Explore the vast range of titles available.

In this trial involving patients with intracerebral hemorrhage, intensive BP lowering (target systolic BP <140 mm Hg) did not significantly reduce the rate of the primary outcome of death or major disability but did significantly improve overall functional outcomes. Acute intracerebral hemorrhage, which is the least treatable form of stroke, affects more than 1 million people worldwide annually, 1 , 2 with the outcome determined by the volume and growth of the underlying hematoma. 3 – 5 Blood pressure often becomes elevated after intracerebral hemorrhage, 6 frequently reaching very high levels, and is a predictor of outcome. 7 – 11 On the basis of the results of the pilot-phase study, Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 1 (INTERACT1), 12 – 14 we conducted the main-phase study, INTERACT2, 15 to determine the safety and effectiveness of early intensive lowering of blood pressure in patients with intracerebral hemorrhage. . . .

Aims/hypothesisFew studies examine the association between age at diagnosis and subsequent complications from type 2 diabetes. This paper aims to summarise the risk of mortality, macrovascular complications and microvascular complications associated with age at diagnosis of type 2 diabetes.MethodsData were sourced from MEDLINE and All EBM (Evidence Based Medicine) databases from inception to July 2018. Observational studies, investigating the effect of age at diabetes diagnosis on macrovascular and microvascular diabetes complications in adults with type 2 diabetes were selected according to pre-specified criteria. Two investigators independently extracted data and evaluated all studies. If data were not reported in a comparable format, data were obtained from authors, presented as minimally adjusted ORs (and 95% CIs) per 1 year increase in age at diabetes diagnosis, adjusted for current age for each outcome of interest. The study protocol was recorded with PROSPERO International Prospective Register of Systematic Reviews (CRD42016043593).ResultsData from 26 observational studies comprising 1,325,493 individuals from 30 countries were included. Random-effects meta-analyses with inverse variance weighting were used to obtain the pooled ORs. Age at diabetes diagnosis was inversely associated with risk of all-cause mortality and macrovascular and microvascular disease (all p < 0.001). Each 1 year increase in age at diabetes diagnosis was associated with a 4%, 3% and 5% decreased risk of all-cause mortality, macrovascular disease and microvascular disease, respectively, adjusted for current age. The effects were consistent for the individual components of the composite outcomes (all p < 0.001).Conclusions/interpretationYounger, rather than older, age at diabetes diagnosis was associated with higher risk of mortality and vascular disease. Early and sustained interventions to delay type 2 diabetes onset and improve blood glucose levels and cardiovascular risk profiles of those already diagnosed are essential to reduce morbidity and mortality.

Background Most clinical trials with time-to-event primary outcomes are designed assuming constant event rates and proportional hazards over time. Non-constant event rates and non-proportional hazards are seen increasingly frequently in trials. The objectives of this review were firstly to identify whether non-constant event rates and time-dependent treatment effects were allowed for in sample size calculations of trials, and secondly to assess the methods used for the analysis and reporting of time-to-event outcomes including how researchers accounted for non-proportional treatment effects. Methods We reviewed all original reports published between January and June 2017 in four high impact medical journals for trials for which the primary outcome involved time-to-event analysis. We recorded the methods used to analyse and present the main outcomes of the trial and assessed the reporting of assumptions underlying these methods. The sample size calculation was reviewed to see if the effect of either non-constant hazard rates or anticipated non-proportionality of the treatment effect was allowed for during the trial design. Results From 446 original reports we identified 66 trials with a time-to-event primary outcome encompassing trial start dates from July 1995 to November 2014. The majority of these trials (73%) had sample size calculations that used standard formulae with a minority of trials (11%) using simulation for anticipated changing event rates and/or non-proportional hazards. Well-established analytical methods, Kaplan-Meier curves (98%), the log rank test (88%) and the Cox proportional hazards model (97%), were used almost exclusively for the main outcome. Parametric regression models were considered in 11% of the reports. Of the trials reporting inference from the Cox model, only 11% reported any results of testing the assumption of proportional hazards. Conclusions Our review confirmed that when designing trials with time-to-event primary outcomes, methodologies assuming constant event rates and proportional hazards were predominantly used despite potential efficiencies in sample size needed or power achieved using alternative methods. The Cox proportional hazards model was used almost exclusively to present inferential results, yet testing and reporting of the pivotal assumption underpinning this estimation method was lacking.

