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Biomedical subjects

A-M Bagnall

Publications and source records attributed to A-M Bagnall.

7 recordsLinked to original sources
PubMed2005

Sertindole for schizophrenia.

BACKGROUND: Sertindole is an atypical antipsychotic, which is thought to give a lower incidence of extrapyramidal side effects at clinically effective doses than typical antipsychotic drugs. In December 1998, Lundbeck Ltd., the manufacturers of sertindole, voluntarily suspended the availability of the drug due to concerns about cardiac arrhythmia and sudden cardiac death associated with its use. However, based on the advice of an appointed expert group, the Committee for Proprietary Medicinal Products (CPMP) lifted the suspension of sertindole in October 2001, a decision that was ratified by the European Commission on the 26th of June 2002. Lundbeck have committed to the CPMP to carry out two post-marketing surveillance (PMS) studies (which were initiated in July 2002) to provide additional epidemiological data under conditions of normal drug usage. Initial marketing of the product will be restricted and Lundbeck is currently in discussions with the US health authorities (FDA) to investigate whether, and if so when, it would be possible to launch Serdolect in the US market. OBJECTIVES: To determine the effects of sertindole compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. SEARCH STRATEGY: Our Initial searches included electronic searches of Biological Abstracts (1980-1999), The Cochrane Library (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (August 2000), EMBASE (1980-1999), LILACS (1982-1996), MEDLINE (1966-1999), PSYNDEX (1977-1995) and PsycLIT (1974-1999). In addition, we searched pharmaceutical databases on the Dialog Corporation Datastar and Dialog services. We searched references of all identified studies for further trials. We contacted the manufacturer of sertindole and authors of trials. We updated the literature search by searching the Cochrane Schizophrenia Group's Trials Register in April 2003. SELECTION CRITERIA: All randomised controlled trials that compared sertindole to placebo or other antipsychotic (atypical or typical) drug treatments for patients with schizophrenia or related psychosis . DATA COLLECTION AND ANALYSIS: We independently inspected citations and, where possible abstracts; ordered papers for re-inspection and quality assessment and independently extracted data. For homogeneous dichotomous data, we calculated the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) or number needed to harm (NNH) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD). We inspected all data for heterogeneity. MAIN RESULTS: Currently the review includes three studies with a total of 1,104 participants. One was a medium term (eight weeks) placebo controlled study that examined three different doses of sertindole (8, 12 and 20mg/day). The remaining two studies compared the use of sertindole with haloperidol (10mg/day). One was a short term study (six weeks) that looked at four different doses of sertindole (8, 16, 20, 24mg/day) and the other was a long term study (one year) that evaluated the use of sertindole 24mg/day in participants attending outpatients. We excluded two large important studies because they did not report any usable data. (Both had greater than 50% loss to follow-up and data on 'leaving the study early' was inadequately reported). SERTINDOLE VERSUS PLACEBO: Sertindole at 20mg/day was found to be more effective than placebo in terms of BPRS total scores (1 study, n=78, MD 6.2, CI -11.8 to -0.6) and CGI total end point scores (1 study, n=78, MD -0.9, CI -1.6 to -0.2). A marginally statistically significantly greater number of participants that were treated with 20 mg of sertindole were reported to have been 'very much improved' as compared to those taking placebo (1 study, n=102, RR 7.6, CI 1.0 to 57.9, NNT 7.9, CI 4.3 to 41.1). There was no statistically significant difference between sertindole at 8 or 12 mg/day and placebo for these three outcome measures. There were no statistically significant differences between sertindole (8, 12 or 20 mg) and placebo for the incidence of extrapyramidal symptoms, extrapyramidal related events or use of medication to avoid extrapyramidal symptoms. There were no statistically significant differences found between sertindole and placebo for the movement disorders akathisia, cogwheel rigidity, hypertonia and tremor or somnolence. At eight weeks a statistically significant difference between placebo and all sertindole groups (8, 12 and 20 mg) for mean change from baseline in the QT and QTc intervals were observed (p values and SD were not reported). There was a statistically significant greater mean weight gain among participants taking sertindole (20 mg, mean weight gain of 3.3 kg) as compared to placebo (mean weight gain of 0.8 kg; p<0.05). SERTINDOLE VERSUS