Using Trial Sequential Analysis for estimating the sample sizes of further trials: example using smoking cessation intervention.

BACKGROUND: Assessing benefits and harms of health interventions is resource-intensive and often requires feasibility and pilot trials followed by adequately powered randomised clinical trials. Data from feasibility and pilot trials are used to inform the design and sample size of the adequately powered randomised clinical trials. When a randomised clinical trial is conducted, results from feasibility and pilot trials may be disregarded in terms of benefits and harms. METHODS: We describe using feasibility and pilot trial data in the Trial Sequential Analysis software to estimate the required sample size for one or more trials investigating a behavioural smoking cessation intervention. We show how data from a new, planned trial can be combined with data from the earlier trials using trial sequential analysis methods to assess the intervention's effects. RESULTS: We provide a worked example to illustrate how we successfully used the Trial Sequential Analysis software to arrive at a sensible sample size for a new randomised clinical trial and use it in the argumentation for research funds for the trial. CONCLUSIONS: Trial Sequential Analysis can utilise data from feasibility and pilot trials as well as other trials, to estimate a sample size for one or more, similarly designed, future randomised clinical trials. As this method uses available data, estimated sample sizes may be smaller than they would have been using conventional sample size estimation methods.

Pharmacological interventions for promoting smoking cessation during pregnancy.

BACKGROUND: Tobacco smoking in pregnancy causes serious health problems for the developing fetus and mother. When used by non-pregnant smokers, pharmacotherapies (nicotine replacement therapy (NRT), bupropion, and varenicline) are effective for increasing smoking cessation, however their efficacy and safety in pregnancy remains unknown. Electronic cigarettes (ECs) are becoming widely used, but their efficacy and safety when used for smoking cessation in pregnancy are also unknown. OBJECTIVES: To determine the efficacy and safety of smoking cessation pharmacotherapies and ECs used during pregnancy for smoking cessation in later pregnancy and after childbirth, and to determine adherence to smoking cessation pharmacotherapies and ECs for smoking cessation during pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (20 May 2019), trial registers, and grey literature, and checked references of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) conducted in pregnant women, comparing smoking cessation pharmacotherapy or EC use with either placebo or no pharmacotherapy/EC control. We excluded quasi-randomised, cross-over, and within-participant designs, and RCTs with additional intervention components not matched between trial arms. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. The primary efficacy outcome was smoking cessation in later pregnancy; safety was assessed by 11 outcomes (principally birth outcomes) that indicated neonatal and infant well-being. We also collated data on adherence to trial treatments. We calculated the risk ratio (RR) or mean difference (MD) and the 95% confidence intervals (CI) for each outcome for each study, where possible. We grouped eligible studies according to the type of comparison. We carried out meta-analyses where appropriate. MAIN RESULTS: We included 11 trials that enrolled a total of 2412 pregnant women who smoked at enrolment, nine trials of NRT and two trials of bupropion as adjuncts to behavioural support, with comparable behavioural support provided in the control arms. No trials investigated varenicline or ECs. We assessed four trials as at low risk of bias overall. The overall certainty of the evidence was low across outcomes and comparisons as assessed using GRADE, with reductions in confidence due to risk of bias, imprecision, and inconsistency. Compared to placebo and non-placebo (behavioural support only) controls, there was low-certainty evidence that NRT increased the likelihood of smoking abstinence in later pregnancy (RR 1.37, 95% CI 1.08 to 1.74; I² = 34%, 9 studies, 2336 women). However, in subgroup analysis by comparator type, there was a subgroup difference between placebo-controlled and non-placebo controlled RCTs (test for subgroup differences P = 0.008). There was unclear evidence of an effect in placebo-controlled RCTs (RR 1.21, 95% CI 0.95 to 1.55; I² = 0%, 6 studies, 2063 women), whereas non-placebo-controlled trials showed clearer evidence of a benefit (RR 8.55, 95% CI 2.05 to 35.71; I² = 0%, 3 studies, 273 women). An additional subgroup analysis in which studies were grouped by the type of NRT used found no difference in the effectiveness of NRT in those using patches or fast-acting NRT (test for subgroup differences P = 0.08). There was no evidence of a difference between NRT and control groups in rates of miscarriage, stillbirth, premature birth, birthweight, low birthweight, admissions to neonatal intensive care, caesarean section, congenital abnormalities, or neonatal death. In one study infants born to women who had been randomised to NRT had higher rates of 'survival without developmental impairment' at two years of age compared to the placebo group. Non-serious adverse effects observed with NRT included headache, nausea, and local reactions (e.g. skin irritation from patches or foul taste from gum), but data could not be pooled. Adherence to NRT treatment regimens was generally low. We identified low-certainty evidence that there was no difference in smoking abstinence rates observed in later pregnancy in women using bupropion when compared to placebo control (RR 0.74, 95% CI 0.21 to 2.64; I² = 0%, 2 studies, 76 women). Evidence investigating the safety outcomes of bupropion use was sparse, but the existing evidence showed no difference between the bupropion and control group. AUTHORS' CONCLUSIONS: NRT used for smoking cessation in pregnancy may increase smoking cessation rates in late pregnancy. However, this evidence is of low certainty, as the effect was not evident when potentially biased, non-placebo-controlled RCTs were excluded from the analysis. Future studies may therefore change this conclusion. We found no evidence that NRT has either positive or negative impacts on birth outcomes; however, the evidence for some of these outcomes was also judged to be of low certainty due to imprecision and inconsistency. We found no evidence that bupropion may be an effective aid for smoking cessation during pregnancy, and there was little evidence evaluating its safety in this population. Further research evidence on the efficacy and safety of pharmacotherapy and EC use for smoking cessation in pregnancy is needed, ideally from placebo-controlled RCTs that achieve higher adherence rates and that monitor infants' outcomes into childhood. Future RCTs of NRT should investigate higher doses than those tested in the studies included in this review.

