The association between dual RAAS inhibition and risk of acute kidney injury and hyperkalemia in patients with diabetic kidney disease: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Dual renin-angiotensin-aldosterone system (RAAS) blockade involves dual therapy with a combination of angiotensin-converting enzyme inhibitors (ACEis), angiotensin-receptor blockers (ARBs), direct renin inhibitors (DRIs), or mineralocorticoid receptor antagonists (MRAs). It is hypothesized that dual RAAS blockade would result in a more complete inhibition of the RAAS cascade. However, large clinical trials on dual RAAS inhibition have shown increased risk of acute kidney injury (AKI) and hyperkalemia without additional benefit on mortality, cardiovascular events, or chronic kidney disease (CKD) progression compared to RAAS inhibitor monotherapy in patients with diabetic kidney disease (DKD). The development of newer, more selective non-steroidal MRAs as cardiorenal protective therapies has created a new opportunity for dual RAAS inhibition. We conducted a systematic review and meta-analysis of the risks of AKI and hyperkalemia with dual RAAS blockade in patients with DKD. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This is a systematic review and meta-analysis of the randomized controlled trials (RCT) published from 1 January 2006 to 30 May 2022. The study population included adult patients with DKD receiving dual RAAS blockade. A total of 31 RCTs and 33 048 patients were included in the systematic review. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random effects. RESULTS: There were 208 AKI events in 2690 patients on ACEi + ARB versus 170 in 4264 patients with ACEi or ARB monotherapy (pooled RR 1.48, 95% CI: 1.23-1.39). There were 304 hyperkalemia events in 2818 patients on ACEi + ARB versus 208 in 4396 patients with ACEi or ARB monotherapy (pooled RR 1.97, 95% CI: 1.32-2.94). A non-steroidal MRA + ACEi or ARB showed no increase in the risk of AKI (pooled RR 0.97, 95% CI: 0.81-1.16) compared to ACEi or ARB monotherapy but had a 2-fold higher risk of hyperkalemia with 953 events in 7837 patients in dual therapy versus 454 events in 6895 patients in monotherapy (pooled RR 2.05, 95% CI: 1.84-2.28). A steroidal MRA + ACEi or ARB had a 5-fold higher risk of hyperkalemia with 28 events in 245 at risk in dual therapy versus five events in 248 at risk in monotherapy (pooled RR 5.42 95% CI: 2.15-13.67). CONCLUSION: Dual therapy with RAASi is associated with an increased risk of AKI and hyperkalemia compared to RAASi monotherapy. Conversely, dual therapy with RAAS inhibitors and non-steroidal MRAs have no additional risk of AKI but a similar risk of hyperkalemia, which is lower than dual therapy with RAAS inhibitors and steroidal MRAs.

Prescription of guideline-directed medical therapies in patients with diabetes and chronic kidney disease from the CURE-CKD Registry, 2019-2020.

AIM: Guideline-directed medical therapy (GDMT) is designed to improve clinical outcomes. The study aim was to assess GDMT prescribing rates and prescribing-persistence predictors in patients with diabetes and chronic kidney disease (CKD) from the Center for Kidney Disease Research, Education, and Hope Registry. MATERIALS AND METHODS: Data were obtained from adults ≥18 years old with diabetes and CKD between 1 January 2019 and 31 December 2020 (N = 39 158). Baseline and persistent (≥90 days) prescriptions for GDMT, including angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), sodium-glucose cotransporter-2 (SGLT2) inhibitor and glucagon-like peptide 1 (GLP-1) receptor agonist were assessed. RESULTS: The population age (mean ± SD) was 70 ± 14 years, and 49.6% (n = 19 415) were women. Baseline estimated glomerular filtration rate (2021 CKD-Epidemiology Collaboration creatinine equation) was 57.5 ± 23.0 ml/min/1.73 m2 and urine albumin/creatinine 57.5 mg/g (31.7-158.2; median, interquartile range). Baseline and ≥90-day persistent prescribing rates, respectively, were 70.7% and 40.4% for ACE inhibitor/ARB, 6.0% and 5.0% for SGLT2 inhibitors, and 6.8% and 6.3% for GLP-1 receptor agonist (all p < .001). Patients lacking primary commercial health insurance coverage were less likely to be prescribed an ACE inhibitor/ARB [odds ratio (OR) = 0.89; 95% confidence interval (CI) 0.84-0.95; p < .001], SGLT2 inhibitor (OR 0.72; 95% CI 0.64-0.81; p < .001) or GLP-1 receptor agonist (OR 0.89; 95% CI 0.80-0.98; p = .02). GDMT prescribing rates were lower at Providence than UCLA Health. CONCLUSIONS: Prescribing for GDMT was suboptimal and waned quickly in patients with diabetes and CKD. Type of primary health insurance coverage and health system were associated with GDMT prescribing.

