Publications by authors named "Mike J Clarke"

28 Publications

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Oral hygiene interventions for people with intellectual disabilities.

Cochrane Database Syst Rev 2019 05 31;5:CD012628. Epub 2019 May 31.

School of Dental Science, Trinity College Dublin, University of Dublin, Lincoln Place, Dublin, Ireland, D02 F859.

Background: Periodontal (gum) disease and dental caries (tooth decay) are the most common causes of tooth loss; dental plaque plays a major role in the development of these diseases. Effective oral hygiene involves removing dental plaque, for example, by regular toothbrushing. People with intellectual disabilities (ID) can have poor oral hygiene and oral health outcomes.

Objectives: To assess the effects (benefits and harms) of oral hygiene interventions, specifically the mechanical removal of plaque, for people with intellectual disabilities (ID).

Search Methods: Cochrane Oral Health's Information Specialist searched the following databases to 4 February 2019: Cochrane Oral Health's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL; Cochrane Register of Studies), MEDLINE Ovid, Embase Ovid and PsycINFO Ovid. ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. The Embase search was restricted by date due to the Cochrane Centralised Search Project, which makes available clinical trials indexed in Embase through CENTRAL. We handsearched specialist conference abstracts from the International Association of Disability and Oral Health (2006 to 2016).

Selection Criteria: We included randomised controlled trials (RCTs) and some types of non-randomised studies (NRS) (non-RCTs, controlled before-after studies, interrupted time series studies and repeated measures studies) that evaluated oral hygiene interventions targeted at people with ID or their carers, or both. We used the definition of ID in the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10). We defined oral hygiene as the mechanical removal of plaque. We excluded studies that evaluated chemical removal of plaque, or mechanical and chemical removal of plaque combined.

Data Collection And Analysis: At least two review authors independently screened search records, identified relevant studies, extracted data, assessed risk of bias and judged the certainty of the evidence according to GRADE criteria. We contacted study authors for additional information if required. We reported RCTs and NRSs separately.

Main Results: We included 19 RCTs and 15 NRSs involving 1795 adults and children with ID and 354 carers. Interventions evaluated were: special manual toothbrushes, electric toothbrushes, oral hygiene training, scheduled dental visits plus supervised toothbrushing, discussion of clinical photographs showing plaque, varied frequency of toothbrushing, plaque-disclosing agents and individualised care plans. We categorised results as short (six weeks or less), medium (between six weeks and 12 months) and long term (more than 12 months).Most studies were small; all were at overall high or unclear risk of bias. None of the studies reported quality of life or dental caries. We present below the evidence available from RCTs (or NRS if the comparison had no RCTs) for gingival health (inflammation and plaque) and adverse effects, as well as knowledge and behaviour outcomes for the training studies.Very low-certainty evidence suggested a special manual toothbrush (the Superbrush) reduced gingival inflammation (GI), and possibly plaque, more than a conventional toothbrush in the medium term (GI: mean difference (MD) -12.40, 95% CI -24.31 to -0.49; plaque: MD -0.44, 95% CI -0.93 to 0.05; 1 RCT, 18 participants); brushing was carried out by the carers. In the short term, neither toothbrush showed superiority (GI: MD -0.10, 95% CI -0.77 to 0.57; plaque: MD 0.20, 95% CI -0.45 to 0.85; 1 RCT, 25 participants; low- to very low-certainty evidence).Moderate- and low-certainty evidence found no difference between electric and manual toothbrushes for reducing GI or plaque, respectively, in the medium term (GI: MD 0.02, 95% CI -0.06 to 0.09; plaque: standardised mean difference 0.29, 95% CI -0.07 to 0.65; 2 RCTs, 120 participants). Short-term findings were inconsistent (4 RCTs; low- to very low-certainty evidence).Low-certainty evidence suggested training carers in oral hygiene care had no detectable effect on levels of GI or plaque in the medium term (GI: MD -0.09, 95% CI -0.63 to 0.45; plaque: MD -0.07, 95% CI -0.26 to 0.13; 2 RCTs, 99 participants). Low-certainty evidence suggested oral hygiene knowledge of carers was better in the medium term after training (MD 0.69, 95% CI 0.31 to 1.06; 2 RCTs, 189 participants); this was not found in the short term, and results for changes in behaviour, attitude and self-efficacy were mixed.One RCT (10 participants) found that training people with ID in oral hygiene care reduced plaque but not GI in the short term (GI: MD -0.28, 95% CI -0.90 to 0.34; plaque: MD -0.47, 95% CI -0.92 to -0.02; very low-certainty evidence).One RCT (304 participants) found that scheduled dental recall visits (at 1-, 3- or 6-month intervals) plus supervised daily toothbrushing were more likely than usual care to reduce GI (pocketing but not bleeding) and plaque in the long term (low-certainty evidence).One RCT (29 participants) found that motivating people with ID about oral hygiene by discussing photographs of their teeth with plaque highlighted by a plaque-disclosing agent, did not reduce plaque in the medium term (very low-certainty evidence).One RCT (80 participants) found daily toothbrushing by dental students was more effective for reducing plaque in people with ID than once- or twice-weekly toothbrushing in the short term (low-certainty evidence).A benefit to gingival health was found by one NRS that evaluated toothpaste with a plaque-disclosing agent and one that evaluated individualised oral care plans (very low-certainty evidence).Most studies did not report adverse effects; of those that did, only one study considered them as a formal outcome. Some studies reported participant difficulties using the electric or special manual toothbrushes.

Authors' Conclusions: Although some oral hygiene interventions for people with ID show benefits, the clinical importance of these benefits is unclear. The evidence is mainly low or very low certainty. Moderate-certainty evidence was available for only one finding: electric and manual toothbrushes were similarly effective for reducing gingival inflammation in people with ID in the medium term. Larger, higher-quality RCTs are recommended to endorse or refute the findings of this review. In the meantime, oral hygiene care and advice should be based on professional expertise and the needs and preferences of the individual with ID and their carers.
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http://dx.doi.org/10.1002/14651858.CD012628.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543590PMC
May 2019

Endovascular coiling versus neurosurgical clipping for people with aneurysmal subarachnoid haemorrhage.

Cochrane Database Syst Rev 2018 08 15;8:CD003085. Epub 2018 Aug 15.

Department of Neurosurgery, Kuopio University Hospital, Puijonlaaksontie 2, Kuopio, Kuopio, Finland, 70029.

Background: Around 30% of people who are admitted to hospital with aneurysmal subarachnoid haemorrhage (SAH) will rebleed in the initial month after the haemorrhage if the aneurysm is not treated. The two most commonly used methods to occlude the aneurysm for prevention of rebleeding are microsurgical clipping of the neck of the aneurysm and occlusion of the lumen of the aneurysm by means of endovascular coiling. This is an update of a systematic review that was previously published in 2005.

Objectives: To compare the effects of endovascular coiling versus neurosurgical clipping in people with aneurysmal SAH on poor outcome, rebleeding, neurological deficit, and treatment complications.

Search Methods: We searched the Cochrane Stroke Group Trials Register (March 2018). In addition, we searched CENTRAL (2018, Issue 2), MEDLINE (1966 to March 2018), Embase (1980 to March 2018), US National Institutes of Health Ongoing Trials Register (March 2018), and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (last searched March 2018). We also contacted trialists.

Selection Criteria: We included randomised trials comparing endovascular coiling with neurosurgical clipping in people with SAH from a ruptured aneurysm.

Data Collection And Analysis: Two review authors independently extracted data, and assessed trial quality and risk of bias using the GRADE approach. We contacted trialists to obtain missing information. We defined poor outcome as death or dependence in daily activities (modified Rankin scale 3 to 6 or Glasgow Outcome Scale (GOS) 1 to 3). In the special worst-case scenario analysis, we assumed all participants in the group with better outcome with missing follow-up information had a poor outcome and those in the other group with missing data a good outcome.

Main Results: We included four randomised trials involving 2458 participants (range per trial: 20 to 2143 participants). Evidence is mostly based on the largest trial. Most participants were in good clinical condition and had an aneurysm on the anterior circulation. None of the included trials was at low risk of bias in all domains. One trial was at unclear risk in one domain, two trials at unclear risk in three domains, and one trial at high risk in one domain.After one year of follow-up, 24% of participants randomised to endovascular treatment and 32% of participants randomised to the surgical treatment group had poor functional outcome. The risk ratio (RR) of poor outcome (death or dependency) for endovascular coiling versus neurosurgical clipping was 0.77 (95% confidence interval (CI) 0.67 to 0.87; 4 trials, 2429 participants, moderate-quality evidence), and the absolute risk reduction was 7% (95% CI 4% to 11%). In the worst-case scenario analysis for poor outcome, the RR for endovascular coiling versus neurosurgical clipping was 0.80 (95% CI 0.71 to 0.91), and the absolute risk reduction was 6% (95% CI 2% to 10%). The RR of death at 12 months was 0.80 (95% CI 0.63 to 1.02; 4 trials, 2429 participants, moderate-quality evidence). In a subgroup analysis of participants with an anterior circulation aneurysm, the RR of poor outcome was 0.78 (95% CI 0.68 to 0.90; 2 trials, 2157 participants, moderate-quality evidence), and the absolute risk decrease was 7% (95% CI 3% to 10%). In subgroup analysis of those with a posterior circulation aneurysm, the RR was 0.41 (95% CI 0.19 to 0.92; 2 trials, 69 participants, low-quality evidence), and the absolute decrease in risk was 27% (95% CI 6% to 48%). At five years, 28% of participants randomised to endovascular treatment and 32% of participants randomised to surgical treatment had poor functional outcome. The RR of poor outcome for endovascular coiling versus neurosurgical clipping was 0.87 (95% CI 0.75 to 1.01, 1 trial, 1724 participants, low-quality evidence). At 10 years, 35% participants allocated to endovascular and 43% participants allocated to surgical treatment had poor functional outcome. At 10 years RR of poor outcome for endovascular coiling versus neurosurgical clipping was 0.81 (95% CI 0.70 to 0.92; 1 trial, 1316 participants, low-quality evidence). The RR of delayed cerebral ischaemia at two to three months for endovascular coiling versus neurosurgical clipping was 0.84 (95% CI 0.74 to 0.96; 4 trials, 2450 participants, moderate-quality evidence). The RR of rebleeding for endovascular coiling versus neurosurgical clipping was 1.83 (95% CI 1.04 to 3.23; 4 trials, 2458 participants, high-quality evidence) at one year, and 2.69 (95% CI 1.50 to 4.81; 1 trial, 1323 participants, low-quality evidence) at 10 years. The RR of complications from intervention for endovascular coiling versus neurosurgical clipping was 1.05 (95% CI 0.44 to 2.53; 2 trials, 129 participants, low-quality evidence).

