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BMJ (Clinical Research Ed.) Jun 2011To systematically review the risk of mortality associated with long term use of tiotropium delivered using a mist inhaler for symptomatic improvement in chronic... (Meta-Analysis)
Meta-Analysis Review
Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials.
OBJECTIVE
To systematically review the risk of mortality associated with long term use of tiotropium delivered using a mist inhaler for symptomatic improvement in chronic obstructive pulmonary disease.
DATA SOURCES
Medline, Embase, the pharmaceutical company clinical trials register, the US Food and Drug Administration website, and ClinicalTrials.gov for randomised controlled trials from inception to July 2010.
STUDY SELECTION
Trials were selected for inclusion if they were parallel group randomised controlled trials of tiotropium solution using a mist inhaler (Respimat Soft Mist Inhaler, Boehringer Ingelheim) versus placebo for chronic obstructive pulmonary disease; the treatment duration was more than 30 days, and they reported data on mortality. Relative risks of all cause mortality were estimated using a fixed effect meta-analysis, and heterogeneity was assessed with the I(2) statistic.
RESULTS
Five randomised controlled trials were eligible for inclusion. Tiotropium mist inhaler was associated with a significantly increased risk of mortality (90/3686 v 47/2836; relative risk 1.52, 95% confidence interval, 1.06 to 2.16; P = 0.02; I(2) = 0%). Both 10 µg (2.15, 1.03 to 4.51; P = 0.04; I(2) = 9%) and 5 µg (1.46, 1.01 to 2.10; P = 0.04; I(2) = 0%) doses of tiotropium mist inhaler were associated with an increased risk of mortality. The overall estimates were not substantially changed by sensitivity analysis of the fixed effect analysis of the five trials combined using the random effects model (1.45, 1.02 to 2.07; P = 0.04), limiting the analysis to three trials of one year's duration each (1.50, 1.05 to 2.15), or the inclusion of additional data on tiotropium mist inhaler from another investigational drug programme (1.42, 1.01 to 2.00). The number needed to treat for a year with the 5 µg dose to see one additional death was estimated to be 124 (95% confidence interval 52 to 5682) based on the average control event rate from the long term trials.
CONCLUSIONS
This meta-analysis explains safety concerns by regulatory agencies and indicates a 52% increased risk of mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease.
Topics: Administration, Inhalation; Bronchodilator Agents; Humans; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Scopolamine Derivatives; Tiotropium Bromide
PubMed: 21672999
DOI: 10.1136/bmj.d3215 -
Harm Reduction Journal Sep 2009Smoking cessation has important immediate health benefits. The comparative short-term effectiveness of smoking cessation interventions is not well known. We aimed to...
BACKGROUND
Smoking cessation has important immediate health benefits. The comparative short-term effectiveness of smoking cessation interventions is not well known. We aimed to determine the relative effectiveness of nicotine replacement therapy (NRT), bupropion and varenicline at 4 weeks post-target quit date.
METHODS
We searched 10 electronic medical databases (inception to October 2008). We selected randomized clinical trials [RCTs] evaluating interventions for our primary outcome of abstinence from smoking at at-least 4 weeks post-target quit date, with biochemical confirmation. We conducted random-effects odds ratio (OR) meta-analysis and meta-regression. We compared treatment effects across interventions using head-to-head trials and calculated indirect comparisons.
RESULTS
We combined a total of 101 trials evaluating delivery of NRT versus inert controls at approximately 4 weeks post-target quit date (total n = 31,321). The pooled overall OR is OR 2.05 (95% Confidence Interval [CI], 1.89-2.23, P =< 0.0001). We pooled data from 31 bupropion trials contributing a total n of 11,118 participants and found a pooled OR of 2.25 (95% CI, 1.94-2.62, P =< 0.0001). We evaluated 9 varenicline trials compared to placebo. Our pooled estimate for cessation at 4 weeks post-target quit date found a pooled OR of 3.16 (95% CI, 2.55-3.91, P =< 0.0001). Two trials evaluated head to head comparisons of varenicline and bupropion and found a pooled estimate of OR 1.86 (95% CI, 1.49-2.33, P =< 0.0001 at 4 weeks post-target quit date. Indirect comparisons were: NRT and bupropion, OR, 1.09, 95% CI, 0.93-1.31, P = 0.28; varenicline and NRT, OR 1.56, 95% CI, 1.23-1.96, P = 0.0002; and, varenicline and bupropion, OR 1.40, 95% CI, 1.08-1.85, P = 0.01.