HALOPERIDOL: At one year, a greater number of participants who were treated with haloperidol as compared to sertindole (24mg/day) were leaving the study early due to any reason (1 study, n=282, RR 0.6, CI 0.4 to 1.0, NNH 8.8, CI 4.7 to 74.0) or non-compliance (1 study, n=282, RR 0.2, CI 0.0 to 0.7, NNH 12.8, CI 7.7 to 37.8). However, at six weeks, there was no statistically significant difference between sertindole (at 8, 16, 20, or 24mg) and haloperidol for this latter outcome. The incidence of EPS was higher among those treated with haloperidol than sertindole at 8, 16, 20 or 24mg/day (8mg: 1 study, n=245, RR 0.1, CI 0.0 to 0.7, NNH 11.4, CI 7.1 to 29.8; 16mg: 1 study, n=252, RR 0.3, CI 0.1 to 1.0, NNH 15.5, CI 8.0 to 217.9; and 20mg: 1 study, n=253, RR 0.2, CI 0.1 to 0.8, NNH 13.7, CI 7.7 to 68.3; 24mg: 2 studies, n=524, RR 0.6, CI 0.4 to 0.8, NNH 8.7, CI 5.4 to 23.0). More participants treated with haloperidol experienced akathisia, tremor and hypertonia than those treated with sertindole (Akathisia - 8mg: 1 study, n=245, RR 0.2, CI 0.1 to 0.5, NNH 6.0, CI 4.1 to 11.2; 16mg: 1 study, n=252, RR 0.1, CI 0.0 to 0.3, NNH 5.4, CI 3.9 9.0; 20mg: 1 study, n=253, RR 0.3, CI 0.2 to 0.7, NNH 7.3, CI 4.6 to 17.9; 24mg: 2 studies, n=524, RR 0.5, CI 0.3 to 0.7, NNH 8.6, CI 5.6 to 18.3. Tremor - 8mg: 1 study, n=245, RR 0.3, CI 0.1 to 0.7, NNH 8.5, CI 5.2 to 24.0; 16mg: 1 study, n=252, RR 0.2, CI 0.1 to 0.5, NNH 7.3, 4.8 to 15.6; 20mg: 1 study, n=253, RR 0.2, CI 0.1 to 0.6, NNH 7.8, CI 4.9 to 18.1; 24mg: 2 studies, n=524, RR 0.4, CI 0.2 to 0.6, NNH 8.2, CI 5.6 to 15.3. For Hypertonic - 24mg: 2 studies, n=524, RR 0.5, CI 0.3 to 0.8, NNH 12.4, CI 7.5 to 35.0; for sertindole 8, 16 and 20mg there was no statistically significant differences between the treatment groups). One study reported that at six weeks, there was a statistically significant greater increase from baseline to final value in mean QTc interval in the sertindole 16, 20 and 24mg groups (20, 26, and 24msec, respectively) than in the haloperidol group (0msec; p value was not reported), but no SD or any other measure of variance for the effect sizes were reported. For one long term study only one participant from the sertindole group (24mg) had a QT interval that exceeded 500msec (1 study, n=282, RR 3.0 CI 0.1 to 73.0), but 11participants treated with Sertindole had QTc intervals of at least 500msec, compared to none in the haloperidol treated group (1 study, n=282, RR 23.0, CI 1.4 to 386.6, NNH 12.8, CI 8.2 to 29.6). At six weeks, fewer participants treated with sertindole at 8mg or 24mg were affected by somnolence than those treated with haloperidol (sertindole 8mg: 1 study, n=245, RR 0.1, CI 0.0 to 0.7, NNH 11.4, CI 7.1 to 29.8; 24mg: 2 studies, n=524, RR 0.6, CI 0.4 to 1.0, NNH 14.8, CI 7.7 to 205.2). The incidence of rhinitis was found to be statistically significantly higher among those taking sertindole at 16 or 24mg as compared to haloperidol (16mg: 1 study, n=252, RR 10.8, CI 1.4 to 82.6, NNH 12.7, CI 7.7 to 36.7; 24mg: 2 studies, n= 524, RR 2.1, CI 1.4 to 3.1, NNH 8.7, CI 5.6 to 18.6). At one year, 33 participants treated with sertindole (24mg) had experienced the sexual adverse event of decreased ejaculatory volume, compared with six participants treated with haloperidol. However the number of included male participants was not reported and therefore the RR could not be calculated. At one year, more participants taking sertindole (24mg/day) had put on weight compared to those taking haloperidol (1 study, n=282, RR 6.3, CI 1.9 to 20.9, NNH 8.8, CI 5.7 to 19.1). At six weeks, all of the sertindole groups showed an increase in body weight from baseline to final evaluation ranging from 1.3kg to 1.9kg, all of which represented a statistically significantly different weight change than that recorded for the haloperidol treatment group (-0.1Kg). However, the actual weight gain for each sertindole dosage group was not reported and no SD or any other measure of variance was given. AUTHORS' CONCLUSIONS: Sertindole at a dose of 20mg/day was found to be more antipsychotic than placebo. When used at 8, 12 or 20mg/day it appears to be as acceptable as placebo (in terms of various adverse events including movement disorders and somnolence), but seems to be associated with more cardiac problems (8, 12 or 20mg/day) and an increase in weight gain (20mg/day) than placebo. Sertindole at a dose of 24mg/day was better tolerated than haloperidol (in terms of participants leaving the study early). It was also found to be was associated with fewer movement disorders (at 8, 16, 20 or 24mg/day) and sedation (8 or 24mg/day) than haloperidol. However, it was shown to cause more cardiac anomalies (16, 20 or 24mg/day), weight gain (all doses combined), rhinitis (16 or 24mg/day), and problems with sexual functioning (24mg/day) than haloperidol. One short term study reported that sertindole 16mg/day was the most optimal dose.

