Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy.

BACKGROUND: Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the trade-off between safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is the third update of a review first published in February 2012. OBJECTIVES: To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis, or an active control intervention. SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 3 August 2020. We also searched the reference lists of identified studies and contacted content experts and trialists for relevant references. SELECTION CRITERIA: Randomised controlled trials comparing any oral or parenteral anticoagulant or mechanical intervention to no thromboprophylaxis or placebo, or comparing two different anticoagulants. DATA COLLECTION AND ANALYSIS: We extracted data on risk of bias, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. We applied GRADE to assess the certainty of evidence. MAIN RESULTS: We identified six additional randomised controlled trials (3326 participants) for this update, bringing the included study total to 32 (15,678 participants), all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The certainty of the evidence ranged from high to very low across the different outcomes and comparisons. The main limiting factors were imprecision and risk of bias. Thromboprophylaxis with direct oral anticoagulants (direct factor Xa inhibitors apixaban and rivaroxaban) may decrease the incidence of symptomatic VTE (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.18 to 1.06; 3 studies, 1526 participants; low-certainty evidence); and probably increases the risk of major bleeding compared with placebo (RR 1.74, 95% CI 0.82 to 3.68; 3 studies, 1494 participants; moderate-certainty evidence). When compared with no thromboprophylaxis, low-molecular-weight heparin (LMWH) reduced the incidence of symptomatic VTE (RR 0.62, 95% CI 0.46 to 0.83; 11 studies, 3931 participants; high-certainty evidence); and probably increased the risk of major bleeding events (RR 1.63, 95% CI 1.12 to 2.35; 15 studies, 7282 participants; moderate-certainty evidence). In participants with multiple myeloma, LMWH resulted in lower symptomatic VTE compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83; 1 study, 439 participants; high-certainty evidence), while LMWH probably lowers symptomatic VTE more than aspirin (RR 0.51, 95% CI 0.22 to 1.17; 2 studies, 781 participants; moderate-certainty evidence). Major bleeding was observed in none of the participants with multiple myeloma treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against no thromboprophylaxis, but did not report on VTE or major bleeding. When compared with placebo or no thromboprophylaxis, warfarin may importantly reduce symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20; 1 study, 311 participants; low-certainty evidence) and may result in a large increase in major bleeding (RR 3.82, 95% CI 0.97 to 15.04; 4 studies, 994 participants; low-certainty evidence). One study evaluated antithrombin versus no antithrombin in children. This study did not report on symptomatic VTE but did report any VTE (symptomatic and incidental VTE). The effect of antithrombin on any VTE and major bleeding is uncertain (any VTE: RR 0.84, 95% CI 0.41 to 1.73; major bleeding: RR 0.78, 95% CI 0.03 to 18.57; 1 study, 85 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: In ambulatory cancer patients, primary thromboprophylaxis with direct factor Xa inhibitors may reduce the incidence of symptomatic VTE (low-certainty evidence) and probably increases the risk of major bleeding (moderate-certainty evidence) when compared with placebo. LMWH decreases the incidence of symptomatic VTE (high-certainty evidence), but increases the risk of major bleeding (moderate-certainty evidence) when compared with placebo or no thromboprophylaxis. Evidence for the use of thromboprophylaxis with anticoagulants other than direct factor Xa inhibitors and LMWH is limited. More studies are warranted to evaluate the efficacy and safety of primary prophylaxis in specific types of chemotherapeutic agents and types of cancer, such as gastrointestinal or genitourinary cancer.

Computerised cognitive training for 12 or more weeks for maintaining cognitive function in cognitively healthy people in late life.

BACKGROUND: Increasing age is associated with a natural decline in cognitive function and is the greatest risk factor for dementia. Cognitive decline and dementia are significant threats to independence and quality of life in older adults. Therefore, identifying interventions that help to maintain cognitive function in older adults or that reduce the risk of dementia is a research priority. Cognitive training uses repeated practice on standardised exercises targeting one or more cognitive domains and may be intended to improve or maintain optimal cognitive function. This review examines the effects of computerised cognitive training interventions lasting at least 12 weeks on the cognitive function of healthy adults aged 65 or older and has formed part of a wider project about modifying lifestyle to maintain cognitive function. We chose a minimum 12 weeks duration as a trade-off between adequate exposure to a sustainable intervention and feasibility in a trial setting. OBJECTIVES: To evaluate the effects of computerised cognitive training interventions lasting at least 12 weeks on cognitive function in cognitively healthy people in late life. SEARCH METHODS: We searched to 31 March 2018 in ALOIS (www.medicine.ox.ac.uk/alois), and we performed additional searches of MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov, and the WHO Portal/ICTRP (www.apps.who.int/trialsearch), to ensure that the search was as comprehensive and as up-to-date as possible to identify published, unpublished, and ongoing trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs, published or unpublished, reported in any language. Participants were cognitively healthy people, and at least 80% of the study population had to be aged 65 or older. Experimental interventions adhered to the following criteria: intervention was any form of interactive computerised cognitive intervention - including computer exercises, computer games, mobile devices, gaming console, and virtual reality - that involved repeated practice on standardised exercises of specified cognitive domain(s) for the purpose of enhancing cognitive function; the duration of the intervention was at least 12 weeks; cognitive outcomes were measured; and cognitive training interventions were compared with active or inactive control interventions. DATA COLLECTION AND ANALYSIS: We performed preliminary screening of search results using a 'crowdsourcing' method to identify RCTs. At least two review authors working independently screened the remaining citations against inclusion criteria. At least two review authors also independently extracted data and assessed the risk of bias of included RCTs. Where appropriate, we synthesised data in random-effects meta-analyses, comparing computerised cognitive training (CCT) separately with active and inactive controls. We expressed treatment effects as standardised mean differences (SMDs) with 95% confidence intervals (CIs). We used GRADE methods to describe the overall quality of the evidence for each outcome. MAIN RESULTS: We identified eight RCTs with a total of 1183 participants. The duration of the interventions ranged from 12 to 26 weeks; in five trials, the duration of intervention was 12 or 13 weeks. The included studies had moderate risk of bias, and the overall quality of evidence was low or very low for all outcomes. We compared CCT first against active control interventions, such as watching educational videos. Negative SMDs favour CCT over control. Trial results suggest slight improvement in global cognitive function at the end of the intervention period (12 weeks) (standardised mean difference (SMD) -0.31, 95% confidence interval (CI) -0.57 to -0.05; 232 participants; 2 studies; low-quality evidence). One of these trials also assessed global cognitive function 12 months after the end of the intervention; this trial provided no clear evidence of a persistent effect (SMD -0.21, 95% CI -0.66 to 0.24; 77 participants; 1 study; low-quality evidence). CCT may result in little or no difference at the end of the intervention period in episodic memory (12 to 17 weeks) (SMD 0.06, 95% CI -0.14 to 0.26; 439 participants; 4 studies; low-quality evidence) or working memory (12 to 16 weeks) (SMD -0.17, 95% CI -0.36 to 0.02; 392 participants; 3 studies; low-quality evidence). Because of the very low quality of the evidence, we are very uncertain about the effects of CCT on speed of processing and executive function. We also compared CCT to inactive control (no interventions). We found no data on our primary outcome of global cognitive function. At the end of the intervention, CCT may lead to slight improvement in episodic memory (6 months) (mean difference (MD) in Rivermead Behavioural Memory Test (RBMT) -0.90 points, 95% confidence interval (CI) -1.73 to -0.07; 150 participants; 1 study; low-quality evidence) but can have little or no effect on executive function (12 weeks to 6 months) (SMD -0.08, 95% CI -0.31 to 0.15; 292 participants; 2 studies; low-quality evidence), working memory (16 weeks) (MD -0.08, 95% CI -0.43 to 0.27; 60 participants; 1 study; low-quality evidence), or verbal fluency (6 months) (MD -0.11, 95% CI -1.58 to 1.36; 150 participants; 1 study; low-quality evidence). We could not determine any effects on speed of processing because the evidence was of very low quality. We found no evidence on quality of life, activities of daily living, or adverse effects in either comparison. AUTHORS' CONCLUSIONS: We found low-quality evidence suggesting that immediately after completion of the intervention, small benefits of CCT may be seen for global cognitive function when compared with active controls, and for episodic memory when compared with an inactive control. These benefits are of uncertain clinical importance. We found no evidence that the effect on global cognitive function persisted 12 months later. Our confidence in the results was low, reflecting the overall quality of the evidence. In five of the eight trials, the duration of the intervention was just three months. The possibility that more extensive training could yield larger benefit remains to be more fully explored. We found substantial literature on cognitive training, and collating all available scientific information posed problems. Duration of treatment may not be the best way to categorise interventions for inclusion. As the primary interest of older people and of guideline writers and policymakers involves sustained cognitive benefit, an alternative would be to categorise by length of follow-up after selecting studies that assess longer-term effects.