Cardiovascular diseases (CVD) are rising in India resulting in major health system challenges. Eighteen primary health centre (PHC) clusters in rural Andhra Pradesh were randomised over three, 6-month steps to an intervention comprising: (1) household CVD risk assessments by village-based community health workers (CHWs) using a mobile tablet device; (2) electronic referral and clinical decision support for PHC doctors; and (3) a tracking system for follow-up care. Independent data collectors screened people aged ≥ 40 years in 54 villages serviced by the PHCs to create a high CVD risk cohort (based on WHO risk charts and blood pressure thresholds). Randomly selected, independent samples, comprising 15% of this cohort, were reviewed at each 6-month step. The primary outcome was the proportion meeting systolic blood pressure (SBP) targets (<140mmHg). Eight-four percent of the eligible population (n = 62,254) were assessed at baseline (18.4% at high CVD risk). Of those at high risk, 75.3% were followed up over two years. CHWs screened 85.9% of the baseline cohort and doctors followed up 70.0% of all high risk referrals. There was no difference in the proportion of people achieving SBP targets (41.2% vs 39.2%; adjusted odds ratio (OR) 1.01 95% CI 0.76-1.35) or receiving BP-lowering medications in the intervention vs control periods respectively. There was a high discordance in risk scores generated by independent data collectors and CHWs, resulting in only 37.2% of the evaluation cohort exposed to the intervention. This discordance was mainly driven by fluctuating BP values (both normal variability and marked seasonal variations). In the pre-specified high risk concordant subgroup, there was greater use of BP-lowering medications in the intervention period (54.3% vs 47.9%, OR 1.22, 95% CI 1.03-1.44) but no impact on BP control. The strategy was well implemented with increased treatment rates among high risk individuals assessed by CHWs, however effects on BP were not demonstrated. Use of guideline-recommended BP thresholds for identifying high risk individuals substantially affected the reproducibility of risk assessment, and thus the ability to reliably evaluate the effectiveness of the intervention. In addition, unanticipated seasonal variation in BP in the context of a stepped-wedge trial highlights the inherent risks of this study design. Clinical Trials Registry of India CTRI/2013/06/ 003753.

Background Non-proportional hazards are common with time-to-event data but the majority of randomised clinical trials (RCTs) are designed and analysed using approaches which assume the treatment effect follows proportional hazards (PH). Recent advances in oncology treatments have identified two forms of non-PH of particular importance - a time lag until treatment becomes effective, and an early effect of treatment that ceases after a period of time. In sample size calculations for treatment effects on time-to-event outcomes where information is based on the number of events rather than the number of participants, there is crucial importance in correct specification of the baseline hazard rate amongst other considerations. Under PH, the shape of the baseline hazard has no effect on the resultant power and magnitude of treatment effects using standard analytical approaches. However, in a non-PH context the appropriateness of analytical approaches can depend on the shape of the underlying hazard. Methods A simulation study was undertaken to assess the impact of clinically plausible non-constant baseline hazard rates on the power, magnitude and coverage of commonly utilized regression-based measures of treatment effect and tests of survival curve difference for these two forms of non-PH used in RCTs with time-to-event outcomes. Results In the presence of even mild departures from PH, the power, average treatment effect size and coverage were adversely affected. Depending on the nature of the non-proportionality, non-constant event rates could further exacerbate or somewhat ameliorate the losses in power, treatment effect magnitude and coverage observed. No single summary measure of treatment effect was able to adequately describe the full extent of a potentially time-limited treatment benefit whilst maintaining power at nominal levels. Conclusions Our results show the increased importance of considering plausible potentially non-constant event rates when non-proportionality of treatment effects could be anticipated. In planning clinical trials with the potential for non-PH, even modest departures from an assumed constant baseline hazard could appreciably impact the power to detect treatment effects depending on the nature of the non-PH. Comprehensive analysis plans may be required to accommodate the description of time-dependent treatment effects.

