Background
Both behavioural support (including brief advice and counselling) and pharmacotherapies (including nicotine replacement therapy (NRT), varenicline and bupropion) are effective in helping ...people to stop smoking. Combining both treatment approaches is recommended where possible, but the size of the treatment effect with different combinations and in different settings and populations is unclear.
Objectives
To assess the effect of combining behavioural support and medication to aid smoking cessation, compared to a minimal intervention or usual care, and to identify whether there are different effects depending on characteristics of the treatment setting, intervention, population treated, or take‐up of treatment.
Search methods
We searched the Cochrane Tobacco Addiction Group Specialised Register in July 2015 for records with any mention of pharmacotherapy, including any type of NRT, bupropion, nortriptyline or varenicline.
Selection criteria
Randomized or quasi‐randomized controlled trials evaluating combinations of pharmacotherapy and behavioural support for smoking cessation, compared to a control receiving usual care or brief advice or less intensive behavioural support. We excluded trials recruiting only pregnant women, trials recruiting only adolescents, and trials with less than six months follow‐up.
Data collection and analysis
Search results were prescreened by one author and inclusion or exclusion of potentially relevant trials was agreed by two authors. Data was extracted by one author and checked by another.
The main outcome measure was abstinence from smoking after at least six months of follow‐up. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. We calculated the risk ratio (RR) and 95% confidence interval (CI) for each study. Where appropriate, we performed meta‐analysis using a Mantel‐Haenszel fixed‐effect model.
Main results
Fifty‐three studies with a total of more than 25,000 participants met the inclusion criteria. A large proportion of studies recruited people in healthcare settings or with specific health needs. Most studies provided NRT. Behavioural support was typically provided by specialists in cessation counselling, who offered between four and eight contact sessions. The planned maximum duration of contact was typically more than 30 minutes but less than 300 minutes. Overall, studies were at low or unclear risk of bias, and findings were not sensitive to the exclusion of any of the six studies rated at high risk of bias in one domain. One large study (the Lung Health Study) contributed heterogeneity due to a substantially larger treatment effect than seen in other studies (RR 3.88, 95% CI 3.35 to 4.50). Since this study used a particularly intensive intervention which included extended availability of nicotine gum, multiple group sessions and long term maintenance and recycling contacts, the results may not be comparable with the interventions used in other studies, and hence it was not pooled in other analyses. Based on the remaining 52 studies (19,488 participants) there was high quality evidence (using GRADE) for a benefit of combined pharmacotherapy and behavioural treatment compared to usual care, brief advice or less intensive behavioural support (RR 1.83, 95% CI 1.68 to 1.98) with moderate statistical heterogeneity (I² = 36%).
The pooled estimate for 43 trials that recruited participants in healthcare settings (RR 1.97, 95% CI 1.79 to 2.18) was higher than for eight trials with community‐based recruitment (RR 1.53, 95% CI 1.33 to 1.76). Compared to the first version of the review, previous weak evidence of differences in other subgroup analyses has disappeared. We did not detect differences between subgroups defined by motivation to quit, treatment provider, number or duration of support sessions, or take‐up of treatment.
Authors' conclusions
Interventions that combine pharmacotherapy and behavioural support increase smoking cessation success compared to a minimal intervention or usual care. Updating this review with an additional 12 studies (5,000 participants) did not materially change the effect estimate. Although trials differed in the details of their populations and interventions, we did not detect any factors that modified treatment effects apart from the recruitment setting. We did not find evidence from indirect comparisons that offering more intensive behavioural support was associated with larger treatment effects.
Background
Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol formed by heating an e‐liquid. People who smoke report using ECs to stop or reduce smoking, but ...some organisations, advocacy groups and policymakers have discouraged this, citing lack of evidence of efficacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit and if they are safe to use for this purpose. This review is an update of a review first published in 2014.
Objectives
To evaluate the effect and safety of using electronic cigarettes (ECs) to help people who smoke achieve long‐term smoking abstinence.
Search methods
We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO for relevant records to January 2020, together with reference‐checking and contact with study authors.
Selection criteria
We included randomized controlled trials (RCTs) and randomized cross‐over trials in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. To be included, studies had to report abstinence from cigarettes at six months or longer and/or data on adverse events (AEs) or other markers of safety at one week or longer.
Data collection and analysis
We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking after at least six months follow‐up, AEs, and serious adverse events (SAEs). Secondary outcomes included changes in carbon monoxide, blood pressure, heart rate, blood oxygen saturation, lung function, and levels of known carcinogens/toxicants. We used a fixed‐effect Mantel‐Haenszel model to calculate the risk ratio (RR) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data from these studies in meta‐analyses.
Main results
We include 50 completed studies, representing 12,430 participants, of which 26 are RCTs. Thirty‐five of the 50 included studies are new to this review update. Of the included studies, we rated four (all which contribute to our main comparisons) at low risk of bias overall, 37 at high risk overall (including the 24 non‐randomized studies), and the remainder at unclear risk.
There was moderate‐certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (risk ratio (RR) 1.69, 95% confidence interval (CI) 1.25 to 2.27; I2 = 0%; 3 studies, 1498 participants). In absolute terms, this might translate to an additional four successful quitters per 100 (95% CI 2 to 8). There was low‐certainty evidence (limited by very serious imprecision) of no difference in the rate of adverse events (AEs) (RR 0.98, 95% CI 0.80 to 1.19; I2 = 0%; 2 studies, 485 participants). SAEs occurred rarely, with no evidence that their frequency differed between nicotine EC and NRT, but very serious imprecision led to low certainty in this finding (RR 1.37, 95% CI 0.77 to 2.41: I2 = n/a; 2 studies, 727 participants).
There was moderate‐certainty evidence, again limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non‐nicotine EC (RR 1.71, 95% CI 1.00 to 2.92; I2 = 0%; 3 studies, 802 participants). In absolute terms, this might again lead to an additional four successful quitters per 100 (95% CI 0 to 12). These trials used EC with relatively low nicotine delivery. There was low‐certainty evidence, limited by very serious imprecision, that there was no difference in the rate of AEs between these groups (RR 1.00, 95% CI 0.73 to 1.36; I2 = 0%; 2 studies, 346 participants). There was insufficient evidence to determine whether rates of SAEs differed between groups, due to very serious imprecision (RR 0.25, 95% CI 0.03 to 2.19; I2 = n/a; 4 studies, 494 participants).
Compared to behavioural support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.50, 95% CI 1.24 to 5.04; I2 = 0%; 4 studies, 2312 participants). In absolute terms this represents an increase of six per 100 (95% CI 1 to 14). However, this finding was very low‐certainty, due to issues with imprecision and risk of bias. There was no evidence that the rate of SAEs varied, but some evidence that non‐serious AEs were more common in people randomized to nicotine EC (AEs: RR 1.17, 95% CI 1.04 to 1.31; I2 = 28%; 3 studies, 516 participants; SAEs: RR 1.33, 95% CI 0.25 to 6.96; I2 = 17%; 5 studies, 842 participants).
Data from non‐randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate over time with continued use. Very few studies reported data on other outcomes or comparisons and hence evidence for these is limited, with confidence intervals often encompassing clinically significant harm and benefit.
Authors' conclusions
There is moderate‐certainty evidence that ECs with nicotine increase quit rates compared to ECs without nicotine and compared to NRT. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the degree of effect, particularly when using modern EC products. Confidence intervals were wide for data on AEs, SAEs and other safety markers. Overall incidence of SAEs was low across all study arms. We did not detect any clear evidence of harm from nicotine EC, but longest follow‐up was two years and the overall number of studies was small.
The main limitation of the evidence base remains imprecision due to the small number of RCTs, often with low event rates. Further RCTs are underway. To ensure the review continues to provide up‐to‐date information for decision‐makers, this review is now a living systematic review. We will run searches monthly from December 2020, with the review updated as relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.
Background
Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and ...reducing smoking satisfaction (acting as an antagonist).
Objectives
To review the efficacy of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation.
Search methods
We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist') in the title or , or as keywords. The register is compiled from searches of MEDLINE, EMBASE, and PsycINFO using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialised register was in May 2015, although we have included a few key trials published after this date. We also searched online clinical trials registers.
Selection criteria
We included randomised controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow‐up period of six months from start of treatment.
Data collection and analysis
We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomisation procedure, concealment of allocation, and completeness of follow‐up.
The main outcome measured was abstinence from smoking at longest follow‐up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs), using the Mantel‐Haenszel fixed‐effect model.
Main results
Two trials of cytisine (937 people) found that more participants taking cytisine stopped smoking compared with placebo at longest follow‐up, with a pooled risk ratio (RR) of 3.98 (95% confidence interval (CI) 2.01 to 7.87; low‐quality evidence). One recent trial comparing cytisine with NRT in 1310 people found a benefit for cytisine at six months (RR 1.43, 95% CI 1.13 to 1.80).
One trial of dianicline (602 people) failed to find evidence that it was effective (RR 1.20, 95% CI 0.82 to 1.75). This drug is no longer in development.
We identified 39 trials that tested varenicline, 27 of which contributed to the primary analysis (varenicline versus placebo). Five of these trials also included a bupropion treatment arm. Eight trials compared varenicline with nicotine replacement therapy (NRT). Nine studies tested variations in varenicline dosage, and 13 tested usage in disease‐specific subgroups of patients. The included studies covered 25,290 participants, 11,801 of whom used varenicline.
The pooled RR for continuous or sustained abstinence at six months or longer for varenicline at standard dosage versus placebo was 2.24 (95% CI 2.06 to 2.43; 27 trials, 12,625 people; high‐quality evidence). Varenicline at lower or variable doses was also shown to be effective, with an RR of 2.08 (95% CI 1.56 to 2.78; 4 trials, 1266 people). The pooled RR for varenicline versus bupropion at six months was 1.39 (95% CI 1.25 to 1.54; 5 trials, 5877 people; high‐quality evidence). The RR for varenicline versus NRT for abstinence at 24 weeks was 1.25 (95% CI 1.14 to 1.37; 8 trials, 6264 people; moderate‐quality evidence). Four trials which tested the use of varenicline beyond the 12‐week standard regimen found the drug to be well‐tolerated during long‐term use. The number needed to treat with varenicline for an additional beneficial outcome, based on the weighted mean control rate, is 11 (95% CI 9 to 13). The most commonly reported adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. Our analysis of reported serious adverse events occurring during or after active treatment suggests there may be a 25% increase in the chance of SAEs among people using varenicline (RR 1.25; 95% CI 1.04 to 1.49; 29 trials, 15,370 people; high‐quality evidence). These events include comorbidities such as infections, cancers and injuries, and most were considered by the trialists to be unrelated to the treatments. There is also evidence of higher losses to follow‐up in the control groups compared with the intervention groups, leading to a likely underascertainment of the true rate of SAEs among the controls. Early concerns about a possible association between varenicline and depressed mood, agitation, and suicidal behaviour or ideation led to the addition of a boxed warning to the labelling in 2008. However, subsequent observational cohort studies and meta‐analyses have not confirmed these fears, and the findings of the EAGLES trial do not support a causal link between varenicline and neuropsychiatric disorders, including suicidal ideation and suicidal behaviour. The evidence is not conclusive, however, in people with past or current psychiatric disorders. Concerns have also been raised that varenicline may slightly increase cardiovascular events in people already at increased risk of those illnesses. Current evidence neither supports nor refutes such an association, but we await the findings of the CATS trial, which should establish whether or not this is a valid concern.
Authors' conclusions
Cytisine increases the chances of quitting, although absolute quit rates were modest in two recent trials. Varenicline at standard dose increased the chances of successful long‐term smoking cessation between two‐ and three‐fold compared with pharmacologically unassisted quit attempts. Lower dose regimens also conferred benefits for cessation, while reducing the incidence of adverse events. More participants quit successfully with varenicline than with bupropion or with NRT. Limited evidence suggests that varenicline may have a role to play in relapse prevention. The most frequently recorded adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Early reports of possible links to suicidal ideation and behaviour have not been confirmed by current research.
Future trials of cytisine may test extended regimens and more intensive behavioural support.
Background
Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol formed by heating an e‐liquid. Some people who smoke use ECs to stop or reduce smoking, but some ...organizations, advocacy groups and policymakers have discouraged this, citing lack of evidence of efficacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit and if they are safe to use for this purpose. This is an update of a review first published in 2014.
Objectives
To examine the effectiveness, tolerability, and safety of using electronic cigarettes (ECs) to help people who smoke achieve long‐term smoking abstinence.
Search methods
We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 February 2021, together with reference‐checking and contact with study authors.
Selection criteria
We included randomized controlled trials (RCTs) and randomized cross‐over trials in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. To be included, studies had to report abstinence from cigarettes at six months or longer and/or data on adverse events (AEs) or other markers of safety at one week or longer.
Data collection and analysis
We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking after at least six months follow‐up, adverse events (AEs), and serious adverse events (SAEs). Secondary outcomes included changes in carbon monoxide, blood pressure, heart rate, blood oxygen saturation, lung function, and levels of known carcinogens/toxicants. We used a fixed‐effect Mantel‐Haenszel model to calculate the risk ratio (RR) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data from these studies in meta‐analyses.
Main results
We included 56 completed studies, representing 12,804 participants, of which 29 were RCTs. Six of the 56 included studies were new to this review update. Of the included studies, we rated five (all contributing to our main comparisons) at low risk of bias overall, 41 at high risk overall (including the 25 non‐randomized studies), and the remainder at unclear risk.