Computerised cognitive training for maintaining cognitive function in cognitively healthy people in late life.

BACKGROUND: Increasing age is associated with a natural decline in cognitive function and is also the greatest risk factor for dementia. Cognitive decline and dementia are significant threats to independence and quality of life in older adults. Therefore, identifying interventions that help to maintain cognitive function in older adults or to reduce the risk of dementia is a research priority. Cognitive training uses repeated practice on standardised exercises targeting one or more cognitive domains and is intended to maintain optimum cognitive function. This review examines the effect of computerised cognitive training interventions lasting at least 12 weeks on the cognitive function of healthy adults aged 65 or older. OBJECTIVES: To evaluate the effects of computerised cognitive training interventions lasting at least 12 weeks for the maintenance or improvement of cognitive function in cognitively healthy people in late life. SEARCH METHODS: We searched to 31 March 2018 in ALOIS (www.medicine.ox.ac.uk/alois) and performed additional searches of MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov, and the WHO Portal/ICTRP (www.apps.who.int/trialsearch) to ensure that the search was as comprehensive and as up-to-date as possible, to identify published, unpublished, and ongoing trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs, published or unpublished, reported in any language. Participants were cognitively healthy people, and at least 80% of the study population had to be aged 65 or older. Experimental interventions adhered to the following criteria: intervention was any form of interactive computerised cognitive intervention - including computer exercises, computer games, mobile devices, gaming console, and virtual reality - that involved repeated practice on standardised exercises of specified cognitive domain(s) for the purpose of enhancing cognitive function; duration of the intervention was at least 12 weeks; cognitive outcomes were measured; and cognitive training interventions were compared with active or inactive control interventions. DATA COLLECTION AND ANALYSIS: We performed preliminary screening of search results using a 'crowdsourcing' method to identify RCTs. At least two review authors working independently screened the remaining citations against inclusion criteria. At least two review authors also independently extracted data and assessed the risk of bias of included RCTs. Where appropriate, we synthesised data in random-effect meta-analyses, comparing computerised cognitive training (CCT) separately with active and inactive controls. We expressed treatment effects as standardised mean differences (SMDs) with 95% confidence intervals (CIs). We used GRADE methods to describe the overall quality of the evidence for each outcome. MAIN RESULTS: We identified eight RCTs with a total of 1183 participants. Researchers provided interventions over 12 to 26 weeks; in five trials, the duration of intervention was 12 or 13 weeks. The included studies had a moderate risk of bias. Review authors noted a lot of inconsistency between trial results. The overall quality of evidence was low or very low for all outcomes.We compared CCT first against active control interventions, such as watching educational videos. Because of the very low quality of the evidence, we were unable to determine any effect of CCT on our primary outcome of global cognitive function or on secondary outcomes of episodic memory, speed of processing, executive function, and working memory.We also compared CCT versus inactive control (no interventions). Negative SMDs favour CCT over control. We found no studies on our primary outcome of global cognitive function. In terms of our secondary outcomes, trial results suggest slight improvement in episodic memory (mean difference (MD) -0.90, 95% confidence interval (CI) -1.73 to -0.07; 150 participants; 1 study; low-quality evidence) and no effect on executive function (SMD -0.08, 95% CI -0.31 to 0.15; 292 participants; 2 studies; low-quality evidence), working memory (MD -0.08, 95% CI -0.43 to 0.27; 60 participants; 1 study; low-quality evidence), or verbal fluency (MD -0.11, 95% CI -1.58 to 1.36; 150 participants; 1 study; low-quality evidence). We could not determine any effects on speed of processing at trial endpoints because the evidence was of very low quality.We found no evidence on quality of life, activities of daily living, or adverse effects in either comparison. AUTHORS' CONCLUSIONS: We found little evidence from the included studies to suggest that 12 or more weeks of CCT improves cognition in healthy older adults. However, our limited confidence in the results reflects the overall quality of the evidence. Inconsistency between trials was a major limitation. In five of the eight trials, the duration of intervention was just three months. The possibility that longer periods of training could be beneficial remains to be more fully explored.

Computerised cognitive training for maintaining cognitive function in cognitively healthy people in midlife.