Authors' Conclusions: The evidence in this systematic review comes mainly from one large trial, and long-term follow-up is available only for a subgroup of participants within that trial. For people in good clinical condition with ruptured aneurysms of either the anterior or posterior circulation the data from randomised trials show that, if the aneurysm is considered suitable for both neurosurgical clipping and endovascular coiling, coiling is associated with a better outcome. There is no reliable trial evidence that can be used directly to guide treatment in people with a poor clinical condition.
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http://dx.doi.org/10.1002/14651858.CD003085.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513627PMC
August 2018

Pharmacological Treatment for Antipsychotic-Related Constipation.

Schizophr Bull 2017 05 14;43(3):490-492. Epub 2017 Feb 14.

Centre for Public Health, Queen's University Belfast, Belfast, UK.

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http://dx.doi.org/10.1093/schbul/sbx011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463924PMC
May 2017

Pharmacological treatment for antipsychotic-related constipation.

Cochrane Database Syst Rev 2017 01 24;1:CD011128. Epub 2017 Jan 24.

Centre for Public Health, Queen's University Belfast, Institute of Clinical Sciences, Block B, Royal Victoria Hospital, Grosvenor Road, Belfast, Northern Ireland, UK, BT12 6BJ.

Background: Antipsychotic-related constipation is a common and serious adverse effect, especially for people taking clozapine. Clozapine has been shown to impede gastrointestinal motility, leading to constipation, and has been reported in up to 60% of patients receiving clozapine. In rare cases, complications can be fatal. Appropriate laxatives should be prescribed to treat constipation in people taking antipsychotics, but there is a lack of guidance on the comparative effectiveness and harms of different agents in this population. An understanding of the effectiveness and safety of treatment for antipsychotic-related constipation is important for clinicians and patients alike.

Objectives: To evaluate the effectiveness and safety of pharmacologic treatment (versus placebo or compared against another treatment) for antipsychotic-related constipation (defined as constipated patients of any age, who are treated with antipsychotics, regardless of dose, in which constipation is considered to be an antipsychotic-related side effect).

Search Methods: We searched the Cochrane Schizophrenia Group's Trials Register (15 June 2015), which is based on regular searches of MEDLINE, Embase, CINAHL, BIOSIS, AMED, PubMed, PsycINFO, and registries of clinical trials, grey literature, and conference proceedings. There are no language, date, document type, or publication status limitations for inclusion of records in this register. We also handsearched bibliographies and contacted relevant authors for additional information.

Selection Criteria: We included all published and unpublished randomised controlled trials (RCTs) investigating the efficacy of pharmacological treatments in patients with antipsychotic-related constipation. Pharmacological treatments included laxatives and other medicines that could reasonably be used to combat constipation in this population (e.g. anticholinergic agents, like bethanecol).

Data Collection And Analysis: Two review authors independently extracted data from all included studies and assessed trials for risk of bias. A third author reviewed 20% of trials. We analysed dichotomous data using relative risks (RR) and the 95% confidence intervals (CI). We assessed risk of bias for included studies and used GRADE to create a 'Summary of findings' table. We discussed any disagreement, documented decisions, and attempted to contact study authors when necessary.

Main Results: We identified two relevant Chinese studies (N = 480) that contributed data to this review. Both studies were over ten years old and poorly reported, lacking descriptions of contemporary CONSORT reporting prerequisites, such as sequence generation, allocation concealment, blinding, participant flow, how the sample size was determined, or how outcomes were measured. The studies also did not report trial registration, pre-specified protocols, consent processes, ethical review, or funding source. We were unsuccessful in making contact with the authors to clarify the missing details. We classified both studies as having an overall high risk of bias.One study compared glycerol suppository with the traditional Chinese medicine (TCM) approaches of tuina massage and acupuncture. Compared to tuina massage, glycerol laxative was less effective in relieving constipation at both two days after treatment (1 RCT; N = 120; RR 2.88, 95% CI 1.89 to 4.39; very low-quality evidence), and three days (1 RCT; N = 120; RR 4.80, CI 1.96 to 11.74, very low-quality evidence). Favourable results were also seen for acupuncture at two days (1 RCT; N = 120; RR 3.50; 95% CI 2.18 to 5.62; very low-quality evidence), and at three days (1 RCT; N = 120; RR 8.00, 95% CI 2.54 to 25.16; very low-quality evidence).The other study compared mannitol, an osmotic laxative, with rhubarb soda or phenolphthalein. Mannitol was more effective than rhubarb soda or phenolphthalein in trelieving constipation within 24 hours of treatment (1 RCT; N = 240; RR 0.07; 95% CI 0.02 to 0.27, very low-quality evidence).No data were reported for our other important outcomes: need for rescue medication, bowel obstruction (a complication of antipsychotic-related constipation), quality of life, adverse events, leaving the study early, and economic costs.

Authors' Conclusions: We had hoped to find clinically useful evidence appraising the relative merits of the interventions routinely used to manage antipsychotic-related constipation, a common and potentially serious adverse effect of the use of these drugs. The results were disappointing. There were no data comparing the common pharmacological interventions for constipation, such as lactulose, polyethylene glycol, stool softeners, lubricant laxatives, or of novel treatments such as linaclotide. Data available were very poor quality and the trials had a high risk of bias. Data from these biased studies suggested that mannitol, an osmotic laxative, was more effective than rhubarb soda and phenolphthalein in relieving constipation, and a two-week course of glycerol suppositories was less effective than the TCM approaches of tuina massage and acupuncture.Overall, there is insufficient trial-based evidence to assess the effectiveness and safety of pharmacological interventions for treating antipsychotic-related constipation, due to limited, poor quality data (few studies with high risk of bias and no meta-analyses). The methodological limitations in the included studies were obvious, and any conclusions based on their results should be made with caution. Methodologically rigorous RCTs evaluating interventions for treating antipsychotic-related constipation are needed.
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http://dx.doi.org/10.1002/14651858.CD011128.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465073PMC
January 2017

Compression stockings for preventing deep vein thrombosis in airline passengers.

Cochrane Database Syst Rev 2016 Sep 14;9:CD004002. Epub 2016 Sep 14.

Centre for Public Health, Queen's University Belfast, Institute of Clinical Sciences, Block B, Royal Victoria Hospital, Grosvenor Road, Belfast, Northern Ireland, UK, BT12 6BJ.

Background: Air travel might increase the risk of deep vein thrombosis (DVT). It has been suggested that wearing compression stockings might reduce this risk. This is an update of the review first published in 2006.

Objectives: To assess the effects of wearing compression stockings versus not wearing them for preventing DVT in people travelling on flights lasting at least four hours.

Search Methods: For this update the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (10 February 2016). In addition, the CIS searched the Cochrane Register of Studies (CENTRAL (2016, Issue 1)).

Selection Criteria: Randomised trials of compression stockings versus no stockings in passengers on flights lasting at least four hours. Trials in which passengers wore a stocking on one leg but not the other, or those comparing stockings and another intervention were also eligible.

Data Collection And Analysis: Two review authors independently selected trials for inclusion and extracted data. We sought additional information from trialists where necessary.

Main Results: One new study that fulfilled the inclusion criteria was identified for this update. Eleven randomised trials (n = 2906) were included in this review: nine (n = 2821) compared wearing graduated compression stockings on both legs versus not wearing them; one trial (n = 50) compared wearing graduated compression tights versus not wearing them; and one trial (n = 35) compared wearing a graduated compression stocking on one leg for the outbound flight and on the other leg on the return flight. Eight trials included people judged to be at low or medium risk of developing DVT (n = 1598) and two included high-risk participants (n = 1273). All flights had a duration of more than five hours.Fifty of 2637 participants with follow-up data available in the trials of wearing compression stockings on both legs had a symptomless DVT; three wore stockings, 47 did not (odds ratio (OR) 0.10, 95% confidence interval (CI) 0.04 to 0.25, P < 0.001; high-quality evidence). There were no symptomless DVTs in three trials. Sixteen of 1804 people developed superficial vein thrombosis, four wore stockings, 12 did not (OR 0.45, 95% CI 0.18 to 1.13, P = 0.09; moderate-quality evidence). No deaths, pulmonary emboli or symptomatic DVTs were reported. Wearing stockings had a significant impact in reducing oedema (mean difference (MD) -4.72, 95% CI -4.91 to -4.52; based on six trials; low-quality evidence). A further two trials showed reduced oedema in the stockings group but could not be included in the meta-analysis as they used different methods to measure oedema. No significant adverse effects were reported.

Authors' Conclusions: There is high-quality evidence that airline passengers similar to those in this review can expect a substantial reduction in the incidence of symptomless DVT and low-quality evidence that leg oedema is reduced if they wear compression stockings. Quality was limited by the way that oedema was measured. There is moderate-quality evidence that superficial vein thrombosis may be reduced if passengers wear compression stockings. We cannot assess the effect of wearing stockings on death, pulmonary embolism or symptomatic DVT because no such events occurred in these trials. Randomised trials to assess these outcomes would need to include a very large number of people.
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http://dx.doi.org/10.1002/14651858.CD004002.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457834PMC
September 2016

Admission avoidance hospital at home.

Cochrane Database Syst Rev 2016 Sep 1;9:CD007491. Epub 2016 Sep 1.

Nuffield Department of Population Health, University of Oxford, Rosemary Rue Building, Old Road Campus, Headington, Oxford, Oxfordshire, UK, OX3 7LF.