Antipsychotic Agents↗
PubMed2005

Systematic review of effectiveness of different treatments for childhood retinoblastoma.

OBJECTIVES: To assess the clinical effectiveness of treatments for childhood retinoblastoma. DATA SOURCES: Electronic databases were searched from inception to April 2004. REVIEW METHODS: Studies of participants diagnosed with childhood retinoblastoma, any interventions and all clinical outcomes were eligible for inclusion. Randomised and non-randomised controlled trials and cohort studies with clear comparisons between treatment groups were included. Methodological quality was assessed. A narrative synthesis was conducted. Where possible, studies assessing common interventions were grouped together, with prospective and retrospective studies grouped separately. Emphasis was placed on prospective studies. RESULTS: Thirty-one individual studies, from 42 publications, were included in the review. Apart from one non-randomised controlled trial, only comparative studies of observational design were available for any of the treatments. Four of the included studies were prospective and the remaining 27 were retrospective. Most of the studies were of radiotherapy or chemotherapy, with few studies available on enucleation or focal treatments such as brachytherapy, photocoagulation, cryotherapy and thermotherapy. The methodological quality was generally poor, with a high risk of bias in all included studies. The main problems were in relation to how treatment was allocated and lack of consideration of potentially confounding factors, such as initial disease severity, in the study design and data analysis. The evidence base for effectiveness of treatments for childhood retinoblastoma is extremely limited. Owing to the considerable limitations of the evidence identified, it was not possible to make meaningful and robust conclusions about the relative effectiveness of different treatment approaches for childhood retinoblastoma. CONCLUSIONS: In the authors' opinion, the evidence base for the effectiveness of treatments for childhood retinoblastoma is not sufficiently robust to provide clear guidance for clinical practice. Ideally, good-quality randomised controlled trials (RCTs) assessing the effectiveness of different treatment options for childhood retinoblastoma are required. Research is required on all the treatments currently used for this condition. Where RCTs are not feasible, for ethical or practical reasons, only high-quality, prospective, non-randomised studies should be given consideration, owing to the generally higher risk of bias in retrospective studies. To reduce the risk of confounding due to allocation by clinical indication, studies should compare patients with similar disease severity rather than compare patients of mixed disease severities. Standardised outcomes should be agreed for use in studies assessing the effectiveness of treatment. These outcomes should encompass potential important adverse effects of treatment such as loss of visual acuity and cosmetic outcome, as well as beneficial effects.