Human SIRT1 regulates DNA binding and stability of the Mcm10 DNA replication factor via deacetylation.

The eukaryotic DNA replication initiation factor Mcm10 is essential for both replisome assembly and function. Human Mcm10 has two DNA-binding domains, the conserved internal domain (ID) and the C-terminal domain (CTD), which is specific to metazoans. SIRT1 is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that belongs to the sirtuin family. It is conserved from yeast to human and participates in cellular controls of metabolism, longevity, gene expression and genomic stability. Here we report that human Mcm10 is an acetylated protein regulated by SIRT1, which binds and deacetylates Mcm10 both in vivo and in vitro, and modulates Mcm10 stability and ability to bind DNA. Mcm10 and SIRT1 appear to act synergistically for DNA replication fork initiation. Furthermore, we show that the two DNA-binding domains of Mcm10 are modulated in distinct fashion by acetylation/deacetylation, suggesting an integrated regulation mechanism. Overall, our study highlights the importance of protein acetylation for DNA replication initiation and progression, and suggests that SIRT1 may mediate a crosstalk between cellular circuits controlling metabolism and DNA synthesis.

Effectiveness and Safety of Rivaroxaban and Low Molecular Weight Heparin in Cancer-Associated Venous Thromboembolism.

Background: Direct-acting oral anticoagulants (DOACs) are alternatives to low molecular weight heparin (LMWH) in most cancer-associated thrombosis (CAT) patients. Objectives: This study sought to compare the effectiveness and safety of rivaroxaban and LMWH for venous thromboembolism (VTE) treatment in patients with an active cancer type not associated with a high risk of DOAC bleeding. Methods: An analysis of electronic health records from January 2012 to December 2020 was performed. Patients were adults, had active cancer, experienced an index CAT event, and were treated with rivaroxaban or LMWH. Patients with cancers with an established high risk of bleeding on DOACs were excluded. Baseline covariates were balanced using propensity score-overlap weighting. HRs with 95% CIs were calculated. Results: We identified 3,708 CAT patients treated with rivaroxaban (29.5%) or LMWH (70.5%). The median (25th-75th percentiles) time on anticoagulation was 180 (69-365) and 96 (40-336) days for rivaroxaban and LMWH patients. At 3 months, rivaroxaban was associated with a 31% reduced risk of recurrent VTE vs LMWH (4.2% vs 6.1%; HR: 0.69; 95% CI: 0.51-0.92). No difference in bleeding-related hospitalizations or all-cause mortality was observed (HR: 0.79; 95% CI: 0.55-1.13 and HR: 1.07; 95% CI: 0.85-1.35, respectively). Rivaroxaban reduced the recurrent VTE risk (HR: 0.74; 95% CI: 0.57-0.97) but not bleeding-related hospitalizations or all-cause mortality at 6 months. At 12 months, no difference was observed between cohorts for any of the previously mentioned outcomes. Conclusions: Among active cancer patients experiencing VTE and not at high risk of bleeding on DOACs, rivaroxaban was associated with a reduced risk of recurrent VTE versus LMWHs at 3 and 6 months but not 12 months. (Observational Study in Cancer-Associated Thrombosis for Rivaroxaban-United States Cohort [OSCAR-US]; NCT04979780).