Background: Admission avoidance hospital at home provides active treatment by healthcare professionals in the patient's home for a condition that otherwise would require acute hospital inpatient care, and always for a limited time period. This is the third update of the original review.

Objectives: To determine the effectiveness and cost of managing patients with admission avoidance hospital at home compared with inpatient hospital care.

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, two other databases, and two trials registers on 2 March 2016. We checked the reference lists of eligible articles. We sought unpublished studies by contacting providers and researchers who were known to be involved in the field.

Selection Criteria: Randomised controlled trials recruiting participants aged 18 years and over. Studies comparing admission avoidance hospital at home with acute hospital inpatient care.

Data Collection And Analysis: We followed the standard methodological procedures expected by Cochrane and the Effective Practice and Organisation of Care (EPOC) Group. We performed meta-analysis for trials that compared similar interventions and reported comparable outcomes with sufficient data, requested individual patient data from trialists, and relied on published data when this was not available. We used the GRADE approach to assess the certainty of the body of evidence for the most important outcomes.

Main Results: We included 16 randomised controlled trials with a total of 1814 participants; three trials recruited participants with chronic obstructive pulmonary disease, two trials recruited participants recovering from a stroke, six trials recruited participants with an acute medical condition who were mainly elderly, and the remaining trials recruited participants with a mix of conditions. We assessed the majority of the included studies as at low risk of selection, detection, and attrition bias, and unclear for selective reporting and performance bias. Admission avoidance hospital at home probably makes little or no difference on mortality at six months' follow-up (risk ratio (RR) 0.77, 95% confidence interval (CI) 0.60 to 0.99; P = 0.04; I = 0%; 912 participants; moderate-certainty evidence), little or no difference on the likelihood of being transferred (or readmitted) to hospital (RR 0.98, 95% CI 0.77 to 1.23; P = 0.84; I = 28%; 834 participants; moderate-certainty evidence), and may reduce the likelihood of living in residential care at six months' follow-up (RR 0.35, 95% CI 0.22 to 0.57; P < 0.0001; I = 78%; 727 participants; low-certainty evidence). Satisfaction with healthcare received may be improved with admission avoidance hospital at home (646 participants, low-certainty evidence); few studies reported the effect on caregivers. When the costs of informal care were excluded, admission avoidance hospital at home may be less expensive than admission to an acute hospital ward (287 participants, low-certainty evidence); there was variation in the reduction of hospital length of stay, estimates ranged from a mean difference of -8.09 days (95% CI -14.34 to -1.85) in a trial recruiting older people with varied health problems, to a mean increase of 15.90 days (95% CI 8.10 to 23.70) in a study that recruited patients recovering from a stroke.

Authors' Conclusions: Admission avoidance hospital at home, with the option of transfer to hospital, may provide an effective alternative to inpatient care for a select group of elderly patients requiring hospital admission. However, the evidence is limited by the small randomised controlled trials included in the review, which adds a degree of imprecision to the results for the main outcomes.
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http://dx.doi.org/10.1002/14651858.CD007491.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457791PMC
September 2016

Non-pharmacological interventions for cognitive impairment due to systemic cancer treatment.

Cochrane Database Syst Rev 2016 Aug 16(8):CD011325. Epub 2016 Aug 16.

Centre for Public Health, Queen's University Belfast, Institute of Clinical Sciences Block B, Royal Victoria Hospital Site, Grosvenor Road, Belfast, Northern Ireland, UK, BT12 6BJ.

Background: It is estimated that up to 75% of cancer survivors may experience cognitive impairment as a result of cancer treatment and given the increasing size of the cancer survivor population, the number of affected people is set to rise considerably in coming years. There is a need, therefore, to identify effective, non-pharmacological interventions for maintaining cognitive function or ameliorating cognitive impairment among people with a previous cancer diagnosis.

Objectives: To evaluate the cognitive effects, non-cognitive effects, duration and safety of non-pharmacological interventions among cancer patients targeted at maintaining cognitive function or ameliorating cognitive impairment as a result of cancer or receipt of systemic cancer treatment (i.e. chemotherapy or hormonal therapies in isolation or combination with other treatments).

Search Methods: We searched the Cochrane Centre Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PUBMED, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and PsycINFO databases. We also searched registries of ongoing trials and grey literature including theses, dissertations and conference proceedings. Searches were conducted for articles published from 1980 to 29 September 2015.

Selection Criteria: Randomised controlled trials (RCTs) of non-pharmacological interventions to improve cognitive impairment or to maintain cognitive functioning among survivors of adult-onset cancers who have completed systemic cancer therapy (in isolation or combination with other treatments) were eligible. Studies among individuals continuing to receive hormonal therapy were included. We excluded interventions targeted at cancer survivors with central nervous system (CNS) tumours or metastases, non-melanoma skin cancer or those who had received cranial radiation or, were from nursing or care home settings. Language restrictions were not applied.

Data Collection And Analysis: Author pairs independently screened, selected, extracted data and rated the risk of bias of studies. We were unable to conduct planned meta-analyses due to heterogeneity in the type of interventions and outcomes, with the exception of compensatory strategy training interventions for which we pooled data for mental and physical well-being outcomes. We report a narrative synthesis of intervention effectiveness for other outcomes.

Main Results: Five RCTs describing six interventions (comprising a total of 235 participants) met the eligibility criteria for the review. Two trials of computer-assisted cognitive training interventions (n = 100), two of compensatory strategy training interventions (n = 95), one of meditation (n = 47) and one of physical activity intervention (n = 19) were identified. Each study focused on breast cancer survivors. All five studies were rated as having a high risk of bias. Data for our primary outcome of interest, cognitive function were not amenable to being pooled statistically. Cognitive training demonstrated beneficial effects on objectively assessed cognitive function (including processing speed, executive functions, cognitive flexibility, language, delayed- and immediate- memory), subjectively reported cognitive function and mental well-being. Compensatory strategy training demonstrated improvements on objectively assessed delayed-, immediate- and verbal-memory, self-reported cognitive function and spiritual quality of life (QoL). The meta-analyses of two RCTs (95 participants) did not show a beneficial effect from compensatory strategy training on physical well-being immediately (standardised mean difference (SMD) 0.12, 95% confidence interval (CI) -0.59 to 0.83; I(2)= 67%) or two months post-intervention (SMD - 0.21, 95% CI -0.89 to 0.47; I(2) = 63%) or on mental well-being two months post-intervention (SMD -0.38, 95% CI -1.10 to 0.34; I(2) = 67%). Lower mental well-being immediately post-intervention appeared to be observed in patients who received compensatory strategy training compared to wait-list controls (SMD -0.57, 95% CI -0.98 to -0.16; I(2) = 0%). We assessed the assembled studies using GRADE for physical and mental health outcomes and this evidence was rated to be low quality and, therefore findings should be interpreted with caution. Evidence for physical activity and meditation interventions on cognitive outcomes is unclear.

Authors' Conclusions: Overall, the, albeit low-quality evidence may be interpreted to suggest that non-pharmacological interventions may have the potential to reduce the risk of, or ameliorate, cognitive impairment following systemic cancer treatment. Larger, multi-site studies including an appropriate, active attentional control group, as well as consideration of functional outcomes (e.g. activities of daily living) are required in order to come to firmer conclusions about the benefits or otherwise of this intervention approach. There is also a need to conduct research into cognitive impairment among cancer patient groups other than women with breast cancer.
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http://dx.doi.org/10.1002/14651858.CD011325.pub2DOI Listing
August 2016

Why do we need evidence-based methods in Cochrane?

Cochrane Database Syst Rev 2015 Jul 24(7):ED000102. Epub 2015 Jul 24.

School of Public Health & Preventive Medicine, Monash University, Melbourne, Australia.

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http://dx.doi.org/10.1002/14651858.ED000102DOI Listing
July 2015

WITHDRAWN: Serotonin receptor antagonists for highly emetogenic chemotherapy in adults.

Cochrane Database Syst Rev 2013 Dec 9(12):CD006272. Epub 2013 Dec 9.

Department of Haematology and Bone Marrow Transplantation, Central Hospital S, Maurizio, Bolzano, Italy, 39100.

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December 2013

Interventions to improve the use of systematic reviews in decision-making by health system managers, policy makers and clinicians.

Cochrane Database Syst Rev 2012 Sep 12(9):CD009401. Epub 2012 Sep 12.

UK Cochrane Centre, National Institute for Health Research, Oxford, UK.

Background: Systematic reviews provide a transparent and robust summary of existing research. However, health system managers, national and local policy makers and healthcare professionals can face several obstacles when attempting to utilise this evidence. These include constraints operating within the health system, dealing with a large volume of research evidence and difficulties in adapting evidence from systematic reviews so that it is locally relevant. In an attempt to increase the use of systematic review evidence in decision-making a number of interventions have been developed. These include summaries of systematic review evidence that are designed to improve the accessibility of the findings of systematic reviews (often referred to as information products) and changes to organisational structures, such as employing specialist groups to synthesise the evidence to inform local decision-making.

Objectives: To identify and assess the effects of information products based on the findings of systematic review evidence and organisational supports and processes designed to support the uptake of systematic review evidence by health system managers, policy makers and healthcare professionals.

Search Methods: We searched The Cochrane Library, MEDLINE, EMBASE, CINAHL, Web of Science, and Health Economic Evaluations Database. We also handsearched two journals (Implementation Science and Evidence and Policy), Cochrane Colloquium abstracts, websites of key organisations and reference lists of studies considered for inclusion. Searches were run from 1992 to March 2011 on all databases, an update search to March 2012 was run on MEDLINE only.

Selection Criteria: Randomised controlled trials (RCTs), interrupted time-series (ITS) and controlled before-after studies (CBA) of interventions designed to aid the use of systematic reviews in healthcare decision-making were considered.

Data Collection And Analysis: Two review authors independently extracted the data and assessed the study quality. We extracted the median value across similar outcomes for each study and reported the range of values for each median value. We calculated the median of the two middlemost values if an even number of outcomes were reported.

