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OBJECTIVE: The study was undertaken because it was unknown whether the duration of type 2 diabetes modifies the effects of sodium–glucose cotransporter 2 inhibitor canagliflozin on cardiovascular (CV) and kidney outcomes. RESEARCH DESIGN AND METHODS: This post hoc analysis of the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program (N = 10,142) and Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial (N = 4,401) evaluated hazard ratios and 95% CIs using Cox proportional hazards for the effects of canagliflozin on CV and kidney outcomes, including progression and regression of albuminuria over 5-year intervals of disease duration. RESULTS: Canagliflozin had ranges of benefit across intervals of diabetes duration, with no heterogeneity for major adverse CV events, CV death or heart failure hospitalization, and kidney failure requiring therapy or doubling serum creatinine. Furthermore, canagliflozin reduced albuminuria progression and increased albuminuria regression with no interaction across all diabetes duration subgroups. CONCLUSIONS: Our findings suggest that earlier treatment with canagliflozin confers consistent cardiorenal benefits to individuals with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Renal denervation reduces office systolic BP by an average of 4-6 mm Hg more than control patients and is proposed as adjunctive treatment to pharmacotherapy for patients with uncontrolled hypertension.[5] How is treatment delivered? Renal denervation will be investigated in populations that have sympathetic overdrive, including patients with chronic kidney disease, heart failure or atrial fibrillation.[4] Renal denervation is an innovative catheter-based intervention for patients with uncontrolled hypertension. Renal denervation (RDN) is a minimally invasive catheter-based intervention that uses 1 of a range of techniques to disrupt renal afferent and efferent nerve signals between the kidney and brain. [Extracted from the article]

Background: Hidradenitis suppurativa (HS) is associated with several comorbidities such as diabetes mellitus and cardiovascular diseases. These comorbidities are also risk factors for chronic kidney disease (CKD), yet little is known about the risk of CKD in HS patients. Objectives: The objective was to study the prevalence of CKD in HS patients. Methods: Cross-sectional population-based study using the United States National Inpatient Sample database between January 1, 2002 and December 31, 2012 was performed. Results: We identified 23,767 hospital admissions for HS patients and 95,068 admissions for age- and gender-matched controls. The prevalence of CKD in HS patients was 6.3% (1,497/23,767) compared to non-HS controls which was 4.3% (4,052/95,068). The association of CKD was strongest in HS patients, who were ≥60 years old, 16.9% (475/2,811), male 7.3% (695/9,556), obese 7.8% (407/5,209), diabetic 12.5% (890/7,105), hyperlipidemic 13.3% (416/3,126), and had cardiovascular diseases 12.5% (631/5,045). The crude odds ratio of CKD in HS patients was 1.5 (95% CI: 1.420–1.605) compared to non-HS patients. The association remained significant after adjusting for important covariates with adjusted odds ratio of CKD in HS patients of 1.1 (95% CI: 1.014–1.176) compared to non-HS patients. Conclusions: Our findings show that there is a possible association of HS with CKD. Any signs of CKD should be assessed by a nephrologist as early diagnosis can hopefully prevent further progression. [ABSTRACT FROM AUTHOR]

Background: Outcomes of diabetes screening in contemporary, multi-ethnic populations are unknown. We examined the association of prior outpatient diabetes screening with the risks of cardiovascular events and mortality in Ontario, Canada. Methods: We conducted a population-based cohort study using administrative databases among adults aged ≥ 20 years with incident diabetes diagnosed during 2014–2016. The exposure was outpatient diabetes screening performed within 3 years prior to diabetes diagnosis. The co-primary outcomes were (1) a composite of all-cause mortality and hospitalization for myocardial infarction, stroke, coronary revascularization, and (2) all-cause mortality (followed up until 2018). We calculated standardized rates of each outcome and conducted cause-specific hazard modelling to determine the adjusted hazard ratio (HR) of the outcomes, adjusting for prespecified confounders and accounting for the competing risk of death. Results: We included 178,753 Ontarians with incident diabetes (70.2% previously screened). Individuals receiving prior screening were older (58.3 versus 53.4 years) and more likely to be women (49.6% versus 40.0%) than previously unscreened individuals. Individuals receiving prior screening had relatively lower standardized event rates than those without prior screening across all outcomes (composite: 12.8 versus 18.1, mortality: 8.2 versus 11.1 per 1000 patient-years). After multivariable adjustment, prior screening was associated with 34% and 32% lower risks of the composite (HR 0.66, 0.63–0.69) and mortality (0.68, 0.64–0.72) outcomes. Among those receiving prior screening, a result in the prediabetes range was associated with lower risks of the composite (0.82, 0.77–0.88) and mortality (0.71, 0.66–0.78) outcomes than a result in the normoglycemic range. Conclusions: Previously screened individuals with diabetes had lower risks of cardiovascular events and mortality versus previously unscreened individuals. Better risk assessment tools are needed to support wider and more appropriate uptake of diabetes screening, especially among young adults. [ABSTRACT FROM AUTHOR]