Systematic review and meta-analysis investigating nicotine, cotinine and carbon monoxide exposures in people who both smoke and use nicotine replacement therapy.

AIMS: To determine effects of concurrent smoking and nicotine replacement therapy (NRT) use on reported heaviness of smoking, nicotine (cotinine) body fluid and exhaled air carbon monoxide (CO) concentrations. METHODS: Systematic review and meta-analysis of RCTs, which test interventions permitting concurrent NRT use and smoking and comparing, within participants, outcomes when smoking with those when smoking and using NRT concurrently. Measurements included reported number of cigarettes smoked per day (CPD), body fluid cotinine and expired air CO concentrations. RESULTS: Twenty-nine studies were included in the review. Meta-analysis of nine showed that, compared with when solely smoking, fewer cigarettes were smoked daily when NRT was used (mean difference during concurrent smoking and NRT use, -2.06 CPD [95% CI = -3.06 to -1.07, P < 0.0001]). Meta-analysis of seven studies revealed a non-significant reduction in exhaled CO during concurrent smoking and NRT use (mean difference, -0.58 ppm [95% CI = -2.18 to 1.03, P = 0.48]), but in the three studies that tested NRT used in the lead-up to quitting (i.e. as preloading), a similar reduction in exhaled CO was statistically significant (mean difference, -2.54 ppm CO [95% CI = -4.14 to -0.95, P = 0.002]). Eleven studies reported cotinine concentrations, but meta-analysis was not possible because of data reporting heterogeneity; of these, seven reported lower cotinine concentrations with concurrent NRT use and smoking, four reported no differences, and none reported higher concentrations. CONCLUSIONS: People who smoke and also use nicotine replacement therapy report smoking less heavily than people who solely smoke. When nicotine replacement therapy is used in the lead-up to quitting (preloading), this reported smoking reduction has been biochemically confirmed. There is no evidence that concurrent smoking and nicotine replacement therapy use result in greater nicotine exposure than solely smoking.

Advancing the use of real world evidence in health technology assessment: insights from a multi-stakeholder workshop.

Introduction: Real-world evidence (RWE) in health technology assessment (HTA) holds significant potential for informing healthcare decision-making. A multistakeholder workshop was organised by the European Health Data and Evidence Network (EHDEN) and the GetReal Institute to explore the status, challenges, and opportunities in incorporating RWE into HTA, with a focus on learning from regulatory initiatives such as the European Medicines Agency (EMA) Data Analysis and Real World Interrogation Network (DARWIN EU®). Methods: The workshop gathered key stakeholders from regulatory agencies, HTA organizations, academia, and industry for three panel discussions on RWE and HTA integration. Insights and recommendations were collected through panel discussions and audience polls. The workshop outcomes were reviewed by authors to identify key themes, challenges, and recommendations. Results: The workshop discussions revealed several important findings relating to the use of RWE in HTA. Compared with regulatory processes, its adoption in HTA to date has been slow. Barriers include limited trust in RWE, data quality concerns, and uncertainty about best practices. Facilitators include multidisciplinary training, educational initiatives, and stakeholder collaboration, which could be facilitated by initiatives like EHDEN and the GetReal Institute. Demonstrating the impact of "driver projects" could promote RWE adoption in HTA. Conclusion: To enhance the integration of RWE in HTA, it is crucial to address known barriers through comprehensive training, stakeholder collaboration, and impactful exemplar research projects. By upskilling users and beneficiaries of RWE and those that generate it, promoting collaboration, and conducting "driver projects," can strengthen the HTA evidence base for more informed healthcare decisions.

Prognostic Factors of COVID-19: An Umbrella Review Endorsed by the International Society for Pharmacoepidemiology.

