Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III—rationale, trial design and baseline data

BACKGROUND: Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis. METHODS: UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor-neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but <60 mL/min/1.73 m2 and urine albumin:creatinine ratio (uACR) >20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m2 (regardless of uACR) were invited to be screened. Following a 4- to 7-week pre-randomization single-blind placebo run-in phase (during which any current renin-angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim was to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD. RESULTS: Between November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol. CONCLUSIONS: UK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD

Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III-rationale, trial design and baseline data

Background Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis. Methods UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor–neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but 20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m2 (regardless of uACR) were invited to be screened. Following a 4- to 7-week pre-randomization single-blind placebo run-in phase (during which any current renin–angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim was to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD. Results Between November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol. Conclusions UK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD

Conventional and Genetic Evidence on the Association between Adiposity and CKD

Background The size of any causal contribution of central and general adiposity to CKD risk and the underlying mechanism of mediation are unknown. Methods Data from 281,228 UK Biobank participants were used to estimate the relevance of waist-to-hip ratio and body mass index (BMI) to CKD prevalence. Conventional approaches used logistic regression. Genetic analyses used Mendelian randomization (MR) and data from 394 waist-to-hip ratio and 773 BMI-associated loci. Models assessed the role of known mediators (diabetes mellitus and BP) by adjusting for measured values (conventional analyses) or genetic associations of the selected loci (multivariable MR). Results Evidence of CKD was found in 18,034 (6.4%) participants. Each 0.06 higher measured waist-to-hip ratio and each 5-kg/m2 increase in BMI were associated with 69% (odds ratio, 1.69; 95% CI, 1.64 to 1.74) and 58% (1.58; 1.55 to 1.62) higher odds of CKD, respectively. In analogous MR analyses, each 0.06–genetically-predicted higher waist-to-hip ratio was associated with a 29% (1.29; 1.20 to 1.38) increased odds of CKD, and each 5-kg/m2 genetically-predicted higher BMI was associated with a 49% (1.49; 1.39 to 1.59) increased odds. After adjusting for diabetes and measured BP, chi-squared values for associations for waist-to-hip ratio and BMI fell by 56%. In contrast, mediator adjustment using multivariable MR found 83% and 69% reductions in chi-squared values for genetically-predicted waist-to-hip ratio and BMI models, respectively. Conclusions Genetic analyses suggest that conventional associations between central and general adiposity with CKD are largely causal. However, conventional approaches underestimate mediating roles of diabetes, BP, and their correlates. Genetic approaches suggest these mediators explain most of adiposity-CKD–associated risk.</p

Impact of CKD on Household Income

Introduction The impact of chronic kidney disease (CKD) on income is unclear. We sought to determine whether CKD severity, serious adverse events, and CKD progression affected household income. Methods Analyses were undertaken in a prospective cohort of adults with moderate-to-severe CKD in the Study of Heart and Renal Protection (SHARP), with household income information available at baseline screening and study end. Logistic regressions, adjusted for sociodemographic characteristics, smoking, and prior diseases at baseline, estimated associations during the 5-year follow-up, among (i) baseline CKD severity, (ii) incident nonfatal serious adverse events (vascular or cancer), and (iii) CKD treatment modality (predialysis, dialysis, or transplanted) at study end and the outcome “fall into relative poverty.” This was defined as household income <50% of country median income. Results A total of 2914 SHARP participants from 14 countries were included in the main analysis. Of these, 933 (32%) were in relative poverty at screening; of the remaining 1981, 436 (22%) fell into relative poverty by study end. Compared with participants with stage 3 CKD at baseline, the odds of falling into poverty were 51% higher for those with stage 4 (odds ratio [OR]: 1.51; 95% confidence interval [CI]: 1.09–2.10), 66% higher for those with stage 5 (OR: 1.66; 95% CI: 1.11–2.47), and 78% higher for those on dialysis at baseline (OR: 1.78, 95% CI: 1.22–2.60). Participants with kidney transplant at study end had approximately half the risk of those on dialysis or those with CKD stages 3 to 5. Conclusion More advanced CKD is associated with increased odds of falling into poverty. Kidney transplantation may have a role in reducing this risk

Intersection Geometric Design and Operational Guidelines for Older Drivers and Pedestrians, Volume III: Guidelines

DTFH61-92-C-00142This project was performed to develop guidelines for changes in the geometric design and operations at intersections with the greatest potential to aid in their use by older drivers and pedestrians. A literature review identified age-related diminished capabilities that affect performance at intersections, and examined current design standards and their adequacy for older road users. A set of problem identification studies (accident database analysis, task analysis, focus group discussions, field observations) were conducted to better define older persons' difficulties in intersection use, and an expert panel met to prioritize variables for more extensive laboratory and field studies later in the project. These studies subsequently focused on age (including both young-old and old-old groups) and the effects of opposite left-turn lane geometry (offset amount and direction), right-turn channelization and curb radius, and varying median pedestrian refuge island configurations, using both objective (performance) and subjective measures. A critique of the data obtained in these studies during a second expert panel meeting concluded that sufficient evidence exists to support guidelines for: (1) geometric design to ensure a minimum required sight distance for drivers turning left from a major roadway, and (2) operational changes to accommodate older drivers where (re)design of an intersection to meet sight distance requirements is not feasible. In addition, a revision of Case V in the AASHTO Green Book to determine sight distance requirements that reflect the perceptual task of gap judgment by a left-turning driver more accurately than the current assumptions in Case IIIB is recommended, and further research needs to enhance the safety and mobility of older road users at intersections are identified