In addition, generalizability of the results may be limited to individuals with previous CV events, high CV risk or nephropathy, similar to the patients enrolled in the CANVAS programme and CREDENCE trial. This post-hoc analysis assessed the effects of canagliflozin versus placebo on CV and kidney outcomes in patients with T2DM and high CV risk, and/or chronic kidney disease according to baseline treatment target achievement and risk factors. Keywords: canagliflozin; cardiovascular disease; diabetic nephropathy; type 2 diabetes EN canagliflozin cardiovascular disease diabetic nephropathy type 2 diabetes 2038 2042 5 06/06/23 20230701 NES 230701 BACKGROUND Management of type 2 diabetes mellitus (T2DM), a progressive metabolic disorder associated with substantial cardiovascular (CV) and kidney complications, includes risk factor optimization of glucose, blood pressure (BP) and lipids. [Extracted from the article]

Background: To assess micro current to improve vision for dry age-related macular degeneration. Dry age-related macular degeneration is a major cause of blindness, disability, and severe erosion of quality of life, throughout the world. Beyond nutritional supplementation, there is no approved therapy. Methods: This was a prospective randomized sham controlled clinical trial for participants with confirmed dry AMD with documented visual loss. Participants were randomized three to one, to receive transpalpebral external micro current electrical stimulation with the MacuMira device. The Treatment group received four treatments in the first two weeks, and two further treatments at weeks 14 and 26. Differences in BCVA and contrast sensitivity (CS) were estimated with mixed-effects repeated measures analysis of variance. Results: Change of visual acuity with ETDRS assessment of number of letters read (NLR) and contrast sensitivity at week 4 and 30, compared to the first visit, between 43 treatment and 19 sham control participants. The Sham Control group had NLR of 24.2 (SD 7.1) at baseline, 24.2 (SD 7.2) at 4 weeks, and 22.1 (SD7.4) at 30 weeks. The Treatment group had NLR of 19.6 (SD 8.9) at baseline, 27.6 (SD 9.1) at 4 weeks, and 27.8 (SD 8.4) at 30 weeks. The change in NLR from baseline in the Treatment compared to the Sham control group was 7.7 (95% CI 5.7, 9.7, p < 0.001) at 4 weeks and 10.4 (95% CI 7.8, 13.1, p < 0.001) at 30 weeks. There were similar benefits in CS. Conclusions: This pilot study of transpalpebral microcurrent demonstrated improved visual measures and is very encouraging as a potential treatment for dry AMD. Trial Registration: NCT02540148, ClinicalTrials.gov. [ABSTRACT FROM AUTHOR]

Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a substudy of the Study of Diabetic Nephropathy With Atrasentan (SONAR) trial which enrolled adults with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate: 25–75 mL/min/1.73 m2, and a urine albumin‐to‐creatinine ratio of 300–5,000 mg/g). Single nucleotide polymorphisms (SNPs) were determined for prespecified membrane transporters, metabolizing enzymes, and the endothelin‐1 peptide. The associations among genotype, atrasentan plasma exposure, and the effect of atrasentan on the prespecified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3,668 patients randomized, 2,329 (63.5%) consented to genotype analysis. Two SNPs in the SLCO1B1 gene (rs4149056 and rs2306283), encoding the hepatic organic anion transporter 1B1 (OATP1B1), showed the strongest association with atrasentan plasma exposure. Based on their SLCO1B1 genotype, patients were classified into normal (atrasentan area under the plasma‐concentration time curve from zero to infinity (AUC0−inf) 41.3 ng·h/mL) or slow (atrasentan AUC0−inf 49.7 ng·h/mL, P < 0.001) OATP1B1 transporter phenotypes. Among patients with a normal OATP1B1 phenotype, the hazard ratio (HR) with atrasentan for the primary kidney and HHF outcomes were 0.61 (95% confidence interval (CI): 0.45–0.81) and 1.35 (95% CI: 0.84–2.13), respectively. In the slow transporter phenotype, HRs for kidney and HHF outcomes were 1.95 (95% CI: 0.95–4.03, P‐interaction normal phenotype = 0.004), and 4.18 (95% CI: 1.37–12.7, P‐interaction normal phenotype = 0.060), respectively. OATP1B1 gene polymorphisms are associated with significant between‐patient variability in atrasentan plasma exposure and long‐term efficacy and safety. [ABSTRACT FROM AUTHOR]

Objective: Heart failure (HF) often develops in patients with diabetes and is recognized for its role in increased cardiovascular morbidity and mortality in this population. Most existing models predict risk in patients with prevalent rather than incident diabetes and fail to account for sex differences in HF risk factors. We derived sex-specific models in Ontario, Canada to predict HF at diabetes onset and externally validated these models in the U.K.Research Design and Methods: Retrospective cohort study using international population-based data. Our derivation cohort comprised all Ontario residents aged ≥18 years who were diagnosed with diabetes between 2009 and 2018. Our validation cohort comprised U.K. patients aged ≥35 years who were diagnosed with diabetes between 2007 and 2017. Primary outcome was incident HF. Sex-stratified multivariable Fine and Gray subdistribution hazard models were constructed, with death as a competing event.Results: A total of 348,027 Ontarians (45% women) and 54,483 U.K. residents (45% women) were included. At 1, 5, and 9 years, respectively, in the external validation cohort, the C-statistics were 0.81 (95% CI 0.79-0.84), 0.79 (0.77-0.80), and 0.78 (0.76-0.79) for the female-specific model; and 0.78 (0.75-0.80), 0.77 (0.76-0.79), and 0.77 (0.75-0.79) for the male-specific model. The models were well-calibrated. Age, rurality, hypertension duration, hemoglobin, HbA1c, and cardiovascular diseases were common predictors in both sexes. Additionally, mood disorder and alcoholism (heavy drinker) were female-specific predictors, while income and liver disease were male-specific predictors.Conclusions: Our findings highlight the importance of developing sex-specific models and represent an important step toward personalized lifestyle and pharmacologic prevention of future HF development. [ABSTRACT FROM AUTHOR]