CONCLUSION
Pharmacotherapeutic interventions are effective for increasing smoking abstinence rates in the short-term.
PubMed: 19761618
DOI: 10.1186/1477-7517-6-25 -
The Cochrane Database of Systematic... Aug 2019Pharmacological treatments for tobacco dependence, such as nicotine replacement therapy (NRT), have been shown to be safe and effective interventions for smoking...
BACKGROUND
Pharmacological treatments for tobacco dependence, such as nicotine replacement therapy (NRT), have been shown to be safe and effective interventions for smoking cessation. Higher levels of adherence to these medications increase the likelihood of sustained smoking cessation, but many smokers use them at a lower dose and for less time than is optimal. It is important to determine the effectiveness of interventions designed specifically to increase medication adherence. Such interventions may address motivation to use medication, such as influencing beliefs about the value of taking medications, or provide support to overcome problems with maintaining adherence.
OBJECTIVES
To assess the effectiveness of interventions aiming to increase adherence to medications for smoking cessation on medication adherence and smoking abstinence compared with a control group typically receiving standard care.
SEARCH METHODS
We searched the Cochrane Tobacco Addiction Group Specialized Register, and clinical trial registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform) to the 3 September 2018. We also conducted forward and backward citation searches.
SELECTION CRITERIA
Randomised, cluster-randomised or quasi-randomised studies in which adults using active pharmacological treatment for smoking cessation were allocated to an intervention arm where there was a principal focus on increasing adherence to medications for tobacco dependence, or a control arm providing standard care. Dependent on setting, standard care may have comprised minimal support or varying degrees of behavioural support. Included studies used a measure that allowed assessment of the degree of medication adherence.
DATA COLLECTION AND ANALYSIS
Two authors independently screened studies for eligibility, extracted data for included studies and assessed risk of bias. For continuous outcome measures, we calculated effect sizes as standardised mean differences (SMDs). For dichotomous outcome measures, we calculated effect sizes as risk ratios (RRs). In meta-analyses for adherence outcomes, we combined dichotomous and continuous data using the generic inverse variance method and reported pooled effect sizes as SMDs; for abstinence outcomes, we reported and pooled dichotomous outcomes. We obtained pooled effect sizes with 95% confidence intervals (CIs) using random-effects models. We conducted subgroup analyses to assess whether the primary focus of the adherence treatment ('practicalities' versus 'perceptions' versus both), the delivery approach (participant versus clinician-centred) or the medication type were associated with effectiveness.
MAIN RESULTS
We identified two new studies, giving a total of 10 studies, involving 3655 participants. The medication adherence interventions studied were all provided in addition to standard behavioural support.They typically provided further information on the rationale for, and emphasised the importance of, adherence to medication or supported the development of strategies to overcome problems with maintaining adherence (or both). Seven studies targeted adherence to NRT, two to bupropion and one to varenicline. Most studies were judged to be at high or unclear risk of bias, with four of these studies judged at high risk of attrition or detection bias. Only one study was judged to be at low risk of bias.Meta-analysis of all 10 included studies (12 comparisons) provided moderate-certainty evidence that adherence interventions led to small improvements in adherence (i.e. the mean amount of medication consumed; SMD 0.10, 95% CI 0.03 to 0.18; I² = 6%; n = 3655), limited by risk of bias. Subgroup analyses for the primary outcome identified no significant subgroup effects, with effect sizes for subgroups imprecisely estimated. However, there was a very weak indication that interventions focused on the 'practicalities' of adhering to treatment (i.e. capabilities, resources, levels of support or skills) may be effective (SMD 0.21, 95% CI 0.03 to 0.38; I² = 39%; n = 1752), whereas interventions focused on treatment 'perceptions' (i.e. beliefs, cognitions, concerns and