Effects of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: a randomised double-blind trial

Background: Sacubitril/valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction, but its effects on kidney function and cardiac biomarkers in people with moderate-to-severe chronic kidney disease are unknown. Methods: UK HARP-III was a randomised double-blind trial which included 414 participants with an estimated glomerular filtration rate (GFR) 20-60 mL/min/1.73m2 who were randomly assigned to sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily. The primary outcome was measured GFR (mGFR) at 12 months using analysis of covariance with adjustment for each individual's baseline mGFR. All analyses were by intention to treat. This trial is registered at ISRCTN11958993. Results: 207 participants were assigned to sacubitril/valsartan and 207 to irbesartan. Baseline mGFR was 34.0 (0.8) and 34.7 (0.8) mL/min/1.73m2 respectively. At 12 months there was no difference in measured GFR: 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (0.5) mL/min/1.73m2 among those assigned irbesartan; difference -0.1 (0.7) mL/min/1.73m2. Effects were similar in all pre-specified subgroups. There was also no significant difference in estimated GFR at 3, 6, 9 or 12 months and no clear difference in urinary albumin:creatinine ratio between treatment arms (study average difference -9%, 95% CI -18% to 1%). However, compared to irbesartan, allocation to sacubitril/valsartan reduced study average systolic and diastolic blood pressure by 5.4 (95% CI 3.4-7.4) and 2.1 (95% CI 1.0-3.3) mmHg, and levels of troponin I and N-terminal of pro-hormone brain natriuretic peptide (tertiary endpoints) by 16% (95% CI 8-23) and 18% (95% CI 11-25), respectively. The incidence of serious adverse events (29.5% vs 28.5%; rate ratio [RR] 1.07, 95% CI 0.75-1.53), non-serious adverse reactions (36.7% vs 28.0%; RR 1.35, 95% CI 0.96-1.90) and potassium ≥ 5.5 mmol/L (32% vs 24%; p=0.10) were not significantly different between randomized groups. Conclusions: Over 12 months, sacubitril/valsartan has similar effects on kidney function and albuminuria to irbesartan, but has the additional effect of lowering blood pressure and cardiac biomarkers in people with chronic kidney disease. Clinical Trial Registration—URL: www.isrctn.com Unique Identifier: ISRCTN11958993

Intersection Geometric Design and Operational Guidelines for Older Drivers and Pedestrians, Volume II: Executive Summary

DTFH61-92-C-00142This project was performed to develop guidelines for changes in the geometric design and operations at intersections with the greatest potential to aid in their use by older drivers and pedestrians. A literature review identified age-related diminished capabilities that affect performance at intersections, and examined current design standards and their adequacy for older road users. Problem identification studies (accident database analysis, task analysis, focus group discussions, field observations) were conducted to better define older persons' difficulties in intersection use, and an expert panel met to prioritize variables for more extensive laboratory and field studies later in the project. These studies subsequently focused on age (including both young-old and old-old groups) and the effects of opposite left-turn lane geometry (offset amount and direction), right-turn channelization and curb radius, and varying median pedestrian refuge island configurations, using both objective (performance) and subjective measures. A critique of the data obtained in these studies during a second expert panel meeting concluded that sufficient evidence exists to support guidelines for: (1) geometric design to ensure a minimum required sight distance for drivers turning left from a major roadway, and (2) operational changes to accommodate older drivers where (re)design of an intersection to meet sight distance requirements is not feasible. In addition, a revision of Case V in the AASHTO Green Book to determine sight distance requirements that reflect the perceptual task of gap judgment by a left-turning driver more accurately than the current assumptions in Case IIIB is recommended, and further research needs to enhance the safety and mobility of older road users at intersections are identified

