A randomised controlled trial evaluating family mediated exercise (FAME) therapy following stroke

Background  

Stroke is a leading cause of disability among adults worldwide. Evidence suggests that increased duration of exercise therapy following stroke has a positive impact on functional outcome following stroke. The main objective of this randomised controlled trial is to evaluate the impact of additional family assisted exercise therapy in people with acute stroke.     

Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled,randomised controlled trials submitted to the MHRA's safety review

Objective To investigate whether selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with an increased risk of suicide related outcomes in adults.Design Meta-analysis of randomised controlled trials of SSRIs compared with placebo in adults submitted by pharmaceutical companies to the safety review of the Medicines and Healthcare products Regulatory Agency (MHRA).Participants Over 40 000 individuals participating in 477 randomised controlled trials.Main outcome measures Suicide, non-fatal self harm, and suicidal thoughts.Results An estimated 16 suicides, 172 episodes of non-fatal self harm, and 177 episodes of suicidal thoughts were reported. We found no evidence that SSRIs increased the risk of suicide, but important protective or hazardous effects cannot be excluded (odds ratio 0.85, 95% credible interval 0.20 to 3.40). We found weak evidence of an increased risk of self harm (1.57, 0.99 to 2.55). Risk estimates for suicidal thoughts were compatible with a modest protective or adverse effect (0.77, 0.37 to 1.55). The relative frequency of reported self harm and suicidal thoughts in the trials compared with suicide indicates non-fatal end points were under-recorded.Conclusion Increased risks of suicide and self harm caused by SSRIs cannot be ruled out, but larger trials with longer follow up are required to assess the balance of risks and benefits fully. Any such risks should be balanced against the effectiveness of SSRIs in treating depression. When prescribing SSRIs, clinicians should warn patients of the possible risk of suicidal behaviour and monitor patients closely in the early stages of treatment.     

Drug-induced orthostatic hypotension: A systematic review and meta-analysis of randomised controlled trials

BackgroundDrug-induced orthostatic hypotension (OH) is common, and its resulting cerebral hypoperfusion is linked to adverse outcomes including falls, strokes, cognitive impairment, and increased mortality. The extent to which specific medications are associated with OH remains unclear.Methods and findingsWe conducted a systematic review and meta-analysis to evaluate the extent to which specific drug groups are associated with OH. EMBASE, MEDLINE, and Web of Science databases were searched from inception through 23 November 2020. Placebo-controlled randomised controlled trials (RCTs) on any drug reporting on OH as an adverse effect in adults (≥18 years) were eligible. Three authors extracted data on the drug, OH, dose, participant characteristics, and study setting. The revised Cochrane risk-of-bias tool for randomised trials (RoB 2) was used to appraise evidence. Summary odds ratios (ORs) were estimated for OH using fixed effects Mantel–Haenszel statistics. We conducted subgroup analysis on validity of OH measurement, drug dose, risk of bias, age, and comorbidity. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool was used to summarise the certainty of evidence. Of 36,940 citations, 69 eligible RCTs were included in the meta-analysis comprising 27,079 participants. Compared with placebo, beta-blockers and tricyclic antidepressants were associated with increased odds of OH (OR 7.76 [95% CI 2.51, 24.03]; OR 6.30 [95% CI 2.86, 13.91]). Alpha-blockers, antipsychotics, and SGLT-2 inhibitors were associated with up to 2-fold increased odds of OH, compared to placebo. There was no statistically significant difference in odds of OH with vasodilators (CCBs, ACE inhibitors/ARBs, SSRIs), compared to placebo. Limitations of this study are as follows: data limited to placebo-controlled studies, (excluding head-to-head trials), many RCTs excluded older participants; therefore results may be amplified in older patients in the clinical setting. The study protocol is publicly available on PROSPERO (CRD42020168697).ConclusionsMedications prescribed for common conditions (including depression, diabetes, and lower urinary tract symptoms) were associated with significantly increased odds of OH. Drugs causing sympathetic inhibition were associated with significantly increased odds of OH, while most vasodilators were associated with small nonsignificant differences in odds of OH, compared to placebo. Drugs targeting multiple parts of the orthostatic blood pressure (BP) reflex pathway (e.g. sympathetic inhibition, vasodilation, cardio-inhibitory effects) may carry cumulative risk, suggesting that individuals with polypharmacy could benefit from postural BP monitoring.

Cini Bhanu and colleagues evaluate the extent to which different drug groups are associated with orthostatic hypertension in this systematic review and meta-analysis.     