During the coronavirus disease 2019 (COVID-19) pandemic, the urgency for updated evidence to inform public health and clinical care placed systematic literature reviews (SLRs) at the cornerstone of research. We aimed to summarize evidence on prognostic factors for COVID-19 outcomes through published SLRs and to critically assess quality elements in the findings' interpretation. An umbrella review was conducted via electronic databases from January 2020 to April 2022. All SLRs (and meta-analyses) in English were considered. Data screening and extraction were conducted by two independent reviewers. AMSTAR 2 tool was used to assess SLR quality. The study was registered with PROSPERO (CRD4202232576). Out of 4,564 publications, 171 SLRs were included of which 3 were umbrella reviews. Our primary analysis included 35 SLRs published in 2022, which incorporated studies since the beginning of the pandemic. Consistent findings showed that, for adults, older age, obesity, heart disease, diabetes, and cancer were more strongly predictive of risk of hospitalization, intensive care unit admission, and mortality due to COVID-19. Male sex was associated with higher risk of short-term adverse outcomes, but female sex was associated with higher risk of long COVID. For children, socioeconomic determinants that may unravel COVID-19 disparities were rarely reported. This review highlights key prognostic factors of COVID-19, which can help clinicians and health officers identify high-risk groups for optimal care. Findings can also help optimize confounding adjustment and patient phenotyping in comparative effectiveness research. A living SLR approach may facilitate dissemination of new findings. This paper is endorsed by the International Society for Pharmacoepidemiology.

Comparison of saliva cotinine and exhaled carbon monoxide concentrations when smoking and after being offered dual nicotine replacement therapy in pregnancy.

BACKGROUND AND AIMS: Although English Stop Smoking Services routinely offer dual nicotine replacement therapy (NRT) to help pregnant women to quit smoking, little is known about how nicotine and tobacco smoke exposures following this compare with that from smoking. We compared, in pregnant women when smoking and after being offered dual NRT, saliva cotinine and exhaled carbon monoxide (CO) concentrations and numbers of daily cigarettes smoked. DESIGN AND SETTING: Secondary analysis of data from three sequential, observational, mixed-methods cohort studies conducted as part of the Nicotine Replacement Effectiveness and Delivery in Pregnancy programme. Participants were recruited on-line or in Nottingham University Hospitals (UK) antenatal clinics between June 2019 and September 2020. PARTICIPANTS: Forty pregnant women, who agreed to try stopping smoking. INTERVENTION: Participants were offered dual NRT, agreed a smoking quit date and received an intervention to improve adherence to NRT. MEASUREMENTS: Saliva cotinine and exhaled CO concentrations and reported number of cigarettes smoked per day. FINDINGS: There were no differences in saliva cotinine concentrations at baseline and day 7 post quit date [n = 20, mean difference = -32.31 ng/ml, 95% confidence interval (CI) = -68.11 to 3.5 ng/ml; P = 0.074, Bayes factor = 0.04]. There were reductions in the reported number of cigarettes smoked per day (n = 26, mean difference = -7 cigarettes, 95% CI = -8.35 to -5.42 cigarettes, P < 0.001) and concurrently in exhaled CO concentrations (n = 17, ratio of geometric means = 0.30 p.p.m., 95% CI = 0.17-0.52 p.p.m.; P < 0.001). CONCLUSION: Pregnant women who smoke and are offered dual nicotine replacement therapy (NRT) appear to show no change in their exposure to cotinine compared with their pre-NRT exposure levels but they report smoking fewer cigarettes, as validated by reductions in exhaled carbon monoxide concentrations.

Fetal safety of nicotine replacement therapy in pregnancy: systematic review and meta-analysis.

BACKGROUND AND AIMS: Smoking in pregnancy causes substantial avoidable harm to mothers and offspring; nicotine replacement therapy (NRT) may prevent this, and is used to help women to quit. A recently updated Cochrane Review of randomized controlled trials (RCTs) investigating impacts of NRT in pregnancy focuses primarily on efficacy data, but also reports adverse impacts from NRT. Here we identify and summarize NRT impacts on adverse pregnancy outcomes reported in non-randomized controlled trials (non-RCTs). METHODS: Systematic reviews and meta-analyses of RCTs and non-RCT studies of NRT in pregnancy, with design-specific risk of bias assessment and grading of recommendations, assessment, development and evaluations (GRADE) criteria applied to selected outcomes. FINDINGS: Relevant Cochrane Review findings are reported alongside those from this new review. Seven RCTs were included; n = 2340. Nine meta-analyses were performed; non-statistically significant estimates indicated potentially reduced risk from NRT compared with smoking for mean birth weight, low birth weight, preterm birth, intensive care admissions, neonatal death, congenital anomalies and caesarean section and potentially increased risks for miscarriage and stillbirth. GRADE assessment for mean birth weight and miscarriage outcomes indicated 'low' confidence in findings. Twenty-three non-RCTs were included; n = 931 163. Eleven large studies from five routine health-care cohorts reported clinical outcomes; 12 small studies investigated mainly physiological outcomes within in-patient women given NRT. Findings from meta-analyses for congenital anomalies, stillbirth and preterm birth were underpowered and not in a consistent direction; GRADE assessment of confidence in findings was 'very low'. Routine health-care studies were of higher quality, but implications of reported findings were unclear as there was inadequate measurement and reporting of women's smoking. CONCLUSIONS: Available evidence from randomized controlled trials and non-randomized comparative studies does not currently provide clear evidence as to whether maternal use of nicotine replacement therapy during pregnancy is harmful to the fetus.