Empagliflozin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background Empagliflozin has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory, metabolic, and haemodynamic effects. The RECOVERY trial aimed to assess its safety and efficacy in patients admitted to hospital with COVID-19. Methods In the randomised, controlled, open-label RECOVERY trial, several possible treatments are compared with usual care in patients hospitalised with COVID-19. In this analysis, we assess eligible and consenting adults who were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus oral empagliflozin 10 mg once daily for 28 days or until discharge (whichever came first) using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality; secondary outcomes were duration of hospitalisation and (among participants not on invasive mechanical ventilation at baseline) the composite of invasive mechanical ventilation or death. On March 3, 2023 the independent data monitoring committee recommended that the investigators review the data and recruitment was consequently stopped on March 7, 2023. The ongoing RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings Between July 28, 2021 and March 6, 2023, 4271 patients were randomly allocated to receive either empagliflozin (2113 patients) or usual care alone (2158 patients). Primary and secondary outcome data were known for greater than 99% of randomly assigned patients. Overall, 289 (14%) of 2113 patients allocated to empagliflozin and 307 (14%) of 2158 patients allocated to usual care died within 28 days (rate ratio 0·96 [95% CI 0·82–1·13]; p=0·64). There was no evidence of significant differences in duration of hospitalisation (median 8 days for both groups) or the proportion of patients discharged from hospital alive within 28 days (1678 [79%] in the empagliflozin group vs 1677 [78%] in the usual care group; rate ratio 1·03 [95% CI 0·96–1·10]; p=0·44). Among those not on invasive mechanical ventilation at baseline, there was no evidence of a significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (338 [16%] of 2084 vs 371 [17%] of 2143; risk ratio 0·95 [95% CI 0·84–1·08]; p=0·44). Two serious adverse events believed to be related to empagliflozin were reported: both were ketosis without acidosis. Interpretation In adults hospitalised with COVID-19, empagliflozin was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death so is not indicated for the treatment of such patients unless there is an established indication due to a different condition such as diabetes. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research (MC_PC_19056), and Wellcome Trust (222406/Z/20/Z)

Intersection Geometric Design and Operational Guidelines for Older Drivers and Pedestrians, Volume I: Final Report

DTFH61-92-C-00142This project was performed to develop guidelines for changes in the geometric design and operations at intersections with the greatest potential to aid in their use by older drivers and pedestrians. A literature review identified age-related diminished capabilities that affect performance at intersections, and examined current design standards and their adequacy for older road users. Problem identification studies (accident database analysis, task analysis, focus group discussions, field observations) were conducted to better define older persons' difficulties in intersection use, and an expert panel met to prioritize variables for more extensive laboratory and field studies later in the project. These studies subsequently focused on age (including both young-old and old-old groups) and the effects of opposite left-turn lane geometry (offset amount and direction), right-turn channelization and curb radius, and varying median pedestrian refuge island configurations, using both objective (performance) and subjective measures. A critique of the data obtained in these studies during a second expert panel meeting concluded that sufficient evidence exists to support guidelines for: (1) geometric design to ensure a minimum required sight distance for drivers turning left from a major roadway, and (2) operational changes to accommodate older drivers where (re)design of an intersection to meet sight distance requirements is not feasible. In addition, a revision of Case V in the AASHTO Green Book to determine sight distance requirements that reflect the perceptual task of gap judgment by a left-turning driver more accurately than the current assumptions in Case IIIB is recommended, and further research needs to enhance the safety and mobility of older road users at intersections are identified

Sodium-Glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear. METHODS: This was a collaborative trial-level meta-analysis from the SGLT2i Meta-analysis Cardio-Renal Trialists Consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across 3 patient populations (patients with diabetes at high risk for atherosclerotic cardiovascular disease, heart failure [HF], or chronic kidney disease). The outcomes of interest were MACE (composite of cardiovascular death, myocardial infarction , or stroke), individual components of MACE (inclusive of fatal and nonfatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i versus placebo were meta-analyzed across trials and examined across key subgroups (established atherosclerotic cardiovascular disease, previous myocardial infarction, diabetes, previous HF, albuminuria, chronic kidney disease stages, and risk groups). RESULTS: A total of 78 607 patients across 11 trials were included: 42 568 (54.2%), 20 725 (26.4%), and 15 314 (19.5%) were included from trials of patients with diabetes at high risk for atherosclerotic cardiovascular disease, HF, or chronic kidney disease, respectively. SGLT2i reduced the rate of MACE by 9% (hazard ration [HR], 0.91 [95% CI, 0.87-0.96], P<0.0001) with a consistent effect across all 3 patient populations (I2=0%) and across all key subgroups. This effect was primarily driven by a reduction in cardiovascular death (HR, 0.86 [95% CI, 0.81-0.92], P<0.0001), with no significant effect for myocardial infarction in the overall population (HR, 0.95 [95% CI, 0.87-1.04], P=0.29), and no effect on stroke (HR, 0.99 [95% CI, 0.91-1.07], P=0.77). The benefit for cardiovascular death was driven primarily by reductions in HF death and sudden cardiac death (HR, 0.68 [95% CI, 0.46-1.02] and HR, 0.86 [95% CI, 0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (Pinteraction=0.02). CONCLUSIONS: SGLT2i reduce the risk of MACE across a broad range of patients irrespective of atherosclerotic cardiovascular disease, diabetes, kidney function, or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of cardiovascular death, particularly HF death and sudden cardiac death, without a significant effect on myocardial infarction in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease