Lower-Risk Cannabis Use Guidelines (LRCUG) for reducing health harms from non-medical cannabis use: A comprehensive evidence and recommendations update.

Lower-Risk Cannabis Use Guidelines (LRCUG) for reducing health harms from non-medical cannabis use: A comprehensive evidence and recommendations update

Objective There is a lack of robust data on significant gastrointestinal bleeding in older people using aspirin. We calculated the incidence, risk factors and absolute risk using data from a large randomised, controlled trial. Design Data were extracted from an aspirin versus placebo primary prevention trial conducted throughout 2010–2017 (‘ASPirin in Reducing Events in the Elderly (ASPREE)’, n=19 114) in community-dwelling persons aged ≥70 years. Clinical characteristics were collected at baseline and annually. The endpoint was major GI bleeding that resulted in transfusion, hospitalisation, surgery or death, adjudicated independently by two physicians blinded to trial arm. Results Over a median follow-up of 4.7 years (88 389 person years), there were 137 upper GI bleeds (89 in aspirin arm and 48 in placebo arm, HR 1.87, 95% CI 1.32 to 2.66, p Conclusion Aspirin increases overall GI bleeding risk by 60%; however, the 5-year absolute risk of serious bleeding is modest in younger, well individuals. These data may assist patients and their clinicians to make informed decisions about prophylactic use of aspirin. Trial registration number ASPREE. NCT01038583.

https://gut.bmj.com/content/gutjnl/70/4/717.full.pdf

Major GI bleeding in older persons using aspirin: incidence and risk factors in the ASPREE randomised controlled trial

In this review, state-of-the-art evidence on the relationship between cannabis use, traffic crash risks, and driving safety were analyzed. Systematic reviews, meta-analyses, and other relevant papers published within the last decade were systematically searched and synthesized. Findings show that meta-analyses and culpability studies consistently indicate a slightly but significantly increased risk of crashes after acute cannabis use. These risks vary across included study type, crash severity, and method of substance application and measurement. Some studies show a significant correlation between high THC blood concentrations and car crash risk. Most studies do not support this relationship at lower THC concentrations. However, no scientifically supported clear cut-off concentration can be derived from these results. Further research is needed to determine dose-response effects on driving skills combined with measures of neuropsychological functioning related to driving skills and crash risk.

/pdf/cannabis-use-and-car-crashes-a-review-2p662asigh.pdf

Cannabis Use and Car Crashes: A Review

Serious motor vehicle collisions involving young drivers on Norwegian roads 2013-2016: Speeding and driver-related errors are the main challenge.

Odds of culpability associated with use of impairing drugs in injured drivers in Victoria, Australia.

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. 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. 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. 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.

/pdf/are-non-constant-rates-and-non-proportional-treatment-1za10alndt.pdf

Are non-constant rates and non-proportional treatment effects accounted for in the design and analysis of randomised controlled trials? A review of current practice

AIM The prevalence of chronic kidney disease (CKD) in the elderly is controversial because age-related decline in kidney function may not truly reflect underlying kidney disease. We estimate the baseline prevalence and predictors of CKD using the CKD Epidemiology Collaboration (CKD-EPIeGFR ) and Berlin Initiative Study 1 (BIS1eGFR ) eGFR equations in the ASPirin in Reducing Events in the Elderly (ASPREE) trial cohort of healthy older participants. METHODS GFR was estimated using CKD-EPI and BIS1 equations. CKD was defined as eGFR <60 mL/min/1.73 m2 or ≥ 60 mL/min/1.73 m2 with urine albumin creatinine ratio (UACR) ≥ 3 mg/mmol. Logistic regression was used to identify predictors of CKD prevalence defined by each eGFR equation. RESULTS Data for analysis were complete for 17,762 participants. Mean age was 75.1 years (SD 5); 56.4% were female, 76.4% had hypertension, 9% had diabetes mellitus. Mean CKD-EPIeGFR was 73.0 (SD 14.2), compared with mean BIS1eGFR of 62.7 (11.4). Median UACR was 0.8 (IQR 0.5, 1.5) mg/mmol. Prevalence of CKD by CKD-EPIeGFR was 27% (predominantly due to normoalbuminuric stage 3a CKD), substantially lower than 47.1% by BIS1eGFR ; the difference was predominantly driven by reclassification of individuals from G1 and G2 CKD to stage G3a without albuminuria. Increased prevalence of CKD by either equation was related to older age, hypertension, diabetes, or higher body mass index. CONCLUSIONS Prevalence of CKD with CKD-EPIeGFR was 27%, and doubled using the elderly specific BIS1eGFR , with most participants reclassified from stage 2 to stage 3a. Increased prevalence of CKD was related older age, hypertension, diabetes, or increased body mass index.

/pdf/prevalence-of-chronic-kidney-disease-in-the-elderly-using-pyz5iubtvf.pdf

Prevalence of chronic kidney disease in the elderly using the ASPirin in Reducing Events in the Elderly study cohort

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.

/pdf/impact-of-a-non-constant-baseline-hazard-on-detection-of-1qae9maair.pdf

Kim Jachno

Papers

Odds of culpability associated with use of impairing drugs in injured drivers in Victoria, Australia.

Are non-constant rates and non-proportional treatment effects accounted for in the design and analysis of randomised controlled trials? A review of current practice

Prevalence of chronic kidney disease in the elderly using the ASPirin in Reducing Events in the Elderly study cohort

Impact of a non-constant baseline hazard on detection of time-dependent treatment effects: a simulation study.