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 clinical practice guideline for the management of blood pressure (BP) in patients with chronic kidney disease (CKD) not receiving dialysis is an update of the KDIGO 2012 guideline on the same topic and reflects new evidence on the risks and benefits of BP-lowering therapy among patients with CKD. It is intended to support shared decision making by health care professionals working with patients with CKD worldwide. This article is a synopsis of the full guideline.Methods: The KDIGO leadership commissioned 2 co-chairs to convene an international Work Group of researchers and clinicians. After a Controversies Conference in September 2017, the Work Group defined the scope of the evidence review, which was undertaken by an evidence review team between October 2017 and April 2020. Evidence reviews were done according to the Cochrane Handbook. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to guide the development of the recommendations and rate the strength and quality of the evidence. Practice points were included to provide guidance when evidence was insufficient to make a graded recommendation. The guideline was revised after public consultation between January and March 2020.Recommendations: The updated guideline comprises 11 recommendations and 20 practice points. This synopsis summarizes key recommendations pertinent to the diagnosis and management of high BP in adults with CKD, excluding those receiving kidney replacement therapy. In particular, the synopsis focuses on recommendations for standardized BP measurement and a target systolic BP of less than 120 mm Hg, because these recommendations differ from some other guidelines. [ABSTRACT FROM AUTHOR]

Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase II trials. We evaluated whether plasma exposure was associated with long‐term outcomes for kidney protection and heart failure in the phase III SONAR trial (n = 3668) in type 2 diabetics with chronic kidney disease. A population pharmacokinetic model was used to estimate plasma exposure of atrasentan 0.75 mg/day. Parametric time‐to‐event models were used to quantify the association between plasma exposure and long‐term outcomes. Mean atrasentan plasma exposure was 41.4 ng.h/mL (2.5th to 97.5th P: 14.2 to 139.9). Compared with placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% confidence interval (CI): 0.28–0.85) for kidney events and 1.13 (95% CI: 1.03–2.20) for heart failure events. At the mean atrasentan exposure, the kidney protective effect was larger than the increase in heart failure supporting the atrasentan 0.75 mg/day dose in this population. [ABSTRACT FROM AUTHOR]

Aim: To better understand the healthcare burden of people with type 2 diabetes (T2D) and estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 in Ontario, Canada. Materials and Methods: We used administrative data to evaluate the prevalence of T2D, eGFR < 90 mL/min/1.73 m2 and adverse cardiovascular co‐morbidities in individuals aged ≥ 30 years living in Ontario, Canada. We also examined incremental healthcare costs and healthcare resource utilization (HCRU) for these patients with specific incident cardiovascular and renal outcomes, in comparison with controls without these outcomes. Results: While the prevalence of T2D in the general population aged ≥ 30 years in Ontario increased by 1.8% over a 5‐year period (2011‐2012 to 2015‐2016), the prevalence of eGFR < 90 mL/min/1.73 m2 among people with T2D increased by 35%. In comparison with corresponding controls without these outcomes, the per patient average total costs (Canadian dollars) over a 2‐year analysis period were higher for patients with cardiovascular disease/chronic kidney disease related death ($69 827; n = 32 407), doubling of serum creatinine ($52 260; n = 22 825), those who started dialysis ($150 627; n = 3499) or received a kidney transplant ($50 664; n = 651). Similarly, HCRU was significantly greater for patients with these incident outcomes. Conclusions: This real‐world retrospective study highlights an increasing prevalence of T2D, eGFR < 90 mL/min/1.73 m2, and the substantially higher healthcare costs and HCRU when these patients have adverse cardiovascular and renal outcomes. The existence of such a large economic burden underpins the importance of preventing these diabetes‐related complications. [ABSTRACT FROM AUTHOR]

Aim: To evaluate whether atrasentan plasma exposure explains between‐patient variability in urinary albumin‐to‐creatinine ratio (UACR) response, a surrogate for kidney protection, and B‐type natriuretic peptide (BNP) response, a surrogate for fluid expansion. Methods: Type 2 diabetic patients with chronic kidney disease (n = 4775) received 0.75 mg atrasentan for 6 weeks in the active run‐in period. Individual area under the concentration‐time‐curve (AUC) was estimated using a population pharmacokinetic model. The association between atrasentan AUC, other clinical characteristics, and UACR and BNP response, was estimated using linear regression. Results: The median atrasentan AUC was 43.8 ng.h/mL with a large variation among patients (2.5th‐97.5th percentiles [P]: 12.6 to 197.5 ng.h/mL). Median UACR change at the end of enrichment was −36.0% and median BNP change was 8.7%, which also varied among patients (UACR, 2.5th‐97.5th P: −76.2% to 44.5%; BNP, 2.5th‐97.5th P: −71.5% to 300.0%). In the multivariable analysis, higher atrasentan AUC was associated with greater UACR reduction (4.88% per doubling in ng.h/mL [95% confidence interval {CI}: 6.21% to 3.52%], P <.01) and greater BNP increase (3.08% per doubling in ng.h/mL [95% CI: 1.12% to 4.11%], P <.01) independent of estimated glomerular filtration rate, haemoglobin or BNP. Caucasian patients compared with black patients had greater UACR reduction (7.06% [95% CI: 1.38% to 13.07%]) and also greater BNP increase (8.75% [95% CI: 1.65% to 15.35%]). UACR response was not associated with BNP response (r = 0.06). Conclusion: Atrasentan plasma exposure varied among individual patients and partially explained between‐patient variability in efficacy and safety response. [ABSTRACT FROM AUTHOR]