Main Results: We included eight studies evaluating the effectiveness of different interventions designed to support the uptake of systematic review evidence. The overall quality of the evidence was very low to moderate.Two cluster RCTs evaluated the effectiveness of multifaceted interventions, which contained access to systematic reviews relevant to reproductive health, to change obstetric care; the high baseline performance in some of the key clinical indicators limited the findings of these studies. There were no statistically significant effects on clinical practice for all but one of the clinical indicators in selected obstetric units in Thailand (median effect size 4.2%, range -11.2% to 18.2%) and none in Mexico (median effect size 3.5%, range 0.1% to 19.0%). In the second cluster RCT there were no statistically significant differences in selected obstetric units in the UK (median effect RR 0.92; range RR 0.57 to RR 1.10). One RCT evaluated the perceived understanding and ease of use of summary of findings tables in Cochrane Reviews. The median effect of the differences in responses for the acceptability of including summary of findings tables in Cochrane Reviews versus not including them was 16%, range 1% to 28%. One RCT evaluated the effect of an analgesic league table, derived from systematic review evidence, and there was no statistically significant effect on self-reported pain. Only one RCT evaluated an organisational intervention (which included a knowledge broker, access to a repository of systematic reviews and provision of tailored messages), and reported no statistically significant difference in evidence informed programme planning.Three interrupted time series studies evaluated the dissemination of printed bulletins based on evidence from systematic reviews. A statistically significant reduction in the rates of surgery for glue ear in children under 10 years (mean annual decline of -10.1%; 95% CI -7.9 to -12.3) and in children under 15 years (quarterly reduction -0.044; 95% CI -0.080 to -0.011) was reported. The distribution to general practitioners of a bulletin on the treatment of depression was associated with a statistically significant lower prescribing rate each quarter than that predicted by the rates of prescribing observed before the distribution of the bulletin (8.2%; P = 0.005).

Authors' Conclusions: Mass mailing a printed bulletin which summarises systematic review evidence may improve evidence-based practice when there is a single clear message, if the change is relatively simple to accomplish, and there is a growing awareness by users of the evidence that a change in practice is required. If the intention is to develop awareness and knowledge of systematic review evidence, and the skills for implementing this evidence, a multifaceted intervention that addresses each of these aims may be required, though there is insufficient evidence to support this approach.
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September 2012

Electric fans for reducing adverse health impacts in heatwaves.

Cochrane Database Syst Rev 2012 Jul 11(7):CD009888. Epub 2012 Jul 11.

Extreme Events andHealth Protection Section, Centre for Radiation, Chemicals and Environmental Hazards, London, UK.

Background: Heatwaves are hot weather events, which breach regional or national thresholds, that last for several days. They are likely to occur with increasing frequency in some parts of the world. The potential consequences were illustrated in Europe in August 2003 when there were an estimated 30,000 excess deaths due to a heatwave. Electric fans might be used with the intention of reducing the adverse health effects of a heatwave. Fans do not cool the ambient air but can be used to draw in cooler air from outside when placed at an open window. The aim of the fans would be to increase heat loss by increasing the efficiency of all normal methods of heat loss, but particularly by evaporation and convection methods. However, it should be noted that increased sweating can lead to dehydration and electrolyte imbalances if these fluids and electrolytes are not replaced quickly enough. Research has also identified important gaps in knowledge about the use of fans, which might lead to their inappropriate use.

Objectives: To determine whether the use of electric fans contributes to, or impedes, heat loss at high ambient temperatures during a heatwave, and to contribute to the evidence base for the public health impacts of heatwaves.

Search Methods: We sought unpublished and published studies that had been published in any language. The review team were able to assess studies reported in English, Chinese, Dutch, French and German; and reports in other languages would have been translated into English as necessary. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, the Indian biomedical literature (IndMED and MedIND) and databases of Chinese literature (Chinese Journal Net and Digital Periodical of WanFang Data). The most recent electronic searches were done in April 2012. We also checked the reference lists of relevant articles and the websites of relevant national and international organisations, and consulted with researchers and policy makers with experience in strategies to manage heatwaves to identify additional studies. The titles and abstracts from each search were checked independently by two review authors. The full text articles that we retrieved were checked independently by at least two authors for their relevance and for references to potentially eligible studies.

Selection Criteria: Randomised trials and other experimental designs, such as interrupted time series and controlled before-and-after studies, comparing the use of electric fans with no fans during a heatwave were eligible for this review. The electric fans could be hand-held (battery operated), portable or mounted on the wall or ceiling, or in a window. We sought interventions delivered to anyone for whom a heatwave was likely to have serious adverse health impacts. This would include people of all ages but with a particular focus on some groups (for example older people). Populations from high-, middle- and low-income countries were eligible for the review.

Data Collection And Analysis: If we had identified eligible studies, they would have been assessed independently by at least two review authors and data would have been extracted on the characteristics of the study, its participants and interventions, as well as the effects on health outcomes. The primary outcomes were mortality, hospital admission and other contacts with healthcare services.

Main Results: We did not identify any eligible studies despite the extensive searching and correspondence with several experts in this topic area. We identified retrospective, observational studies, usually with a case-control design, that investigated the association between the use of electric fans and health outcomes, including death. The results of these studies were mixed. Some studies found that the use of fans was associated with better health outcomes, others found the reverse.

Authors' Conclusions: The evidence we identified does not resolve uncertainties about the health effects of electric fans during heatwaves. Therefore, this review does not support or refute the use of electric fans during a heatwave. People making decisions about electric fans should consider the current state of the evidence base, and they might also wish to make themselves aware of local policy or guidelines when making a choice about whether or not to use or supply electric fans. The main implication of this review is that high quality research is needed to resolve the long standing and ongoing uncertainty about the benefits and harms of using electric fans during a heatwave, for example randomised trials comparing the health effects in people with electric fans to those in people without them.
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http://dx.doi.org/10.1002/14651858.CD009888.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457598PMC
July 2012

Long-term effects of autologous bone marrow stem cell treatment in acute myocardial infarction: factors that may influence outcomes.

PLoS One 2012 24;7(5):e37373. Epub 2012 May 24.

Stem Cell Research Laboratory, NHS-Blood and Transplant, John Radcliffe Hospital, Oxford, United Kingdom.

Aims: To investigate whether there are important sources of heterogeneity between the findings of different clinical trials which administer autologous stem cell treatment for acute myocardial infarction (AMI) and to evaluate what factors may influence the long-term effects of this treatment.

Methods And Results: MEDLINE (1950-January 2011), EMBASE (1974-January 2011), CENTRAL (The Cochrane Library 2011, Issue 1), CINAHL (1982-January 2011), and ongoing trials registers were searched for randomised trials of bone marrow stem cells as treatment for AMI. Hand-searching was used to screen recent, relevant conference proceedings (2005-2010/11). Meta-analyses were conducted using random-effects models and heterogeneity between subgroups was assessed using chi-squared tests. Planned analyses included length of follow-up, timing of cell infusion and dose, patient selection, small trial size effect, methodological quality, loss of follow-up and date of publication. Thirty-three trials with a total of 1,765 participants were included. There was no evidence of bias due to publication or time-lag, methodological quality of included studies, participant drop-out, duration of follow-up or date of the first disclosure of results. However, in long-term follow-ups the treatment seemed more effective when administered at doses greater than 10(8) cells and to patients with more severe heart dysfunction.

Conclusions: Evaluation of heterogeneity between trials has not identified significant sources of bias in this study. However, clinical differences between trials are likely to exist which should be considered when undertaking future trials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0037373PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360027PMC
September 2012

Predicting the extent of heterogeneity in meta-analysis, using empirical data from the Cochrane Database of Systematic Reviews.

Int J Epidemiol 2012 Jun 29;41(3):818-27. Epub 2012 Mar 29.

MRC Biostatistics Unit, Institute of Public Health, Cambridge, UK.

Background: Many meta-analyses contain only a small number of studies, which makes it difficult to estimate the extent of between-study heterogeneity. Bayesian meta-analysis allows incorporation of external evidence on heterogeneity, and offers advantages over conventional random-effects meta-analysis. To assist in this, we provide empirical evidence on the likely extent of heterogeneity in particular areas of health care.

Methods: Our analyses included 14 886 meta-analyses from the Cochrane Database of Systematic Reviews. We classified each meta-analysis according to the type of outcome, type of intervention comparison and medical specialty. By modelling the study data from all meta-analyses simultaneously, using the log odds ratio scale, we investigated the impact of meta-analysis characteristics on the underlying between-study heterogeneity variance. Predictive distributions were obtained for the heterogeneity expected in future meta-analyses.

Results: Between-study heterogeneity variances for meta-analyses in which the outcome was all-cause mortality were found to be on average 17% (95% CI 10-26) of variances for other outcomes. In meta-analyses comparing two active pharmacological interventions, heterogeneity was on average 75% (95% CI 58-95) of variances for non-pharmacological interventions. Meta-analysis size was found to have only a small effect on heterogeneity. Predictive distributions are presented for nine different settings, defined by type of outcome and type of intervention comparison. For example, for a planned meta-analysis comparing a pharmacological intervention against placebo or control with a subjectively measured outcome, the predictive distribution for heterogeneity is a log-normal (-2.13, 1.58(2)) distribution, which has a median value of 0.12. In an example of meta-analysis of six studies, incorporating external evidence led to a smaller heterogeneity estimate and a narrower confidence interval for the combined intervention effect.

Conclusions: Meta-analysis characteristics were strongly associated with the degree of between-study heterogeneity, and predictive distributions for heterogeneity differed substantially across settings. The informative priors provided will be very beneficial in future meta-analyses including few studies.
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http://dx.doi.org/10.1093/ije/dys041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396310PMC
June 2012

Characteristics of meta-analyses and their component studies in the Cochrane Database of Systematic Reviews: a cross-sectional, descriptive analysis.

BMC Med Res Methodol 2011 Nov 24;11:160. Epub 2011 Nov 24.

MRC Biostatistics Unit, Institute of Public Health, Cambridge, UK.

Background: Cochrane systematic reviews collate and summarise studies of the effects of healthcare interventions. The characteristics of these reviews and the meta-analyses and individual studies they contain provide insights into the nature of healthcare research and important context for the development of relevant statistical and other methods.

Methods: We classified every meta-analysis with at least two studies in every review in the January 2008 issue of the Cochrane Database of Systematic Reviews (CDSR) according to the medical specialty, the types of interventions being compared and the type of outcome. We provide descriptive statistics for numbers of meta-analyses, numbers of component studies and sample sizes of component studies, broken down by these categories.

Results: We included 2321 reviews containing 22,453 meta-analyses, which themselves consist of data from 112,600 individual studies (which may appear in more than one meta-analysis). Meta-analyses in the areas of gynaecology, pregnancy and childbirth (21%), mental health (13%) and respiratory diseases (13%) are well represented in the CDSR. Most meta-analyses address drugs, either with a control or placebo group (37%) or in a comparison with another drug (25%). The median number of meta-analyses per review is six (inter-quartile range 3 to 12). The median number of studies included in the meta-analyses with at least two studies is three (inter-quartile range 2 to 6). Sample sizes of individual studies range from 2 to 1,242,071, with a median of 91 participants.

Discussion: It is clear that the numbers of studies eligible for meta-analyses are typically very small for all medical areas, outcomes and interventions covered by Cochrane reviews. This highlights the particular importance of suitable methods for the meta-analysis of small data sets. There was little variation in number of studies per meta-analysis across medical areas, across outcome data types or across types of interventions being compared.
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http://dx.doi.org/10.1186/1471-2288-11-160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3247075PMC
November 2011

Treating pneumonia in critical care in the United Kingdom following failure of initial antibiotic: a cost-utility analysis comparing meropenem with piperacillin/tazobactam.

Eur J Health Econ 2012 Apr 18;13(2):181-92. Epub 2011 Jan 18.

Kellogg College, University of Oxford, Oxford, UK.

Background: Treating patients admitted to critical care with severe pneumonia requires timely intervention with an effective antibiotic. This reduces the risk of dying of pneumonia and minimises complications associated with a prolonged stay in critical care.

Objective: To compare the cost-effectiveness of meropenem 1 g/8 h with piperacillin/tazobactam 4.5 g/8 h for treating pneumonia in UK critical care.

Methods: A Markov model was built to estimate lifetime costs and quality-adjusted life years (QALYs) of using meropenem versus piperacillin/tazobactam to treat severe pneumonia. Estimates of effectiveness, utility weights and costs were obtained from published sources. Probabilistic sensitivity analysis was conducted to address uncertainty in the model results.

Results: Cost of treating a patient with severe pneumonia was estimated as £19,026 with meropenem and £19,978 with piperacillin/tazobactam, respectively. QALYs gained were 4.768 with meropenem and 4.654 with piperacillin/tazobactam. Probabilistic sensitivity analysis showed meropenem to be consistently less costly and more effective than piperacillin/tazobactam.

Conclusion: The additional efficacy of meropenem translates into more patients surviving critical care and leaving this high-cost service more quickly than if they had been treated with piperacillin/tazobactam. As meropenem is more effective and less expensive than piperacillin/tazobactam at treating patients with severe pneumonia, it is the dominant treatment option.
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April 2012

Serotonin receptor antagonists for highly emetogenic chemotherapy in adults.

Cochrane Database Syst Rev 2010 Jan 20(1):CD006272. Epub 2010 Jan 20.

Department of Haematology and Bone Marrow Transplantation, Central Hospital S, Maurizio, Bolzano, Italy, 39100.

Background: Serotonin receptor antagonists (5-HT(3) RAs) are used to control chemotherapy-induced emesis. Although they have the same general mechanism of action (blockade of serotonin receptors), they have different chemical structures and may have different effects.

Objectives: To compare efficacy of different serotonin receptor antagonists (5-HT(3) RAs) in the control of acute and delayed emesis induced by highly emetogenic chemotherapy.

Search Strategy: We searched CENTRAL, the Specialised Register of the Cochrane PaPaS Group, PubMed, EMBASE, and LILACS databases. Our most recent search was in March 2009.

Selection Criteria: Randomised trials comparing 5-HT(3) RAs in an adult cancer population.

Data Collection And Analysis: We extracted information from the included studies on the control of acute and delayed nausea and vomiting, either as a single or a combined outcome. Where appropriate, we combined the results of similar trials. We carried out sensitivity and subgroup analyses to test the robustness of our findings.

Main Results: We included 16 randomised trials (7808 participants). Nine of the trials compared granisetron versus ondansetron. No other drug comparison was studied in more than one trial. The meta-analyses of the granisetron versus ondansetron trials found similar results for the two drugs on acute vomiting (eight trials, 4256 participants, odds ratio (OR) 0.89; 95% CI 0.78 to 1.02), acute nausea (seven trials, 4160 participants, OR 0.97; 95% CI 0.85 to 1.10), delayed vomiting (three trials, 1119 participants, OR 1.00; 95% CI 0.74 to 1.34) and delayed nausea (two trials, 1024 participants, OR 0.96; 95% CI 0.75 to 1.24). Granisetron and ondansetron showed similar effects on headache and diarrhoea, with the possible exception of less constipation associated with ondansetron.One study of 1114 participants comparing palonosetron plus dexamethasone versus granisetron plus dexamethasone showed superiority of palonosetron in controlling delayed vomiting (OR 1.45; 95% CI 1.14 to 1.85) and delayed nausea (OR 1.63; 95% CI 1.27 to 2.10). Complete response for delayed nausea and vomiting was also in favour of the combination palonosetron and dexamethasone (OR 1.63; 95% CI 1.29 to 2.07).

Authors' Conclusions: Ondansetron and granisetron appear to be equivalent drugs for the prevention of acute and delayed emesis following the use of highly emetogenic chemotherapy.According to one single trial the combination of palonosetron and dexamethasone was superior to granisetron and dexamethasone in controlling delayed emesis. However, more evidence is needed before palonosetron could become the candidate 5-HT(3) RA for the control of delayed emesis induced by highly emetogenic chemotherapy.
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January 2010

Methods to increase response to postal and electronic questionnaires.

Cochrane Database Syst Rev 2009 Jul 8(3):MR000008. Epub 2009 Jul 8.

Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, Keppel Street, London, UK, WC1E 7HT.

Background: Postal and electronic questionnaires are widely used for data collection in epidemiological studies but non-response reduces the effective sample size and can introduce bias. Finding ways to increase response to postal and electronic questionnaires would improve the quality of health research.

Objectives: To identify effective strategies to increase response to postal and electronic questionnaires.

Search Strategy: We searched 14 electronic databases to February 2008 and manually searched the reference lists of relevant trials and reviews, and all issues of two journals. We contacted the authors of all trials or reviews to ask about unpublished trials. Where necessary, we also contacted authors to confirm methods of allocation used and to clarify results presented. We assessed the eligibility of each trial using pre-defined criteria.

Selection Criteria: Randomised controlled trials of methods to increase response to postal or electronic questionnaires.

Data Collection And Analysis: We extracted data on the trial participants, the intervention, the number randomised to intervention and comparison groups and allocation concealment. For each strategy, we estimated pooled odds ratios (OR) and 95% confidence intervals (CI) in a random-effects model. We assessed evidence for selection bias using Egger's weighted regression method and Begg's rank correlation test and funnel plot. We assessed heterogeneity among trial odds ratios using a Chi(2) test and the degree of inconsistency between trial results was quantified using the I(2) statistic.

Main Results: PostalWe found 481 eligible trials. The trials evaluated 110 different ways of increasing response to postal questionnaires. We found substantial heterogeneity among trial results in half of the strategies. The odds of response were at least doubled using monetary incentives (odds ratio 1.87; 95% CI 1.73 to 2.04; heterogeneity P < 0.00001, I(2) = 84%), recorded delivery (1.76; 95% CI 1.43 to 2.18; P = 0.0001, I(2) = 71%), a teaser on the envelope - e.g. a comment suggesting to participants that they may benefit if they open it (3.08; 95% CI 1.27 to 7.44) and a more interesting questionnaire topic (2.00; 95% CI 1.32 to 3.04; P = 0.06, I(2) = 80%). The odds of response were substantially higher with pre-notification (1.45; 95% CI 1.29 to 1.63; P < 0.00001, I(2) = 89%), follow-up contact (1.35; 95% CI 1.18 to 1.55; P < 0.00001, I(2) = 76%), unconditional incentives (1.61; 1.36 to 1.89; P < 0.00001, I(2) = 88%), shorter questionnaires (1.64; 95% CI 1.43 to 1.87; P < 0.00001, I(2) = 91%), providing a second copy of the questionnaire at follow up (1.46; 95% CI 1.13 to 1.90; P < 0.00001, I(2) = 82%), mentioning an obligation to respond (1.61; 95% CI 1.16 to 2.22; P = 0.98, I(2) = 0%) and university sponsorship (1.32; 95% CI 1.13 to 1.54; P < 0.00001, I(2) = 83%). The odds of response were also increased with non-monetary incentives (1.15; 95% CI 1.08 to 1.22; P < 0.00001, I(2) = 79%), personalised questionnaires (1.14; 95% CI 1.07 to 1.22; P < 0.00001, I(2) = 63%), use of hand-written addresses (1.25; 95% CI 1.08 to 1.45; P = 0.32, I(2) = 14%), use of stamped return envelopes as opposed to franked return envelopes (1.24; 95% CI 1.14 to 1.35; P < 0.00001, I(2) = 69%), an assurance of confidentiality (1.33; 95% CI 1.24 to 1.42) and first class outward mailing (1.11; 95% CI 1.02 to 1.21; P = 0.78, I(2) = 0%). The odds of response were reduced when the questionnaire included questions of a sensitive nature (0.94; 95% CI 0.88 to 1.00; P = 0.51, I(2) = 0%).ElectronicWe found 32 eligible trials. The trials evaluated 27 different ways of increasing response to electronic questionnaires. We found substantial heterogeneity among trial results in half of the strategies. The odds of response were increased by more than a half using non-monetary incentives (1.72; 95% CI 1.09 to 2.72; heterogeneity P < 0.00001, I(2) = 95%), shorter e-questionnaires (1.73; 1.40 to 2.13; P = 0.08, I(2) = 68%), including a statement that others had responded (1.52; 95% CI 1.36 to 1.70), and a more interesting topic (1.85; 95% CI 1.52 to 2.26). The odds of response increased by a third using a lottery with immediate notification of results (1.37; 95% CI 1.13 to 1.65), an offer of survey results (1.36; 95% CI 1.15 to 1.61), and using a white background (1.31; 95% CI 1.10 to 1.56). The odds of response were also increased with personalised e-questionnaires (1.24; 95% CI 1.17 to 1.32; P = 0.07, I(2) = 41%), using a simple header (1.23; 95% CI 1.03 to 1.48), using textual representation of response categories (1.19; 95% CI 1.05 to 1.36), and giving a deadline (1.18; 95% CI 1.03 to 1.34). The odds of response tripled when a picture was included in an e-mail (3.05; 95% CI 1.84 to 5.06; P = 0.27, I(2) = 19%). The odds of response were reduced when "Survey" was mentioned in the e-mail subject line (0.81; 95% CI 0.67 to 0.97; P = 0.33, I(2) = 0%), and when the e-mail included a male signature (0.55; 95% CI 0.38 to 0.80; P = 0.96, I(2) = 0%).