BACKGROUND: Normal aging is associated with changes in cognitive function that are non-pathological and are not necessarily indicative of future neurocognitive disease. Low cognitive and brain reserve and limited cognitive stimulation are associated with increased risk of dementia. Emerging evidence now suggests that subtle cognitive changes, detectable years before criteria for mild cognitive impairment are met, may be predictive of future dementia. Important for intervention and reduction in disease risk, research also suggests that engaging in stimulating mental activity throughout adulthood builds cognitive and brain reserve and reduces dementia risk. Therefore, midlife (defined here as 40 to 65 years) may be a suitable time to introduce cognitive interventions for maintaining cognitive function and, in the longer term, possibly preventing or delaying the onset of clinical dementia. OBJECTIVES: To evaluate the effects of computerised cognitive training interventions lasting at least 12 weeks for maintaining or improving cognitive function in cognitively healthy people in midlife. SEARCH METHODS: We searched up to 31 March 2018 in ALOIS (www.medicine.ox.ac.uk/alois), the specialised register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG). We ran additional searches in MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov, and the WHO Portal/ICTRP at www.apps.who.int/trialsearch, to ensure that the search was as comprehensive and as up-to-date as possible, to identify published, unpublished, and ongoing trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs, published or unpublished, reported in any language. Participants were cognitively healthy people between 40 and 65 years of age (80% of study population within this age range). Experimental interventions adhered to the following criteria: intervention was any form of interactive computerised cognitive intervention - including computer exercises, computer games, mobile devices, gaming console, and virtual reality - that involved repeated practice on standardised exercises of specified cognitive domain(s) for the purpose of enhancing cognitive function; duration of the intervention was at least 12 weeks; cognitive outcomes were measured; and cognitive training interventions were compared with active or inactive control interventions. DATA COLLECTION AND ANALYSIS: For preliminary screening of search results, we used a 'crowd' method to identify RCTs. At least two review authors working independently screened remaining citations against inclusion criteria; independently extracted data; and assessed the quality of the included trial, using the Cochrane risk of bias assessment tool. We used GRADE to describe the overall quality of the evidence. MAIN RESULTS: We identified one eligible study that examined the effect of computerised cognitive training (CCT) in 6742 participants over 50 years of age, with training and follow-up duration of six months. We considered the study to be at high risk of attrition bias and the overall quality of the evidence to be low.Researchers provided no data on our primary outcome. Results indicate that there may be a small advantage for the CCT group for executive function (mean difference (MD) -1.57, 95% confidence interval (CI) -1.85 to -1.29; participants = 3994; low-quality evidence) and a very small advantage for the control group for working memory (MD 0.09, 95% CI 0.03 to 0.15; participants = 5831; low-quality evidence). The intervention may have had little or no effect on episodic memory (MD -0.03, 95% CI -0.10 to 0.04; participants = 3090; low-quality evidence). AUTHORS' CONCLUSIONS: We found low-quality evidence from only one study. We are unable to determine whether computerised cognitive training is effective in maintaining global cognitive function among healthy adults in midlife. We strongly recommend that high-quality studies be undertaken to investigate the effectiveness and acceptability of cognitive training in midlife, using interventions that last long enough that they may have enduring effects on cognitive and brain reserve, and with investigators following up long enough to assess effects on clinically important outcomes in later life.

Computerised cognitive training for preventing dementia in people with mild cognitive impairment.

BACKGROUND: The number of people living with dementia is increasing rapidly. Clinical dementia does not develop suddenly, but rather is preceded by a period of cognitive decline beyond normal age-related change. People at this intermediate stage between normal cognitive function and clinical dementia are often described as having mild cognitive impairment (MCI). Considerable research and clinical efforts have been directed toward finding disease-modifying interventions that may prevent or delay progression from MCI to clinical dementia. OBJECTIVES: To evaluate the effects of at least 12 weeks of computerised cognitive training (CCT) on maintaining or improving cognitive function and preventing dementia in people with mild cognitive impairment. SEARCH METHODS: We searched to 31 May 2018 in ALOIS (www.medicine.ox.ac.uk/alois) and ran additional searches in MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov, and the WHO portal/ICTRP (www.apps.who.int/trialsearch) to identify published, unpublished, and ongoing trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in which cognitive training via interactive computerised technology was compared with an active or inactive control intervention. Experimental computerised cognitive training (CCT) interventions had to adhere to the following criteria: minimum intervention duration of 12 weeks; any form of interactive computerised cognitive training, including computer exercises, computer games, mobile devices, gaming console, and virtual reality. Participants were adults with a diagnosis of mild cognitive impairment (MCI) or mild neurocognitive disorder (MND), or otherwise at high risk of cognitive decline. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias of the included RCTs. We expressed treatment effects as mean differences (MDs) or standardised mean differences (SMDs) for continuous outcomes and as risk ratios (RRs) for dichotomous outcomes. We used the GRADE approach to describe the overall quality of evidence for each outcome. MAIN RESULTS: Eight RCTs with a total of 660 participants met review inclusion criteria. Duration of the included trials varied from 12 weeks to 18 months. Only one trial used an inactive control. Most studies were at unclear or high risk of bias in several domains. Overall, our ability to draw conclusions was hampered by very low-quality evidence. Almost all results were very imprecise; there were also problems related to risk of bias, inconsistency between trials, and indirectness of the evidence.No trial provided data on incident dementia. For comparisons of CCT with both active and inactive controls, the quality of evidence on our other primary outcome of global cognitive function immediately after the intervention period was very low. Therefore, we were unable to draw any conclusions about this outcome.Due to very low quality of evidence, we were also unable to determine whether there was any effect of CCT compared to active control on our secondary outcomes of episodic memory, working memory, executive function, depression, functional performance, and mortality. We found low-quality evidence suggesting that there is probably no effect on speed of processing (SMD 0.20, 95% confidence interval (CI) -0.16 to 0.56; 2 studies; 119 participants), verbal fluency (SMD -0.16, 95% CI -0.76 to 0.44; 3 studies; 150 participants), or quality of life (mean difference (MD) 0.40, 95% CI -1.85 to 2.65; 1 study; 19 participants).When CCT was compared with inactive control, we obtained data on five secondary outcomes, including episodic memory, executive function, verbal fluency, depression, and functional performance. We found very low-quality evidence; therefore, we were unable to draw any conclusions about these outcomes. AUTHORS' CONCLUSIONS: Currently available evidence does not allow us to determine whether or not computerised cognitive training will prevent clinical dementia or improve or maintain cognitive function in those who already have evidence of cognitive impairment. Small numbers of trials, small samples, risk of bias, inconsistency between trials, and highly imprecise results mean that it is not possible to derive any implications for clinical practice, despite some observed large effect sizes from individual studies. Direct adverse events are unlikely to occur, although the time and sometimes the money involved in computerised cognitive training programmes may represent significant burdens. Further research is necessary and should concentrate on improving methodological rigour, selecting suitable outcomes measures, and assessing generalisability and persistence of any effects. Trials with long-term follow-up are needed to determine the potential of this intervention to reduce the risk of dementia.

Tramadol for osteoarthritis.

