Open Access Research BMJ Open: first published as 10.1136/bmjopen-2014-005090 on 30 July 2014. Downloaded from A systematic review and meta-analysis assessing adverse event profile and tolerability of nicergoline Mario Fioravanti,1 Taku Nakashima,2 Jun Xu,3 Amit Garg4 To cite: Fioravanti M, ABSTRACT et al Strengths and limitations of this study Nakashima T, Xu J, .A Objective: To evaluate the safety profile of nicergoline systematic review and meta- compared with placebo and other active agents from ▪ analysis assessing adverse First meta-analysis on nicergoline to understand published randomised controlled trials. event profile and tolerability the adverse clinical profile. of nicergoline. BMJ Open Design: Systematic review and meta-analysis of ▪ Critical in wake of recent European Medicines 2014;4:e005090. nicergoline compared with placebo and other active Agency’s (EMEA) view of blanket limitation on doi:10.1136/bmjopen-2014- agents across various indications. use of all ergot derivatives. 005090 Data sources: MEDLINE, Medline-in-process, Cochrane, ▪ Limited by the availability of long-term (more EMBASE, EMBASE alerts, Cochrane Central Register of than 2 years) and high-dose studies for cognitive ▸ Prepublication history and Controlled Trials (CENTRAL), Cochrane Database of impairment. additional material is Systematic Reviews (CDSR) and Cochrane Methodology available. To view these files Register (CMR) for all the randomised controlled trials, please visit the journal open-label or blinded, in adults treated with nicergoline. countries and has been used for more than (http://dx.doi.org/10.1136/ Studies published until August 2013 were included. bmjopen-2014-005090). four decades for the treatment of cognitive, Review method: 29 studies were included for data affective and behavioural disorders in older extraction. The studies included in this review were majorly Received 20 February 2014 people.1 During the time it has been in use, from European countries and mostly in cerebrovascular Revised 5 June 2014 the rationale for its clinical use has evolved. disease (n=15) and dementia (n=8). Accepted 11 July 2014 Initially regarded as a vasoactive drug, it was Results: The treatment withdrawals were comparatively lower in the nicergoline group as compared with the mainly prescribed for cerebrovascular disor- ders. Although cholinergic deficits are the placebo group (RR=0.92; 95% CI 0.7 to 1.21) and other http://bmjopen.bmj.com/ active comparators (RR=0.45; 95% CI 0.10 to 1.95), but major current targets for pharmacological the difference was non-significant. Incidence of any intervention in Alzheimer’s dementia, a wide adverse events (AEs) was slightly higher (RR=1.05; 95% CI variety of other neurotransmitter changes 0.93 to 1.2) while incidence of serious AEs was lower can be identified in the disease. (RR=0.85; 95% CI 0.50 to 1.45) in the nicergoline Nicergoline has been demonstrated to compared with placebo group. Frequency of anxiety was increase the availability of acetylcholine significantly lower in nicergoline as compared with placebo through an increased release from choliner- (p=0.01). Other AEs including diarrhoea, gastric upset, gic terminals and a selective inhibition of dizziness and drowsiness were less frequent in the on September 24, 2021 by guest. Protected copyright. acetyl cholinesterase.2 Nicergoline may also nicergoline group when compared with placebo/active enhance norepinephrine and dopamine drugs, but the difference was non-significant. Frequency of 3 hypotension and hot flushes was slightly higher in the turnover in some areas of the brain. nicergoline group but the difference was non-significant. Nicergoline has a positive effect on the signal None of the studies reported any incidence of fibrosis or transduction system stimulating the phosphoi- ergotism with nicergoline treatment. nositide pathway which is specifically Conclusions: Nicergoline is an ergot derivative, but its impaired in Alzheimer’s dementia.4 Other safety profile is better than other ergot derivatives like useful actions of nicergoline in dementia are ergotamine and ergotoxine. This systematic review and an increase of phosphoinositide-protein meta-analysis suggests that nicergoline has a good kinase C (PKC) translocation which helps in safety profile. None of the studies included in this combating β-amyloid deposition and in systematic review reported any incidence of fibrosis or retarding the reduction in nerve-growth ergotism with nicergoline. factor which may help in preventing the loss 4 For numbered affiliations see of cholinergic neurons. end of article. The side effects of nicergoline are usually limited to nausea, hot flushes, mild gastric Correspondence to BACKGROUND upset, hypotension and dizziness. At high Dr Amit