Methylxanthines for exacerbations of chronic obstructive pulmonary disease: meta-analysis of randomised trials

Objective To evaluate the addition of methylxanthines to standard treatments in patients presenting with acute exacerbations of chronic obstructive pulmonary disease (COPD).Design Meta-analysis of randomised controlled trials.Data source The Cochrane airways review group''s COPD register. Two reviewers independently selected articles for inclusion, assessed methodological quality, and extracted data.Selection of studies Four trials met the inclusion criteria, with 169 patients.Main outcome measures Mean change in spirometry, clinical end points, symptom scores, and adverse events.Results Mean change in forced expiratory volume at one second at two hours was similar in methylxanthine and placebo groups but transiently increased with methylxanthines at three days. Non-significant reductions in admissions to hospital and length of stay were offset by a non-significant increase in relapses at one week. Changes in symptom scores did not reach significance. Methylxanthines caused more nausea and vomiting than placebo (odds ratio 4.6, 95% confidence interval 1.7 to 12.6), and non-significant increases in tremor, palpitations, and arrhythmias were also observed.Conclusions The available data do not support the use of methylxanthines for the treatment of exacerbations of chronic obstructive pulmonary disease. Potential benefits of methylxanthines for lung function and symptoms were generally not confirmed at standard levels of significance, whereas the potentially important adverse events of nausea and vomiting were significantly increased in patients receiving methylxanthines.     

St John's wort for depression--an overview and meta-analysis of randomised clinical trials.

OBJECTIVE--To investigate if extracts of Hypericum perforatum (St John''s wort) are more effective than placebo in the treatment of depression, are as effective as standard antidepressive treatment, and have fewer side effects than standard antidepressant drugs. DESIGN--Systematic review and meta-analysis of trials revealed by searches. TRIALS--23 randomised trials including a total of 1757 outpatients with mainly mild or moderately severe depressive disorders: 15 (14 testing single preparations and one a combination with other plant extracts) were placebo controlled, and eight (six testing single preparations and two combinations) compared hypericum with another drug treatment. MAIN OUTCOME MEASURES--A pooled estimate of the responder rate ratio (responder rate in treatment group/responder rate in control group), and numbers of patients reporting and dropping out for side effects. RESULTS--Hypericum extracts were significantly superior to placebo (ratio = 2.67; 95% confidence interval 1.78 to 4.01) and similarly effective as standard antidepressants (single preparations 1.10; 0.93 to 1.31, combinations 1.52; 0.78 to 2.94). There were two (0.8%) drop outs for side effects with hypericum and seven (3.0%) with standard antidepressant drugs. Side effects occurred in 50 (19.8%) patients on hypericum and 84 (52.8%) patients on standard antidepressants. CONCLUSION--There is evidence that extracts of hypericum are more effective than placebo for the treatment of mild to moderately severe depressive disorders. Further studies comparing extracts with standard antidepressants in well defined groups of patients and comparing different extracts and doses are needed.     

Blood pressure control by home monitoring: meta-analysis of randomised trials

Objective To determine the effect of home blood pressure monitoring on blood pressure levels and proportion of people with essential hypertension achieving targets.Design Meta-analysis of 18 randomised controlled trials.Participants 1359 people with essential hypertension allocated to home blood pressure monitoring and 1355 allocated to the “control” group seen in the healthcare system for 2-36 months.Main outcome measures Differences in systolic (13 studies), diastolic (16 studies), or mean (3 studies) blood pressures, and proportion of patients achieving targets (6 studies), between intervention and control groups.Results Systolic blood pressure was lower in people with hypertension who had home blood pressure monitoring than in those who had standard blood pressure monitoring in the healthcare system (standardised mean difference 4.2 (95% confidence interval 1.5 to 6.9) mm Hg), diastolic blood pressure was lower by 2.4 (1.2 to 3.5) mm Hg, and mean blood pressure was lower by 4.4 (2.0 to 6.8) mm Hg. The relative risk of blood pressure above predetermined targets was lower in people with home blood pressure monitoring (risk ratio 0.90, 0.80 to 1.00). When publication bias was allowed for, the differences were attenuated: 2.2 (-0.9 to 5.3) mm Hg for systolic blood pressure and 1.9 (0.6 to 3.2) mm Hg for diastolic blood pressure.Conclusions Blood pressure control in people with hypertension (assessed in the clinic) and the proportion achieving targets are increased when home blood pressure monitoring is used rather than standard blood pressure monitoring in the healthcare system. The reasons for this are not clear. The difference in blood pressure control between the two methods is small but likely to contribute to an important reduction in vascular complications in the hypertensive population.     

