Frailty, multimorbidity and polypharmacy: exploratory analyses of the effects of empagliflozin from the EMPA-KIDNEY trial.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are recommended treatment for adults with chronic kidney disease (CKD), but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin's risk-benefit profile in a post-hoc analysis of the double-blind, placebo-controlled EMPA-KIDNEY trial. METHODS: The EMPA-KIDNEY trial randomized 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20<45 mL/min/1.73m2, or ≥45<90 mL/min/1.73m2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed for two years (median). Additional characteristics analysed in subgroups were multimorbidity, polypharmacy and health-related quality of life (HRQoL) at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. RESULTS: The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility and diabetes; then eGFR and other comorbidities. Empagliflozin was generally well-tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.64-0.82); and all-cause hospitalization by 14% (HR 0.86, 95% CI 0.78-0.95); with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy or HRQoL. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. CONCLUSIONS: These findings support the use of SGLT2 inhibitors in CKD, irrespective of frailty, multimorbidity or polypharmacy.

Clinical trial results in context: comparison of baseline characteristics and outcomes of 38,510 RECOVERY trial participants versus a reference population of 346,271 people hospitalised with COVID-19 in England.

BACKGROUND: Randomised trials are essential to reliably assess medical interventions. Nevertheless, interpretation of such studies, particularly when considering absolute effects, is enhanced by understanding how the trial population may differ from the populations it aims to represent. METHODS: We compared baseline characteristics and mortality of RECOVERY participants recruited in England (n = 38,510) with a reference population hospitalised with COVID-19 in England (n = 346,271) from March 2020 to November 2021. We used linked hospitalisation and mortality data for both cohorts to extract demographics, comorbidity/frailty scores, and crude and age- and sex-adjusted 28-day all-cause mortality. RESULTS: Demographics of RECOVERY participants were broadly similar to the reference population, but RECOVERY participants were younger (mean age [standard deviation]: RECOVERY 62.6 [15.3] vs reference 65.7 [18.5] years) and less frequently female (37% vs 45%). Comorbidity and frailty scores were lower in RECOVERY, but differences were attenuated after age stratification. Age- and sex-adjusted 28-day mortality declined over time but was similar between cohorts across the study period (RECOVERY 23.7% [95% confidence interval: 23.3-24.1%]; vs reference 24.8% [24.6-25.0%]), except during the first pandemic wave in the UK (March-May 2020) when adjusted mortality was lower in RECOVERY. CONCLUSIONS: Adjusted 28-day mortality in RECOVERY was similar to a nationwide reference population of patients admitted with COVID-19 in England during the same period but varied substantially over time in both cohorts. Therefore, the absolute effect estimates from RECOVERY were broadly applicable to the target population at the time but should be interpreted in the light of current mortality estimates. TRIAL REGISTRATION: ISRCTN50189673- Feb. 04, 2020, NCT04381936- May 11, 2020.

A meta-analysis of randomized controlled clinical trials for implications of acute treatment effects on glomerular filtration rate for long-term kidney protection.

Pharmacologic interventions to slow chronic kidney disease progression, such as ACE-inhibitors, angiotensin receptor blockers, or sodium glucose co-transporter 2 inhibitors, often produce acute treatment effects on glomerular filtration rate (GFR) that differ from their long-term chronic treatment effects. Observational studies assessing the implications of acute effects cannot distinguish acute effects from GFR changes unrelated to the treatment. Here, we performed meta-regression analysis of multiple trials to isolate acute effects to determine their long-term implications. In 64 randomized controlled trials (RCTs), enrolling 154,045 participants, we estimated acute effects as the mean between-group difference in GFR slope from baseline to three months, effects on chronic GFR slope (starting at three months after randomization), and effects on three composite kidney endpoints defined by kidney failure (GFR 15 ml/min/1.73m2 or less, chronic dialysis, or kidney transplantation) or sustained GFR declines of 30%, 40% or 57% decline, respectively. We used Bayesian meta-regression to relate acute effects with treatment effects on chronic slope and the composite kidney endpoints. Overall, acute effects were not associated with treatment effects on chronic slope. Acute effects were associated with the treatment effects on composite kidney outcomes such that larger negative acute effects were associated with lesser beneficial effects on the composite kidney endpoints. Associations were stronger when the kidney composite endpoints were defined by smaller thresholds of GFR decline (30% or 40%). Results were similar in a subgroup of interventions with supposedly hemodynamic effects that acutely reduce GFR. For studies with GFR 60 mL/min/1.73m2 or under, negative acute effects were associated with larger beneficial effects on chronic GFR slope. Thus, our data from a large and diverse set of RCTs suggests that acute effects of interventions may influence the treatment effect on clinical kidney outcomes.

Effects of empagliflozin in patients with chronic kidney disease from Japan: exploratory analyses from EMPA-KIDNEY.

BACKGROUND: EMPA-KIDNEY assessed the effects of empagliflozin 10 mg once daily vs. placebo in 6609 patients with chronic kidney disease (CKD) at risk of progression, including 612 participants from Japan. METHODS: Eligibility required an estimated glomerular filtration rate (eGFR) of ≥ 20 < 45; or ≥ 45 < 90 ml/min/1.73m2 with a urinary albumin-to-creatinine ratio (uACR) of ≥ 200 mg/g. The primary outcome was a composite of kidney disease progression (end-stage kidney disease, a sustained eGFR decline to < 10 ml/min/1.73m2 or ≥ 40% from randomization, or renal death) or cardiovascular death. In post-hoc analyses, we explored the effects of empagliflozin in participants from Japan vs. non-Japan regions, including additional models assessing whether differences in treatment effects between these regions could result from differences in baseline characteristics. RESULTS: Japanese participants had higher levels of albuminuria and eGFR than those from non-Japan regions. During a median of 2.0 year follow-up, a primary outcome occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group (hazard ratio [HR], 0.72, 95% confidence interval [95%CI] 0.64-0.82; P < 0.0001). Among the participants from non-Japan regions, there were 399 vs. 494 primary outcomes (0.75, 0.66-0.86), and 33 vs. 64 (0.49, 0.32-0.75; heterogeneity p = 0.06) in Japan. Results were similar when models explicitly considered treatment interactions with diabetes status, categories of eGFR/uACR, and recruitment in Japan (heterogeneity p = 0.08). Safety outcomes were broadly comparable between the two groups, and by Japanese status. CONCLUSIONS: Empagliflozin safely reduced the risk of "kidney disease progression or cardiovascular death" in patients with CKD, with consistent effects in participants from Japan.

Accuracy of heart failure ascertainment using routinely collected healthcare data: a systematic review and meta-analysis.

BACKGROUND: Ascertainment of heart failure (HF) hospitalizations in cardiovascular trials is costly and complex, involving processes that could be streamlined by using routinely collected healthcare data (RCD). The utility of coded RCD for HF outcome ascertainment in randomized trials requires assessment. We systematically reviewed studies assessing RCD-based HF outcome ascertainment against "gold standard" (GS) methods to study the feasibility of using such methods in clinical trials. METHODS: Studies assessing International Classification of Disease (ICD) coded RCD-based HF outcome ascertainment against GS methods and reporting at least one agreement statistic were identified by searching MEDLINE and Embase from inception to May 2021. Data on study characteristics, details of RCD and GS data sources and definitions, and test statistics were reviewed. Summary sensitivities and specificities for studies ascertaining acute and prevalent HF were estimated using a bivariate random effects meta-analysis. Heterogeneity was evaluated using I2 statistics and hierarchical summary receiver operating characteristic (HSROC) curves. RESULTS: A total of 58 studies of 48,643 GS-adjudicated HF events were included in this review. Strategies used to improve case identification included the use of broader coding definitions, combining multiple data sources, and using machine learning algorithms to search free text data, but these methods were not always successful and at times reduced specificity in individual studies. Meta-analysis of 17 acute HF studies showed that RCD algorithms have high specificity (96.2%, 95% confidence interval [CI] 91.5-98.3), but lacked sensitivity (63.5%, 95% CI 51.3-74.1) with similar results for 21 prevalent HF studies. There was considerable heterogeneity between studies. CONCLUSIONS: RCD can correctly identify HF outcomes but may miss approximately one-third of events. Methods used to improve case identification should also focus on minimizing false positives.

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

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome.

Effects of Empagliflozin on Fluid Overload, Weight, and Blood Pressure in CKD.