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Background: The prevalence of adult chronic kidney disease and cardiovascular comorbidities in Canadian Indigenous communities is largely unknown. We conducted a study to document the prevalence of chronic kidney disease and concurrent diabetes mellitus, hypertension and dyslipidemia in a First Nations population in northwest Ontario. Methods: In this observational study, we used retrospective data collected from regional electronic medical records of 16 170 adults (age ≥ 18 yr) from 26 First Nations communities in northwest Ontario from May 2014 to May 2017. Demographic and laboratory data included age, gender, prescribed medications, estimated glomerular filtration rate, urine albumin:creatinine ratio, low-density lipoprotein cholesterol (LDL-C) level and glycated hemoglobin (HbA1c) concentration. We identified patients with diabetes by an HbA1c concentration of 6.5% or higher, or the use of a diabetic medication, those with dyslipidemia by an elevated LDL-C level (≥ 2.0 mmol/L) or use of lipid-lowering medication, and those with hypertension by use of antihypertensive medication. Results: Of the 16 170 adults residing in the communities, 5224 unique patients (32.3%) had renal testing (albumin:creatinine ratio and/or estimated glomerular filtration rate). The age-adjusted prevalence of chronic kidney disease was 14.5%, and the prevalence of stage 3–5 chronic kidney disease (estimated glomerular filtration rate < 60 mL/min) was 7.0%. Most patients with chronic kidney disease (1487 [80.0%]) had at least 1 cardiovascular comorbidity. A total of 1332 patients (71.6%) had diabetes, 1313 (70.6%) had dyslipidemia, and 1098 (59.1%) had hypertension; all 3 comorbidities were present in 716 patients (38.5%). Interpretation: We document a high prevalence of advanced chronic kidney disease in this First Nations population, 7.0%, double the rate in the general population. High rates of cardiovascular comorbidities were also common in these patients with chronic kidney disease, which places them at increased risk for cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Data derived from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study were analyzed in an effort to employ machine learning methods to predict the composite endpoint described in the original study. Methods: We identified 573 CORAL subjects with complete baseline data and the presence or absence of a composite endpoint for the study. These data were subjected to several models including a generalized linear (logistic-linear) model, support vector machine, decision tree, feed-forward neural network, and random forest, in an effort to attempt to predict the composite endpoint. The subjects were arbitrarily divided into training and testing subsets according to an 80%:20% distribution with various seeds. Prediction models were optimized within the CARET package of R. Results: The best performance of the different machine learning techniques was that of the random forest method which yielded a receiver operator curve (ROC) area of 68.1%±4.2% (mean ± SD) on the testing subset with ten different seed values used to separate training and testing subsets. The four most important variables in the random forest method were SBP, serum creatinine, glycosylated hemoglobin, and DBP. Each of these variables was also important in at least some of the other methods. The treatment assignment group was not consistently an important determinant in any of the models. Conclusion: Prediction of a composite cardiovascular outcome was difficult in the CORAL population, even when employing machine learning methods. Assignment to either the stenting or best medical therapy group did not serve as an important predictor of composite outcome. Clinical Trial Registration: ClinicalTrials.gov, NCT00081731 [ABSTRACT FROM AUTHOR]

Hypertension, the leading cause of cardiovascular morbidity and mortality, affects more than 1 billion people globally. The rise in mobile health in particular the use of mobile phones and short message service (SMS) to support disease management provides an opportunity to improve hypertension awareness, treatment, and control, in remote and vulnerable patient populations. The primary objective of this randomized controlled study was to assess the effect of active (with hypertension specific management SMS) or passive (health behaviors SMS alone) on the difference in blood pressure (BP) reduction between the active and passive SMS groups in hypertensive Canadian First Nations people from six rural and remote communities. Pragmatic features of the study included shifting of BP measures to non-medical health workers. Despite an overall reduction in BP over the study, there was no difference in the BP change between groups from baseline to final for systolic 0.8 (95% CI -4.2 to 5.8 mm Hg) or diastolic -1.0 (95% CI -3.7 to 1.8 mm Hg, P = 0.5) BP. Achieved BP control was 37.5% (25.6%-49.4%, 95% CI) in the active group and 32.8% (20.6%-44.8%, 95% CI) in the passive group (difference in proportions -4.74% (-21.7% to 12.2%, 95% CI, P = 0.6). The study looked at changes in health services delivery, mobile health technologies, and patient engagement to support better management of hypertension in Canadian First Nations communities. The active hypertension specific SMS did not lead to improvements in BP control. [ABSTRACT FROM AUTHOR]

