Dataset Information

Risk of neuropsychiatric adverse events associated with varenicline: systematic review and meta-analysis.

ABSTRACT:

Objective

To determine the risk of neuropsychiatric adverse events associated with use of varenicline compared with placebo in randomised controlled trials.

Design

Systematic review and meta-analysis comparing study effects using two summary estimates in fixed effects models, risk differences, and Peto odds ratios.

Data sources

Medline, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov.

Eligibility criteria for selecting studies

Randomised 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.

Results

In 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).

Conclusions

This 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 registration

PROSPERO 2014:CRD42014009224.

SUBMITTER: Thomas KH

PROVIDER: S-EPMC4357491 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:To examine the risk of treatment emergent, cardiovascular serious adverse events associated with varenicline use for tobacco cessation.Meta-analysis comparing study effects using four summary estimates.Medline, Cochrane Library, online clinical trials registries, and reference lists of identified articles.We included randomised controlled trials of current tobacco users of adult age comparing use of varenicline with an inactive control and reporting adverse events. We defined treatment emergent, cardiovascular serious adverse events as occurring during drug treatment or within 30 days of discontinuation, and included any ischaemic or arrhythmic adverse cardiovascular event (myocardial infarction, unstable angina, coronary revascularisation, coronary artery disease, arrhythmias, transient ischaemic attacks, stroke, sudden death or cardiovascular related death, or congestive heart failure).We identified 22 trials; all were double blinded and placebo controlled; two included participants with active cardiovascular disease and 11 enrolled participants with a history of cardiovascular disease. Rates of treatment emergent, cardiovascular serious adverse events were 0.63% (34/5431) in the varenicline groups and 0.47% (18/3801) in the placebo groups. The summary estimate for the risk difference, 0.27% (95% confidence interval -0.10 to 0.63; P = 0.15), based on all 22 trials, was neither clinically nor statistically significant. For comparison, the relative risk (1.40, 0.82 to 2.39; P = 0.22), Mantel-Haenszel odds ratio (1.41, 0.82 to 2.42; P = 0.22), and Peto odds ratio (1.58, 0.90 to 2.76; P = 0.11), all based on 14 trials with at least one event, also indicated a non-significant difference between varenicline and placebo groups.This meta--analysis--which included all trials published to date, focused on events occurring during drug exposure, and analysed findings using four summary estimates-found no significant increase in cardiovascular serious adverse events associated with varenicline use. For rare outcomes, summary estimates based on absolute effects are recommended and estimates based on the Peto odds ratio should be avoided.

Project description:Cardiovascular adverse events (CVAE) with carfilzomib in patients with multiple myeloma can be potentially life-threatening and remain incompletely characterized. We performed the first systematic review and meta-analysis of carfilzomib-associated CVAE.To determine the incidence of carfilzomib-associated CVAE and to compare the rates of carfilzomib CVAE among different doses and companion therapies.PubMed, EMBASE, Web of Science, and clinicaltrials.gov were queried for the keywords "carfilzomib," "Kyprolis," and "PX-171" through January 1, 2017.Phase 1 to 3 prospective clinical trials of carfilzomib in patients with multiple myeloma with evaluable toxic effects data were eligible for meta-analysis.Data were independently extracted by 2 reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Pooled incidence rates and relative risks (for randomized trials) and 95% confidence intervals were calculated using a random effects model. Subgroup analyses were performed to assess study-level characteristics associated with CVAE.Cardiovascular adverse events were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and grades 3 or higher AEs and study characteristics were recorded.A total of 514 studies were assessed for eligibility. Of those, 24 studies were eligible, including a total of 2594 patients with multiple myeloma. All-grade and grades 3 and higher CVAE were seen in 617 (18.1%) and 274 (8.2%), respectively. Phase 2 or 3 studies and carfilzomib doses of 45 mg/m2 or higher were associated with high-grade CVAE. Median age older than 65 years, prior myeloma therapies, and concurrent myeloma therapies were not associated with CVAE. For the 3 randomized clinical trials, the summary relative risk of all-grade and grade 3 or higher CVAE for patients receiving carfilzomib compared with noncarfilzomib-receiving control patients were 1.8 and 2.2, respectively.Carfilzomib was associated with a significant incidence of CVAE, with higher rates seen with higher doses of carfilzomib. Phase 1 studies may be underdetecting CVAE. Future studies are needed to identify patients at high risk for CVAE, develop optimal monitoring strategies, and explore strategies to mitigate these risks.

Project description:BackgroundMetamizole is used to treat pain in many parts of the world. Information on the safety profile of metamizole is scarce; no conclusive summary of the literature exists.ObjectiveTo determine whether metamizole is clinically safe compared to placebo and other analgesics.MethodsWe searched CENTRAL, MEDLINE, EMBASE, CINAHL, and several clinical trial registries. We screened the reference lists of included trials and previous systematic reviews. We included randomized controlled trials that compared the effects of metamizole, administered to adults in any form and for any indication, to other analgesics or to placebo. Two authors extracted data regarding trial design and size, indications for pain medication, patient characteristics, treatment regimens, and methodological characteristics. Adverse events (AEs), serious adverse events (SAEs), and dropouts were assessed. We conducted separate meta-analyses for each metamizole comparator, using standard inverse-variance random effects meta-analysis to pool the estimates across trials, reported as risk ratios (RRs). We calculated the DerSimonian and Laird variance estimate T2 to measure heterogeneity between trials. The pre-specified primary end point was any AE during the trial period.ResultsOf the 696 potentially eligible trials, 79 trials including almost 4000 patients with short-term metamizole use of less than two weeks met our inclusion criteria. Fewer AEs were reported for metamizole compared to opioids, RR = 0.79 (confidence interval 0.79 to 0.96). We found no differences between metamizole and placebo, paracetamol and NSAIDs. Only a few SAEs were reported, with no difference between metamizole and other analgesics. No agranulocytosis or deaths were reported. Our results were limited by the mediocre overall quality of the reports.ConclusionFor short-term use in the hospital setting, metamizole seems to be a safe choice when compared to other widely used analgesics. High-quality, adequately sized trials assessing the intermediate- and long-term safety of metamizole are needed.