SIGNIFICANCE STATEMENT: SGLT2 inhibitors reduce risk of kidney progression, AKI, and cardiovascular disease, but the mechanisms of benefit are incompletely understood. Bioimpedance spectroscopy can estimate body water and fat mass. One quarter of the EMPA-KIDNEY bioimpedance substudy CKD population had clinically significant levels of bioimpedance-derived "Fluid Overload" at recruitment. Empagliflozin induced a prompt and sustained reduction in "Fluid Overload," irrespective of sex, diabetes, and baseline N-terminal pro B-type natriuretic peptide or eGFR. No significant effect on bioimpedance-derived fat mass was observed. The effects of SGLT2 inhibitors on body water may be one of the contributing mechanisms by which they mediate effects on cardiovascular risk. BACKGROUND: CKD is associated with fluid excess that can be estimated by bioimpedance spectroscopy. We aimed to assess effects of sodium glucose co-transporter 2 inhibition on bioimpedance-derived "Fluid Overload" and adiposity in a CKD population. METHODS: EMPA-KIDNEY was a double-blind placebo-controlled trial of empagliflozin 10 mg once daily in patients with CKD at risk of progression. In a substudy, bioimpedance measurements were added to the main trial procedures at randomization and at 2- and 18-month follow-up visits. The substudy's primary outcome was the study-average difference in absolute "Fluid Overload" (an estimate of excess extracellular water) analyzed using a mixed model repeated measures approach. RESULTS: The 660 substudy participants were broadly representative of the 6609-participant trial population. Substudy mean baseline absolute "Fluid Overload" was 0.4±1.7 L. Compared with placebo, the overall mean absolute "Fluid Overload" difference among those allocated empagliflozin was -0.24 L (95% confidence interval [CI], -0.38 to -0.11), with similar sized differences at 2 and 18 months, and in prespecified subgroups. Total body water differences comprised between-group differences in extracellular water of -0.49 L (95% CI, -0.69 to -0.30, including the -0.24 L "Fluid Overload" difference) and a -0.30 L (95% CI, -0.57 to -0.03) difference in intracellular water. There was no significant effect of empagliflozin on bioimpedance-derived adipose tissue mass (-0.28 kg [95% CI, -1.41 to 0.85]). The between-group difference in weight was -0.7 kg (95% CI, -1.3 to -0.1). CONCLUSIONS: In a broad range of patients with CKD, empagliflozin resulted in a sustained reduction in a bioimpedance-derived estimate of fluid overload, with no statistically significant effect on fat mass. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03594110 ; EuDRACT: 2017-002971-24 ( https://eudract.ema.europa.eu/ ).

Staff perceptions towards virtual reality-motivated treadmill exercise for care home residents: a qualitative feedback study with key stakeholders and follow-up interview with technology developer.

OBJECTIVES: Health and care resources are under increasing pressure, partly due to the ageing population. Physical activity supports healthy ageing, but motivating exercise is challenging. We aimed to explore staff perceptions towards a virtual reality (VR) omnidirectional treadmill (MOTUS), aimed at increasing physical activity for older adult care home residents. DESIGN: Interactive workshops and qualitative evaluation. SETTINGS: Eight interactive workshops were held at six care homes and two university sites across Cornwall, England, from September to November 2021. PARTICIPANTS: Forty-four staff participated, including care home, supported living, clinical care and compliance managers, carers, activity coordinators, occupational therapists and physiotherapists. INTERVENTIONS: Participants tried the VR treadmill system, followed by focus groups exploring device design, potential usefulness or barriers for care home residents. Focus groups were audio-recorded, transcribed verbatim and thematically analysed. We subsequently conducted a follow-up interview with the technology developer (September 2022) to explore the feedback impact. RESULTS: The analysis produced seven key themes: anticipated benefits, acceptability, concerns of use, concerns of negative effects, suitability/unsuitability, improvements and current design. Participants were generally positive towards VR to motivate care home residents' physical activity and noted several potential benefits (increased exercise, stimulation, social interaction and rehabilitation). Despite the reported potential, staff had safety concerns for frail older residents due to their standing position. Participants suggested design improvements to enhance safety, usability and accessibility. Feedback to the designers resulted in the development of a new seated VR treadmill to address concerns about falls while maintaining motivation to exercise. The follow-up developer interview identified significant value in academia-industry collaboration. CONCLUSION: The use of VR-motivated exercise holds the potential to increase exercise, encourage reminiscence and promote meaningful activity for care home residents. Staff concerns resulted in a redesigned seated treadmill for those too frail to use the standing version. This novel study demonstrates the importance of stakeholder feedback in product design.

Development of a HPLC Method for Analysis of a Combination of Clofazimine, Isoniazid, Pyrazinamide, and Rifampicin Incorporated into a Dermal Self-Double-Emulsifying Drug Delivery System.

We describe the development and validation of a new high performance liquid chromatography (HPLC) method for analysis of a combination of the first-line anti-tubercular drugs isoniazid, pyrazinamide, and rifampicin together with clofazimine. This is a unique challenge since clofazimine and rifampicin are relatively highly lipophilic drugs, whereas isoniazid and pyrazinamide are considerably more hydrophilic. Thus, clear separation of peaks and quantification of four individual drugs can present difficulties during the development of an analytical method. Detection was established at two wavelengths-254 nm for isoniazid and pyrazinamide and 320 nm for clofazimine and rifampicin. Gradient elution was employed using 0.1% aqueous formic acid (A) and acetonitrile (B); clear separation of the four drugs was achieved within 10 min. A linear relationship was indicated by a correlation coefficient (r2) of 0.9999 for each anti-tubercular drug, respectively. The limit of detection (LOD) for the individual drugs was 0.70 µg/mL (isoniazid), 0.30 µg/mL (pyrazinamide), 0.20 µg/mL (rifampicin) and 0.20 µg/mL (clofazimine). Precision experiments rendered a mean recovery percentage of 101.25% (isoniazid), 98.70% (pyrazinamide), 99.68% (rifampicin) and 97.14% (clofazimine). This HPLC method was validated and is reliable, repeatable, and accurate for the purpose of conducting simultaneous HPLC analyses of the four anti-tubercular drugs.

Single and combination treatment of Toxoplasma gondii infections with a bumped kinase inhibitor and artemisone in vitro and with artemiside in experimentally infected mice.

In previous studies, the artemisinin derivatives artemisone, its pro-drug artemiside and the bumped-kinase inhibitor BKI-1748 were effective against T. gondii via different modes of action. This suggests that they may act synergistically resulting in improved efficacies in vitro and in vivo. To test this hypothesis, the compounds were applied alone and in combination to T. gondii infected human fibroblast host cells in order to determine their inhibition constants and effects on cellular ultrastructure. In addition, the efficacy of either single- or combined treatments were assessed in an acute TgShSp1-oocyst infection model based on CD1 outbred mice. Whereas the IC50 of the compounds in combination (42 nM) was close to the IC50 of BKI-1748 alone (46 nM) and half of the IC50 of artemisone alone (92 nM), the IC90 of the combination was half of the values found with the single compounds (138 nM vs. ca. 270 nM). Another indication for synergistic effects in vitro were distinct alterations of the cellular ultrastructure of tachyzoites observed in combination, but not with the single compounds. These promising results could not be reproduced in vivo. There was no decrease in number of T. gondii positive brains by either treatment. However, the levels of infection in these brains, i. e. the number of tachyzoites, was significantly decreased upon BKI-1748 treatment alone, and the combination with artemiside did not produce any further decrease. The treatment with artemiside alone had no significant effects. A vertical transmission model could not be established since artemiside strongly interfered with pregnancy and caused abortion. These results show that is difficult to extrapolate from promising in vitro results to the situation in vivo.

The Development of Dermal Self-Double-Emulsifying Drug Delivery Systems: Preformulation Studies as the Keys to Success.

Self-emulsifying drug delivery systems (SEDDSs) are lipid-based systems that are superior to other lipid-based oral drug delivery systems in terms of providing drug protection against the gastrointestinal (GI) environment, inhibition of drug efflux as mediated by P-glycoprotein, enhanced lymphatic drug uptake, improved control over plasma concentration profiles of drugs, enhanced stability, and drug loading efficiency. Interest in dermal spontaneous emulsions has increased, given that systems have been reported to deliver drugs across mucus membranes, as well as the outermost layer of the skin into the underlying layers. The background and development of a double spontaneous emulsion incorporating four anti-tubercular drugs, clofazimine (CFZ), isoniazid (INH), pyrazinamide (PZY), and rifampicin (RIF), are described here. Our methods involved examination of oil miscibility, the construction of pseudoternary phase diagrams, the determination of self-emulsification performance and the emulsion stability index of primary emulsions (PEs), solubility, and isothermal micro calorimetry compatibility and examination of emulsions via microscopy. Overall, the potential of self-double-emulsifying drug delivery systems (SDEDDSs) as a dermal drug delivery vehicle is now demonstrated. The key to success here is the conduct of preformulation studies to enable the development of dermal SDEDDSs. To our knowledge, this work represents the first successful example of the production of SDEDDSs capable of incorporating four individual drugs.

Delivering trials in the NHS: more than worth it.