There was moderate‐certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (risk ratio (RR) 1.69, 95% confidence interval (CI) 1.25 to 2.27; I2 = 0%; 3 studies, 1498 participants). In absolute terms, this might translate to an additional four successful quitters per 100 (95% CI 2 to 8). There was low‐certainty evidence (limited by very serious imprecision) that the rate of occurrence of AEs was similar) (RR 0.98, 95% CI 0.80 to 1.19; I2 = 0%; 2 studies, 485 participants). SAEs occurred rarely, with no evidence that their frequency differed between nicotine EC and NRT, but very serious imprecision led to low certainty in this finding (RR 1.37, 95% CI 0.77 to 2.41: I2 = n/a; 2 studies, 727 participants).
There was moderate‐certainty evidence, again limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non‐nicotine EC (RR 1.70, 95% CI 1.03 to 2.81; I2 = 0%; 4 studies, 1057 participants). In absolute terms, this might again lead to an additional four successful quitters per 100 (95% CI 0 to 11). These trials mainly used older EC with relatively low nicotine delivery. There was moderate‐certainty evidence of no difference in the rate of AEs between these groups (RR 1.01, 95% CI 0.91 to 1.11; I2 = 0%; 3 studies, 601 participants). There was insufficient evidence to determine whether rates of SAEs differed between groups, due to very serious imprecision (RR 0.60, 95% CI 0.15 to 2.44; I2 = n/a; 4 studies, 494 participants).
Compared to behavioral support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.70, 95% CI 1.39 to 5.26; I2 = 0%; 5 studies, 2561 participants). In absolute terms this represents an increase of seven per 100 (95% CI 2 to 17). However, this finding was of very low certainty, due to issues with imprecision and risk of bias. There was no evidence that the rate of SAEs differed, but some evidence that non‐serious AEs were more common in people randomized to nicotine EC (AEs: RR 1.22, 95% CI 1.12 to 1.32; I2 = 41%, low certainty; 4 studies, 765 participants; SAEs: RR 1.17, 95% CI 0.33 to 4.09; I2 = 5%; 6 studies, 1011 participants, very low certainty).
Data from non‐randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate with continued use. Very few studies reported data on other outcomes or comparisons and hence evidence for these is limited, with confidence intervals often encompassing clinically significant harm and benefit.
Authors' conclusions
There is moderate‐certainty evidence that ECs with nicotine increase quit rates compared to ECs without nicotine and compared to NRT. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the size of effect, particularly when using modern EC products. Confidence intervals were for the most part wide for data on AEs, SAEs and other safety markers, though evidence indicated no difference in AEs between nicotine and non‐nicotine ECs. Overall incidence of SAEs was low across all study arms. We did not detect any clear evidence of harm from nicotine EC, but longest follow‐up was two years and the overall number of studies was small.
The evidence is limited mainly by imprecision due to the small number of RCTs, often with low event rates. Further RCTs are underway. To ensure the review continues to provide up‐to‐date information, this review is now a living systematic review. We run searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.
Temporal trends in comparative meta-analyses of interventions are well-recognised in the medical literature. For studies of diagnostic test accuracy (DTA), evidence of temporal trends is growing and ...the importance of assessing and reporting them has been highlighted in recent guidelines on post-market surveillance in several jurisdictions. In this study we evaluate the prevalence and patterns of time trends using a larger and more up-to-date set of DTA systematic reviews than has previously been examined, from the Cochrane Database of Systematic Reviews.
Cumulative meta-analysis was conducted on bivariate random effects meta-analysis estimates of sensitivity and specificity, after ranking studies by publication date. Trends for all studies were assessed graphically using plots of summary estimates by study rank, and using ROC plots of sensitivity vs. specificity. Linear trends were also described using weighted linear regression with autocorrelated errors of summary estimates against study rank. Various patterns of non-linear trends were characterised descriptively.
The analysis included 46 reviews (92 meta-analyses) conducted between 2017 and 2022. The total number of studies within all reviews was 1,486, with a median IQR 7,134 2,782, 16,406 participants per review. Reviews had a median IQR time span of 19 15,25 publication years. Time trends in at least one DTA measure were observed in 40 (87%) reviews, and statistically significant linear trends in 32 (71%) reviews. Non-linear time trends were observed in 16 (35%) reviews. There was no evidence for a trend in either DTA measure in 27 (59%) reviews.
The study contributes evidence on the variety in patterns of linear and non-linear temporal DTA trends which has not previously been described. We recommended researchers check statistical assumptions of trend analysis methods, for example using graphical methods. Further research into potential reasons for time trends could contribute to the robustness of future meta-analyses.
Nicotine receptor partial agonists for smoking cessation Livingstone-Banks, Jonathan; Livingstone-Banks, Jonathan; Fanshawe, Thomas R ...
Cochrane database of systematic reviews,
05/2023, Letnik:
2023, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Background
Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and ...reducing smoking satisfaction (acting as an antagonist). This is an update of a Cochrane Review first published in 2007.
Objectives
To assess the effectiveness of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation.
Search methods
We searched the Cochrane Tobacco Addiction Group's Specialised Register in April 2022 for trials, using relevant terms in the title or , or as keywords. The register is compiled from searches of CENTRAL, MEDLINE, Embase, and PsycINFO.
Selection criteria
We included randomised controlled trials that compared the treatment drug with placebo, another smoking cessation drug, e‐cigarettes, or no medication. We excluded trials that did not report a minimum follow‐up period of six months from baseline.
Data collection and analysis
We followed standard Cochrane methods. Our main outcome was abstinence from smoking at longest follow‐up using the most rigorous definition of abstinence, preferring biochemically validated rates where reported. We pooled risk ratios (RRs), using the Mantel‐Haenszel fixed‐effect model. We also reported the number of people reporting serious adverse events (SAEs).
Main results
We included 75 trials of 45,049 people; 45 were new for this update. We rated 22 at low risk of bias, 18 at high risk, and 35 at unclear risk.
We found moderate‐certainty evidence (limited by heterogeneity) that cytisine helps more people to quit smoking than placebo (RR 1.30, 95% confidence interval (CI) 1.15 to 1.47; I2 = 83%; 4 studies, 4623 participants), and no evidence of a difference in the number reporting SAEs (RR 1.04, 95% CI 0.78 to 1.37; I2 = 0%; 3 studies, 3781 participants; low‐certainty evidence). SAE evidence was limited by imprecision. We found no data on neuropsychiatric or cardiac SAEs.
We found high‐certainty evidence that varenicline helps more people to quit than placebo (RR 2.32, 95% CI 2.15 to 2.51; I2 = 60%, 41 studies, 17,395 participants), and moderate‐certainty evidence that people taking varenicline are more likely to report SAEs than those not taking it (RR 1.23, 95% CI 1.01 to 1.48; I2 = 0%; 26 studies, 14,356 participants). While point estimates suggested increased risk of cardiac SAEs (RR 1.20, 95% CI 0.79 to 1.84; I2 = 0%; 18 studies, 7151 participants; low‐certainty evidence), and decreased risk of neuropsychiatric SAEs (RR 0.89, 95% CI 0.61 to 1.29; I2 = 0%; 22 studies, 7846 participants; low‐certainty evidence), in both cases evidence was limited by imprecision, and confidence intervals were compatible with both benefit and harm.
Pooled results from studies that randomised people to receive cytisine or varenicline showed that more people in the varenicline arm quit smoking (RR 0.83, 95% CI 0.66 to 1.05; I2 = 0%; 2 studies, 2131 participants; moderate‐certainty evidence) and reported SAEs (RR 0.67, 95% CI 0.44 to 1.03; I2 = 45%; 2 studies, 2017 participants; low‐certainty evidence). However, the evidence was limited by imprecision, and confidence intervals incorporated the potential for benefit from either cytisine or varenicline. We found no data on neuropsychiatric or cardiac SAEs.
We found high‐certainty evidence that varenicline helps more people to quit than bupropion (RR 1.36, 95% CI 1.25 to 1.49; I2 = 0%; 9 studies, 7560 participants), and no clear evidence of difference in rates of SAEs (RR 0.89, 95% CI 0.61 to 1.31; I2 = 0%; 5 studies, 5317 participants), neuropsychiatric SAEs (RR 1.05, 95% CI 0.16 to 7.04; I2 = 10%; 2 studies, 866 participants), or cardiac SAEs (RR 3.17, 95% CI 0.33 to 30.18; I2 = 0%; 2 studies, 866 participants). Evidence of harms was of low certainty, limited by imprecision.
We found high‐certainty evidence that varenicline helps more people to quit than a single form of nicotine replacement therapy (NRT) (RR 1.25, 95% CI 1.14 to 1.37; I2 = 28%; 11 studies, 7572 participants), and low‐certainty evidence, limited by imprecision, of fewer reported SAEs (RR 0.70, 95% CI 0.50 to 0.99; I2 = 24%; 6 studies, 6535 participants). We found no data on neuropsychiatric or cardiac SAEs.