preferences; SMD 0.10, 95% CI -0.03 to 0.24; I² = 0%; n = 839) or on both (SMD 0.04, 95% CI -0.08 to 0.16; I² = 0%; n = 1064), may not be effective. Participant-centred interventions may be effective (SMD 0.12, 95% CI 0.02 to 0.23; I² = 20%; n = 2791), whereas those that are clinician-centred may not (SMD 0.09, 95% CI -0.05 to 0.23; I² = 0%; n = 864).Five studies assessed short-term smoking abstinence (five comparisons), while an overlapping set of five studies (seven comparisons) assessed long-term smoking abstinence of six months or more. Meta-analyses resulted in low-certainty evidence that adherence interventions may slightly increase short-term smoking cessation rates (RR 1.08, 95% CI 0.96 to 1.21; I² = 0%; n = 1795) and long-term smoking cessation rates (RR 1.16, 95% CI 0.96 to 1.40; I² = 48%; n = 3593). In both cases, the evidence was limited by risk of bias and imprecision, with CIs encompassing minimal harm as well as moderate benefit, and a high likelihood that further evidence will change the estimate of the effect. There was no evidence that interventions to increase adherence to medication led to any adverse events. Studies did not report on factors plausibly associated with increases in adherence, such as self-efficacy, understanding of and attitudes toward treatment, and motivation and intentions to quit.
AUTHORS' CONCLUSIONS
In people who are stopping smoking and receiving behavioural support, there is moderate-certainty evidence that enhanced behavioural support focusing on adherence to smoking cessation medications can modestly improve adherence. There is only low-certainty evidence that this may slightly improve the likelihood of cessation in the shorter or longer-term. Interventions to increase adherence can aim to address the practicalities of taking medication, change perceptions about medication, such as reasons to take it or concerns about doing so, or both. However, there is currently insufficient evidence to confirm which approach is more effective. There is no evidence on whether such interventions are effective for people who are stopping smoking without standard behavioural support.
Topics: Benzazepines; Bupropion; Drug Therapy, Combination; Humans; Medication Adherence; Nicotinic Agonists; Nortriptyline; Quinoxalines; Randomized Controlled Trials as Topic; Smoking Cessation; Smoking Prevention; Tobacco Use Cessation Devices; Tobacco Use Disorder
PubMed: 31425618
DOI: 10.1002/14651858.CD009164.pub3 -
The Cochrane Database of Systematic... Jun 2019Pharmacotherapies for smoking cessation increase the likelihood of achieving abstinence in a quit attempt. It is plausible that providing support, or, if support is...
BACKGROUND
Pharmacotherapies for smoking cessation increase the likelihood of achieving abstinence in a quit attempt. It is plausible that providing support, or, if support is offered, offering more intensive support or support including particular components may increase abstinence further.
OBJECTIVES
To evaluate the effect of adding or increasing the intensity of behavioural support for people using smoking cessation medications, and to assess whether there are different effects depending on the type of pharmacotherapy, or the amount of support in each condition. We also looked at studies which directly compare behavioural interventions matched for contact time, where pharmacotherapy is provided to both groups (e.g. tests of different components or approaches to behavioural support as an adjunct to pharmacotherapy).
SEARCH METHODS
We searched the Cochrane Tobacco Addiction Group Specialised Register, clinicaltrials.gov, and the ICTRP in June 2018 for records with any mention of pharmacotherapy, including any type of nicotine replacement therapy (NRT), bupropion, nortriptyline or varenicline, that evaluated the addition of personal support or compared two or more intensities of behavioural support.
SELECTION CRITERIA
Randomised or quasi-randomised controlled trials in which all participants received pharmacotherapy for smoking cessation and conditions differed by the amount or type of behavioural support. The intervention condition had to involve person-to-person contact (defined as face-to-face or telephone). The control condition could receive less intensive personal contact, a different type of personal contact, written information, or no behavioural support at all. We excluded trials recruiting only pregnant women and trials which did not set out to assess smoking cessation at six months or longer.