Sex differences in the generalizability of randomized clinical trials in heart failure with reduced ejection fraction.

AIMS: In order to understand how sex differences impact the generalizability of randomized clinical trials (RCTs) in patients with heart failure (HF) and reduced ejection fraction (HFrEF), we sought to compare clinical characteristics and clinical outcomes between RCTs and HF observational registries stratified by sex. METHODS AND RESULTS: Data from two HF registries and five HFrEF RCTs were used to create three subpopulations: one RCT population (n = 16 917; 21.7% females), registry patients eligible for RCT inclusion (n = 26 104; 31.8% females), and registry patients ineligible for RCT inclusion (n = 20 810; 30.2% females). Clinical endpoints included all-cause mortality, cardiovascular mortality, and first HF hospitalization at 1 year. Males and females were equally eligible for trial enrolment (56.9% of females and 55.1% of males in the registries). One-year mortality rates were 5.6%, 14.0%, and 28.6% for females and 6.9%, 10.7%, and 24.6% for males in the RCT, RCT-eligible, and RCT-ineligible groups, respectively. After adjusting for 11 HF prognostic variables, RCT females showed higher survival compared to RCT-eligible females (standardized mortality ratio [SMR] 0.72; 95% confidence interval [CI] 0.62-0.83), while RCT males showed higher adjusted mortality rates compared to RCT-eligible males (SMR 1.16; 95% CI 1.09-1.24). Similar results were also found for cardiovascular mortality (SMR 0.89; 95% CI 0.76-1.03 for females, SMR 1.43; 95% CI 1.33-1.53 for males). CONCLUSION: Generalizability of HFrEF RCTs differed substantially between the sexes, with females having lower trial participation and female trial participants having lower mortality rates compared to similar females in the registries, while males had higher than expected cardiovascular mortality rates in RCTs compared to similar males in registries.

Safety and effectiveness of appropriately and inappropriately dosed rivaroxaban or apixaban versus warfarin in patients with atrial fibrillation: a cohort study with nested case-control analyses from UK primary care.

OBJECTIVES: To investigate effects of appropriately and inappropriately dosed apixaban/rivaroxaban versus warfarin on effectiveness and safety outcomes in patients with non-valvular atrial fibrillation (NVAF). DESIGN: Cohort study with nested case-control analyses using primary care electronic health records (IQVIA Medical Research Data UK database). SETTING: UK primary care. PARTICIPANTS: Patients aged ≥18 years with NVAF newly prescribed apixaban (N=14 701), rivaroxaban (N=14 288) or warfarin (N=16 175) between 1 January 2012 and 30 June 2018, and followed up to 31 December 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: Incident cases of ischaemic stroke/systemic embolism (IS/SE) and intracranial bleeding (ICB). Cases were matched to controls on age, sex and OAC naïve status. Using logistic regression, adjusted ORs with 95% CIs were calculated for the outcomes comparing apixaban/rivaroxaban use (appropriate or inappropriate dosing based on the product label criteria) and warfarin. RESULTS: For IS/SE, ORs (95% CIs) for apixaban versus warfarin were 1.19 (0.92-1.52) for appropriate dose and 1.01 (0.67-1.51) for inappropriate dose; for rivaroxaban versus warfarin, estimates were 1.07 (0.83-1.37) for appropriate dose and 1.21 (0.78-1.88) for inappropriate dose. For ICB, ORs (95% CIs) for apixaban versus warfarin were 0.67 (0.44-1.00) for appropriate dose and 0.45 (0.21-0.95) for inappropriate dose; for rivaroxaban versus warfarin, estimates were 0.81 (0.55-1.20) for appropriate dose and 1.14 (0.56-2.31) for inappropriate dose. CONCLUSIONS: Dosing appropriateness in NVAF was not associated with a significant difference in IS/SE risk or increase in ICB risk versus warfarin. These findings may reflect residual confounding and biases that were difficult to control, as also seen in other observational studies. They should, therefore, be interpreted with caution, and prescribers should adhere to the dosing instructions in the respective Summary of Product Characteristics. Further studies on this topic from real-world populations are needed.