Authors' Conclusions: Health researchers using postal and electronic questionnaires can increase response using the strategies shown to be effective in this systematic review.
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July 2009

Erythropoietin or Darbepoetin for patients with cancer--meta-analysis based on individual patient data.

Cochrane Database Syst Rev 2009 Jul 8(3):CD007303. Epub 2009 Jul 8.

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland, 3012.

Background: Erythropoiesis-stimulating agents (ESAs) reduce anemia in cancer patients and may improve quality of life, but there are concerns that ESAs might increase mortality.

Objectives: Our objectives were to examine the effect of ESAs and identify factors that modify the effects of ESAs on overall survival, progression free survival, thromboembolic and cardiovascular events as well as need for transfusions and other important safety and efficacy outcomes in cancer patients.

Search Strategy: We searched the Cochrane Library, Medline, Embase and conference proceedings for eligible trials. Manufacturers of ESAs were contacted to identify additional trials.

Selection Criteria: We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusions (as necessary) versus red blood cell transfusions (as necessary) alone, to prevent or treat anemia in adult or pediatric cancer patients with or without concurrent antineoplastic therapy.

Data Collection And Analysis: We performed a meta-analysis of randomized controlled trials comparing epoetin alpha, epoetin beta or darbepoetin alpha plus red blood cell transfusions versus transfusion alone, for prophylaxis or therapy of anemia while or after receiving anti-cancer treatment. Patient-level data were obtained and analyzed by independent statisticians at two academic departments, using fixed-effects and random-effects meta-analysis. Analyses were according to the intention-to-treat principle. Primary endpoints were on study mortality and overall survival during the longest available follow-up, regardless of anticancer treatment, and in patients receiving chemotherapy. Tests for interactions were used to identify differences in effects of ESAs on mortality across pre-specified subgroups. The present review reports only the results for the primary endpoint.

Main Results: A total of 13933 cancer patients from 53 trials were analyzed, 1530 patients died on-study and 4993 overall. ESAs increased on study mortality (combined hazard ratio [cHR] 1.17; 95% CI 1.06-1.30) and worsened overall survival (cHR 1.06; 95% CI 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 and I(2) 7.1%, p=0.33, respectively). Thirty-eight trials enrolled 10441 patients receiving chemotherapy. The cHR for on study mortality was 1.10 (95% CI 0.98-1.24) and 1.04; 95% CI 0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients receiving different cancer treatments (P for interaction=0.42).

Authors' Conclusions: ESA treatment in cancer patients increased on study mortality and worsened overall survival. For patients undergoing chemotherapy the increase was less pronounced, but an adverse effect could not be excluded.
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http://dx.doi.org/10.1002/14651858.CD007303.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7208183PMC
July 2009

Carbapenems versus other beta-lactams in the treatment of hospitalised patients with infection: a mixed treatment comparison.

Curr Med Res Opin 2009 Jan;25(1):251-61

Kellogg College, University of Oxford, Oxford, UK.

Objective: To compare the effectiveness of meropenem with cefepime and piperacillin/tazobactam in the absence of direct comparisons in randomised controlled trials.

Data Sources: Two previously conducted systematic reviews, one comparing the carbapenems (ertapenem and imipenem/cilastatin) versus 4th-generation cephalosporins (cefepime) or antipseudomonal penicillins (piperacillin/tazobactam), and the other comparing the carbapenems (imipenem/cilastatin versus meropenem), were updated to provide the basis for this mixed treatment comparison. Searching was completed in April 2007. No restriction was placed on language of publication.

Study Selection And Data Extraction: Randomised controlled trials of adult patients hospitalised with infection and treated with a carbapenem or cefepime or piperacillin/tazobactam. Two reviewers independently assessed the papers against the inclusion/exclusion criteria and for methodological quality with any differences in opinion adjudicated by a third party. Two reviewers independently extracted data on clinical response, bacteriological response, mortality, and adverse events.

Data Synthesis: A mixed treatment comparison meta-analysis using Bayesian Markov Chain Monte Carlo simulation was used to perform the indirect comparison. The dataset comprised 34 trials: four comparing ertapenem versus piperacillin/tazobactam, one imipenem/cilastatin versus cefepime, 26 imipenem/cilastatin versus meropenem, three imipenem/cilastatin versus piperacillin/tazobactam. We calculated odds ratios (OR) using imipenem/cilastatin as the common comparator. Meropenem was associated with the highest probability of being the most effective treatment for clinical response (OR 1.52, 95% credible interval [CrI] 1.23-1.87) and bacteriological response (OR 1.45, 95% CrI 1.15-1.80) with a reduced risk of serious adverse events (overall: OR 0.88, 95% CrI 0.76-1.02; serious adverse events leading to withdrawal: OR 0.73, 95% CrI 0.42-1.20; and GI-related: OR 0.76, 95% CrI 0.55-1.02). There was little difference between the three carbapenems and cefepime on all-cause mortality.

Conclusions: This mixed treatment comparison suggests meropenem has substantial advantages over cefepime, ertapenem, imipenem/cilastatin and piperacillin/tazobactam in the treatment of hospitalised patients with infection.
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January 2009

Publication bias in clinical trials due to statistical significance or direction of trial results.

Cochrane Database Syst Rev 2009 Jan 21(1):MR000006. Epub 2009 Jan 21.

UK Cochrane Centre, National Institute for Health Research, Summertown Pavilion, Middle Way, Oxford, Oxfordshire, UK, OX2 7LG.

Background: The tendency for authors to submit, and of journals to accept, manuscripts for publication based on the direction or strength of the study findings has been termed publication bias.

Objectives: To assess the extent to which publication of a cohort of clinical trials is influenced by the statistical significance, perceived importance, or direction of their results.

Search Strategy: We searched the Cochrane Methodology Register (The Cochrane Library [Online] Issue 2, 2007), MEDLINE (1950 to March Week 2 2007), EMBASE (1980 to Week 11 2007) and Ovid MEDLINE In-Process & Other Non-Indexed Citations (March 21 2007). We also searched the Science Citation Index (April 2007), checked reference lists of relevant articles and contacted researchers to identify additional studies.

Selection Criteria: Studies containing analyses of the association between publication and the statistical significance or direction of the results (trial findings), for a cohort of registered clinical trials.

Data Collection And Analysis: Two authors independently extracted data. We classified findings as either positive (defined as results classified by the investigators as statistically significant (P < 0.05), or perceived as striking or important, or showing a positive direction of effect) or negative (findings that were not statistically significant (P >/= 0.05), or perceived as unimportant, or showing a negative or null direction in effect). We extracted information on other potential risk factors for failure to publish, when these data were available.

Main Results: Five studies were included. Trials with positive findings were more likely to be published than trials with negative or null findings (odds ratio 3.90; 95% confidence interval 2.68 to 5.68). This corresponds to a risk ratio of 1.78 (95% CI 1.58 to 1.95), assuming that 41% of negative trials are published (the median among the included studies, range = 11% to 85%). In absolute terms, this means that if 41% of negative trials are published, we would expect that 73% of positive trials would be published.Two studies assessed time to publication and showed that trials with positive findings tended to be published after four to five years compared to those with negative findings, which were published after six to eight years. Three studies found no statistically significant association between sample size and publication. One study found no significant association between either funding mechanism, investigator rank, or sex and publication.

Authors' Conclusions: Trials with positive findings are published more often, and more quickly, than trials with negative findings.
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January 2009

Avoiding hospital admission through provision of hospital care at home: a systematic review and meta-analysis of individual patient data.

CMAJ 2009 Jan;180(2):175-82

Department of Public Health, University of Oxford, Old Road Campus, Headington, Oxford, United Kingdom.

Background: Avoidance of admission through provision of hospital care at home is a scheme whereby health care professionals provide active treatment in the patient's home for a condition that would otherwise require inpatient treatment in an acute care hospital. We sought to compare the effectiveness of this method of caring for patients with that type of in-hospital care.

Methods: We searched the MEDLINE, EMBASE, CINAHL and EconLit databases and the Cochrane Effective Practice and Organisation of Care Group register from the earliest date in each database until January 2008. We included randomized controlled trials that evaluated a service providing an alternative to admission to an acute care hospital. We excluded trials in which the program did not offer a substitute for inpatient care. We performed meta-analyses for trials for which the study populations had similar characteristics and for which common outcomes had been measured.

Results: We included 10 randomized trials (with a total of 1327 patients) in our systematic review. Seven of these trials (with a total of 969 patients) were deemed eligible for meta-analysis of individual patient data, but we were able to obtain data for only 5 of these trials (with a total of 844 patients [87%]). There was no significant difference in mortality at 3 months for patients who received hospital care at home (adjusted hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.54-1.09, p = 0.15). However, at 6 months, mortality was significantly lower for these patients (adjusted HR 0.62, 95% CI 0.45-0.87, p = 0.005). Admissions to hospital were greater, but not significantly so, for patients receiving hospital care at home (adjusted HR 1.49, 95% CI 0.96-2.33, p = 0.08). Patients receiving hospital care at home reported greater satisfaction than those receiving inpatient care. These programs were less expensive than admission to an acute care hospital ward when the analysis was restricted to treatment actually received and when the costs of informal care were excluded.

