Dataset Information

Risk of neuropsychiatric and cardiovascular adverse events following treatment with varenicline and nicotine replacement therapy in the UK Clinical Practice Research Datalink: a case-cross-over study.

ABSTRACT:

Background and aims

Varenicline and nicotine replacement therapy (NRT) are the most commonly used medications to quit smoking. Given their widespread use, monitoring adverse risks remains important. This study aimed to estimate the neuropsychiatric and cardiovascular risks associated with varenicline and NRT as used in routine UK care.

Design

Case-cross-over study.

Setting

UK-based electronic primary care records in the Clinical Practice Research Datalink from 2006 to 2015 linked to hospital and mortality data sets.

Participants

Adult smokers (n =282,429) observed during periods when exposed and not exposed to either varenicline or NRT.

Measurements

Main outcomes included suicide, self-harm, myocardial infarction (MI), all-cause death and cause-specific death [MI, chronic obstructive pulmonary disease (COPD)]. In primary analyses, conditional logistic regression was used to compare the chance of varenicline or NRT exposure during the risk period (90 days prior to the event) with the chance of exposure during an earlier single reference period (91-180 days prior to the event) or multiple 90-day reference periods to increase statistical power.

Findings

In the primary analyses, findings were inconclusive for the associations between varenicline and the main outcomes using a single reference period, while NRT was associated with MI [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.18-1.67]. Using multiple reference periods, varenicline was associated with an increased risk of self-harm (OR = 1.32, 95% CI = 1.12-1.56) and suicide (OR = 3.56, 95% CI = 1.32-9.60) but a reduction in all-cause death (OR = 0.75, 95% CI = 0.61-0.93). NRT was associated with MI (OR = 1.54, 95% CI = 1.36-1.74), self-harm (OR = 1.30, 95% CI = 1.18-1.44) and deaths from MI (OR = 1.53, 95% CI = 1.11-2.10), COPD (OR = 1.33, 95% CI = 1.14-1.56) and all causes (OR = 1.28, 95% CI = 1.18-1.40) when using multiple reference periods.

Conclusions

There appear to be positive associations between (1) nicotine replacement therapy (NRT) and myocardial infarction, death and risk of self-harm and (2) varenicline and increased risk of self-harm and suicide, as well as a negative association between varenicline and all-cause death. The associations may not be causal. They may reflect health changes at the time of smoking cessation (nicotine replacement therapy is prescribed for people with cardiac problems) or be associated with quit attempts (exposure to both medicines was associated with self-harm).

SUBMITTER: Thomas KH

PROVIDER: S-EPMC8246946 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo determine the risk of neuropsychiatric adverse events associated with use of varenicline compared with placebo in randomised controlled trials.DesignSystematic review and meta-analysis comparing study effects using two summary estimates in fixed effects models, risk differences, and Peto odds ratios.Data sourcesMedline, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov.Eligibility criteria for selecting studiesRandomised controlled trials with a placebo comparison group that reported on neuropsychiatric adverse events (depression, suicidal ideation, suicide attempt, suicide, insomnia, sleep disorders, abnormal dreams, somnolence, fatigue, anxiety) and death. Studies that did not involve human participants, did not use the maximum recommended dose of varenicline (1 mg twice daily), and were cross over trials were excluded.ResultsIn the 39 randomised controlled trials (10,761 participants), there was no evidence of an increased risk of suicide or attempted suicide (odds ratio 1.67, 95% confidence interval 0.33 to 8.57), suicidal ideation (0.58, 0.28 to 1.20), depression (0.96, 0.75 to 1.22), irritability (0.98, 0.81 to 1.17), aggression (0.91, 0.52 to 1.59), or death (1.05, 0.47 to 2.38) in the varenicline users compared with placebo users. Varenicline was associated with an increased risk of sleep disorders (1.63, 1.29 to 2.07), insomnia (1.56, 1.36 to 1.78), abnormal dreams (2.38, 2.05 to 2.77), and fatigue (1.28, 1.06 to 1.55) but a reduced risk of anxiety (0.75, 0.61 to 0.93). Similar findings were observed when risk differences were reported. There was no evidence for a variation in depression and suicidal ideation by age group, sex, ethnicity, smoking status, presence or absence of psychiatric illness, and type of study sponsor (that is, pharmaceutical industry or other).ConclusionsThis meta-analysis found no evidence of an increased risk of suicide or attempted suicide, suicidal ideation, depression, or death with varenicline. These findings provide some reassurance for users and prescribers regarding the neuropsychiatric safety of varenicline. There was evidence that varenicline was associated with a higher risk of sleep problems such as insomnia and abnormal dreams. These side effects, however, are already well recognised.Systematic review registrationPROSPERO 2014:CRD42014009224.