We found no clear evidence of a difference in quit rates between varenicline and dual‐form NRT (RR 1.02, 95% CI 0.87 to 1.20; I2 = 0%; 5 studies, 2344 participants; low‐certainty evidence, downgraded because of imprecision). While pooled point estimates suggested increased risk of SAEs (RR 2.15, 95% CI 0.49 to 9.46; I2 = 0%; 4 studies, 1852 participants) and neuropsychiatric SAEs (RR 4.69, 95% CI 0.23 to 96.50; I2 not estimable as events only in 1 study; 2 studies, 764 participants), and reduced risk of cardiac SAEs (RR 0.32, 95% CI 0.01 to 7.88; I2 not estimable as events only in 1 study; 2 studies, 819 participants), in all three cases evidence was of low certainty and confidence intervals were very wide, encompassing both substantial harm and benefit.
Authors' conclusions
Cytisine and varenicline both help more people to quit smoking than placebo or no medication. Varenicline is more effective at helping people to quit smoking than bupropion, or a single form of NRT, and may be as or more effective than dual‐form NRT. People taking varenicline are probably more likely to experience SAEs than those not taking it, and while there may be increased risk of cardiac SAEs and decreased risk of neuropsychiatric SAEs, evidence was compatible with both benefit and harm. Cytisine may lead to fewer people reporting SAEs than varenicline. Based on studies that directly compared cytisine and varenicline, there may be a benefit from varenicline for quitting smoking, however further evidence could strengthen this finding or demonstrate a benefit from cytisine.
Future trials should test the effectiveness and safety of cytisine compared with varenicline and other pharmacotherapies, and should also test variations in dose and duration. There is limited benefit to be gained from more trials testing the effect of standard‐dose varenicline compared with placebo for smoking cessation. Further trials on varenicline should test variations in dose and duration, and compare varenicline with e‐cigarettes for smoking cessation.
Background
Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol by heating an e‐liquid. Some people who smoke use ECs to stop or reduce smoking, although some ...organizations, advocacy groups and policymakers have discouraged this, citing lack of evidence of efficacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit smoking, and if they are safe to use for this purpose. This is a review update conducted as part of a living systematic review.
Objectives
To examine the effectiveness, tolerability, and safety of using electronic cigarettes (ECs) to help people who smoke tobacco achieve long‐term smoking abstinence.
Search methods
We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 July 2022, and reference‐checked and contacted study authors.
Selection criteria
We included randomized controlled trials (RCTs) and randomized cross‐over trials, in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. Studies had to report abstinence from cigarettes at six months or longer or data on safety markers at one week or longer, or both.
Data collection and analysis
We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking after at least six months follow‐up, adverse events (AEs), and serious adverse events (SAEs). Secondary outcomes included the proportion of people still using study product (EC or pharmacotherapy) at six or more months after randomization or starting EC use, changes in carbon monoxide (CO), blood pressure (BP), heart rate, arterial oxygen saturation, lung function, and levels of carcinogens or toxicants, or both. We used a fixed‐effect Mantel‐Haenszel model to calculate risk ratios (RRs) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data in meta‐analyses.
Main results
We included 78 completed studies, representing 22,052 participants, of which 40 were RCTs. Seventeen of the 78 included studies were new to this review update. Of the included studies, we rated ten (all but one contributing to our main comparisons) at low risk of bias overall, 50 at high risk overall (including all non‐randomized studies), and the remainder at unclear risk.
There was high certainty that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (RR 1.63, 95% CI 1.30 to 2.04; I2 = 10%; 6 studies, 2378 participants). In absolute terms, this might translate to an additional four quitters per 100 (95% CI 2 to 6). There was moderate‐certainty evidence (limited by imprecision) that the rate of occurrence of AEs was similar between groups (RR 1.02, 95% CI 0.88 to 1.19; I2 = 0%; 4 studies, 1702 participants). SAEs were rare, but there was insufficient evidence to determine whether rates differed between groups due to very serious imprecision (RR 1.12, 95% CI 0.82 to 1.52; I2 = 34%; 5 studies, 2411 participants).
There was moderate‐certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non‐nicotine EC (RR 1.94, 95% CI 1.21 to 3.13; I2 = 0%; 5 studies, 1447 participants). In absolute terms, this might lead to an additional seven quitters per 100 (95% CI 2 to 16). There was moderate‐certainty evidence of no difference in the rate of AEs between these groups (RR 1.01, 95% CI 0.91 to 1.11; I2 = 0%; 5 studies, 1840 participants). There was insufficient evidence to determine whether rates of SAEs differed between groups, due to very serious imprecision (RR 1.00, 95% CI 0.56 to 1.79; I2 = 0%; 8 studies, 1272 participants).