Project description:Biliary and pancreatic diseases are common in the elderly; however, few studies have addressed the occurrence of adverse events in elderly patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). Our objective was to determine the incidence rates of specific adverse events in this group and calculate incidence rate ratios (IRRs) for selected comparison groups.Bibliographical searches were conducted in Medline, EMBASE, and Cochrane library databases. The studies included documented the incidence of adverse events (perforation, pancreatitis, bleeding, cholangitis, cardiopulmonary adverse events, mortality) in patients aged ≥ 65 who underwent ERCP. Pooled incidence rates were calculated for each reported adverse event and IRRs were determined for available comparison groups. A parallel analysis was performed in patients aged ≥ 80 and ≥ 90.Our literature search yielded 7429 articles, of which 69 studies met our inclusion criteria. Pooled incidence rates for adverse events (per 1000 ERCPs) in patients aged ≥ 65 were as follows: perforation 3.8 (95 %CI 1.8 - 7.0), pancreatitis 13.1 (95 %CI 11.0 - 15.5), bleeding 7.7 (95 %CI 5.7 - 10.1), cholangitis 16.1 (95 %CI 11.7 - 21.7), cardiopulmonary events 3.7 (95 %CI 1.5 - 7.6), and death 7.1 (95 %CI 5.2 - 9.4). Patients ≥ 65 had lower rates of pancreatitis (IRR 0.3, 95 %CI 0.3 - 0.4) compared with younger patients. Octogenarians had higher rates of death (IRR 2.4, 95 %CI 1.3 - 4.5) compared with younger patients, whereas nonagenarians had increased rates of bleeding (IRR 2.4, 95 %CI 1.1 - 5.2), cardiopulmonary events (IRR 3.7, 95 %CI 1.0 - 13.9), and death (IRR 3.8, 95 %CI 1.0 - 14.4). Conclusions ERCP appears to be safe in elderly patients, except in the very elderly who are at higher risk of some adverse events. These data on adverse event rates can help to inform clinical decision-making, the consent process, and comparative effectiveness analyses.

Project description:ImportanceCardiovascular adverse events (CVAEs) after treatment with BRAF and MEK inhibitors in patients with melanoma remain incompletely characterized.ObjectiveTo determine the association of BRAF and MEK inhibitor treatment with CVAEs in patients with melanoma compared with BRAF inhibitor monotherapy.Data sourcesPubMed, Cochrane, and Web of Science were systematically searched for keywords vemurafenib, dabrafenib, encorafenib, trametinib, binimetinib, and cobinimetinib from database inception through November 30, 2018.Study selectionRandomized clinical trials reporting on CVAEs in patients with melanoma being treated with BRAF and MEK inhibitors compared with patients with melanoma being treated with BRAF inhibitor monotherapy were selected.Data extraction and synthesisData assessment followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Pooled relative risks (RRs) and 95% CIs were determined using random-effects and fixed-effects analyses. Subgroup analyses were conducted to assess study-level characteristics associated with CVAEs.Main outcomes and measuresThe selected end points were pulmonary embolism, a decrease in left ventricular ejection fraction, arterial hypertension, myocardial infarction, atrial fibrillation, and QTc interval prolongation. All-grade and high-grade (≥3) CVAEs were recorded.ResultsOverall, 5 randomized clinical trials including 2317 patients with melanoma were selected. Treatment with BRAF and MEK inhibitors was associated with an increased risk of pulmonary embolism (RR, 4.36; 95% CI, 1.23-15.44; P = .02), a decrease in left ventricular ejection fraction (RR, 3.72; 95% CI, 1.74-7.94; P < .001), and arterial hypertension (RR, 1.49; 95% CI, 1.12-1.97; P = .005) compared with BRAF inhibitor monotherapy. The RRs for myocardial infarction, atrial fibrillation, and QTc prolongation were similar between the groups. These results were consistent when assessing high-grade CVAEs (left ventricular ejection fraction: RR, 2.79; 95% CI, 1.36-5.73; P = .005; I2 = 29%; high-grade arterial hypertension: RR, 1.54; 95% CI, 1.14-2.08; P = .005; I2 = 0%), but RRs for high-grade pulmonary embolism were similar between groups. A higher risk of a decrease in left ventricular ejection fraction was associated with patients with a mean age younger than 55 years (RR, 26.50; 95% CI, 3.58-196.10; P = .001), and the associated risk of pulmonary embolism was higher for patients with a mean follow-up time longer than 15 months (RR, 7.70; 95% CI, 1.40-42.12; P = .02).Conclusions and relevanceTherapy with BRAF and MEK inhibitors was associated with a higher risk of CVAEs compared with BRAF inhibitor monotherapy. The findings may help to balance between beneficial melanoma treatment and cardiovascular morbidity and mortality.