There is much uncertainty about the effects of early lowering of elevated blood pressure (BP) after acute intracerebral haemorrhage (ICH). Our aim was to assess the safety and efficiency of this treatment, as a run-in phase to a larger trial. Patients who had acute spontaneous ICH diagnosed by CT within 6 h of onset, elevated systolic BP (150–220 mm Hg), and no definite indication or contraindication to treatment were randomly assigned to early intensive lowering of BP (target systolic BP 140 mm Hg; n=203) or standard guideline-based management of BP (target systolic BP 180 mm Hg; n=201). The primary efficacy endpoint was proportional change in haematoma volume at 24 h; secondary efficacy outcomes included other measurements of haematoma volume. Safety and clinical outcomes were assessed for up to 90 days. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00226096. Baseline characteristics of patients were similar between groups, but mean haematoma volumes were smaller in the guideline group (12·7 mL, SD 11·6) than in the intensive group (14·2 mL, SD 14·5). From randomisation to 1 h, mean systolic BP was 153 mm Hg in the intensive group and 167 mm Hg in the guideline group (difference 13·3 mm Hg, 95% CI 8·9–17·6 mm Hg; p<0·0001); from 1 h to 24 h, BP was 146 mm Hg in the intensive group and 157 mm Hg in the guideline group (10·8 mm Hg, 95% CI 7·7–13·9 mm Hg; p<0·0001). Mean proportional haematoma growth was 36·3% in the guideline group and 13·7% in the intensive group (difference 22·6%, 95% CI 0·6–44·5%; p=0·04) at 24 h. After adjustment for initial haematoma volume and time from onset to CT, median haematoma growth differed between the groups with p=0·06; the absolute difference in volume between groups was 1·7 mL (95% CI −0·5 to 3·9, p=0·13). Relative risk of haematoma growth ≥33% or ≥12·5 mL was 36% lower (95% CI 0–59%, p=0·05) in the intensive group than in the guideline group. The absolute risk reduction was 8% (95% CI −1·0 to 17%, p=0·05). Intensive BP-lowering treatment did not alter the risks of adverse events or secondary clinical outcomes at 90 days. Early intensive BP-lowering treatment is clinically feasible, well tolerated, and seems to reduce haematoma growth in ICH. A large randomised trial is needed to define the effects on clinical outcomes across a broad range of patients with ICH. National Health and Medical Research Council of Australia.

Background Stepped wedge trials are an appealing and potentially powerful cluster randomized trial design. However, they are frequently implemented with a small number of clusters. Standard analysis methods for these trials such as a linear mixed model with estimation via maximum likelihood or restricted maximum likelihood (REML) rely on asymptotic properties and have been shown to yield inflated type I error when applied to studies with a small number of clusters. Small-sample methods such as the Kenward-Roger approximation in combination with REML can potentially improve estimation of the fixed effects such as the treatment effect. A Bayesian approach may also be promising for such multilevel models but has not yet seen much application in cluster randomized trials. Methods We conducted a simulation study comparing the performance of REML with and without a Kenward-Roger approximation to a Bayesian approach using weakly informative prior distributions on the intracluster correlation parameters. We considered a continuous outcome and a range of stepped wedge trial configurations with between 4 and 40 clusters. To assess method performance we calculated bias and mean squared error for the treatment effect and correlation parameters and the coverage of 95% confidence/credible intervals and relative percent error in model-based standard error for the treatment effect. Results Both REML with a Kenward-Roger standard error and degrees of freedom correction and the Bayesian method performed similarly well for the estimation of the treatment effect, while intracluster correlation parameter estimates obtained via the Bayesian method were less variable than REML estimates with different relative levels of bias. Conclusions The use of REML with a Kenward-Roger approximation may be sufficient for the analysis of stepped wedge cluster randomized trials with a small number of clusters. However, a Bayesian approach with weakly informative prior distributions on the intracluster correlation parameters offers a viable alternative, particularly when there is interest in the probability-based inferences permitted within this paradigm.

Digitally enabled rehabilitation may lead to better outcomes but has not been tested in large pragmatic trials. We aimed to evaluate a tailored prescription of affordable digital devices in addition to usual care for people with mobility limitations admitted to aged care and neurological rehabilitation. We conducted a pragmatic, outcome-assessor-blinded, parallel-group randomised trial in 3 Australian hospitals in Sydney and Adelaide recruiting adults 18 to 101 years old with mobility limitations undertaking aged care and neurological inpatient rehabilitation. Both the intervention and control groups received usual multidisciplinary inpatient and post-hospital rehabilitation care as determined by the treating rehabilitation clinicians. In addition to usual care, the intervention group used devices to target mobility and physical activity problems, individually prescribed by a physiotherapist according to an intervention protocol, including virtual reality video games, activity monitors, and handheld computer devices for 6 months in hospital and at home. Co-primary outcomes were mobility (performance-based Short Physical Performance Battery [SPPB]; continuous version; range 0 to 3; higher score indicates better mobility) and upright time as a proxy measure of physical activity (proportion of the day upright measured with activPAL) at 6 months. The dataset was analysed using intention-to-treat principles. The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000936628). Between 22 September 2014 and 10 November 2016, 300 patients (mean age 74 years, SD 14; 50% female; 54% neurological condition causing activity limitation) were randomly assigned to intervention (n = 149) or control (n = 151) using a secure online database (REDCap) to achieve allocation concealment. Six-month assessments were completed by 258 participants (129 intervention, 129 control). Intervention participants received on average 12 (SD 11) supervised inpatient sessions using 4 (SD 1) different devices and 15 (SD 5) physiotherapy contacts supporting device use after hospital discharge. Changes in mobility scores were higher in the intervention group compared to the control group from baseline (SPPB [continuous, 0-3] mean [SD]: intervention group, 1.5 [0.7]; control group, 1.5 [0.8]) to 6 months (SPPB [continuous, 0-3] mean [SD]: intervention group, 2.3 [0.6]; control group, 2.1 [0.8]; mean between-group difference 0.2 points, 95% CI 0.1 to 0.3; p = 0.006). However, there was no evidence of a difference between groups for upright time at 6 months (mean [SD] proportion of the day spent upright at 6 months: intervention group, 18.2 [9.8]; control group, 18.4 [10.2]; mean between-group difference -0.2, 95% CI -2.7 to 2.3; p = 0.87). Scores were higher in the intervention group compared to the control group across most secondary mobility outcomes, but there was no evidence of a difference between groups for most other secondary outcomes including self-reported balance confidence and quality of life. No adverse events were reported in the intervention group. Thirteen participants died while in the trial (intervention group: 9; control group: 4) due to unrelated causes, and there was no evidence of a difference between groups in fall rates (unadjusted incidence rate ratio 1.19, 95% CI 0.78 to 1.83; p = 0.43). Study limitations include 15%-19% loss to follow-up at 6 months on the co-primary outcomes, as anticipated; the number of secondary outcome measures in our trial, which may increase the risk of a type I error; and potential low statistical power to demonstrate significant between-group differences on important secondary patient-reported outcomes. In this study, we observed improved mobility in people with a wide range of health conditions making use of digitally enabled rehabilitation, whereas time spent upright was not impacted. The trial was prospectively registered with the Australian New Zealand Clinical Trials Register; ACTRN12614000936628.