BACKGROUND: Tramadol is often prescribed to treat pain and is associated physical disability in osteoarthritis (OA). Due to the pharmacologic mechanism of tramadol, it may lead to fewer associated adverse effects (i.e. gastrointestinal bleeding or renal problems) compared to non-steroidal anti-inflammatory drugs (NSAIDs). This is an update of a Cochrane Review originally published in 2006. OBJECTIVES: To determine the benefits and harms of oral tramadol or tramadol combined with acetaminophen or NSAIDs in people with osteoarthritis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase databases, as well as the US National Institutes of Health and World Health Organization trial registries up to February 2018. We searched the LILACS database up to August 2015. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated the effect of tramadol, or tramadol in combination with acetaminophen (paracetamol) or NSAIDs versus placebo or any comparator in people with osteoarthritis. DATA COLLECTION AND ANALYSIS: We used standard methodologic procedures expected by Cochrane. MAIN RESULTS: We included 22 RCTs (11 more than the previous review) of which 21 RCTs were included in meta-analyses for 3871 participants randomized to tramadol alone or tramadol in combination with another analgesic and 2625 participants randomized to placebo or active control. Seventeen studies evaluated tramadol alone and five evaluated tramadol plus acetaminophen. Thirteen studies used placebo controls and eleven studies used active controls (two trials had both placebo and active arms). The dose of tramadol ranged from 37.5 mg to 400 mg daily; all doses were pooled. Most trials were multicenter with a mean duration of two months. Participants were predominantly women with hip or knee osteoarthritis, with a mean age of 63 years and moderate to severe pain. There was a high risk of selection bias as only four trials reported both adequate sequence generation and allocation concealment. There was a low risk for performance bias as most studies blinded participants. There was a high risk of attrition bias as 10/22 trials showed incomplete outcome data. Most of the trials were funded by the pharmaceutical industry.Moderate quality evidence (downgraded due to risk of bias) indicated that tramadol alone and in combination with acetaminophen had no important benefit on pain reduction compared to placebo control (tramadol alone: 4% absolute improvement, 95% confidence interval (CI) 3% to 5%; 8 studies, 3972 participants; tramadol in combination with acetaminophen: 4% absolute improvement, 95% CI 2% to 6%; 2 studies, 614 participants).Fifteen out of 100 people in the tramadol group improved by 20% (which corresponded to a clinically important difference in pain) compared to 10/100 in the placebo group (5% absolute improvement). Twelve out of 100 people improved by 20% in the tramadol in combination with acetaminophen group compared to 7/100 in the placebo group (5% absolute improvement).Moderate quality evidence (downgraded due to risk of bias) indicated that tramadol alone and in combination with acetaminophen led to no important benefit in physical function compared to placebo (tramadol alone: 4% absolute improvement, 95% CI 2% to 6%; 5 studies, 2550 participants; tramadol in combination with acetaminophen: 4% absolute improvement, 95% CI 2% to 7%; 2 studies, 614 participants).Twenty-one out of 100 people in the tramadol group improved by 20% (which corresponded to a clinically important difference in physical function) compared to 16/100 in the placebo group (5% absolute improvement). Fifteen out of 100 people improved by 20% in the tramadol in combination with acetaminophen group compared to 10/100 in the placebo group (5% absolute improvement).Moderate quality evidence (downgraded due to risk of bias) indicated that, compared to placebo, there was a greater risk of developing adverse events with tramadol alone (risk ratio (RR) 1.34, 95% CI 1.24 to 1.46; 4 studies, 2039 participants) and tramadol in combination with acetaminophen compared to placebo (RR 1.91, 95% CI 1.32 to 2.76; 1 study, 308 participants). This corresponded to a 17% increase (95% CI 12% to 23%) with tramadol alone and 22% increase (95% CI 8% to 41%) with tramadol in combination with acetaminophen.The three most frequent adverse events were nausea, dizziness and tiredness. Moderate quality evidence (downgraded due to risk of bias) indicated that there was a greater risk of withdrawing from the study because of adverse events with tramadol alone compared to placebo (RR 2.64, 95% CI 2.17 to 3.20; 9 studies, 4533 participants), which corresponded to a 12% increase (95% CI 9% to 16%).Low quality evidence (downgraded due to risk of bias and inconsistency) indicated that there was a greater risk of withdrawing from the study because of adverse events with tramadol in combination with acetaminophen compared to placebo (RR 2.78, 95% CI 1.50 to 5.16; 2 studies, 614 participants), which corresponded to a 8% absolute improvement (95% CI 2% to 19%).Low quality evidence (downgraded due to risk of bias and imprecision) indicated that there was a greater risk of developing serious adverse events with tramadol alone compared to placebo (110/2459 participants with tramadol compared to 22/1153 participants with placebo; RR 1.78, 95% CI 1.11 to 2.84; 7 studies, 3612 participants), which corresponded to a 1% increase (95% CI 0% to 4%). There were no serious adverse events reported in one small study (15 participants) of tramadol with acetaminophen compared to placebo. AUTHORS' CONCLUSIONS: Moderate quality evidence indicates that compared to placebo, tramadol alone or in combination with acetaminophen probably has no important benefit on mean pain or function in people with osteoarthritis, although slightly more people in the tramadol group report an important improvement (defined as 20% or more). Moderate quality evidence shows that adverse events probably cause substantially more participants to stop taking tramadol. The increase in serious adverse events with tramadol is less certain, due to the small number of events.

Vitamin and mineral supplementation for maintaining cognitive function in cognitively healthy people in mid and late life.

BACKGROUND: Vitamins and minerals play multiple functions within the central nervous system which may help to maintain brain health and optimal cognitive functioning. Supplementation of the diet with various vitamins and minerals has been suggested as a means of maintaining cognitive function, or even of preventing dementia, in later life. OBJECTIVES: To evaluate the effects of vitamin and mineral supplementation on cognitive function in cognitively healthy people aged 40 years or more. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's (CDCIG) specialised register, as well as MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov and the WHO Portal/ICTRP from inception to 26th January 2018. SELECTION CRITERIA: We included randomised controlled trials that evaluated the cognitive effects on people aged 40 years or more of any vitamin or mineral supplements taken by mouth for at least three months. DATA COLLECTION AND ANALYSIS: Study selection, data extraction, and quality assessments were done in duplicate. Vitamins were considered broadly in the categories of B vitamins, antioxidant vitamins, and combinations of both. Minerals were considered separately, where possible. If interventions and outcomes were considered sufficiently similar, then data were pooled. In order to separate short-term cognitive effects from possible longer-term effects on the trajectory of cognitive decline, data were pooled for various treatment durations from 3 months to 12 months and up to 10 years or more. MAIN RESULTS: In total, we included 28 studies with more than 83,000 participants. There were some general limitations of the evidence. Most participants were enrolled in studies which were not designed primarily to assess cognition. These studies often had no baseline cognitive assessment and used only brief cognitive assessments at follow-up. Very few studies assessed the incidence of dementia. Most study reports did not mention adverse events or made only very general statements about them. Only 10 studies had a mean follow-up > 5 years. Only two studies had participants whose mean age was < 60 years at baseline. The risk of bias in the included studies was generally low, other than a risk of attrition bias for longer-term outcomes. We considered the certainty of the evidence behind almost all results to be moderate or low.We included 14 studies with 27,882 participants which compared folic acid, vitamin B12, vitamin B6, or a combination of these to placebo. The majority of participants were aged over 60 years and had a history of cardio- or cerebrovascular disease. We found that giving B vitamin supplements to cognitively healthy adults, mainly in their 60s and 70s, probably has little or no effect on global cognitive function at any time point up to 5 years (SMD values from -0.03 to 0.06) and may also have no effect at 5-10 years (SMD -0.01). There were very sparse data on adverse effects or on incidence of cognitive impairment or dementia.We included 8 studies with 47,840 participants in which the active intervention was one or more of the antioxidant vitamins: ß-carotene, vitamin C or vitamin E. Results were mixed. For overall cognitive function, there was low-certainty evidence of benefit associated with ß-carotene after a mean of 18 years of treatment (MD 0.18 TICS points, 95% CI 0.01 to 0.35) and of vitamin C after 5 years to 10 years (MD 0.46 TICS points, 95% CI 0.14 to 0.78), but not at earlier time points. From two studies which reported on dementia incidence, there was low-certainty evidence of no effect of an antioxidant vitamin combination or of vitamin E, either alone or combined with selenium. One of the included studies had been designed to look for effects on the incidence of prostate cancer; it found a statistically significant increase in prostate cancer diagnoses among men taking vitamin E.One trial with 4143 participants compared vitamin D3 (400 IU/day) and calcium supplements to placebo. We found low- to moderate-certainty evidence of no effect of vitamin D3 and calcium supplements at any time-point up to 10 years on overall cognitive function (MD after a mean of 7.8 years -0.1 MMSE points, 95% CI -0.81 to 0.61) or the incidence of dementia (HR 0.94, 95% CI 0.72 to 1.24). A pilot study with 60 participants used a higher dose of vitamin D3 (4000 IU on alternate days) and found preliminary evidence that this dose probably has no effect on cognitive function over six months.We included data from one trial of zinc and copper supplementation with 1072 participants. There was moderate-certainty evidence of little or no effect on overall cognitive function (MD 0.6 MMSE points, 95% CI -0.19 to 1.39) or on the incidence of cognitive impairment after 5 years to 10 years. A second smaller trial provided no usable data, but reported no cognitive effects of six months of supplementation with zinc gluconate.From one study with 3711 participants, there was low-certainty evidence of no effect of approximately five years of selenium supplementation on the incidence of dementia (HR 0.83, 95% CI 0.61 to 1.13).Finally, we included three trials of complex supplements (combinations of B vitamins, antioxidant vitamins, and minerals) with 6306 participants. From the one trial which assessed overall cognitive function, there was low-certainty evidence of little or no effect on the TICS (MD after a mean of 8.5 years 0.12, 95% CI -0.14 to 0.38). AUTHORS' CONCLUSIONS: We did not find evidence that any vitamin or mineral supplementation strategy for cognitively healthy adults in mid or late life has a meaningful effect on cognitive decline or dementia, although the evidence does not permit definitive conclusions. There were very few data on supplementation starting in midlife (< 60 years); studies designed to assess cognitive outcomes tended to be too short to assess maintenance of cognitive function; longer studies often had other primary outcomes and used cognitive measures which may have lacked sensitivity. The only positive signals of effect came from studies of long-term supplementation with antioxidant vitamins. These may be the most promising for further research.

Vitamin and mineral supplementation for preventing dementia or delaying cognitive decline in people with mild cognitive impairment.

BACKGROUND: Vitamins and minerals have many functions in the nervous system which are important for brain health. It has been suggested that various different vitamin and mineral supplements might be useful in maintaining cognitive function and delaying the onset of dementia. In this review, we sought to examine the evidence for this in people who already had mild cognitive impairment (MCI). OBJECTIVES: To evaluate the effects of vitamin and mineral supplementation on cognitive function and the incidence of dementia in people with mild cognitive impairment. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's (CDCIG) specialised register, as well as MEDLINE, Embase, PsycINFO, CENTRAL, CINAHL, LILACs, Web of Science Core Collection, ClinicalTrials.gov, and the WHO Portal/ICTRP, from inception to 25 January 2018. SELECTION CRITERIA: We included randomised or quasi-randomised, placebo-controlled trials which evaluated orally administered vitamin or mineral supplements in participants with a diagnosis of mild cognitive impairment and which assessed the incidence of dementia or cognitive outcomes, or both. We were interested in studies applicable to the general population of older people and therefore excluded studies in which participants had severe vitamin or mineral deficiencies. DATA COLLECTION AND ANALYSIS: We sought data on our primary outcomes of dementia incidence and overall cognitive function and on secondary outcomes of episodic memory, executive function, speed of processing, quality of life, functional performance, clinical global impression, adverse events, and mortality. We conducted data collection and analysis according to standard Cochrane systematic review methods. We assessed the risk of bias of included studies using the Cochrane 'Risk of bias' assessment tool. We grouped vitamins and minerals according to their putative mechanism of action and, where we considered it to be clinically appropriate, we pooled data using random-effects methods. We used GRADE methods to assess the overall quality of evidence for each comparison and outcome. MAIN RESULTS: We included five trials with 879 participants which investigated B vitamin supplements. In four trials, the intervention was a combination of vitamins B6, B12, and folic acid; in one, it was folic acid only. Doses varied. We considered there to be some risks of performance and attrition bias and of selective outcome reporting among these trials. Our primary efficacy outcomes were the incidence of dementia and scores on measures of overall cognitive function. None of the trials reported the incidence of dementia and the evidence on overall cognitive function was of very low-quality. There was probably little or no effect of B vitamins taken for six to 24 months on episodic memory, executive function, speed of processing, or quality of life. The evidence on our other secondary clinical outcomes, including harms, was very sparse or very low-quality. There was evidence from one study that there may be a slower rate of brain atrophy over two years in participants taking B vitamins. The same study reported subgroup analyses based on the level of serum homocysteine (tHcy) at baseline and found evidence that B vitamins may improve episodic memory in those with tHcy above the median at baseline.We included one trial (n = 516) of vitamin E supplementation. Vitamin E was given as 1000 IU of alpha-tocopherol twice daily. We considered this trial to be at risk of attrition and selective reporting bias. There was probably no effect of vitamin E on the probability of progression from MCI to Alzheimer's dementia over three years (HR 1.02; 95% CI 0.74 to 1.41; n = 516; 1 study, moderate-quality evidence). There was also no evidence of an effect at intermediate time points. The available data did not allow us to conduct analyses, but the authors reported no significant effect of three years of supplementation with vitamin E on overall cognitive function, episodic memory, speed of processing, clinical global impression, functional performance, adverse events, or mortality (five deaths in each group). We considered this to be low-quality evidence.We included one trial (n = 256) of combined vitamin E and vitamin C supplementation and one trial (n = 26) of supplementation with chromium picolinate. In both cases, there was a single eligible cognitive outcome, but we considered the evidence to be very low-quality and so could not be sure of any effects. AUTHORS' CONCLUSIONS: The evidence on vitamin and mineral supplements as treatments for MCI is very limited. Three years of treatment with high-dose vitamin E probably does not reduce the risk of progression to dementia, but we have no data on this outcome for other supplements. Only B vitamins have been assessed in more than one RCT. There is no evidence for beneficial effects on cognition of supplementation with B vitamins for six to 24 months. Evidence from a single study of a reduced rate of brain atrophy in participants taking vitamin B and a beneficial effect of vitamin B on episodic memory in those with higher tHcy at baseline warrants attempted replication.

Trigger Tool-Based Automated Adverse Event Detection in Electronic Health Records: Systematic Review.

BACKGROUND: Adverse events in health care entail substantial burdens to health care systems, institutions, and patients. Retrospective trigger tools are often manually applied to detect AEs, although automated approaches using electronic health records may offer real-time adverse event detection, allowing timely corrective interventions. OBJECTIVE: The aim of this systematic review was to describe current study methods and challenges regarding the use of automatic trigger tool-based adverse event detection methods in electronic health records. In addition, we aimed to appraise the applied studies' designs and to synthesize estimates of adverse event prevalence and diagnostic test accuracy of automatic detection methods using manual trigger tool as a reference standard. METHODS: PubMed, EMBASE, CINAHL, and the Cochrane Library were queried. We included observational studies, applying trigger tools in acute care settings, and excluded studies using nonhospital and outpatient settings. Eligible articles were divided into diagnostic test accuracy studies and prevalence studies. We derived the study prevalence and estimates for the positive predictive value. We assessed bias risks and applicability concerns using Quality Assessment tool for Diagnostic Accuracy Studies-2 (QUADAS-2) for diagnostic test accuracy studies and an in-house developed tool for prevalence studies. RESULTS: A total of 11 studies met all criteria: 2 concerned diagnostic test accuracy and 9 prevalence. We judged several studies to be at high bias risks for their automated detection method, definition of outcomes, and type of statistical analyses. Across all the 11 studies, adverse event prevalence ranged from 0% to 17.9%, with a median of 0.8%. The positive predictive value of all triggers to detect adverse events ranged from 0% to 100% across studies, with a median of 40%. Some triggers had wide ranging positive predictive value values: (1) in 6 studies, hypoglycemia had a positive predictive value ranging from 15.8% to 60%; (2) in 5 studies, naloxone had a positive predictive value ranging from 20% to 91%; (3) in 4 studies, flumazenil had a positive predictive value ranging from 38.9% to 83.3%; and (4) in 4 studies, protamine had a positive predictive value ranging from 0% to 60%. We were unable to determine the adverse event prevalence, positive predictive value, preventability, and severity in 40.4%, 10.5%, 71.1%, and 68.4% of the studies, respectively. These studies did not report the overall number of records analyzed, triggers, or adverse events; or the studies did not conduct the analysis. CONCLUSIONS: We observed broad interstudy variation in reported adverse event prevalence and positive predictive value. The lack of sufficiently described methods led to difficulties regarding interpretation. To improve quality, we see the need for a set of recommendations to endorse optimal use of research designs and adequate reporting of future adverse event detection studies.

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy.

BACKGROUND: Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the trade-off between safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is the second update of a review first published in February 2012. OBJECTIVES: To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis. SEARCH METHODS: For this update the Cochrane Vascular Information Specialist searched the Cochrane Vascular Group Specialised Register (June 2016). In addition, the Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 5). Clinical trials registries were searched up to June 2016. SELECTION CRITERIA: Randomised controlled trials comparing any oral or parenteral anticoagulant or mechanical intervention to no thromboprophylaxis or placebo, or comparing two different anticoagulants. DATA COLLECTION AND ANALYSIS: We extracted data on methodological quality, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. MAIN RESULTS: We identified five additional randomised controlled trials (2491 participants) in the updated search, considering in this update 26 trials with a total of 12,352 participants, all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The quality of the evidence ranged from high to very low across the different outcomes and comparisons. The main limiting factors were imprecision and risk of bias. One large trial of 3212 participants found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). When compared with no thromboprophylaxis, LMWH significantly reduced the incidence of symptomatic VTE (RR 0.54, 95% CI 0.38 to 0.75; no heterogeneity, Tau2 = 0.00%) with a non-statistically significant 44% higher risk of major bleeding events (RR 1.44, 95% CI 0.98 to 2.11). In participants with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95% CI 0.22 to 1.17). Major bleeding was observed in none of the participants treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against no thromboprophylaxis but did not report on VTE or major bleeding. When compared with placebo, warfarin was associated with a non-statistically significant reduction of symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving paediatric patients, had no significant effect on VTE or on major bleeding when compared with no antithrombin. The direct oral factor Xa inhibitor apixaban was evaluated in a phase II dose-finding study that suggested a low rate of major bleeding (2.1% versus 3.4%) and symptomatic VTE (1.1% versus 13.8%) in comparison with placebo. AUTHORS' CONCLUSIONS: In this second update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin, which is not commercially available, significantly reduced the incidence of symptomatic VTE. The risk of major bleeding associated with LMWH, while not reaching statistical significance, suggest caution and mandate additional studies to determine the risk-to-benefit ratio of LMWH in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed. We need additional studies investigating targeted primary prophylaxis in people with specific types or stages of cancer associated with a higher risk of VTE.

Extended venous thromboprophylaxis in patients hospitalized for acute ischemic stroke: A systematic review and meta-analysis.

INTRODUCTION: Patients hospitalized for acute ischemic stroke have an increased risk of venous thromboembolism (VTE) that may persist beyond the currently recommended period of 6 to 14 days of thromboprophylaxis. This systematic review evaluated the efficacy and safety of extended venous thromboprophylaxis in patients hospitalized for acute ischemic stroke. MATERIALS AND METHODS: MEDLINE, EMBASE and Clinicaltrials.gov were searched up to December 2020 for randomized controlled trials comparing extended versus standard venous thromboprophylaxis in patients hospitalized for acute ischemic stroke. The efficacy outcome was a composite of asymptomatic or symptomatic deep vein thrombosis, symptomatic pulmonary embolism, and VTE-related death. The safety outcome was major bleeding. Summary risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were calculated using random-effects models. RESULTS: Four randomized controlled trials enrolling 33718 patients were included. Of 4330 (12.8%) patients hospitalized for acute ischemic stroke, 2152 (49.7%) received extended thromboprophylaxis for four to five weeks with betrixaban (n = 405, 18.8%), enoxaparin (n = 198, 9.2%), or rivaroxaban (n = 1549, 72.0%), and 2178 (50.3%) received standard venous thromboprophylaxis with enoxaparin. VTE risk was lower in acute ischemic stroke patients receiving extended thromboprophylaxis (RR 0.67; 95% CI, 0.43 to 1.04; 13 fewer per 1000), whereas the increase in major bleeding seemed trivial when compared with standard prophylaxis (RR 1.10; 95% CI, 0.31 to 3.95; 1 more per 1000). CONCLUSION: In patients hospitalized for acute ischemic stroke, the net clinical benefit may favor extended venous thromboprophylaxis for four to five weeks over standard thromboprophylaxis.

Therapeutic ultrasound for osteoarthritis of the knee or hip.

BACKGROUND: Osteoarthritis is the most common form of joint disease and the leading cause of pain and physical disability in the elderly. Therapeutic ultrasound is one of several physical therapy modalities suggested for the management of pain and loss of function due to osteoarthritis (OA). OBJECTIVES: To compare therapeutic ultrasound with sham or no specific intervention in terms of effects on pain and function safety outcomes in patients with knee or hip OA. SEARCH STRATEGY: We updated the search in CENTRAL, CINAHL, EMBASE, MEDLINE and PEDro up to 23 July 2009, checked conference proceedings, reference lists, and contacted authors. SELECTION CRITERIA: Studies were included if they were randomised or quasi-randomised controlled trials that compared therapeutic ultrasound with a sham intervention or no intervention in patients with osteoarthritis of the knee or hip. DATA COLLECTION AND ANALYSIS: Two independent review authors extracted data using standardized forms. Investigators were contacted to obtain missing outcome information. Standardised mean differences (SMDs) were calculated for pain and function, relative risks for safety outcomes. Trials were combined using inverse-variance random-effects meta-analysis. MAIN RESULTS: Compared to the previous version of the review, four additional trials were identified resulting in the inclusion of five small sized trials in a total of 341 patients with knee OA. No trial included patients with hip OA. Two evaluated pulsed ultrasound, two continuous and one evaluated both pulsed and continuous ultrasound as the active treatment. The methodological quality and the quality of reporting was poor and a high degree of heterogeneity among the trials was revealed for function (88%). For pain, there was an effect in favour of ultrasound therapy, which corresponded to a difference in pain scores between ultrasound and control of -1.2 cm on a 10-cm VAS (95% CI -1.9 to -0.6 cm). For function, we found a trend in favour of ultrasound, which corresponded to a difference in function scores of -1.3 units on a standardised WOMAC disability scale ranging from 0 to 10 (95% CI -3.0 to 0.3). Safety was evaluated in two trials including up to 136 patients; no adverse event, serious adverse event or withdrawals due to adverse events occurred in either trial. AUTHORS' CONCLUSIONS: In contrast to the previous version of this review, our results suggest that therapeutic ultrasound may be beneficial for patients with osteoarthritis of the knee. Because of the low quality of the evidence, we are uncertain about the magnitude of the effects on pain relief and function, however. Therapeutic ultrasound is widely used for its potential benefits on both knee pain and function, which may be clinically relevant. Appropriately designed trials of adequate power are therefore warranted.

Joint lavage for osteoarthritis of the knee.

BACKGROUND: Osteoarthritis is the most common form of joint disorder and a leading cause of pain and physical disability. Observational studies suggested a benefit for joint lavage, but recent, sham-controlled trials yielded conflicting results, suggesting joint lavage not to be effective. OBJECTIVES: To compare joint lavage with sham intervention, placebo or non-intervention control in terms of effects on pain, function and safety outcomes in patients with knee osteoarthritis. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, EMBASE, and CINAHL up to 3 August 2009, checked conference proceedings, reference lists, and contacted authors. SELECTION CRITERIA: We included studies if they were randomised or quasi-randomised trials that compared arthroscopic and non-arthroscopic joint lavage with a control intervention in patients with osteoarthritis of the knee. We did not apply any language restrictions. DATA COLLECTION AND ANALYSIS: Two independent review authors extracted data using standardised forms. We contacted investigators to obtain missing outcome information. We calculated standardised mean differences (SMDs) for pain and function, and risk ratios for safety outcomes. We combined trials using inverse-variance random-effects meta-analysis. MAIN RESULTS: We included seven trials with 567 patients. Three trials examined arthroscopic joint lavage, two non-arthroscopic joint lavage and two tidal irrigation. The methodological quality and the quality of reporting was poor and we identified a moderate to large degree of heterogeneity among the trials (I(2) = 65%). We found little evidence for a benefit of joint lavage in terms of pain relief at three months (SMD -0.11, 95% CI -0.42 to 0.21), corresponding to a difference in pain scores between joint lavage and control of 0.3 cm on a 10-cm visual analogue scale (VAS). Results for improvement in function at three months were similar (SMD -0.10, 95% CI -0.30 to 0.11), corresponding to a difference in function scores between joint lavage and control of 0.2 cm on a WOMAC disability sub-scale from 0 to 10. For pain, estimates of effect sizes varied to some degree depending on the type of lavage, but this variation was likely to be explained by differences in the credibility of control interventions: trials using sham interventions to closely mimic the process of joint lavage showed a null-effect. Reporting on adverse events and drop out rates was unsatisfactory, and we were unable to draw conclusions for these secondary outcomes. AUTHORS' CONCLUSIONS: Joint lavage does not result in a relevant benefit for patients with knee osteoarthritis in terms of pain relief or improvement of function.

S-Adenosylmethionine for osteoarthritis of the knee or hip.

BACKGROUND: Osteoarthritis is the most common form of joint disease and the leading cause of pain and disability in the elderly. S-Adenosylmethionine may be a viable treatment option but the evidence about its effectiveness and safety is equivocal. OBJECTIVES: We set out to compare S-Adenosylmethionine (SAMe) with placebo or no specific intervention in terms of effects on pain and function and safety outcomes in patients with knee or hip osteoarthritis. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, EMBASE, CINAHL and PEDro up to 5 August 2008, checked conference proceedings and reference lists, and contacted authors. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared SAMe at any dosage and in any formulation with placebo or no intervention in patients with osteoarthritis of the knee or hip. DATA COLLECTION AND ANALYSIS: Two independent authors extracted data using standardised forms. We contacted investigators to obtain missing outcome information. We calculated standardised mean differences (SMDs) for pain and function, and relative risks for safety outcomes. We combined trials using inverse-variance random-effects meta-analysis. MAIN RESULTS: Four trials including 656 patients were included in the systematic review, all compared SAMe with placebo. The methodological quality and the quality of reporting were poor. For pain, the analysis indicated a small SMD of -0.17 (95% CI -0.34 to 0.01), corresponding to a difference in pain scores between SAMe and placebo of 0.4 cm on a 10 cm VAS, with no between trial heterogeneity (I(2) = 0). For function, the analysis suggested a SMD of 0.02 (95% CI -0.68 to 0.71) with a moderate degree of between-trial heterogeneity (I2 = 54%). The meta-analyses of the number of patients experiencing any adverse event, and withdrawals or drop-outs due to adverse events, resulted in relative risks of 1.27 (95% CI 0.94 to 1.71) and 0.94 (95% CI 0.48 to 1.86), respectively, but confidence intervals were wide and tests for overall effect were not significant. No trial provided information concerning the occurrence of serious adverse events. AUTHORS' CONCLUSIONS: The current systematic review is inconclusive, hampered by the inclusion of mainly small trials of questionable quality. The effects of SAMe on both pain and function may be potentially clinically relevant and, although effects are expected to be small, deserve further clinical evaluation in adequately sized randomised, parallel-group trials in patients with knee or hip osteoarthritis. Meanwhile, routine use of SAMe should not be advised.

Oral or transdermal opioids for osteoarthritis of the knee or hip.

BACKGROUND: Osteoarthritis is the most common form of joint disease and the leading cause of pain and physical disability in the elderly. Opioids may be a viable treatment option if patients suffer from severe pain or if other analgesics are contraindicated. However, the evidence about their effectiveness and safety is contradictory. OBJECTIVES: To determine the effects on pain and function and the safety of oral or transdermal opioids as compared with placebo or no intervention in patients with osteoarthritis of the hip or knee. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, EMBASE, and CINAHL (up to 28 July 2008), checked conference proceedings, reference lists, and contacted authors. SELECTION CRITERIA: Studies were included if they were randomised or quasi-randomised controlled trials that compared oral or transdermal opioids with placebo or no treatment in patients with osteoarthritis of the knee or hip. Studies of tramadol were excluded. No language restrictions were applied. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate. Standardised mean differences (SMDs) and 95% confidence intervals (CI) were calculated for pain and function, and risk ratios for safety outcomes. Trials were combined using inverse-variance random-effects meta-analysis. MAIN RESULTS: Ten trials with 2268 participants were included. Oral codeine was studied in three trials, transdermal fentanyl and oral morphine in one trial each, oral oxycodone in four, and oral oxymorphone in two trials. Overall, opioids were more effective than control interventions in terms of pain relief (SMD -0.36, 95% CI -0.47 to -0.26) and improvement of function (SMD -0.33, 95% CI -0.45 to -0.21). We did not find substantial differences in effects according to type of opioid, analgesic potency (strong or weak), daily dose, duration of treatment or follow up, methodological quality of trials, and type of funding. Adverse events were more frequent in patients receiving opioids compared to control. The pooled risk ratio was 1.55 (95% CI 1.41 to 1.70) for any adverse event (4 trials), 4.05 (95% CI 3.06 to 5.38) for dropouts due to adverse events (10 trials), and 3.35 (95% CI 0.83 to 13.56) for serious adverse events (2 trials). Withdrawal symptoms were more severe after fentanyl treatment compared to placebo (SMD 0.60, 95% CI 0.42 to 0.79; 1 trial). AUTHORS' CONCLUSIONS: The small to moderate beneficial effects of non-tramadol opioids are outweighed by large increases in the risk of adverse events. Non-tramadol opioids should therefore not be routinely used, even if osteoarthritic pain is severe.

Doxycycline for osteoarthritis of the knee or hip.

BACKGROUND: Osteoarthritis is a chronic joint disease that involves degeneration of articular cartilage. Pre-clinical data suggest that doxycycline might act as a disease-modifying agent for the treatment of osteoarthritis, with the potential to slow cartilage degeneration. OBJECTIVES: To examine the effects of doxycycline compared with placebo or no intervention on pain and function in patients with osteoarthritis of the hip or knee. SEARCH STRATEGY: We searched CENTRAL ( The Cochrane Library 2008, issue 3), MEDLINE, EMBASE and CINAHL up to 28 July 2008, checked conference proceedings, reference lists, and contacted authors. SELECTION CRITERIA: We included studies if they were randomised or quasi-randomised controlled trials that compared doxycycline at any dosage and any formulation with placebo or no intervention in patients with osteoarthritis of the knee or hip. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate. We contacted investigators to obtain missing outcome information. We calculated differences in means at follow-up between experimental and control groups for continuous outcomes and risk ratios for binary outcomes. MAIN RESULTS: We found one randomised controlled trial that compared doxycycline with placebo in 431 obese women. After 30 months of treatment, clinical outcomes were similar between the two treatment groups, with a mean difference of -0.20 cm (95% confidence interval (CI) -0.77 to 0.37 cm) on a visual analogue scale from 0 to 10 cm for pain and -1.10 units (95% CI -3.86 to 1.66) for function on the WOMAC disability subscale, which ranges from 17 to 85. These differences correspond to clinically irrelevant effect sizes of -0.08 and -0.09 standard deviation units for pain and function, respectively. The difference in changes in minimum joint space narrowing was in favour of doxycycline (-0.15 mm, 95% CI -0.28 to -0.02 mm), which corresponds to a small effect size of -0.23 standard deviation units. More patients withdrew from the doxycycline group compared with placebo due to adverse events (risk ratio 1.69, 95% CI 1.03 to 2.75). AUTHORS' CONCLUSIONS: The symptomatic benefit of doxycycline is minimal to non-existent. The small benefit in terms of joint space narrowing is of questionable clinical relevance and outweighed by safety problems. Doxycycline should not be recommended for the treatment of osteoarthritis of the knee or hip.

Transcutaneous electrostimulation for osteoarthritis of the knee.

BACKGROUND: Osteoarthritis is the most common form of joint disease and the leading cause of pain and physical disability in the elderly. Transcutaneous electrical nerve stimulation (TENS), interferential current stimulation and pulsed electrostimulation are used widely to control both acute and chronic pain arising from several conditions, but some policy makers regard efficacy evidence as insufficient. OBJECTIVES: To compare transcutaneous electrostimulation with sham or no specific intervention in terms of effects on pain and withdrawals due to adverse events in patients with knee osteoarthritis. SEARCH STRATEGY: We updated the search in CENTRAL, MEDLINE, EMBASE, CINAHL and PEDro up to 5 August 2008, checked conference proceedings and reference lists, and contacted authors. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared transcutaneously applied electrostimulation with a sham intervention or no intervention in patients with osteoarthritis of the knee. DATA COLLECTION AND ANALYSIS: We extracted data using standardised forms and contacted investigators to obtain missing outcome information. Main outcomes were pain and withdrawals or dropouts due to adverse events. We calculated standardised mean differences (SMDs) for pain and relative risks for safety outcomes and used inverse-variance random-effects meta-analysis. The analysis of pain was based on predicted estimates from meta-regression using the standard error as explanatory variable. MAIN RESULTS: In this update we identified 14 additional trials resulting in the inclusion of 18 small trials in 813 patients. Eleven trials used TENS, four interferential current stimulation, one both TENS and interferential current stimulation, and two pulsed electrostimulation. The methodological quality and the quality of reporting was poor and a high degree of heterogeneity among the trials (I(2) = 80%) was revealed. The funnel plot for pain was asymmetrical (P < 0.001). The predicted SMD of pain intensity in trials as large as the largest trial was -0.07 (95% CI -0.46 to 0.32), corresponding to a difference in pain scores between electrostimulation and control of 0.2 cm on a 10 cm visual analogue scale. There was little evidence that SMDs differed on the type of electrostimulation (P = 0.94). The relative risk of being withdrawn or dropping out due to adverse events was 0.97 (95% CI 0.2 to 6.0). AUTHORS' CONCLUSIONS: In this update, we could not confirm that transcutaneous electrostimulation is effective for pain relief. The current systematic review is inconclusive, hampered by the inclusion of only small trials of questionable quality. Appropriately designed trials of adequate power are warranted.