Background: Curcumin, a popular herbal supplement from the plant turmeric, has prevented ischemic reperfusion and toxin-induced injury in many animal studies and a single-centre randomized human trial. We sought to test whether perioperative oral curcumin (compared with placebo) affects the inflammatory response and risk of postrepair complications after elective abdominal aortic aneurysm repair in humans.Methods: We conducted a parallel-group, randomized, placebo-controlled trial of patients from 10 hospitals in Canada who were scheduled to undergo elective repair of an unruptured abdominal aortic aneurysm (November 2011 to November 2014). Patients in the treatment group received perioperative oral curcumin (2000-mg doses 8 times over 4 d). Patients, health care providers and local research staff were unaware of the treatment assignment. The primary outcomes were median concentrations of 4 bio markers indicating injury and inflammation (postoperative urine interleukin-18 and perioperative rise in serum creatinine, plasma N-terminal pro-B-type natriuretic peptide and plasma high-sensitivity C-reactive protein).Results: Baseline characteristics were similar in the 2 groups (606 patients overall; median age 76 yr). More than 85% of patients in each group took more than 80% of their scheduled capsules. Neither curcumin nor placebo significantly affected any of the 4 biomarkers (p > 0.05 for all comparisons). Regarding the secondary outcomes, there was a higher risk of acute kidney injury with curcumin than with placebo (17% v. 10%, p = 0.01), but no between-group difference in the median length of hospital stay (5 v. 5 days, p > 0.9) or the risk of clinical events (9% v. 9%, p = 0.9).Interpretation: Curcumin had no beneficial effects when used in elective abdominal aortic aneurysm repair. These findings emphasize the importance of testing turmeric and curcumin before espousing their health benefits, as is currently done in the popular media.Trial Registration: ClinicalTrials.gov, no. NCT01225094. [ABSTRACT FROM AUTHOR]

The article discusses the 2018 update to the Canadian Cardiovascular Harmonized National Guideline Endeavour (C-CHANGE), a guideline which targets primary care health care practitioners. The 2018 update includes a total of 77 recommendations and 52 new recommendations, including multifaceted care for patients with cardiovascular risks. The guideline added a new category for hypertension for high-risk individuals and lists of risk factors of heart failure, hypertension and stroke.

Aim: The SONAR trial uses an enrichment design based on the individual response to the selective endothelin receptor antagonist atrasentan on efficacy (the degree of the individual response in the urinary albumin‐to‐creatinine ratio [UACR]) and safety/tolerability (signs of sodium retention and acute increases in serum creatinine) to assess the effects of this agent on major renal outcomes. The patient population and enrichment results are described here. Methods: Patients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) within 25 to 75 mL/min/1.73 m2 and UACR between 300 and 5000 mg/g were enrolled. After a run‐in period, eligible patients received 0.75 mg/d of atrasentan for 6 weeks. A total of 2648 responder patients in whom UACR decreased by ≥30% compared to baseline were enrolled, as were 1020 non‐responders with a UACR decrease of <30%. Patients who experienced a weight gain of >3 kg and in whom brain natriuretic peptide exceeded ≥300 pg/mL, or who experienced an increase in serum creatinine >20% (0.5 mg/dL), were not randomized. Results: Baseline characteristics were similar for atrasentan responders and non‐responders. Upon entry to the study, median UACR was 802 mg/g in responders and 920 mg/g in non‐responders. After 6 weeks of treatment with atrasentan, the UACR change in responders was −48.8% (95% CI, −49.8% to −47.9%) and in non‐responders was −1.2% (95% CI, −6.4% to 3.9%). Changes in other renal risk markers were similar between responders and non‐responders except for a marginally greater reduction in systolic blood pressure and eGFR in responders. Conclusions: The enrichment period has successfully identified a population with a profound UACR reduction without clinical signs of sodium retention in whom a large atrasentan effect on clinically important renal outcomes is possible. The SONAR trial aims to establish whether atrasentan confers renal protection. [ABSTRACT FROM AUTHOR]

Aims: Individuals with diabetes and chronic kidney disease (CKD) are at high risk for renal events. Recent trials of novel treatments have been negative, possibly because of variability in response to treatment of the target risk factor. Atrasentan is a selective endothelin A receptor antagonist that reduces urinary albumin‐to‐creatinine ratio (UACR), with a large variability between patients. We are assessing its effect on renal outcomes in the Study Of diabetic Nephropathy with AtRasentan (SONAR; NCT01858532) with an enrichment design (>30% lowering of albuminuria) to select patients most likely to benefit. Materials and Methods: SONAR is a randomized, double‐blind, placebo‐controlled trial with approximately 3500 participants who have stage 2–4 CKD and macroalbuminuria and are receiving a maximum tolerated dose of a renin‐angiotensin system inhibitor. Results: After 6 weeks of exposure to atrasentan 0.75 mg once daily (enrichment period), participants with ≥30% UACR decrease and no tolerability issues (responders) were randomly assigned to placebo or atrasentan 0.75 mg/day. The responder group will be used for primary efficacy and safety analyses. Approximately 1000 participants with <30% UACR reduction (non‐responders) were also randomized to placebo or atrasentan. The primary endpoint is a composite of a sustained doubling of serum creatinine or end‐stage renal disease. The original power calculation indicated that a total of 425 primary renal events in the responder group provides 90% power to detect a 27% reduction in relative risk (alpha level of .05). Conclusion: SONAR aims to determine whether atrasentan added to guideline‐recommended therapies safely reduces the risk of CKD progression and delays the onset of end‐stage renal disease in patients with type 2 diabetes and nephropathy. SONAR also aims to establish whether the enrichment of patients based on their initial “surrogate” response to atrasentan will deliver a trial design in accord with personalized treatment of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Background Fluid retention is a common adverse event in patients who receive endothelin (ET) receptor antagonist therapy, including the highly selective ETA receptor antagonist, atrasentan. Objective We performed longitudinal assessments of thoracic bioimpedance in patients with type 2 diabetes mellitus and nephropathy to determine whether a decrease in bioimpedance accurately reflected fluid retention during treatment with atrasentan. Study Design We conducted a randomized, double-blind, placebo-controlled study in 48 patients with type 2 diabetes mellitus and nephropathy who were receiving stable doses of renin angiotensin system inhibitors and diuretics. Methods Patients were randomized 1:1:1 to placebo, atrasentan 0.5 mg, or atrasentan 1.25 mg once daily for 8 weeks. Thoracic bioimpedance, vital signs, clinical exams, and serologies were taken at weeks 1, 2, 4, 6, and 8, with the exception of serum hemoglobin, which was not taken at week 1, and serum brain natriuretic peptide, which was only taken at baseline, week 4, and week 8. Results Alterations in bioimpedance were more often present in those who received atrasentan than in those who received placebo, though overall differences were not statistically significant. Transient declines in thoracic bioimpedance during the first 2 weeks of atrasentan exposure occurred before or during peak increases in body weight and hemodilution (decreased serum hemoglobin). [ABSTRACT FROM AUTHOR]