DATA COLLECTION AND ANALYSIS
For this update, screening and data extraction followed standard Cochrane methods. 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 random-effects model.
MAIN RESULTS
Eighty-three studies, 36 of which were new to this update, met the inclusion criteria, representing 29,536 participants. Overall, we judged 16 studies to be at low risk of bias and 21 studies to be at high risk of bias. All other studies were judged to be at unclear risk of bias. Results were not sensitive to the exclusion of studies at high risk of bias. We pooled all studies comparing more versus less support in the main analysis. Findings demonstrated a benefit of behavioural support in addition to pharmacotherapy. When all studies of additional behavioural therapy were pooled, there was evidence of a statistically significant benefit from additional support (RR 1.15, 95% CI 1.08 to 1.22, I² = 8%, 65 studies, n = 23,331) for abstinence at longest follow-up, and this effect was not different when we compared subgroups by type of pharmacotherapy or intensity of contact. This effect was similar in the subgroup of eight studies in which the control group received no behavioural support (RR 1.20, 95% CI 1.02 to 1.43, I² = 20%, n = 4,018). Seventeen studies compared interventions matched for contact time but that differed in terms of the behavioural components or approaches employed. Of the 15 comparisons, all had small numbers of participants and events. Only one detected a statistically significant effect, favouring a health education approach (which the authors described as standard counselling containing information and advice) over motivational interviewing approach (RR 0.56, 95% CI 0.33 to 0.94, n = 378).
AUTHORS' CONCLUSIONS
There is high-certainty evidence that providing behavioural support in person or via telephone for people using pharmacotherapy to stop smoking increases quit rates. Increasing the amount of behavioural support is likely to increase the chance of success by about 10% to 20%, based on a pooled estimate from 65 trials. Subgroup analysis suggests that the incremental benefit from more support is similar over a range of levels of baseline support. More research is needed to assess the effectiveness of specific components that comprise behavioural support.
Topics: Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Nicotinic Agonists; Nortriptyline; Pregnancy; Smoking; Smoking Cessation; Tobacco Use Cessation Devices; Tobacco Use Disorder; Varenicline
PubMed: 31166007
DOI: 10.1002/14651858.CD009670.pub4 -
Family Practice Mar 2022Dealing with the opioid crisis, medical doctors are keen to learn how to best treat opioid dependency in patients with chronic non-cancer pain. Opioid replacement...
BACKGROUND
Dealing with the opioid crisis, medical doctors are keen to learn how to best treat opioid dependency in patients with chronic non-cancer pain. Opioid replacement therapy is commonly used, but success rates vary widely. Since many patients still experience severe withdrawal symptoms, additional interventions are necessary.
OBJECTIVE
To review the effectiveness of interventions in the treatment of withdrawal symptoms during opioid tapering or acute withdrawal in patients with long-term non-cancer pain.
METHODS
A systematic review was conducted in Embase.com, MEDLINE, Web of Science, PsycINFO, and Cochrane CENTRAL register of trials. Studies eligible for inclusion were (non-)randomized controlled trials in adults with long-term opioid prescriptions for non-cancer pain. Included trials had to compare a non-opioid intervention to placebo, usual care, no treatment, or non-opioid drug and had to report on withdrawal symptoms as an outcome. Study quality was assessed with the 2.0 Cochrane risk of bias (RoB) tool. Evidence quality was rated following the GRADE approach.
RESULTS
One trial (n = 21, some concerns regarding RoB) compared Varenicline to placebo. There was no statistically significant between-group reduction of withdrawal symptoms (moderate-quality evidence).
CONCLUSIONS
Evidence from clinical trials on interventions reducing withdrawal symptoms is scarce. Based on one trial with a small sample size, no firm conclusion can be drawn. Meanwhile, doctors are in dire need for therapeutic options to tackle withdrawal symptoms while tapering patients with prescription opioid dependence. We hope this review draws attention to this unfortunate research gap so that future research can provide doctors with answers.
Topics: Adult; Analgesics, Opioid; Chronic Pain; Humans; Opioid-Related Disorders; Substance Withdrawal Syndrome
PubMed: 34849764
DOI: 10.1093/fampra/cmab159