Zinc and glycemic control: A meta-analysis of randomised placebo controlled supplementation trials in humans

BackgroundImpaired zinc metabolism is prominent in chronic disorders including cardiovascular disease and diabetes. Zinc has the potential to affect glucose homeostasis in animals and humans and hence impact the risk of type 2 diabetes mellitus.MethodsA systematic review and meta-analysis of randomised placebo controlled trials was conducted to determine the effect of zinc supplementation on fasting blood glucose, HbA1c, serum insulin and serum zinc concentrations. Relevant studies for inclusion were identified from a literature search of electronic databases up to July 2011.ResultsFourteen reports (n = 3978 subjects) were included in the meta-analysis. In the overall analysis, a small but statistically significant reduction in fasting glucose concentrations was observed (?0.19 ± 0.08 mmol/L, P = 0.013) after zinc supplementation. HbA1c tended to decrease in zinc-supplemented individuals (?0.64 ± 0.36%, P = 0.072). No significant effect was observed for serum insulin concentrations. Plasma zinc concentrations increased significantly following supplementation (+4.03 ± 0.81 μmol/L, P = 0.001). In secondary analyses of participants with chronic metabolic disease (types 1 and 2 diabetes mellitus, metabolic syndrome and obesity), zinc supplementation produced a greater reduction in glucose concentrations (?0.49 ± 0.11 mmol/L, P = 0.001) compared to the effect that was observed in healthy participants.ConclusionThe significant albeit modest reduction in glucose concentrations and tendency for a decrease in HbA1c following zinc supplementation suggest that zinc may contribute to the management of hyperglycemia in individuals with chronic metabolic disease.     

Methods of hysterectomy: systematic review and meta-analysis of randomised controlled trials

Objective To evaluate the most appropriate surgical method of hysterectomy (abdominal, vaginal, or laparoscopic) for women with benign disease.Design Systematic review and meta-analysis.Data sources Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials, Medline, Embase, and Biological Abstracts.Selection of studies Only randomised controlled trials were selected; participants had to have benign gynaecological disease; interventions had to comprise at least one hysterectomy method compared with another; and trials had to report primary outcomes (time taken to return to normal activities, intraoperative visceral injury, and major long term complications) or secondary outcomes (operating time, other immediate complications of surgery, short term complications, and duration of hospital stay).Results 27 trials (total of 3643 participants) were included. Return to normal activities was quicker after vaginal than after abdominal hysterectomy (weighted mean difference 9.5 (95% confidence interval 6.4 to 12.6) days) and after laparoscopic than after abdominal hysterectomy (difference 13.6 (11.8 to 15.4) days), but was not significantly different for laparoscopic versus vaginal hysterectomy (difference -1.1 (-4.2 to 2.1) days). There were more urinary tract injuries with laparoscopic than with abdominal hysterectomy (odds ratio 2.61 (95% confidence interval 1.22 to 5.60)), but no other intraoperative visceral injuries showed a significant difference between surgical approaches. Data were notably absent for many important long term patient outcome measures, where the analyses were underpowered to detect important differences, or they were simply not reported in trials.Conclusions Significantly speedier return to normal activities and other improved secondary outcomes (shorter duration of hospital stay and fewer unspecified infections or febrile episodes) suggest that vaginal hysterectomy is preferable to abdominal hysterectomy where possible. Where vaginal hysterectomy is not possible, laparoscopic hysterectomy is preferable to abdominal hysterectomy, although it brings a higher chance of bladder or ureter injury.     

Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy

Background

Statin therapy reduces the risk of occlusive vascular events, but uncertainty remains about potential effects on cancer. We sought to provide a detailed assessment of any effects on cancer of lowering LDL cholesterol (LDL-C) with a statin using individual patient records from 175,000 patients in 27 large-scale statin trials.