Interpretation: For selected patients, avoiding admission through provision of hospital care at home yielded similar outcomes to inpatient care, at a similar or lower cost.
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http://dx.doi.org/10.1503/cmaj.081491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2621299PMC
January 2009

How to connect the gap between clinical trials and clinical practice.

Chin J Integr Med 2008 Dec 12;14(4):309-11. Epub 2008 Dec 12.

West China Hospital of Sichuan University, Chengdu (610041) China.

Clinical research methods have been rapidly developing, and the design of clinical trials including traditional Chinese medicine is advancing. To a certain extent, all of these ensure that the results of clinical research are objective and scientific, but whether these results and the resulting guidelines or consensus have much practical significance on clinical practice is still controversial. The authors engage in both clinical practice and clinical research; they strongly feel that it is necessary to discuss the relationship between clinical trials and clinical practice. This essay discusses this relationship in four parts.
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December 2008

Admission avoidance hospital at home.

Cochrane Database Syst Rev 2008 Oct 8(4):CD007491. Epub 2008 Oct 8.

Department of Public Health, University of Oxford, Rosemary Rue Building, Headington, Oxford, Oxfordshire, UK, OX3 7LF.

Background: Admission avoidance hospital at home is a service that provides active treatment by health care professionals in the patient's home for a condition that otherwise would require acute hospital in-patient care, and always for a limited time period. In particular, hospital at home has to offer a specific service to patients in their home requiring health care professionals to take an active part in the patients' care. If hospital at home were not available then the patient would be admitted to an acute hospital ward. Many countries are adopting this type of care in an attempt to reduce the demand for acute hospital admission.

Objectives: To determine, in the context of a systematic review and meta analysis, the effectiveness and cost of managing patients with admission avoidance hospital at home compared with in-patient hospital care.

Search Strategy: The following databases were searched through to January 2008: MEDLINE, EMBASE, CINAHL, EconLit and the Cochrane Effective Practice and Organisation of Care Group (EPOC) register. We checked the reference lists of articles identified electronically for evaluations of hospital at home and obtained potentially relevant articles. Unpublished studies were sought by contacting providers and researchers who were known to be involved in this field.

Selection Criteria: Randomised controlled trials recruiting patients aged 18 years and over. Studies comparing admission avoidance hospital at home with acute hospital in-patient care. The admission avoidance hospital at home interventions may admit patients directly from the community thereby avoiding physical contact with the hospital, or may admit from the emergency room.

Data Collection And Analysis: Two authors independently extracted data and assessed study quality. Our statistical analyses sought to include all randomised patients and were done on an intention to treat basis. We requested individual patient data (IPD) from trialists, and relied on published data when we did not receive trial data sets or the IPD did not include the relevant outcomes. When combining outcome data was not possible because of differences in the reporting of outcomes we have presented the data in narrative summary tables.For the IPD meta-analysis, where at least one event was reported in both study groups in a trial, Cox regression models were used to calculate the log hazard ratio and its standard error for mortality and readmission separately for each data set (where both outcomes were available). We included randomisation group (admission avoidance hospital at home versus control), age (above or below the median), and gender in the models. The calculated log hazard ratios were combined using fixed effects inverse variance meta analysis. If there were no events in one group we used the Peto odds ratio method to calculate a log odds ratio from the sum of the log-rank test 'O-E' statistics from a Kaplan Meier survival analysis. Statistical significance throughout was taken at the two-sided 5% level (p<0.05) and data are presented as the estimated effect with 95% confidence intervals. For each comparison using published data for dichotomous outcomes we calculated risk ratios using a fixed effects model to combine data.

Main Results: We included 10 RCTs (n=1333), 7 of which were eligible for the IPD. Five out of these seven trials contributed to the IPD meta-analysis (n=850/975; 87%). There was a non significant reduction in mortality at three months for the admission avoidance hospital at home group (adjusted HR 0.77, 95% CI 0.54 to 1.09; p=0.15), which reached significance at six months follow-up (adjusted HR 0.62, 95% CI 0.45 to 0.87; p=0.005). A non significant increase in admissions was observed for patients allocated to hospital at home (adjusted HR 1.49, 95% CI 0.96 to 2.33; p=0.08). Few differences were reported for functional ability, quality of life or cognitive ability. Patients reported increased satisfaction with admission avoidance hospital at home. Two trials conducted a full economic analysis, when the costs of informal care were excluded admission avoidance hospital at home was less expensive than admission to an acute hospital ward.

Authors' Conclusions: We performed meta-analyses where there was sufficient similarity among the trials and where common outcomes had been measured. There is no evidence from the analysis to suggest that admission avoidance hospital at home leads to outcomes that differ from inpatient hospital care.
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http://dx.doi.org/10.1002/14651858.CD007491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033791PMC
October 2008

WITHDRAWN: Radiotherapy for early breast cancer.

Authors:
Mike J Clarke

Cochrane Database Syst Rev 2008 Oct 8(4):CD003647. Epub 2008 Oct 8.

UK Cochrane Centre, National Institute for Health Research, Summertown Pavilion, Middle Way, Oxford, UK, OX2 7LG.

Background: The long-term effects of radiotherapy on mortality from breast cancer and other causes remain uncertain.

Objectives: In this report the Early Breast Cancer Trialists' Collaborative Group present their systematic overview of treatment with radiotherapy.

Search Strategy: Trial identification procedures for the EBCTCG overviews have been described elsewhere. See under "EBCTCG" in the Breast Cancer Group module.

Selection Criteria: A meta-analysis was done of 10-year and 20-year results from 40 unconfounded randomised trials of radiotherapy for early breast cancer. Radiotherapy fields generally included not only chest wall (or breast) but also axillary, supraclavicular, and internal mammary nodes.

Data Collection And Analysis: Data collection involved central review of individual patient data on recurrence and cause-specific mortality from 20,000 women.

Main Results: A reduction of approximately two-thirds in local recurrence was seen in all trials, largely independent of the type of patient or type of radiotherapy (8.8% vs 27.2% local recurrence by year 10). Hence, to assess effects on breast cancer mortality of substantially better local control, results from all trials were combined. Breast cancer mortality was reduced (2p=0.0001) but other, particularly vascular, mortality was increased (2p=0.0003), and overall 20-year survival was 37.1% with radiotherapy versus 35.9% control (2p=0.06). There was little effect on early deaths, but logrank analyses of later deaths indicate that, on average after year 2, radiotherapy reduced annual mortality rates from breast cancer by 13.2% (SE 2.5) but increased those from other causes by 21.2% (SE 5.4). Nodal status, age, and decade of follow-up strongly affected the ratio of breast cancer mortality to other mortality, and hence affected the ratio of absolute benefit to absolute hazard from these proportional changes in mortality.

Authors' Conclusions: Radiotherapy regimens able to produce the two-thirds reduction in local recurrence seen in these trials, but without long-term hazard, would be expected to produce an absolute increase in 20-year survival of about 2-4% (except for women at particularly low risk of local recurrence). The average hazard seen in these trials would, however, reduce this 20-year survival benefit in young women and reverse it in older women.
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October 2008

WITHDRAWN: Multi-agent chemotherapy for early breast cancer.

Authors:
Mike J Clarke

Cochrane Database Syst Rev 2008 Oct 8(4):CD000487. Epub 2008 Oct 8.

UK Cochrane Centre, National Institute for Health Research, Summertown Pavilion, Middle Way, Oxford, UK, OX2 7LG.

Background: There have been many randomised trials of adjuvant prolonged polychemotherapy among women with early breast cancer, and an updated overview of their results is presented.

Objectives: In this report, the Early Breast Cancer Trialists' Collaborative Group present their updated systematic overview (meta-analysis) of treatment with polychemotherapy.

Search Strategy: Trial identification procedures for the EBCTCG overviews have been described elsewhere. See under "EBCTCG" in the Breast Cancer Collaborative Review Group module.

Selection Criteria: All randomised trials that began before 1990 and involved treatment groups that differed only with respect to the chemotherapy regimens that were being compared.

Data Collection And Analysis: In 1995, information was sought on each woman in any randomised trial that began before 1990 and involved treatment groups that differed only with respect to the chemotherapy regimens that were being compared. Analyses involved about 18,000 women in 47 trials of prolonged polychemotherapy versus no chemotherapy, about 6000 in 11 trials of longer versus shorter polychemotherapy, and about 6000 in 11 trials of anthracycline-containing regimens versus CMF (cyclophosphamide, methotrexate, and fluorouracil).

Main Results: For recurrence, polychemotherapy produced substantial and highly significant proportional reductions both among women aged under 50 at randomisation (35% [SD 4] reduction; 2p<0.00001) and among those aged 50-69 (20% [SD 3] reduction; 2p<0.00001); few women aged 70 or over had been studied. For mortality, the reductions were also significant both among women aged under 50 (27% [SD 5] reduction; 2p<0.00001) and among those aged 50-69 (11% [SD 3] reduction; 2p=0.0001). The recurrence reductions emerged chiefly during the first 5 years of follow-up, whereas the difference in survival grew throughout the first 10 years. After standardisation for age and time since randomisation, the proportional reductions in risk were similar for women with node-negative and node-positive disease. Applying the proportional mortality reduction observed in all women aged under 50 at randomisation would typically change a 10-year survival of 71% for those with node-negative disease to 78% (an absolute benefit of 7%), and of 42% for those with node-positive disease to 53% (an absolute benefit of 11%). The smaller proportional mortality reduction observed in all women aged 50-69 at randomisation would translate into smaller absolute benefits, changing a 10-year survival of 67% for those with node-negative disease to 69% (an absolute gain of 2%) and of 46% for those with node-positive disease to 49% (an absolute gain of 3%). The age-specific benefits of polychemotherapy appeared to be largely irrespective of menopausal status at presentation, oestrogen receptor status of the primary tumour, and of whether adjuvant tamoxifen had been given. In terms of other outcomes, there was a reduction of about one-fifth (2p=0.05) in contralateral breast cancer, which has already been included in the analyses of recurrence, and no apparent adverse effect on deaths from causes other than breast cancer (death rate ratio 0.89 [SD 0.09]). The directly randomised comparisons of longer versus shorter durations of polychemotherapy did not indicate any survival advantage with the use of more than about 3-6 months of polychemotherapy. By contrast, directly randomised comparisons did suggest that, compared with CMF alone, the anthracycline-containing regimens studied produced somewhat greater effects on recurrence (2p=0.006) and mortality (69% vs 72% 5-year survival; log-rank 2p=0.02). But this comparison is one of many that could have been selected for emphasis, the 99% CI reaches zero, and the results of several of the relevant trials are not yet available.