Anticoagulation Treatment in Cancer-Associated Venous Thromboembolism: Assessment of Patient Preferences Using a Discrete Choice Experiment (COSIMO Study).

INTRODUCTION: Clinical guidelines recommend anticoagulation therapy for the treatment of cancer-associated venous thromboembolism (VTE), but little is known about preferences. Therefore, the objective of this discrete choice experiment (DCE) was to elucidate patient preferences regarding anticoagulation convenience attributes. METHODS: Adult patients with cancer-associated VTE who switched to direct oral anticoagulants were included in a single-arm study (COSIMO). Patients were asked to decide between hypothetical treatment options based on a combination of the following attributes: route of administration (injection/tablet), frequency of intake (once/twice daily), need for regular controls of the international normalized ratio (INR) at least every 3 to 4 weeks (yes/no), interactions with food/alcohol (yes/no), and distance to treating physician (1 vs. 20 km) as an additional neutral attribute. DCE data were collected by structured telephone interviews and analyzed based on a conditional logit regression. RESULTS: Overall, 163 patients (mean age 63.7 years, 49.1% female) were included. They strongly preferred oral administration compared with self-injections (importance of this attribute for overall treatment decisions: 73.8%), and a treatment without dietary restrictions (11.8%). Even if these attributes were less important (7.2% and 6.5%, respectively), patients indicated a preference for a shorter distance to the treating physician and once-daily dosing compared with twice-daily intake. "Need for regular controls of INR at least every 3 to 4 weeks" showed no significant impact on the treatment decision (0.7%). CONCLUSION: This study showed that treatment-related decision making in cancer-associated VTE, assuming comparable effectiveness and safety of anticoagulant treatments, is predominantly driven by "route of administration," with patients strongly preferring oral administration.

Cancer-Associated ThrOmboSIs - Patient-Reported OutcoMes With RivarOxaban (COSIMO) - Baseline characteristics and clinical outcomes.

BACKGROUND: Patients with cancer-associated thrombosis (CAT) have a high risk of recurrent venous thromboembolic events, which contribute to significant morbidity and mortality. Direct oral anticoagulants may provide a convenient treatment option for these patients. OBJECTIVES: To assess clinical characteristics and outcomes of patients with active cancer changing to rivaroxaban after ≥4 weeks of standard therapy for the treatment of venous thromboembolism (VTE) in clinical practice. This analysis focused on secondary outcomes of Cancer-associated thrOmboSIs - Patient-reported outcoMes with rivarOxaban (COSIMO). PATIENTS: COSIMO was a multinational, prospective, noninterventional, single-arm cohort study. Overall, 505 patients received at least one dose of rivaroxaban; 96.6% changing from low-molecular-weight heparin, 1.6% from a vitamin K antagonist, and 1.8% from fondaparinux. RESULTS: Most patients had solid tumors (n = 449; 88.9%) and approximately half of these patients had metastases. The qualifying venous thromboembolic event was deep vein thrombosis (DVT) in 45.3% of patients, pulmonary embolism (PE) in 37.2% of patients, DVT with PE in 9.7% of patients, and catheter-associated DVT in 7.5% of patients. Approximately 75.1% of patients received rivaroxaban for at least 3 months; 150 (29.7%) patients received concomitant chemotherapy during the study. VTE recurrence, major bleeding, nonmajor bleeding, and major adverse cardiovascular events occurred in 18 (3.6%), 18 (3.6%), 81 (16.0%), and 12 (2.4%) patients, respectively. CONCLUSIONS: In patients with CAT who changed to rivaroxaban treatment after ≥4 weeks of standard therapy, the observed incidence proportions of recurrent VTE and bleeding events were in keeping with the recognized effectiveness and safety profile of rivaroxaban for the treatment of CAT.

