. The trial includes a mixed-methods process evaluation and cost-effectiveness evaluation. ETHICS AND DISSEMINATION: This trial has been approved by London Bridge Research Ethics Committee (ref: 19/LO/0176). It will be conducted in compliance with Good Clinical Practice guidelines according to the Declaration of Helsinki. Informed consent will be obtained from all subjects involved in the study. The primary trial results will be submitted for publication to an international, peer-reviewed journal. TRIAL REGISTRATION: ISRCTN20579216.
Predicting the risk of acute kidney injury in primary care: derivation and validation of STRATIFY-AKI
BACKGROUND: Antihypertensives reduce the risk of cardiovascular disease but are also associated with harms including acute kidney injury (AKI). Few data exist to guide clinical decision making regarding these risks. AIM: To develop a prediction model estimating the risk of AKI in people potentially indicated for antihypertensive treatment. DESIGN AND SETTING: Observational cohort study using routine primary care data from the Clinical Practice Research Datalink (CPRD) in England. METHOD: People aged ≥40 years, with at least one blood pressure measurement between 130 mmHg and 179 mmHg were included. Outcomes were admission to hospital or death with AKI within 1, 5, and 10 years. The model was derived with data from CPRD GOLD (n = 1 772 618), using a Fine-Gray competing risks approach, with subsequent recalibration using pseudo-values. External validation used data from CPRD Aurum (n = 3 805 322). RESULTS: The mean age of participants was 59.4 years and 52% were female. The final model consisted of 27 predictors and showed good discrimination at 1, 5, and 10 years (C-statistic for 10-year risk 0.821, 95% confidence interval [CI] = 0.818 to 0.823). There was some overprediction at the highest predicted probabilities (ratio of observed to expected event probability for 10-year risk 0.633, 95% CI = 0.621 to 0.645), affecting patients with the highest risk. Most patients (>95%) had a low 1- to 5-year risk of AKI, and at 10 years only 0.1% of the population had a high AKI and low CVD risk. CONCLUSION: This clinical prediction model enables GPs to accurately identify patients at high risk of AKI, which will aid treatment decisions. As the vast majority of patients were at low risk, such a model may provide useful reassurance that most antihypertensive treatment is safe and appropriate while flagging the few for whom this is not the case.
The early use of Antibiotics for At-risk children with InfluEnza in Primary Care (the ARCHIE programme)
Background: Influenza and influenza-like illness place significant burden on the NHS. Children with underlying health conditions are vulnerable to developing bacterial complications. Objective: To strengthen the evidence base underlying antibiotic use in at-risk children with influenza-like illness. Design: This programme comprised five separate work packages. Work package A investigated published and unpublished data from previously published literature and work package B explored attitudes of parents and general practitioners to influenza-like illness and antibiotics in at-risk children. This was followed by a clinical trial to assess the effectiveness of early co-amoxiclav (Augmentin®, GlaxoSmithKline UK) use at reducing reconsultation due to clinical deterioration (work package C), a nested sub-study to examine bacterial carriage indicators of antibiotic resistance (work package D) and a within-trial economic evaluation and clinical risk prediction analysis (work package E). Setting: Interviews were conducted by telephone with general practitioners across the UK and parents/ guardians in England (work package B). We conducted the clinical trial (work package C and nested work packages D and E) in general practices and ambulatory care services in England and Wales. Participants: General practitioners and parents/guardians of at-risk children who previously had influenza-like illness participated in work package B. At-risk children with influenza-like illness aged 6 months to 12 years participated in work packages C and E and optionally in work package D. Interventions: The intervention for the clinical trial was a 5-day course of co-amoxiclav 400/57 with dosing regimens based on British National Formulary guidance. Main outcome measures: Hospital admission (work package A); findings from semi-structured interviews with patients and health-care professionals (work package B); proportion of patients who reconsulted owing to clinical deterioration (work package C); respiratory bacterial carriage and antibiotic resistance of potentially pathogenic respiratory tract bacteria at 3, 6, 9 and 12 months (work package D); and risk factors for reconsultation owing to clinical deterioration, quality of life (EuroQol-5 Dimensions, three-level youth version), symptoms (Canadian Acute Respiratory Infection and Flu Scale), health-care use and costs (work package E). Review methods: For work package A, we searched the MEDLINE, MEDLINE In-Process, EMBASE, Science Citation Index and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases until 3 April 2013 with no language restrictions and requested unpublished data from authors of studies which had collected but not published relevant data. We included studies involving children up to 18 years of age with influenza or influenza-like illness from primary or