Project description:Background and aimsAnalysed using classical frequentist hypothesis testing with alpha set to 0.05, the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) did not find enough evidence to reject the hypothesis of no difference in neuropsychiatric adverse events (NPSAEs) attributable to varenicline, bupropion, or nicotine patch compared with placebo. This might be because the null hypothesis was true or because the data were insensitive. The present study aimed to test the hypothesis more directly using Bayes factors.DesignEAGLES was a randomised, double-blind, triple-dummy, controlled trial.SettingGlobal (16 countries across five continents), between November 2011 and January 2015.ParticipantsParticipants were smokers with (n = 4116) and without (n = 4028) psychiatric disorders.InterventionsVarenicline (1 mg twice daily), bupropion (150 mg twice daily), nicotine patch (21 mg once daily with taper) and matched placebos.MeasurementsThe outcomes included: (i) a composite measure of moderate/severe NPSAEs; and (ii) a composite measure of severe NPSAEs. The relative evidence for there being no difference in NPSAEs versus data insensitivity for the medications was calculated in the full and sub-samples using Bayes factors and corresponding robustness regions.FindingsFor all but two comparisons, Bayes factors were <1/3, indicating moderate to strong evidence for no difference in risk of NPSAEs between active medications and placebo (Bayes factor = 0.02-0.23). In the psychiatric cohort versus placebo, the data were suggestive, but not conclusive of no increase in NPSAEs with varenicline (Bayes factor = 0.52) and bupropion (Bayes factor = 0.71). Here, the robustness regions ruled out a ≥7% and ≥8% risk increase with varenicline and bupropion, respectively.ConclusionsSecondary analysis of the Evaluating Adverse Events in a Global Smoking Cessation Study trial using Bayes factors provides moderate to strong evidence that use of varenicline, bupropion or nicotine patches for smoking cessation does not increase the risk of neuropsychiatric adverse events relative to use of placebo in smokers without a history of psychiatric disorder. For smokers with a history of psychiatric disorder the evidence also points to no increased risk but with less confidence.

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Project description:INTRODUCTION:Varenicline (VAR) is an effective smoking-cessation therapy compared to the commonly used nicotine-replacement therapy patch (NRT-P). However, comparative real-world evidence on smoking-cessation therapies is limited, especially for economic outcomes. METHODS:Using national claims databases (2012-2016) in the United States (US), adults initiating VAR or NRT-P without use of any other smoking-cessation products were followed for up to 1 year on a quarterly basis. Outcomes included smoking-attributable (SA) (cardiovascular, diabetes, pulmonary diseases, and smoking cessation) and all-cause costs (2017 US dollars). Adjusted mean costs were estimated from multivariable regressions, with baseline characteristics and propensity scores as covariates. Annual adjusted costs were calculated from quarterly averages. RESULTS:The VAR cohort (n = 209,284) was younger (mean age 46.7 vs. 49.0 years) and had fewer comorbidities [mean Charlson Comorbidity Index (CCI): 0.8 vs. 1.6] than the NRT-P cohort (n = 34,593). After adjustment, VAR cohort had lower SA and all-cause medical costs than NRT-P cohort in Quarters 1-4 (Q1-Q4) of follow-up, and had lower SA and all-cause total costs in Q2-Q4. Annually, VAR cohort had higher SA total costs ($307) and lower all-cause costs (- $2089) than NRT-P cohort. Annual medical costs were lower in VAR cohort (- $640 for SA and - $2876 for all-cause), and pharmacy costs were higher ($762 for SA and $777 for all-cause). In adherent patients (VAR: n = 38,744; NRT-P: n = 2702), VAR patients had lower annual medical costs (- $794 for SA and - $1636 for all-cause) and higher pharmacy costs ($1175 for SA and $1269 for all-cause); differences in SA and all-cause total costs were not statistically significant between treatment groups. CONCLUSIONS:Lower SA and all-cause medical costs associated with the use of VAR versus NRT-P resulted in savings in all-cause total costs and, among adherent patients, potentially offset the high pharmacy costs of VAR. FUNDING:Pfizer, Inc.

Project description:BackgroundPrimary care databases represent a rich source of data for health care research; however, the quality of recording of secondary care events in these databases is uncertain. This study sought to investigate the completeness of recording of hospital admissions for bleeds in primary care records and explore the impact of incomplete recording on estimates of bleeding risk associated with antithrombotic treatment.MethodsThe study population consisted of adults with non-valvular atrial fibrillation who had at least one bleed recorded in either the Clinical Practice Research Datalink (CPRD) or Hospital Episode Statistics (HES) while receiving prescriptions for an oral anticoagulant. The proportion of bleeds recorded in HES that had a corresponding bleed recorded in the subsequent 12 weeks in CPRD was calculated, and factors associated with having a corresponding record were identified. Cox proportional hazards analyses investigating the hazard of subsequent bleeding associated with antithrombotic treatment were carried out using linked CPRD-HES data and using CPRD only data, and the results were compared.ResultsLess than 20% of the 14,361 bleeds recorded in the HES data had a corresponding bleed coded in the CPRD in the subsequent 12 weeks. This proportion varied by bleed characteristics, calendar time, day of week of admission (weekday vs weekend) and oral anticoagulant treatment at the time of the bleed. The hazard of subsequent bleeding associated with vitamin K antagonists (VKAs) and antiplatelet agents (APAs) relative to no antithrombotic treatment were similar using the linked primary and secondary care dataset (VKA HRadj 1.06 CI95 0.96-1.16; APA HRadj 1.08 CI95 0.96-1.21) and the unlinked primary care data (VKA HRadj 1.12 CI95 1.01-1.24; APA HRadj 1.06 CI95 0.95-1.20).ConclusionSecondary care bleeding events are not completely recorded in primary care records and under-recording may be differential with respect to a variety of factors, including antithrombotic treatment. While the impact of under-recording on estimates of the comparative safety of antithrombotic drugs was limited, the extent of the under-recording suggests its potential impact should be considered, and ideally evaluated in future studies utilizing standalone primary care data.

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