Discontinuation of non-Vitamin K antagonist oral anticoagulants in patients with non-valvular atrial fibrillation: a population-based cohort study using primary care data from The Health Improvement Network in the UK.

OBJECTIVE: To determine discontinuation rates, patterns of use and predictors of discontinuation of non-vitamin K antagonist oral anticoagulants (NOACs) among patients with non-valvular atrial fibrillation (NVAF) in the first year of therapy. DESIGN: Population-based cohort study. SETTING: UK primary care. POPULATION: 11 481 patients with NVAF and a first prescription (index date) for apixaban, dabigatran or rivaroxaban (January 2012 to December 2016) with at least 1 year of follow-up and at least one further NOAC prescription in the year following the index date were identified. 1 year rates and patterns of discontinuation were described. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcome measures were the percentage of patients who, in the first year from starting NOAC therapy, discontinued with their oral anticoagulant (OAC) therapy (discontinuation was defined as a gap in OAC therapy of >30 days); switched OAC within 30 days; discontinued and reinitiated OAC therapy. Predictors of discontinuation were also evaluated. RESULTS: 1 year discontinuation rates according to the index NOAC were 26.1% for apixaban, 40.0% for dabigatran and 29.6% for rivaroxaban. Reinitiation rates were 18.1% for apixaban, 21.7% for dabigatran and 17.3% for rivaroxaban, and switching rates were 2.8% for apixaban, 8.8% for dabigatran and 4.9% for rivaroxaban. More than 93% of reinitiations were with the index NOAC. Patients starting on dabigatran were more likely to switch OAC therapy than those starting on apixaban; ORs 4.28 (95% CI 3.24 to 5.65) for dabigatran and 1.89 (95% CI 1.49 to 2.39) for rivaroxaban. Severely reduced renal function was a predictor of any discontinuation, OR 1.77 (95% CI 1.28 to 2.44). CONCLUSION: While the majority of patients with NVAF in the UK initiating NOAC treatment received continuous therapy in the first year of treatment, a substantial proportion of patients experienced gaps in treatment leaving them less protected against thromboembolism during these periods.

Appropriateness of initial dose of non-vitamin K antagonist oral anticoagulants in patients with non-valvular atrial fibrillation in the UK.

OBJECTIVE: To evaluate the appropriateness of the initial prescribed daily dose of non-vitamin K antagonist oral anticoagulants (NOACs) according to label in patients with non-valvular atrial fibrillation (NVAF) in the UK. DESIGN: Population-based cross-sectional study. SETTING: UK primary care. POPULATION: 30 467 patients with NVAF and a first prescription for apixaban, dabigatran or rivaroxaban between January 2011 and December 2016. MAIN OUTCOME MEASURES: Percentage of patients prescribed a NOAC dose according to the European Union (EU) labels (appropriately dosed), and not according to the EU labels (inappropriately dosed-including both underdosed and overdosed patients); percentage of patients prescribed an initial NOAC dose according to renal function status. RESULTS: A total of 15 252 (50.1%) patients started NOAC therapy on rivaroxaban, 10 834 (35.6%) on apixaban and 4381 (14.4%) on dabigatran. Among patients starting NOAC therapy on rivaroxaban, 17.3% were eligible to receive a reduced dose compared with 12.8% of patients starting on apixaban and 53.8% of patients starting on dabigatran. The majority of patients were prescribed an appropriate dose according to the EU labels: apixaban 74.9 %, dabigatran, 74.4%; rivaroxaban, 84.2%. Underdosing occurred in 21.6% (apixaban), 8.7% (dabigatran), 9.1% (rivaroxaban). Overdosing was more frequent for dabigatran (16.9%) than for rivaroxaban (6.6%) or apixaban (3.5%). There was a trend towards dose reduction with increasing renal impairment. Among patients with severe renal impairment, the majority received a reduced dose NOAC: apixaban, 91.1%, dabigatran, 80.0%, rivaroxaban, 83.0%. CONCLUSION: Between 2011 and 2016, the majority of patients starting NOAC therapy in UK primary care were prescribed a daily dose in line with the approved EU drug label. Underdosing was more than twice as common among patients starting on apixaban than those starting on dabigatran or rivaroxaban. Research into the patient characteristics that may influence inappropriate underdosing of NOACs in UK primary care is warranted.