Background: Hypertension is an important risk factor for Alzheimer's disease (AD) and cerebral small vessel disease. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are common anti-hypertensive treatments, but have differential effects on cortical amyloid.Objective: The objective of this study was to evaluate associations between anti-hypertensive treatment, brain volume, and cognition, using a propensity-weighted analysis to account for confounding by indication.Methods: We identified a cohort of normal elderly adults and individuals with mild cognitive impairment (MCI) or AD (N = 886; mean age = 75.0) from the Alzheimer's Disease Neuroimaging Initiative. Primary outcomes were brain parenchymal fraction, total hippocampal volume, and white matter hyperintensity (WMH) volume. Secondary outcomes were standardized scores on neuropsychological tests. Propensity-weighted adjusted multivariate linear regression was used to estimate associations between anti-hypertensive treatment class and MRI volumes and cognition.Results: Individuals treated with ARBs showed larger hippocampal volumes (R2 = 0.83, p = 0.05) and brain parenchymal fraction (R2 = 0.83, p = 0.01) than those treated with ACEIs. When stratified by diagnosis, this effect remained only in normal elderly adults and MCI patients, and a significant association between ARBs and lower WMH volume (R2 = 0.83, p = 0.03) emerged for AD patients only. ARBs were also associated with significantly better performance on tests of episodic and verbal memory, language, and executive function (all p < 0.05).Conclusions: Findings are consistent with evidence for a neuroprotective effect of treatment with ARBs for brain structure and cognition. This study has potential implications for the treatment of hypertension, particularly in elderly adults at risk of cognitive decline and AD. [ABSTRACT FROM AUTHOR]

We assessed the effect of atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, 4 of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and 6 were reduced in patients with eGFR < 60 mL/min/1.73 m2. After 12 weeks of atrasentan treatment in patients with eGFR < 60 mL/min/1.73 m2, a single-value index of the metabolites changed by −0.31 (95%CI −0.60 to −0.02; P = .035), −0.08 (−12 to 0.29; P = .43) and 0.01 (−0.21 to 0.19; P = .913) in placebo, atrasentan 0.75 and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (−0.17 to 0.43; P = .40) and 0.35 (0.05-0.65; P = .02) for atrasentan 0.75 and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy and eGFR < 60 mL/min/1.73 m2, suggesting that atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with atrasentan are indicated. [ABSTRACT FROM AUTHOR]

Background: High-quality ambulatory care can reduce cardiovascular disease risk, but important gaps exist in the provision of cardiovascular preventive care. We sought to develop a set of key performance indicators that can be used to measure and improve cardiovascular care in the primary care setting. Methods: As part of the Cardiovascular Health in Ambulatory Care Research Team initiative, we established a 14-member multidisciplinary expert panel to develop a set of indicators for measuring primary prevention performance in ambulatory cardiovascular care. We used a 2-stage modified Delphi panel process to rate potential indicators, which were identified from the literature and national cardiovascular organizations. The top-rated indicators were pilot tested to determine their measurement feasibility with the use of data routinely collected in the Canadian health care system. Results: A set of 28 indicators of primary prevention performance were identified, which were grouped into 5 domains: risk factor prevalence, screening, management, intermediate outcomes and long-term outcomes. The indicators reflect the major cardiovascular risk factors including smoking, obesity, hypertension, diabetes, dyslipidemia and atrial fibrillation. All indicators were determined to be amenable to measurement with the use of population-based administrative (physician claims, hospital admission, laboratory, medication), survey or electronic medical record databases. Interpretation: The Cardiovascular Health in Ambulatory Care Research Team indicators of primary prevention performance provide a framework for the measurement of cardiovascular primary prevention efforts in Canada. The indicators may be used by clinicians, researchers and policy-makers interested in measuring and improving the prevention of cardiovascular disease in ambulatory care settings. [ABSTRACT FROM AUTHOR]