Adolescent↗
PubMed2004

A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder.

OBJECTIVES: To evaluate the clinical and cost-effectiveness of quetiapine, olanzapine and valproate semisodium in the treatment of mania associated with bipolar disorder. DATA SOURCES: Electronic databases; industry submissions made to the National Institute for Clinical Excellence. REVIEW METHODS: Randomised trials and economic evaluations that evaluated the effectiveness of quetiapine, olanzapine or valproate semisodium in the treatment of mania associated with bipolar disorder were selected for inclusion. Data were extracted by one reviewer into a Microsoft Access database and checked for quality and accuracy by a second. The quality of the cost-effectiveness studies was assessed using a checklist updated from that developed by Drummond and colleagues. Relative risk and mean difference data were presented as Forest plots but only pooled where this made sense clinically and statistically. Studies were grouped by drug and, within each drug, by comparator used. Chi-squared tests of heterogeneity were performed for the outcomes if pooling was indicated. A probabilistic model was developed to estimate costs from the perspective of the NHS, and health outcomes in terms of response rate, based on an improvement of at least 50% in a patient's baseline manic symptoms derived from an interview-based mania assessment scale. The model evaluated the cost-effectiveness of the alternative drugs when used as part of treatment for the acute manic episode only. RESULTS: Eighteen randomised trials met the inclusion criteria. Aspects of three of the quetiapine studies were commercial-in-confidence. The quality of the included trials was limited and overall, key methodological criteria were not met in most trials. Quetiapine, olanzapine and valproate semisodium appear superior to placebo in reducing manic symptoms, but may cause side-effects. There appears to be little difference between these treatments and lithium in terms of effectiveness, but quetiapine is associated with somnolence and weight gain, whereas lithium is associated with tremor. Olanzapine as adjunct therapy to mood stabilisers may be more effective than placebo in reducing mania and improving global health, but it is associated with more dry mouth, somnolence, weight gain, increased appetite, tremor and speech disorder. There was little difference between these treatments and haloperidol in reducing mania, but haloperidol was associated with more extrapyramidal side-effects and negative implications for health-related quality of life. Intramuscular olanzapine and lorazepam were equally effective and safe in one very short (24 hour) trial. Valproate semisodium and carbamazepine were equally effective and safe in one small trial in children. Olanzapine may be more effective than valproate semisodium in reducing mania, but was associated with more dry mouth, increased appetite, oedema, somnolence, speech disorder, Parkinson-like symptoms and weight gain. Valproate semisodium was associated with more nausea than olanzapine. The results from the base-case analysis demonstrate that choice of optimal strategy is dependent on the maximum that the health service is prepared to pay per additional responder. For a figure of less than 7179 British pounds per additional responder, haloperidol is the optimal decision; for a spend in excess of this, it would be olanzapine. Under the most favourable scenario in relation to the costs of responders and non-responders beyond the 3-week period considered in the base-case analysis, the incremental cost-effectiveness ratio of olanzapine is reduced to 1236 British pounds. CONCLUSIONS: In comparison with placebo, quetiapine, olanzapine and valproate semisodium appear superior in reducing manic symptoms, but all drugs are associated with adverse events. In comparison with lithium, no significant differences were found between the three drugs in terms of effectiveness, and all were associated with adverse events. Several limitations of the cost-effectiveness analysis exist, which inevitably means that the results should be treated with some caution. There remains a need for well-conducted, randomised, double-blind head-to-head comparisons of drugs used in the treatment of mania associated with bipolar disorder and their cost-effectiveness. Participant demographic, diagnostic characteristics, the treatment of mania in children, the use of adjunctive therapy and long-term safety issues in the elderly population, and acute and long-term treatment are also subjects for further study.