Global Prevalence of Chronic Kidney Disease - A Systematic Review and Meta-Analysis.

Chronic kidney disease (CKD) is a global health burden with a high economic cost to health systems and is an independent risk factor for cardiovascular disease (CVD). All stages of CKD are associated with increased risks of cardiovascular morbidity, premature mortality, and/or decreased quality of life. CKD is usually asymptomatic until later stages and accurate prevalence data are lacking. Thus we sought to determine the prevalence of CKD globally, by stage, geographical location, gender and age. A systematic review and meta-analysis of observational studies estimating CKD prevalence in general populations was conducted through literature searches in 8 databases. We assessed pooled data using a random effects model. Of 5,842 potential articles, 100 studies of diverse quality were included, comprising 6,908,440 patients. Global mean(95%CI) CKD prevalence of 5 stages 13·4%(11·7-15·1%), and stages 3-5 was 10·6%(9·2-12·2%). Weighting by study quality did not affect prevalence estimates. CKD prevalence by stage was Stage-1 (eGFR>90+ACR>30): 3·5% (2·8-4·2%); Stage-2 (eGFR 60-89+ACR>30): 3·9% (2·7-5·3%); Stage-3 (eGFR 30-59): 7·6% (6·4-8·9%); Stage-4 = (eGFR 29-15): 0·4% (0·3-0·5%); and Stage-5 (eGFR<15): 0·1% (0·1-0·1%). CKD has a high global prevalence with a consistent estimated global CKD prevalence of between 11 to 13% with the majority stage 3. Future research should evaluate intervention strategies deliverable at scale to delay the progression of CKD and improve CVD outcomes.

The Oxford Renal (OxRen) cross-sectional study of chronic kidney disease in the UK.

INTRODUCTION: Chronic kidney disease (CKD) diagnosed with objective measures of kidney damage and function has been recognised as a major public health burden. Independent of age, sex, ethnicity and comorbidity, strong associations exist between cardiovascular disease, mortality, morbidity and CKD, defined by reduced glomerular filtration rate and increased urinary albumin excretion. Detection of CKD within the population is therefore a priority for health systems. METHODS AND ANALYSIS: 15 000 patients aged 60 years or over meeting the inclusion criteria will be invited to the study. Recruitment will be stratified to represent the distribution of socioeconomic position in the UK general population. Patients will be excluded if terminally ill (expected survival <1 year), or if they have received a solid organ transplant. Patients will attend up to two screening visits, to determine if they have CKD, followed by an assessment visit where demographic and physiological parameters will be recorded alongside questionnaires on exercise, diet, cognitive assessment and quality of life. Blood and urine specimens will be taken for immediate routine assays as well as for freezing pending peptide and genetic studies. Patients will have office and home blood pressure measurements as well as pulse wave velocity assessment. Healthcare costs of screening and subsequent monitoring will be calculated. ETHICS AND DISSEMINATION: The protocol and related documents have been approved by NRES Committee South Central-Oxford B-Reference 13/SC/0020.

Human SIRT1 associates with mitotic chromatin and contributes to chromosomal condensation.

SIRT1 is a NAD-dependent deacetylase that participates in cellular controls of gene expression, metabolism, genomic stability and anti-aging. Here we report that SIRT1 levels rise in prometaphase leading to SIRT1 global association with mitotic chromatin until telophase. Moreover, SIRT1 contributes to chromosomal condensation by mediating chromosomal loading of histone H1 and the condensin I complex. Consistently, SIRT1 knockdown led to improper condensation and overall aberrant mitosis. Our data highlight new role for SIRT1 in maintenance of chromosome stability in mitosis and suggests how diminished SIRT1 activity during aging and tumorigenesis may lead to aneuploidy and genomic instability.