Background: Patients with acute ischemic stroke (AIS) have impaired vasomotor reactivity, especially in the affected cerebral hemisphere, such that they may depend directly on systemic blood pressure to maintain perfusion to vulnerable ‘at risk' penumbral tissue. As the sitting up position may affect cerebral perfusion by decreasing cerebral blood flow (CBF) in salvageable tissue, positioning AIS patients with their head in a lying flat position could increase CBF through collateral circulation or gravitational force. We wished to quantify the effect of different head positions on mean flow velocity (MFV) by transcranial Doppler ultrasonography (TCD) in AIS patients to assess the potential for benefit (or harm) of head positioning in a clinical trial. Methods: We performed a systematic review and meta-analysis of observational studies with TCD to evaluate differences in cerebral MFV between the lying flat and sitting up head positions in AIS. For each study and each comparison, we obtained the mean value of changes in MFV and its variance. Results: A total of 303 studies were identified, but 298 were excluded for varying reasons; 4 papers met the inclusion criteria and 57 patients were included in the meta-analysis for calculation of the overall mean difference in MFV. We found a significant increase in MFV from a bed angle of 30 to 15° (4.6 cm/s, 95% confidence interval, CI, 2.9-6.2, p < 0.001) and from 30 to 0° (8.3 cm/s, 95% CI 5.3-11.3, p < 0.001) in the affected hemisphere but not on the normal side in AIS patients. Conclusions: In AIS patients, MFV increased significantly in the side affected by the stroke but not in the unaffected side when they were positioned in a lying flat head position at 0 or 15° compared to an upright head position at 30°. The clinical significance of these findings is now undergoing further randomized evaluation in the international multicenter Head Position in Acute Stroke Trial (HeadPoST).

IntroductionOver half of the populations with knee osteoarthritis (OA) have obesity. These individuals have many other shared metabolic risk factors. Metformin is a safe, inexpensive, well-tolerated drug that has pleiotropic effects, including structural protection, anti-inflammatory and analgesic effects in OA, specifically the knee. The aim of this randomised, double-blind, placebo-controlled trial is to determine whether metformin reduces knee pain over 6 months in individuals with symptomatic knee OA who are overweight or obese.Methods and analysisOne hundred and two participants with symptomatic knee OA and overweight or obesity will be recruited from the community in Melbourne, Australia, and randomly allocated in a 1:1 ratio to receive either metformin 2 g or identical placebo daily for 6 months. The primary outcome is reduction of knee pain [assessed by 100 mm Visual Analogue Scale (VAS)] at 6 months. The secondary outcomes are OMERACT-OARSI (Outcome Measures in Rheumatology-Osteoarthritis Research Society International) responder criteria [Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function and participant’s global assessment (VAS)] at 6 months; change in knee pain, stiffness, function using WOMAC at 6 months and quality of life at 6 months. Adverse events will be recorded. The primary analysis will be by intention to treat, including all participants in their randomised groups.Ethics and disseminationEthics approval has been obtained from the Alfred Hospital Ethics Committee (708/20) and Monash University Human Research Ethics Committee (28498). Written informed consent will be obtained from all the participants. The findings will be disseminated through peer-review publications and conference presentations.Trial registration numberACTRN12621000710820 .