Norman Muirhead’s research while affiliated with Western University and other places

Background and Purpose Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. Methods CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis. Results In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55–1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61–1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19–1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20–1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53–1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HR pooled , 0.96 [95% CI, 0.82–1.12]), ischemic stroke (HR pooled , 1.01 [95% CI, 0.89–1.14]), hemorrhagic stroke (HR pooled , 0.50 [95% CI, 0.30–0.83]), undetermined stroke (HR pooled , 0.86 [95% CI, 0.49–1.51]), and AF/AFL (HR pooled , 0.81 [95% CI, 0.71–0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate ( P =0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m ² ]) subgroup (HR pooled , 0.50 [95% CI, 0.31–0.79]). Conclusions Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02065791.

Aims Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular and non-cardiovascular causes of death. Methods and results DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200–5000 mg/g and an estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n = 2152) or placebo (n = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio [HR] [95% confidence interval (CI)] 0.69 [0.53, 0.88]; P = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR [95% CI] 0.54 [0.36, 0.82]). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo. Conclusion In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death.

Introduction: Low‐molecular weight heparin, such as dalteparin, is an alternative anticoagulation method in conventional hemodialysis (HD). However, there are limited studies on its use in quotidian and nocturnal HD. We assessed the optimal dose, treatment efficacy, and patient safety of dalteparin in quotidian and nocturnal HD populations. Methods: This study included 10 quotidian (7 in‐center and 3 home) and 8 nocturnal home HD patients. Dalteparin was initiated and titrated based on clotting score in these patients. Trough anti‐Xa levels were measured. The dalteparin dose, the dialyzer and HD circuit clotting scores, and bleeding episodes were recorded at 4 weeks. Patients who continued dalteparin were followed to 12 months. Findings: For the 10 quotidian HD patients, the median dalteparin dose was 1875 units [1250, 2500] after 4 weeks. For nocturnal HD patients, five of the eight patients switched back to heparin due to high clotting scores while on dalteparin within 4 weeks. However, three patients continued on dalteparin at 4 weeks. After 12 months, one maintained on 5000 units and the other two maintained on 7500 units of dalteparin. All the clotting scores at month 12 were ≤2. One patient died due to an unrelated cause. For all patients who continued on dalteparin, only 9% of the HD treatments had circuit clotting score >2 after reaching stable dose. All trough anti‐Xa levels were <0.1 IU/mL. There were no episodes of bleeding. Fistula compression times were not increased. Discussion: This small pilot study suggests that dalteparin can be used effectively and relatively safety in quotidian HD. However, its use in nocturnal HD was only successful in a small proportion of patients. Alternative methods, including second dalteparin bolus after 4 hours of HD treatment, should be assessed for efficacy and practicality.

Background Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. Methods In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m² of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m²), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. Results The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. Conclusions In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.)

Supplement_2 – Supplemental material for An Adjustable Dalteparin Sodium Dose Regimen for the Prevention of Clotting in the Extracorporeal Circuit in Hemodialysis: A Clinical Trial of Safety and Efficacy (the PARROT Study)

Background Dalteparin sodium, a low-molecular-weight heparin, is indicated for prevention of clotting in the extracorporeal circuit during hemodialysis (HD). Product labeling recommends a fixed single-bolus dose of 5000 international units (IU) for HD sessions lasting up to 4 hours, but adjustable dosing may be beneficial in clinical practice. Objective The aim of the PARROT study was to investigate the safety and efficacy of an adjustable dose of dalteparin in patients with end-stage renal disease requiring 3 to 4 HD sessions per week. Design A 7-week, open-label, multicenter study with a single treatment arm, conducted between October 2013 and March 2016. Setting Ten sites in Canada. Patients A total of 152 patients with end-stage renal disease requiring 3 to 4 HD sessions per week. Measurements The primary outcome was the proportion of HD sessions completed without premature termination due to inadequate anticoagulation. Methods All participants initially received a dose of 5000 IU dalteparin, which could be adjusted at subsequent HD sessions when clinically indicated, by increment or decrement of 500 or 1000 IU, with no specified dose limits. Results Patients were followed for 256 patient-months. Nearly all (99.9%; 95% confidence interval [CI]: 99.7-100) evaluable HD sessions were completed without premature clotting. Dose was adjusted for more than half (52.3%) of participants, mostly owing to clotting or access compression time >10 minutes. Median dalteparin dose was 5000 IU (range: 500-13 000 IU). There were no major bleeds, and minor bleeding was reported in 2.3% of all HD sessions. There was no evidence of bioaccumulation. Limitations This short-term study, with a single treatment arm, was designed to optimize dalteparin dose using a flexible dosing schedule; it was not designed to specifically evaluate dalteparin dose minimization, provide a direct comparison of dalteparin versus unfractionated heparin, or provide information on long-term safety for flexible dalteparin dosing. Patients were excluded if they were at high risk of bleeding, including those on anticoagulants and those on antiplatelet agents other than aspirin <100 mg/d. Conclusions Overall, an adjustable dalteparin sodium dose regimen allowed safe completion of HD, with clinical benefits over fixed dosing. Trial Registration ClinicalTrials.gov NCT01879618, registered June 13, 2013.