Compared to behavioural support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.66, 95% CI 1.52 to 4.65; I2 = 0%; 7 studies, 3126 participants). In absolute terms, this represents an additional two quitters per 100 (95% CI 1 to 3). However, this finding was of very low certainty, due to issues with imprecision and risk of bias. There was some evidence that (non‐serious) AEs were more common in people randomized to nicotine EC (RR 1.22, 95% CI 1.12 to 1.32; I2 = 41%, low certainty; 4 studies, 765 participants) and, again, insufficient evidence to determine whether rates of SAEs differed between groups (RR 1.03, 95% CI 0.54 to 1.97; I2 = 38%; 9 studies, 1993 participants).
Data from non‐randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate with continued EC use. Very few studies reported data on other outcomes or comparisons, hence evidence for these is limited, with CIs often encompassing clinically significant harm and benefit.
Authors' conclusions
There is high‐certainty evidence that ECs with nicotine increase quit rates compared to NRT and moderate‐certainty evidence that they increase quit rates compared to ECs without nicotine. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the effect size. Confidence intervals were for the most part wide for data on AEs, SAEs and other safety markers, with no difference in AEs between nicotine and non‐nicotine ECs nor between nicotine ECs and NRT. Overall incidence of SAEs was low across all study arms. We did not detect evidence of serious harm from nicotine EC, but longest follow‐up was two years and the number of studies was small.
The main limitation of the evidence base remains imprecision due to the small number of RCTs, often with low event rates, but further RCTs are underway. To ensure the review continues to provide up‐to‐date information to decision‐makers, this review is a living systematic review. We run searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.
Background
Practitioners who enhance how they express empathy and create positive expectations of benefit could improve patient outcomes. However, the evidence in this area has not been recently ...synthesised.
Objective
To estimate the effects of empathy and expectations interventions for any clinical condition.
Design
Systematic review and meta-analysis of randomised trials.
Data sources
Six databases from inception to August 2017.
Study selection
Randomised trials of empathy or expectations interventions in any clinical setting with patients aged 12 years or older.
Review methods
Two reviewers independently screened citations, extracted data, assessed risk of bias and graded quality of evidence using GRADE. Random effects model was used for meta-analysis.
Results
We identified 28 eligible (n = 6017). In seven trials, empathic consultations improved pain, anxiety and satisfaction by a small amount (standardised mean difference −0.18 95% confidence interval −0.32 to −0.03). Twenty-two trials tested the effects of positive expectations. Eighteen of these (n = 2014) reported psychological outcomes (mostly pain) and showed a modest benefit (standardised mean difference −0.43 95% confidence interval −0.65 to −0.21); 11 (n = 1790) reported physical outcomes (including bronchial function/ length of hospital stay) and showed a small benefit (standardised mean difference −0.18 95% confidence interval −0.32 to −0.05). Within 11 trials (n = 2706) assessing harms, there was no evidence of adverse effects (odds ratio 1.04; 95% confidence interval 0.67 to 1.63). The risk of bias was low. The main limitations were difficulties in blinding and high heterogeneity for some comparisons.
Conclusions
Greater practitioner empathy or communication of positive messages can have small patient benefits for a range of clinical conditions, especially pain.
Protocol registration
Cochrane Database of Systematic Reviews (protocol) DOI: 10.1002/14651858.CD011934.pub2.
Background
Nicotine replacement therapy (NRT) aims to replace nicotine from cigarettes to ease the transition from cigarette smoking to abstinence. It works by reducing the intensity of craving and ...withdrawal symptoms. Although there is clear evidence that NRT used after smoking cessation is effective, it is unclear whether higher doses, longer durations of treatment, or using NRT before cessation add to its effectiveness.
Objectives
To determine the effectiveness and safety of different forms, deliveries, doses, durations and schedules of NRT, for achieving long‐term smoking cessation, compared to one another.
Search methods
We searched the Cochrane Tobacco Addiction Group trials register, and trial registries for papers mentioning NRT in the title, or keywords. Date of most recent search: April 2018.
Selection criteria
Randomized trials in people motivated to quit, comparing one type of NRT use with another. We excluded trials that did not assess cessation as an outcome, with follow‐up less than six months, and with additional intervention components not matched between arms. Trials comparing NRT to control, and trials comparing NRT to other pharmacotherapies, are covered elsewhere.
Data collection and analysis
We followed standard Cochrane methods. Smoking abstinence was measured 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. We calculated the risk ratio (RR) and the 95% confidence interval (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, using a Mantel‐Haenszel fixed‐effect model.