Aims The selective endothelin ( ET) A receptor antagonist atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to atrasentan. Materials and methods Two 12-week double-blind randomised controlled trials were performed with atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in Asians ( N = 77) and North Americans ( N = 134). Atrasentan plasma concentration was measured in 161 atrasentan-treated patients. Results Mean albuminuria reduction in Asian, compared to North American, patients was, respectively, −34.4% vs −26.3% for 0.75 mg/d ( P = .44) and −48.0% vs −28.9% for 1.25 mg/d ( P = .035). Bodyweight gain did not differ between North American and Asian populations. Atrasentan plasma concentrations were higher in Asians compared to North Americans and correlated with albuminuria response (7.2% albuminuria reduction per doubling atrasentan concentration; P = .024). Body surface area (β = −1.09 per m2; P < .001) and bilirubin, as a marker of hepatic organic anion transporter activity, (β = 0.69 per mg/ dL increment; P = .010) were independent determinants of atrasentan plasma concentration; correction by body surface area and bilirubin left no significant difference in plasma concentration between Asian and North American populations. Conclusion The higher exposure and albuminuria reduction of atrasentan in Asian patients is not associated with more fluid retention, suggesting that Asian patients are less sensitive to atrasentan-induced sodium retention. [ABSTRACT FROM AUTHOR]

Background: The imperative to improve global health has prompted transnational research partnerships to investigate common health issues on a larger scale. The Global Alliance for Chronic Diseases (GACD) is an alliance of national research funding agencies. To enhance research funded by GACD members, this study aimed to standardise data collection methods across the 15 GACD hypertension research teams and evaluate the uptake of these standardised measurements. Furthermore we describe concerns and difficulties associated with the data harmonisation process highlighted and debated during annual meetings of the GACD funded investigators. With these concerns and issues in mind, a working group comprising representatives from the 15 studies iteratively identified and proposed a set of common measures for inclusion in each of the teams' data collection plans. One year later all teams were asked which consensus measures had been implemented.Results: Important issues were identified during the data harmonisation process relating to data ownership, sharing methodologies and ethical concerns. Measures were assessed across eight domains; demographic; dietary; clinical and anthropometric; medical history; hypertension knowledge; physical activity; behavioural (smoking and alcohol); and biochemical domains. Identifying validated measures relevant across a variety of settings presented some difficulties. The resulting GACD hypertension data dictionary comprises 67 consensus measures. Of the 14 responding teams, only two teams were including more than 50 consensus variables, five teams were including between 25 and 50 consensus variables and four teams were including between 6 and 24 consensus variables, one team did not provide details of the variables collected and two teams did not include any of the consensus variables as the project had already commenced or the measures were not relevant to their study.Conclusions: Deriving consensus measures across diverse research projects and contexts was challenging. The major barrier to their implementation was related to the time taken to develop and present these measures. Inclusion of consensus measures into future funding announcements would facilitate researchers integrating these measures within application protocols. We suggest that adoption of consensus measures developed here, across the field of hypertension, would help advance the science in this area, allowing for more comparable data sets and generalizable inferences. [ABSTRACT FROM AUTHOR]

Rates of cardiovascular mortality and morbidity in Russia have been among the highest in Europe. A comprehensive health system improvement program targeting better diagnosis and control of hypertension was undertaken in the Yaroslavl Region of Russia. This initiative was a joint program between clinicians, the Department of Health and Pharmacy of the Yaroslavl Region, and Novartis Pharma LLC. From 2011 to 2014, the blood pressure control rate improved substantially (94% relative improvement), the percentage of patients with a systolic blood pressure ≥180 mm Hg decreased (from 10% to 5%), and there was a reduction in stroke incidence rate from 4.6 to 3.7 per 1000 population. During this same period, significant changes were made to the way hypertension was diagnosed and treated across all regional government polyclinics, and the use of antihypertensive therapies increased. [ABSTRACT FROM AUTHOR]

Endothelin receptor antagonists (ERAs) have the potential to be a new paradigm in the treatment of chronic kidney disease (CKD). ERAs inhibit the effects of endothelin-1 (ET-1), which is known to promote CKD by causing renal cellular injury, proteinuria, inflammation, fibrosis, and hypertrophy. ERAs have been extensively studied preclinically in models of CKD and now in a large clinical trial to determine their effect on slowing the progression of CKD. Initial clinical trials show promise with regard to ERA effects on reducing proteinuria in patients with diabetic nephropathy (DN) who are already on renin-angiotensin system (RAS) blocking agents. A common side effect of peripheral edema has been consistently reported in clinical trials using ERAs; hence, finding a safe balance between renoprotective actions and side effects needs to be achieved. [ABSTRACT FROM AUTHOR]

Background: Non-communicable chronic diseases are the leading causes of mortality globally, and nearly 80% of these deaths occur in low- and middle-income countries (LMICs). In high-income countries (HICs), inequitable distribution of resources affects poorer and otherwise disadvantaged groups including Aboriginal peoples. Cardiovascular mortality in high-income countries has recently begun to fall; however, these improvements are not realized among citizens in LMICs or those subgroups in high-income countries who are disadvantaged in the social determinants of health including Aboriginal people. It is critical to develop multi-faceted, affordable and realistic health interventions in collaboration with groups who experience health inequalities. Based on community-based participatory research (CBPR), we aimed to develop implementation tools to guide complex interventions to ensure that health gains can be realized in low-resource environments. Methods: We developed the I-RREACH (Intervention and Research Readiness Engagement and Assessment of Community Health Care) tool to guide implementation of interventions in low-resource environments. We employed CBPR and a consensus methodology to (1) develop the theoretical basis of the tool and (2) to identify key implementation factor domains; then, we (3) collected participant evaluation data to validate the tool during implementation. Results: The I-RREACH tool was successfully developed using a community-based consensus method and is rooted in participatory principles, equalizing the importance of the knowledge and perspectives of researchers and community stakeholders while encouraging respectful dialogue. The I-RREACH tool consists of three phases: fact finding, stakeholder dialogue and community member/patient dialogue. The evaluation for our first implementation of I-RREACH by participants was overwhelmingly positive, with 95% or more of participants indicating comfort with and support for the process and the dialogue it creates. Conclusions: The I-RREACH tool was designed to (1) pinpoint key domains required for dialogue between the community and the research team to facilitate implementation of complex health interventions and research projects and (2) to identify existing strengths and areas requiring further development for effective implementation. I-RREACH has been found to be easily adaptable to diverse geographical and cultural settings and can be further adapted to other complex interventions. Further research should include the potential use of the I-RREACH tool in the development of blue prints for scale-up of successful interventions, particularly in low-resource environments. [ABSTRACT FROM AUTHOR]

Despite progress in automated blood pressure measurement (BPM) technology, there is limited research linking hard outcomes to automated office BPM (OBPM) treatment targets and thresholds. Equivalences for automated BPM devices have been estimated from approximations of standardized manual measurements of 140/90 mmHg. Until outcome-driven targets and thresholds become available for automated measurement methods, deriving evidence-based equivalences between automated methods and standardized manual OBPM is the next best solution. The MeasureBP study group was initiated by the Canadian Hypertension Education Program to close this critical knowledge gap. MeasureBP aims to define evidence-based equivalent values between standardized manual OBPM and automated BPM methods by synthesizing available evidence using a systematic review and individual subject-level data meta-analyses. This manuscript provides a review of the literature and MeasureBP study protocol. These results will lay the evidenced-based foundation to resolve uncertainties within blood pressure guidelines which, in turn, will improve the management of hypertension. [ABSTRACT FROM AUTHOR]

The article highlights the new and important changes in the 2014 Canadian Cardiovascular Harmonized National Guidelines Endeavour guideline. It cites several topic areas of change such as lifestyle management, risk-factor screening and risk stratification, and treatment targets for dyslipidemia. Information is also presented on the composition of the guideline panel, guideline development, and guideline tools and resources for providers and patients.

BACKGROUND The HARMONY study was a randomized, controlled trial examining the efficacy of an 8-week mindfulness-based stress reduction (MBSR) program for blood pressure (BP) lowering among unmedicated stage 1 hypertensive participants. METHODS Participants diagnosed with stage 1 hypertension based on ambulatory BP were randomized to either immediate treatment of MBSR for 8 weeks or wait-list control. Primary outcome analysis evaluated whether change in awake and 24-hour ambulatory BP from baseline to week 12 was significantly different between the 2 groups. A within-group before and after MBSR analysis was also performed. RESULTS The study enrolled 101 adults (38% male) with baseline average 24-hour ambulatory BP of 135±7.9/82±5.8mm Hg and daytime ambulatory BP of 140±7.7/87±6.3 mmHg. At week 12, the change from baseline in 24-hour ambulatory BP was 0.4±6.7/0.0±4.9mm Hg for the immediate intervention and 0.4±7.8/−0.4±4.6mm Hg for the wait-list control. There were no significant differences between intervention and wait-list control for all ambulatory BP parameters. The secondary within-group analysis found a small reduction in BP after MBSR compared with baseline, a finding limited to female subjects in a sex analysis. CONCLUSIONS MBSR did not lower ambulatory BP by a statistically or clinically significant amount in untreated, stage 1 hypertensive patients when compared with a wait-list control group. It leaves untested whether MBSR might be useful for lowering BP by improving adherence in treated hypertensive participants. CLINICAL TRIALS REGISTRATION NCT00825526. [ABSTRACT FROM AUTHOR]

This prospective before-and-after survey of hypertensive patients visiting government-run outpatient health facilities in the Yaroslavl Region of Russia assessed blood pressure (BP)-related endpoints following initiation of a comprehensive health system improvement program for hypertension. Two cross-sectional surveys, one at baseline and the other approximately 1 year after program initiation, evaluated the primary measure of BP control rate. Secondary measures included mean BP levels and distribution, cardiovascular risk factors, and associated conditions, heart rate levels, and antihypertensive therapy. From the 2011 survey (n=1794) to the 2012 survey (n=2992), BP control rate (<140/90 mm Hg) significantly increased from 16.8% to 23.0%, reflecting a 37% relative improvement ( P<.0001). Mean BP level was significantly reduced from 151/90 mm Hg to 147/88 mm Hg ( P<.0001). Severe uncontrolled hypertension ( systolic BP ≥180 mm Hg) was reduced from 9.7% to 6.4% ( P<.0001). Implementing a guidelines-based treatment protocol with medical and patient education programs resulted in physician behavior change and improved patient BP control. [ABSTRACT FROM AUTHOR]

The article offers information on the theories of doctors related to the need of appropriate blood pressure targets for patients suffering from hypertension and diabetes. It discusses the possibility of adverse cardiovascular events for patients suffering from both hypertension and diabetes which also increases the possibility of stroke and myocardial infarction.