Randomised trials are the best method to determine the efficacy and safety of health technologies. A recent report by Lord O'Shaughnessy highlighted many of the current challenges to delivering trials in the UK and proposed potential solutions. Among these, making trials the business of all NHS institutions and a valued part of all doctors' work, while leveraging the potential of the data that the NHS collects routinely, offers an opportunity to improve NHS efficiency, doctors' job satisfaction and population health simultaneously.

Impact of outcome adjudication in kidney disease trials: observations from the Study of Heart and Renal Protection (SHARP).

Introduction: We aimed to assess opportunities for trial streamlining and the scientific impact of adjudication on kidney and cardiovascular outcomes in CKD. Methods: We analysed the effects of adjudication of ~2100 maintenance kidney replacement therapy (KRT) and ~1300 major atherosclerotic events (MAEs) recorded in SHARP. We first compared outcome classification before versus after adjudication, and then re-ran randomised comparisons using pre-adjudicated follow-up data. Results: For maintenance KRT, adjudication had little impact with only 1% of events being refuted (28/2115). Consequently, randomised comparisons using pre-adjudication reports found almost identical results (pre-adjudication: simvastatin/ezetimibe 1038 vs placebo 1077; risk ratio [RR] 0.95, 95%CI 0.88-1.04; post-adjudicated: 1057 vs 1084; RR=0.97, 95%CI 0.89-1.05). For MAEs, about one-quarter of patient reports were refuted (324/1275 [25%]), and reviewing 3538 other potential vascular events and death reports identified only 194 additional MAEs. Nevertheless, randomised analyses using SHARP's pre-adjudicated data alone found similar results to analyses based on adjudicated outcomes (pre-adjudication: 573 vs 702; RR=0.80, 95%CI 0.72-0.89; adjudicated: 526 vs 619; RR=0.83, 95%CI 0.74- 0.94), and also suggested refuted MAEs were likely to represent atherosclerotic disease (RR for refuted MAEs=0.80, 95%CI 0.65-1.00). Conclusions: These analyses provide three key insights. First, they provide a rationale for nephrology trials not to adjudicate maintenance KRT. Secondly, when an event that mimics an atherosclerotic outcome is not expected to be influenced by the treatment under study (e.g. heart failure), the aim of adjudicating atherosclerotic outcomes should be to remove such events. Lastly, restrictive definitions for the remaining suspected atherosclerotic outcomes may reduce statistical power.

Reliability of major bleeding events in UK routine data versus clinical trial adjudicated follow-up data.

OBJECTIVE: To assess how reliable UK routine data are for ascertaining major bleeding events compared with adjudicated follow-up. METHODS: The ASCEND (A Study of Cardiovascular Events iN Diabetes) primary prevention trial randomised 15 480 UK people with diabetes to aspirin versus matching placebo. The primary safety outcome was major bleeding (including intracranial haemorrhage, sight-threatening eye bleeding, serious gastrointestinal bleeding and other major bleeding (epistaxis, haemoptysis, haematuria, vaginal and other bleeding)) ascertained by direct-participant mail-based follow-up, with >90% of outcomes undergoing adjudication. Nearly all participants were linked to routinely collected hospitalisation and death data (ie, routine data). An algorithm categorised bleeding events from routine data as major/minor. Kappa statistics were used to assess agreement between data sources, and randomised comparisons were re-run using routine data. RESULTS: When adjudicated follow-up and routine data were compared, there was agreement for 318 major bleeding events, with routine data identifying 281 additional-potential events, and not identifying 241 participant-reported events (kappa 0.53, 95% CI 0.49 to 0.57). Repeating ASCEND's randomised comparisons using routine data only found estimated relative and absolute effects of allocation to aspirin versus placebo on major bleeding similar to adjudicated follow-up (adjudicated follow-up: aspirin 314 (4.1%) vs placebo 245 (3.2%); rate ratio (RR) 1.29, 95% CI 1.09 to 1.52; absolute excess +6.3/5000 person-years (mean SE±2.1); vs routine data: 327 (4.2%) vs 272 (3.5%); RR 1.21, 95% CI 1.03 to 1.41; absolute excess +5.0/5000 (±2.2)). CONCLUSIONS: Analyses of the ASCEND randomised trial found that major bleeding events ascertained via UK routine data sources provided relative and absolute treatment effects similar to adjudicated follow-up. TRIAL REGISTRATION NUMBER: ISRCTN60635500; NCT00135226.