Main results
We identified 63 trials with 41,509 participants. Most recruited adults either from the community or from healthcare clinics. People enrolled in the studies typically smoked at least 15 cigarettes a day. We judged 24 of the 63 studies to be at high risk of bias, but restricting the analysis only to those studies at low or unclear risk of bias did not significantly alter results, apart from in the case of the preloading comparison. There is high‐certainty evidence that combination NRT (fast‐acting form + patch) results in higher long‐term quit rates than single form (RR 1.25, 95% CI 1.15 to 1.36, 14 studies, 11,356 participants; I2 = 4%). Moderate‐certainty evidence, limited by imprecision, indicates that 42/44 mg are as effective as 21/22 mg (24‐hour) patches (RR 1.09, 95% CI 0.93 to 1.29, 5 studies, 1655 participants; I2 = 38%), and that 21 mg 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, 3 studies, 3446 participants; I2 = 0%). Five studies comparing 4 mg gum to 2 mg gum found a benefit of the higher dose (RR 1.43, 95% CI 1.12 to 1.83, 5 studies, 856 participants; I2 = 63%); however, results of a subgroup analysis suggest that only smokers who are highly dependent may benefit. 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, 9 studies, 4395 participants; I2 = 0%). 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, 8 studies, 3319 participants; I2 = 0%). We found no evidence of an effect of duration of nicotine patch use (low‐certainty evidence); 16‐hour versus 24‐hour daily patch use; duration of combination NRT use (low‐ and very low‐certainty evidence); tapering of patch dose versus abrupt patch cessation; fast‐acting NRT type (very low‐certainty evidence); duration of nicotine gum use; ad lib versus fixed dosing of fast‐acting NRT; free versus purchased NRT; length of provision of free NRT; ceasing versus continuing patch use on lapse; and participant‐ versus clinician‐selected NRT. However, in most cases these findings are based on very low‐ or low‐certainty evidence, and are the findings from single studies.
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 evidence of an effect on cardiac AEs, SAEs or withdrawals. Rates of these were low overall. Significantly more withdrawals due to treatment were reported in participants using nasal spray in comparison to patch in one trial (RR 3.47, 95% CI 1.15 to 10.46, 922 participants; very low certainty) and in participants using 42/44 mg patches in comparison to 21/22 mg patches across two trials (RR 4.99, 95% CI 1.60 to 15.50, 2 studies, 544 participants; I2 = 0%; low certainty).
Authors' conclusions
There is high‐certainty evidence that using combination NRT versus single‐form NRT, and 4 mg versus 2 mg nicotine gum, can increase the chances of successfully stopping smoking. For patch dose comparisons, evidence was of moderate certainty, due to imprecision. Twenty‐one mg patches resulted in higher quit rates than 14 mg (24‐hour) patches, and using 25 mg patches resulted in higher quit rates than using 15 mg (16‐hour) patches, although in the latter case the CI included one. There was no clear evidence of superiority for 42/44 mg over 21/22 mg (24‐hour) patches. 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 prior to 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 of low and very low certainty. New studies should ensure that AEs, SAEs and withdrawals due to treatment are both measured and reported.
A stepped wedge cluster randomised trial (SWCRT) is a multicentred study which allows an intervention to be rolled out at sites in a random order. Once the intervention is initiated at a site, all ...participants within that site remain exposed to the intervention for the remainder of the study. The time since the start of the study ("calendar time") may affect outcome measures through underlying time trends or periodicity. The time since the intervention was introduced to a site ("exposure time") may also affect outcomes cumulatively for successful interventions, possibly in addition to a step change when the intervention began.
Motivated by a SWCRT of self-monitoring for bipolar disorder, we conducted a simulation study to compare model formulations to analyse data from a SWCRT under 36 different scenarios in which time was related to the outcome (improvement in mood score). The aim was to find a model specification that would produce reliable estimates of intervention effects under different scenarios. Nine different formulations of a linear mixed effects model were fitted to these datasets. These models varied in the specification of calendar and exposure times.
Modelling the effects of the intervention was best accomplished by including terms for both calendar time and exposure time. Treating time as categorical (a separate parameter for each measurement time-step) achieved the best coverage probabilities and low bias, but at a cost of wider confidence intervals compared to simpler models for those scenarios which were sufficiently modelled by fewer parameters. Treating time as continuous and including a quadratic time term performed similarly well, with slightly larger variations in coverage probability, but narrower confidence intervals and in some cases lower bias. The impact of misspecifying the covariance structure was comparatively small.
We recommend that unless there is a priori information to indicate the form of the relationship between time and outcomes, data from SWCRTs should be analysed with a linear mixed effects model that includes separate categorical terms for calendar time and exposure time. Prespecified sensitivity analyses should consider the different formulations of these time effects in the model, to assess their impact on estimates of intervention effects.
PDF