Methods and Findings

Individual records of 134,537 participants in 22 randomised trials of statin versus control (median duration 4.8 years) and 39,612 participants in 5 trials of more intensive versus less intensive statin therapy (median duration 5.1 years) were obtained. Reducing LDL-C with a statin for about 5 years had no effect on newly diagnosed cancer or on death from such cancers in either the trials of statin versus control (cancer incidence: 3755 [1.4% per year [py]] versus 3738 [1.4% py], RR 1.00 [95% CI 0.96-1.05]; cancer mortality: 1365 [0.5% py] versus 1358 [0.5% py], RR 1.00 [95% CI 0.93–1.08]) or in the trials of more versus less statin (cancer incidence: 1466 [1.6% py] vs 1472 [1.6% py], RR 1.00 [95% CI 0.93–1.07]; cancer mortality: 447 [0.5% py] versus 481 [0.5% py], RR 0.93 [95% CI 0.82–1.06]). Moreover, there was no evidence of any effect of reducing LDL-C with statin therapy on cancer incidence or mortality at any of 23 individual categories of sites, with increasing years of treatment, for any individual statin, or in any given subgroup. In particular, among individuals with low baseline LDL-C (<2 mmol/L), there was no evidence that further LDL-C reduction (from about 1.7 to 1.3 mmol/L) increased cancer risk (381 [1.6% py] versus 408 [1.7% py]; RR 0.92 [99% CI 0.76–1.10]).

Conclusions

In 27 randomised trials, a median of five years of statin therapy had no effect on the incidence of, or mortality from, any type of cancer (or the aggregate of all cancer).     

Parenteral dexamethasone for acute severe migraine headache: meta-analysis of randomised controlled trials for preventing recurrence

Objective To examine the effectiveness of parenteral corticosteroids for the relief of acute severe migraine headache and prevention of recurrent headaches.Design Meta-analysis.Data sources Electronic databases (Cochrane Central Register of Controlled Trials, Medline, Embase, LILACS, and CINAHL), conference proceedings, clinical practice guidelines, contacts with industry, and correspondence with authors.Selection criteria Randomised controlled trials in which corticosteroids (alone or combined with standard abortive therapy) were compared with placebo or any other standard treatment for acute migraine in adults.Review methods Two reviewers independently assessed relevance, inclusion, and study quality. Weighted mean differences and relative risks were calculated and are reported with 95% confidence intervals.Results From 666 potentially relevant abstracts, seven studies met the inclusion criteria. All included trials used standard abortive therapy and subsequently compared single dose parenteral dexamethasone with placebo, examining pain relief and recurrence of headache within 72 hours. Dexamethasone and placebo provided similar acute pain reduction (weighted mean difference 0.37, 95% confidence interval −0.20 to 0.94). Dexamethasone was, however, more effective than placebo in reducing recurrence rates (relative risk 0.74, 95% confidence interval 0.60 to 0.90). Side effect profiles between dexamethasone and placebo groups were similar.Conclusion When added to standard abortive therapy for migraine headache, single dose parenteral dexamethasone is associated with a 26% relative reduction in headache recurrence (number needed to treat=9) within 72 hours.     

Modelling multivariate outcomes in hierarchical data, with application to cluster randomised trials

In the cluster randomised study design, the data collected have a hierarchical structure and often include multivariate outcomes. We present a flexible modelling strategy that permits several normally distributed outcomes to be analysed simultaneously, in which intervention effects as well as individual-level and cluster-level between-outcome correlations are estimated. This is implemented in a Bayesian framework which has several advantages over a classical approach, for example in providing credible intervals for functions of model parameters and in allowing informative priors for the intracluster correlation coefficients. In order to declare such informative prior distributions, and fit models in which the between-outcome covariance matrices are constrained, priors on parameters within the covariance matrices are required. Careful specification is necessary however, in order to maintain non-negative definiteness and symmetry between the different outcomes. We propose a novel solution in the case of three multivariate outcomes, and present a modified existing approach and novel alternative for four or more outcomes. The methods are applied to an example of a cluster randomised trial in the prevention of coronary heart disease. The modelling strategy presented would also be useful in other situations involving hierarchical multivariate outcomes.     

Complex adaptive landscapes (CAL): A conceptual framework of multi-functional,non-linear ecohydrological feedback systems

Landscape ecology and complex adaptive systems (CAS) research provide numerous examples of systems with complex non-linear feedbacks, but our understanding of these systems is severely limited by a lack of conceptual frameworks built on these foundations. Here, we develop a conceptual framework by combining CAS organisation with landscape structure, functioning and change. The resulting framework, ‘complex adaptive landscapes’ (CAL), explicitly captures the reciprocal feedbacks and non-linear nature of interactions between components within and between system levels, and the consequent possibility of multiple functional states (alternate systems functioning). The CAL framework highlights six core tenets that describe landscape complexity and dynamics. CAL provides examples of how the complex ecohydrological interactions at finer-scale hillslope levels manifest changes to broader landscape levels, as well as multi-temporal feedbacks and change (days to decades). Understanding the specific feedback and non-linear responses of different components of the landscape, such as plant functional types, are of paramount importance for adequately designing monitoring and analytical frameworks for adaptive natural resource management. The CAL framework allows us to better understand the scale of ecohydrological functions within the landscape, and how substituted component types and their spatial and temporal configuration may cause dysfunctional states to arise as a result of human land use.     

Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials

Objective: To determine the size of reduction in homocysteine concentrations produced by dietary supplementation with folic acid and with vitamins B-12 or B-6. Design: Meta-analysis of randomised controlled trials that assessed the effects of folic acid based supplements on blood homocysteine concentrations. Multivariate regression analysis was used to determine the effects on homocysteine concentrations of different doses of folic acid and of the addition of vitamin B-12 or B-6. Subjects: Individual data on 1114 people included in 12 trials. Findings: The proportional and absolute reductions in blood homocysteine produced by folic acid supplements were greater at higher pretreatment blood homocysteine concentrations (P<0.001) and at lower pretreatment blood folate concentrations (P<0.001). After standardisation to pretreatment blood concentrations of homocysteine of 12 μmol/l and of folate of 12 nmol/l (approximate average concentrations for Western populations), dietary folic acid reduced blood homocysteine concentrations by 25% (95% confidence interval 23% to 28%; P<0.001), with similar effects in the range of 0.5-5 mg folic acid daily. Vitamin B-12 (mean 0.5 mg daily) produced an additional 7% (3% to 10%) reduction in blood homocysteine. Vitamin B-6 (mean 16.5 mg daily) did not have a significant additional effect. Conclusions: Typically in Western populations, daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B-12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 μmol/l to 8-9 μmol/l). Large scale randomised trials of such regimens in high risk populations are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease.

Key messages

• Higher blood homocysteine concentrations seem to be associated with higher risks of occlusive vascular disease and with lower blood concentrations of folate and vitamins B-12 and B-6
• Proportional and absolute reductions in blood homocysteine concentrations with folic acid supplements are greater at higher pretreatment blood homocysteine concentrations and at lower pretreatment blood folate concentrations
• In typical Western populations, supplementation with both 0.5-5 mg daily folic acid and about 0.5 mg daily vitamin B-12 should reduce blood homocysteine concentrations by about a quarter to a third
• Large scale randomised trials of such regimens in people at high risk are now needed to determine whether lowering blood homocysteine concentrations reduces the risk of vascular disease

     

A statistical framework for differential network analysis from microarray data

Background  

It has been long well known that genes do not act alone; rather groups of genes act in consort during a biological process. Consequently, the expression levels of genes are dependent on each other. Experimental techniques to detect such interacting pairs of genes have been in place for quite some time. With the advent of microarray technology, newer computational techniques to detect such interaction or association between gene expressions are being proposed which lead to an association network. While most microarray analyses look for genes that are differentially expressed, it is of potentially greater significance to identify how entire association network structures change between two or more biological settings, say normal versus diseased cell types.     

Induction of labour at 41 weeks or expectant management until 42 weeks: A systematic review and an individual participant data meta-analysis of randomised trials