Authors' Conclusions: Some months of adjuvant polychemotherapy (eg, with CMF or an anthracycline-containing regimen) typically produces an absolute improvement of about 7-11% in 10-year survival for women aged under 50 at presentation with early breast cancer, and of about 2-3% for those aged 50-69 (unless their prognosis is likely to be extremely good even without such treatment). Treatment decisions involve consideration not only of improvements in cancer recurrence and survival but also of adverse side-effects of treatment, and this report makes no recommendations as to who should or should not be treated.
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October 2008

WITHDRAWN: Tamoxifen for early breast cancer.

Authors:
Mike J Clarke

Cochrane Database Syst Rev 2008 Oct 8(4):CD000486. Epub 2008 Oct 8.

UK Cochrane Centre, National Institute for Health Research, Summertown Pavilion, Middle Way, Oxford, UK, OX2 7LG.

Background: There have been many randomised trials of adjuvant tamoxifen among women with early breast cancer, and an updated overview of their results is presented.

Objectives: In this report, the Early Breast Cancer Trialists' Collaborative Group present their third 5-yearly systematic overview (meta-analysis) of treatment with tamoxifen.

Search Strategy: Trial identification procedures for the EBCTCG overviews have been described elsewhere. See under "EBCTCG" in the Breast Cancer Collaborative Review Group module.

Selection Criteria: All randomised trials that began before 1990 and compared adjuvant tamoxifen for any duration versus no such treatment for women with early breast cancer.

Data Collection And Analysis: In 1995, information was sought on each woman in any randomised trial that began before 1990 of adjuvant tamoxifen versus no tamoxifen before recurrence. Information was obtained and analysed centrally on each of 37,000 women in 55 such trials, comprising about 87% of the worldwide evidence. Compared with the previous such overview, this approximately doubles the amount of evidence from trials of about 5 years of tamoxifen and, taking all trials together, on events occurring more than 5 years after randomisation.

Main Results: Nearly 8000 of the women had a low, or zero, level of the oestrogen-receptor protein (ER) measured in their primary tumour. Among them, the overall effects of tamoxifen appeared to be small, and subsequent analyses of recurrence and total mortality are restricted to the remaining women (18,000 with ER-positive tumours, plus nearly 12,000 more with untested tumours, of which an estimated 8000 would have been ER-positive). For trials of 1 year, 2 years, and about 5 years of adjuvant tamoxifen, the proportional recurrence reductions produced among these 30,000 women during about 10 years of follow-up were 21% (SD 3), 29% (SD 2), and 47% (SD 3), respectively, with a highly significant trend towards greater effect with longer treatment (2p<0.00001). The corresponding proportional mortality reductions were 12% (SD 3), 17% (SD 3), and 26% (SD 4), respectively, and again the test for trend was significant (2p=0.003). The absolute improvement in recurrence was greater during the first 5 years, whereas the improvement in survival grew steadily larger throughout the first 10 years. The proportional mortality reductions were similar for women with node-positive and node-negative disease, but the absolute mortality reductions were greater in node-positive women. In the trials of about 5 years of adjuvant tamoxifen the absolute improvements in 10-year survival were 10.9% (SD 2.5) for node-positive (61.4% vs 50.5% survival, 2p<0.00001) and 5.6% (SD 1.3) for node-negative (78.9% vs 73.3% survival, 2p<0.00001). These benefits appeared to be largely irrespective of age, menopausal status, daily tamoxifen dose (which was generally 20 mg), and of whether chemotherapy had been given to both groups. In terms of other outcomes among all women studied (ie, including those with "ER-poor" tumours), the proportional reductions in contralateral breast cancer were 13% (SD 13), 26% (SD 9), and 47% (SD 9) in the trials of 1, 2, or about 5 years of adjuvant tamoxifen. The incidence of endometrial cancer was approximately doubled in trials of 1 or 2 years of tamoxifen and approximately quadrupled in trials of 5 years of tamoxifen (although the number of cases was small and these ratios were not significantly different from each other). The absolute decrease in contralateral breast cancer was about twice as large as the absolute increase in the incidence of endometrial cancer. Tamoxifen had no apparent effect on the incidence of colorectal cancer or, after exclusion of deaths from breast or endometrial cancer, on any of the other main categories of cause of death (total nearly 2000 such deaths; overall relative risk 0.99 [SD 0.05]).

Authors' Conclusions: For women with tumours that have been reliably shown to be ER-negative, adjuvant tamoxifen remains a matter for research. However, some years of adjuvant tamoxifen treatment substantially improves the 10-year survival of women with ER-positive tumours and of women whose tumours are of unknown ER status, with the proportional reductions in breast cancer recurrence and in mortality appearing to be largely unaffected by other patient characteristics or treatments.
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October 2008

WITHDRAWN: Ovarian ablation for early breast cancer.

Authors:
Mike J Clarke

Cochrane Database Syst Rev 2008 Oct 8(4):CD000485. Epub 2008 Oct 8.

UK Cochrane Centre, National Institute for Health Research, Summertown Pavilion, Middle Way, Oxford, UK, OX2 7LG.

Background: Among women with early breast cancer, the effects of ovarian ablation on recurrence and death have been assessed by several randomised trials that now have long follow-up.

Objectives: In this report, the Early Breast Cancer Trialists' Collaborative Group present their third 5-yearly systematic overview (meta-analysis), now with 15 years' follow-up.

Search Strategy: Trial identification procedures for the EBCTCG overviews have been described elsewhere. See under "EBCTCG" in the Breast Cancer Collaborative Review Group module.

Selection Criteria: All properly randomised trials that began recruiting before 1990 which compared the ablation or suppression of ovarian function, sometimes with the addition of prednisone, versus no such adjuvant treatment for women with operable breast cancer. In practice, all the trials that can be reviewed here began before 1980, and all involved surgical or therapeutic ablation.

Data Collection And Analysis: In 1995, information was sought on each patient in any randomised trial of ovarian ablation or suppression versus control that began before 1990. Data were obtained for 12 of the 13 studies that assessed ovarian ablation by irradiation or surgery, all of which began before 1980, but not for the four studies that assessed ovarian suppression by drugs, all of which began after 1985. Menopausal status was not consistently defined across trials; therefore, the main analyses are limited to women aged under 50 (rather than "premenopausal") when randomised. Oestrogen receptors were measured only in the trials of ablation plus cytotoxic chemotherapy versus the same chemotherapy alone.

Main Results: Among 2102 women aged under 50 when randomised, most of whom would have been premenopausal at diagnosis, 1130 deaths and an additional 153 recurrences were reported. 15-year survival was highly significantly improved among those allocated ovarian ablation (52.4 vs 46.1%, 6.3 [SD 2.3] fewer deaths per 100 women, logrank 2p=0.001), as was recurrence-free survival (45.0 vs 39.0%, 2p=0.0007). The numbers of events were too small for any subgroup analyses to be reliable. The benefit was, however, significant both for those with ("node positive") and for those without ("node negative") axillary spread when diagnosed. In the trials of ablation plus cytotoxic chemotherapy versus the same chemotherapy alone, the benefit appeared smaller (even for women with oestrogen receptors detected on the primary tumour) than in the trials in the absence of chemotherapy (where the observed survival improvements were about six per 100 node-negative women and 12 per 100 node-positive women). Among 1354 women aged 50 or over when randomised, most of whom would have been perimenopausal or postmenopausal, there was only a non-significant improvement in survival and recurrence-free survival.

Authors' Conclusions: In women aged under 50 with early breast cancer, ablation of functioning ovaries significantly improves long-term survival, at least in the absence of chemotherapy. Further randomised evidence is needed on the additional effects of ovarian ablation in the presence of other adjuvant treatments, and to assess the relevance of hormone-receptor measurements.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669263PMC
October 2008

Meta-analysis of individual patient data from randomized trials: a review of methods used in practice.

Clin Trials 2005 ;2(3):209-17

MRC Biostatistics Unit, Robinson Way, Cambridge, UK.

Background: Meta-analyses based on individual patient data (IPD) are regarded as the gold standard for systematic reviews. However, the methods used for analysing and presenting results from IPD meta-analyses have received little discussion.

Methods: We review 44 IPD meta-analyses published during the years 1999-2001. We summarize whether they obtained all the data they sought, what types of approaches were used in the analysis, including assumptions of common or random effects, and how they examined the effects of covariates.

Results: Twenty-four out of 44 analyses focused on time-to-event outcomes, and most analyses (28) estimated treatment effects within each trial and then combined the results assuming a common treatment effect across trials. Three analyses failed to stratify by trial, analysing the data is if they came from a single mega-trial. Only nine analyses used random effects methods. Covariate-treatment interactions were generally investigated by subgrouping patients. Seven of the meta-analyses included data from less than 80% of the randomized patients sought, but did not address the resulting potential biases.

Conclusions: Although IPD meta-analyses have many advantages in assessing the effects of health care, there are several aspects that could be further developed to make fuller use of the potential of these time-consuming projects. In particular, IPD could be used to more fully investigate the influence of covariates on heterogeneity of treatment effects, both within and between trials. The impact of heterogeneity, or use of random effects, are seldom discussed. There is thus considerable scope for enhancing the methods of analysis and presentation of IPD meta-analysis.
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http://dx.doi.org/10.1191/1740774505cn087oaDOI Listing
December 2005