Garg; Nicergoline is a semisynthetic ergot deriva- dosages bradycardia, increased appetite, agi- [email protected] tive which has been registered in over 50 tation, diarrhoea and perspiration have been Fioravanti M, et al. BMJ Open 2014;4:e005090. doi:10.1136/bmjopen-2014-005090 1 Open Access BMJ Open: first published as 10.1136/bmjopen-2014-005090 on 30 July 2014. Downloaded from known to occur. Nicergoline has a better safety profile Endnotes V.X3. Cochrane methodology was used to compared with ergot derivates which are associated with conduct this systematic review. All studies were screened increased risk of fibrosis (formation of excess connective by two independent reviewers with discrepancies tissue that can damage organs and body structures) and resolved by a third reviewer. ergotism (symptoms of ergot poisoning, such as spasms and obstructed blood circulation) with these medicines. Study quality and risk of bias Nicergoline is not associated with either fibrosis or The Jadad score was used to assess the quality of ergotism; however, concerns about its safety have been included studies. Risk of bias in the individual studies raised, especially after the European Medicines Agency’s included for meta-analysis was assessed using the (EMEA) restriction on nicergoline, because it is an Cochrane risk assessment tool.6 ergot derivative.5 Most of the available literature suggests that the adverse events (AEs) with nicergoline are mild Outcomes assessed and transient. Hence, a systematic review of literature In most of the included studies, safety evaluation and meta-analysis was conducted to compare the safety included monitoring of AEs, vital signs, haematology fi pro le of nicergoline with placebo and other active and blood chemistry. Haematology and blood chemistry comparators. were assessed at baseline and at the last assessment. Tolerability evaluation included monitoring of METHODS treatment-emergent AEs (elicited or observed); physical Search strategy examination including ECG recording; vital signs, A comprehensive search strategy was designed to retrieve haematology and blood chemistry testing. Withdrawals, due to any reason or due to AE, were reported. relevant clinical data from published literature. The follow- ing databases were examined since inception up to 16 The data from these studies were pooled for total with- August 2013; MEDLINE, Medline-in-process, EMBASE, drawals, withdrawals due to AEs, incidence rates for any AEs, serious AEs (SAEs) and specific AEs including EMBASE alerts, Cochrane Central Register of Controlled fl Trials (CENTRAL), Cochrane Database of Systematic anxiety, constipation, diarrhoea, hot ushes, itching, Reviews (CDSR) and Cochrane Methodology Register. gastric upset, hypotension, headache, dizziness, insom- Medical subject headings (MeSH terms) and free key- nia, drowsiness and fatigue. Only studies which pre- words like “randomised controlled trial”, “Nicergoline”, sented data for same comparators were included in “Adverse effects”, “toxicity” and “side effects” were used direct meta-analysis for each outcome. (see online supplementary appendix 1). This review was not restricted to studies conducted in the English lan- Statistical analysis http://bmjopen.bmj.com/ guage and hence studies published in other languages Comparison of safety and tolerability outcomes was made were also included and translated for data extraction. between interventions by pooling data from studies using a direct meta-analysis technique. Only head-to-head compari- Selection criteria sons between interventions were included for meta-analysis. Review Manager (RevMan V.5.1) software was used for To meet the study objective, we predecided on inclusion meta-analysis of the available data. Dichotomous outcomes criteria which include randomised controlled trials were summarised as risk (relative) ratios. (RCTs) reporting AEs in patients undergoing nicergo- line treatment for psychiatric disorders. To be included on September 24, 2021 by guest. Protected copyright. in the analysis, a trial had to fulfil the following criteria: RESULTS (1) randomised trials which could be open-label, single- Study selection blind or double-blind, parallel group studies; (2) use of A trial flow of the review process (as per PRISMA state- nicergoline for Alzheimer’s disease, dementia or cogni- ment) is presented along with manuscript (figure 1). tive disorders; (3) use of nicergoline as one of the inter- The search of the literature yielded 437 separate refer- ventions; (4) studies comparing nicergoline with ergot ences. Owing to the overlap of coverage between the derivatives, placebo or other active agents were included databases, 96 of the references were found to be dupli- and (5) studies should report safety and tolerability