BackgroundThe risk of perinatal death and severe neonatal morbidity increases gradually after 41 weeks of pregnancy. Several randomised controlled trials (RCTs) have assessed if induction of labour (IOL) in uncomplicated pregnancies at 41 weeks will improve perinatal outcomes. We performed an individual participant data meta-analysis (IPD-MA) on this subject.Methods and findingsWe searched PubMed, Excerpta Medica dataBASE (Embase), The Cochrane Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and PsycINFO on February 21, 2020 for RCTs comparing IOL at 41 weeks with expectant management until 42 weeks in women with uncomplicated pregnancies. Individual participant data (IPD) were sought from eligible RCTs. Primary outcome was a composite of severe adverse perinatal outcomes: mortality and severe neonatal morbidity. Additional outcomes included neonatal admission, mode of delivery, perineal lacerations, and postpartum haemorrhage. Prespecified subgroup analyses were conducted for parity (nulliparous/multiparous), maternal age (<35/≥35 years), and body mass index (BMI) (<30/≥30). Aggregate data meta-analysis (MA) was performed to include data from RCTs for which IPD was not available.From 89 full-text articles, we identified three eligible RCTs (n = 5,161), and two contributed with IPD (n = 4,561). Baseline characteristics were similar between the groups regarding age, parity, BMI, and higher level of education. IOL resulted overall in a decrease of severe adverse perinatal outcome (0.4% [10/2,281] versus 1.0% [23/2,280]; relative risk [RR] 0.43 [95% confidence interval [CI] 0.21 to 0.91], p-value 0.027, risk difference [RD] −57/10,000 [95% CI −106/10,000 to −8/10,000], I² 0%). The number needed to treat (NNT) was 175 (95% CI 94 to 1,267).Perinatal deaths occurred in one (<0.1%) versus eight (0.4%) pregnancies (Peto odds ratio [OR] 0.21 [95% CI 0.06 to 0.78], p-value 0.019, RD −31/10,000, [95% CI −56/10,000 to −5/10,000], I² 0%, NNT 326, [95% CI 177 to 2,014]) and admission to a neonatal care unit ≥4 days occurred in 1.1% (24/2,280) versus 1.9% (46/2,273), (RR 0.52 [95% CI 0.32 to 0.85], p-value 0.009, RD −97/10,000 [95% CI −169/10,000 to −26/10,000], I² 0%, NNT 103 [95% CI 59 to 385]). There was no difference in the rate of cesarean delivery (10.5% versus 10.7%; RR 0.98, [95% CI 0.83 to 1.16], p-value 0.81) nor in other important perinatal, delivery, and maternal outcomes. MA on aggregate data showed similar results.Prespecified subgroup analyses for the primary outcome showed a significant difference in the treatment effect (p = 0.01 for interaction) for parity, but not for maternal age or BMI. The risk of severe adverse perinatal outcome was decreased for nulliparous women in the IOL group (0.3% [4/1,219] versus 1.6% [20/1,264]; RR 0.20 [95% CI 0.07 to 0.60], p-value 0.004, RD −127/10,000, [95% CI −204/10,000 to −50/10,000], I² 0%, NNT 79 [95% CI 49 to 201]) but not for multiparous women (0.6% [6/1,219] versus 0.3% [3/1,264]; RR 1.59 [95% CI 0.15 to 17.30], p-value 0.35, RD 27/10,000, [95% CI −29/10,000 to 84/10,000], I² 55%).A limitation of this IPD-MA was the risk of overestimation of the effect on perinatal mortality due to early stopping of the largest included trial for safety reasons after the advice of the Data and Safety Monitoring Board. Furthermore, only two RCTs were eligible for the IPD-MA; thus, the possibility to assess severe adverse neonatal outcomes with few events was limited.ConclusionsIn this study, we found that, overall, IOL at 41 weeks improved perinatal outcome compared with expectant management until 42 weeks without increasing the cesarean delivery rate. This benefit is shown only in nulliparous women, whereas for multiparous women, the incidence of mortality and morbidity was too low to demonstrate any effect. The magnitude of risk reduction of perinatal mortality remains uncertain. Women with pregnancies approaching 41 weeks should be informed on the risk differences according to parity so that they are able to make an informed choice for IOL at 41 weeks or expectant management until 42 weeks.Study Registration: PROSPERO CRD42020163174

Mårten Alkmark and co-workers report on a meta-analysis of randomized trials of labour induction at 41 weeks'' gestation as compared with expectant management until 42 weeks.     

Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients

ObjectiveTo determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events.DesignCollaborative meta-analyses (systematic overviews).ResultsOverall, among these high risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P<0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000.ConclusionsAspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed.

What is already known on this topic

Antiplatelet therapy is effective for short term treatment of patients with suspected acute myocardial infarction and unstable anginaLong term treatment is beneficial for patients who have had a myocardial infarction, stroke, or transient ischaemic attackDaily aspirin doses of 75-325 mg are effective

What this study adds

Antiplatelet therapy protects against vascular events among patients with stable angina, intermittent claudication, and (if oral anticoagulants are unsuitable) atrial fibrillationAntiplatelet therapy can be started promptly during acute presumed ischaemic stroke and continued long termDaily aspirin doses of 75-150 mg seem to be as effective as higher doses for long term treatments (and clopidrogel is an appropriate alternative for patients with a contraindication to aspirin)Short term addition of a glycoprotein IIb/IIIa antagonist to aspirin prevents vascular events in patients having percutaneous coronary intervention and those with unstable angina but causes increased bleeding