Antimanic Agents↗
PubMed2003

Effectiveness and cost-effectiveness of acute hospital-based spinal cord injuries services: systematic review.

OBJECTIVES: To examine four key areas: (1) the effectiveness and cost-effectiveness of spinal fixation surgery, (2) the consequences of immediate versus delayed referral to a spinal injuries unit (SIU), (3) the number of people with a new spinal cord injury (SCI) who are discharged from hospital without ever being transferred to an SIU, and (4) the effectiveness and cost-effectiveness of steroids for people with SCI. DATA SOURCES: Searches were carried out on several databases and also on the Internet. Specialist SCI and spinal injury related websites were searched, specifically the Spinal Injuries Association, the British Association of Spinal Cord Injury Specialists and the National Spinal Cord Injury Association. REVIEW METHODS: Three separate search strategies were devised to find studies relating to the four key areas. Two reviewers independently screened all study citations for inclusion. The lists of all retrieved studies were scanned for additional studies. Quality of studies was assessed and data were extracted by one reviewer then checked by the second. Data from included studies were summarised within each key area. For dichotomous data, relative risks were calculated with 95% confidence intervals. Pooled relative risks were calculated as appropriate. For continuous data, mean differences with 95% confidence intervals were calculated and, if data were pooled, weighted mean differences were calculated. Searches were carried out to identify economic evaluations, details of these together with a critical appraisal of quality are presented in structured tables. Quality was assessed using a checklist supplemented with additional comments on the adequacy of methodology where appropriate. RESULTS: For spinal fixation versus no fixation, 68 retrospective observational studies were found that suggested some benefits of fixation surgery. Only four studies were found on fixation surgery in SIUs compared with non-SIU hospitals and no significant differences were seen. All 28 studies concerning delayed referral to a SIU were retrospective observational studies. In most, study details were poorly reported and there was doubt over the comparability of groups at baseline and on confounding factors. Times of referral and transfer were not reported separately. Evidence suggested an effect in favour of the SIU group for neurological improvement. No relevant published studies of any design were found regarding how many people with a new SCI are discharged from hospital without ever being transferred to an SIU. Two systematic reviews were found that assessed the effectiveness of steroids. No studies were identified that considered both costs and the impact on patient outcomes of a given intervention. CONCLUSIONS: Although there was evidence to suggest some benefits of fixation surgery and also a benefit of immediate referral to SIUs compared with delayed or no referral, owing to the limitations of the data these should be interpreted with caution. Not enough data were found to assess whether surgery is more beneficial when carried out in SIUs and further research is required in this area. Well-designed prospective observational studies with appropriately matched controls are needed. High-dose methylprednisolone steroid therapy may be effective in promoting some degree of neurological recovery if given within 8 hours of injury. There is a need for more randomised controlled trials (RCTs) of pharmacological therapy for acute SCI. No published studies of any design were found to answer the question of how many people with acute SCI are discharged from hospital without ever being transferred to an SIU. Primary research involving audit of selected hospital records should be commissioned and published. The search strategy did not identify any full economic evaluations. Future research should include full economic evaluations, possibly alongside a large RCT, which fully consider the costs and consequences of implementing interventions.

Anti-Inflammatory Agents↗