Saliva cotinine concentrations in pregnant women who smoke and use nicotine patches.

BACKGROUND AND AIMS: Due to concerns about increased exposure to nicotine, pregnant women using nicotine replacement therapy (NRT) to stop smoking are usually advised to stop using NRT if they relapse to smoking. This study investigated whether this is justified. We compared changes in saliva cotinine from baseline to 2 weeks post-target quit date pregnant smokers who relapsed to smoking and continued to use their patches having been assigned to use nicotine patches or placebo. DESIGN AND SETTING: Controlled pre-post design stratified by intervention condition from the 'Study of Nicotine Patch in Pregnancy', a randomized, placebo-controlled trial. PARTICIPANTS: A sample of 268 pregnant women, assigned placebo (n = 122) or nicotine (n = 146) patches, who returned for further supplies of patches and who reported any smoking in the week prior to a visit at 2 weeks after their target quit date. MEASUREMENTS: Saliva cotinine concentrations were measured at baseline and 2 weeks after participants' target quit dates. Any smoking in the previous week was assessed by self-report, validated by expired air carbon monoxide (CO). FINDINGS: There was no change in saliva cotinine concentrations between baseline and 2 weeks post-target quit date in saliva cotinine concentration in the nicotine patch group [ratio of geometric means = 0.94, 95% confidence interval (CI) = 0.83 to 1.07; P = 0.37, Bayes factor = 0.15]. However, there was a reduction in reported number of cigarettes smoked/day (mean difference -6, 95% CIs -7 to -5, P < 0.001) and in CO concentrations (mean difference -3.0 parts per million, 95% CIs -4.2 to -1.9, P < 0.001). These changes were not significantly different from changes in the placebo group except for cigarette consumption, which reduced more in the nicotine group (P = 0.046). CONCLUSIONS: In women trying to stop smoking with the aid of a nicotine patch but having smoked at 2 weeks post-target quit, their nicotine concentration did not change from baseline, but they reported smoking fewer cigarettes and had lower carbon monoxide concentrations.

Comparison of nicotine exposure during pregnancy when smoking and abstinent with nicotine replacement therapy: systematic review and meta-analysis.

BACKGROUND AND AIMS: Smoking during pregnancy is strongly associated with negative pregnancy and perinatal outcomes. Some guidelines recommend nicotine replacement therapy (NRT) for smoking cessation during pregnancy, but adherence with NRT is generally poor and could be partially explained by nicotine-related safety concerns. We compared pregnant women's cotinine and nicotine exposures from smoking with those when they were abstinent from smoking and using NRT. DESIGN: Systematic review with meta-analysis and narrative reporting. Twelve studies were included: in most, only one type of NRT was used. Seven were quality-assessed and judge of variable quality. SETTING: Studies from any setting that reported nicotine or cotinine levels when smoking and later when abstinent and using NRT. PARTICIPANTS: Pregnant women who smoked and became abstinent but used NRT either in a cessation study or in a study investigating other impacts of NRT. MEASUREMENTS: We quality-assessed longitudinal cohort studies using a modified version of the Newcastle-Ottawa scale. For meta-analysis, we used mean within-person differences in cotinine or nicotine levels when smoking and at later follow-up when abstinent and using NRT. Where such data were not available, we calculated differences in group mean levels and reported these narratively, indicating where data were not completely longitudinal. FINDINGS: Of the 12 included studies, four cotinine-measuring studies (n = 83) were combined in a random effects meta-analysis; the pooled estimate for the mean difference (95% confidence intervals) in cotinine levels between when women were smoking and abstinent but using NRT was 75.3 (57.1 to 93.4) ng/ml (I2  = 42.1%, P = 0.11). Of eight narratively-described studies, six reported lower cotinine and/or nicotine levels when abstinent and using NRT; two had mixed findings, with higher levels when abstinent but using NRT reported from at least one assay time-point. CONCLUSIONS: Pregnant women who use nicotine replacement therapy instead of smoking reduce their nicotine exposure.