ambulatory care settings. We used univariable meta-analysis methods to calculate odds ratios with 95% confidence intervals for individual risk factors. We reported our systematic review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2009 statement. Results: Work package A analysed data from 28 articles reporting data from 27 studies. Neurological disorders, sickle cell disease, immunosuppression, diabetes and an age of <2 years were risk factors for hospital admission. Work package B interviewed 41 general practitioners and found that decision-making in at-risk children with influenza-like illness varies considerably. Parents/guardians were interviewed for work package B and spoke of how quickly their at-risk child could deteriorate. They were supportive of antibiotic use while being aware of antibiotic resistance. The trial (work package C) recruited 271 at-risk children. Primary outcome data were available for 265 children. There was no evidence of benefit from treatment with co-amoxiclav versus placebo (adjusted risk ratio 1.16, 95% confidence interval 0.75 to 1.80). Work package D collected 285 additional throat swabs over 12 months. At 3 months, the proportion of Haemophilus influenzae isolates was greater in the placebo than co-amoxiclav group (29% vs. 18%). No association was found between antibiotic resistance and early co-amoxiclav use. No clinical features were significantly associated with risk of reconsultation due to clinical deterioration except respiratory rate (coefficient 0.046, 95% confidence interval 0.010 to 0.081). Work package E found no evidence that early co-amoxiclav treatment improves quality of life or reduces health-care use and costs. Total costs per patient were highly skewed in both groups (co-amoxiclav: median £4, range £4–5258; placebo: median £0, range £0–5177). Limitations: We were not able to recruit our target sample size for the trial. This impacted the data available for microbiology, health economics and risk reduction score analyses. Conclusions: Our results do not support early antibiotic prescribing to at-risk children with influenza-like illness during influenza season. Future work: Further research is required to determine if antibiotic treatment would be beneficial during periods of higher influenza activity such as influenza pandemics, to identify children who would gain most clinical benefit and to better understand families’ reconsultation decisions. Trial registration: This trial is registered as ISRCTN70714783 and EudraCT 2013-002822-21.
Thrombocytopenic, thromboembolic and haemorrhagic events following second dose with BNT162b2 and ChAdOx1: self-controlled case series analysis of the English national sentinel cohort
Background: Thrombosis associated with thrombocytopenia was a matter of concern post first and second doses of BNT162b2 and ChAdOx1 COVID-19 vaccines. Therefore, it is important to investigate the risk of thrombocytopenic, thromboembolic and haemorrhagic events following a second dose of BNT162b2 and ChAdOx1 COVID-19 vaccines. Methods: We conducted a large-scale self-controlled case series analysis, using routine primary care data linked to hospital data, among 12.3 million individuals (16 years old and above) in England. We used the nationally representative Oxford-Royal College of General Practitioners (RCGP) sentinel network database with baseline and risk periods between 8th December 2020 and 11th June 2022. We included individuals who received two vaccine (primary) doses of the BNT162b2 mRNA (Pfizer-BioNTech) and two vaccine doses of ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines in our analyses. We carried out a self-controlled case series (SCCS) analysis for each outcome using a conditional Poisson regression model with an offset for the length of risk period. We reported the incidence rate ratios (IRRs) and 95% confidence intervals (CI) of thrombocytopenic, thromboembolic (including arterial and venous events) and haemorrhagic events, in the period of 0–27 days after receiving a second dose of BNT162b2 or ChAdOx1 vaccines compared to the baseline period (14 or more days prior to first dose, 28 or more days after the second dose and the time between 28 or more days after the first and 14 or more days prior to the second dose). We adjusted for a range of potential confounders, including age, sex, comorbidities and deprivation. Findings: Between December 8, 2020 and February 11, 2022, 6,306,306 individuals were vaccinated with two doses of BNT162b2 and 6,046,785 individuals were vaccinated with two doses of ChAdOx1. Compared to the baseline, our analysis show no increased risk of venous thromboembolic events (VTE) for both BNT162b2 (IRR 0.71, 95% CI: 0.65–0.770) and ChAdOx1 (IRR 0.91, 95% CI: 0.84–0.98); and similarly there was no increased risk for cerebral venous sinus thrombosis (CVST) for both BNT162b2 (IRR 0.87, 95% CI: 0.41–1.85) and ChAdOx1 (IRR 1.73, 95% CI: 0.82–3.68). We additionally report no difference in IRR for pulmonary embolus, and deep vein thrombosis, thrombocytopenia, including idiopathic thrombocytopenic purpura (ITP), and haemorrhagic events post second dose for both BNT162b2. Interpretation: Reassuringly, we found no associations between increased risk of thrombocytopenic, thromboembolic and haemorrhagic events post vaccination with second dose for either of these vaccines. Funding: Data and Connectivity: COVID-19 Vaccines Pharmacovigilance study.