Supplement_3 – Supplemental material for An Adjustable Dalteparin Sodium Dose Regimen for the Prevention of Clotting in the Extracorporeal Circuit in Hemodialysis: A Clinical Trial of Safety and Efficacy (the PARROT Study)

Supplement_1 – Supplemental material for An Adjustable Dalteparin Sodium Dose Regimen for the Prevention of Clotting in the Extracorporeal Circuit in Hemodialysis: A Clinical Trial of Safety and Efficacy (the PARROT Study)

Background Several studies have demonstrated harm associated with using erythropoiesis-stimulating agents (ESA) to achieve higher hemoglobin (Hb) levels. Subsequently, more conservative use of ESAs has changed anemia therapy in patients with chronic renal failure. Objective The objectives were to identify transfusion rates in hemodialysis (HD) patients during the first year of therapy, to identify factors associated with the probability of transfusion, describe reasons for the transfusions, and identify the Hb values associated with each transfusion. An exploratory objective was to describe the age of red blood cell transfusions. Design This was a multicenter prospective observational cohort study. Setting There were 12 study sites in 5 Canadian provinces. The study was performed from 2012 to 2014. Methods The study patients were adult incident chronic HD patients in these centers. Patients with acute kidney injury, peritoneal dialysis, and planned transfer to satellite units were excluded. Patients had to receive at least 1 month of chronic HD to be eligible. Data for 3 months prior to HD were obtained by retrospective chart review. Prospectively, charts were reviewed monthly for 12 months for data abstraction. Results There were 314 patients enrolled and 79.9% completed 12 month follow-up. Ninety-four (29.9%) patients received at least 1 unit of blood. During the first 90 days, the transfusion episode rate was 148.4 per 100 patient-years compared with 62.6 per 100 patient-years post 90 days. The most frequent indication was a low Hb value (92%) with gastrointestinal bleeding, surgical blood loss, and fatigue accounting for 9.9%, 8.6%, and 4.5%, respectively. Some patients had >1 indication. The mean Hb values prior to transfusion episodes ranged from 75.3 to 78.6 g/L. Cox regression analysis on time to first transfusion and time to first hospitalization/death both showed an association with inpatient initiation of HD. Some 37.5% initiated HD as an inpatient and differed from those starting as an outpatient. They had less predialysis care and laboratory data suggested more inflammation. The mean and median ages of the blood units transfused were 24.9 (SD = 10.0) and 23 days (interquartile range = 17-33). Conclusions This work reported the blood transfusion rate in incident HD patients in Canada during a period associated with conservative ESA prescription. The major indication for transfusion was a low Hb rather than clinical symptoms. Initiation of HD as an inpatient was independently associated with the probability of receiving a blood transfusion. These findings require further investigation.

Importance In observational studies, increased water intake is associated with better kidney function. Objective To determine the effect of coaching to increase water intake on kidney function in adults with chronic kidney disease. Design, Setting, and Participants The CKD WIT (Chronic Kidney Disease Water Intake Trial) randomized clinical trial was conducted in 9 centers in Ontario, Canada, from 2013 until 2017 (last day of follow-up, May 25, 2017). Patients had stage 3 chronic kidney disease (estimated glomerular filtration rate [eGFR] 30-60 mL/min/1.73 m² and microalbuminuria or macroalbuminuria) and a 24-hour urine volume of less than 3.0 L. Interventions Patients in the hydration group (n = 316) were coached to drink more water, and those in the control group (n = 315) were coached to maintain usual intake. Main Outcomes and Measures The primary outcome was change in kidney function (eGFR from baseline to 12 months). Secondary outcomes included 1-year change in plasma copeptin concentration, creatinine clearance, 24-hour urine albumin, and patient-reported overall quality of health (0 [worst possible] to 10 [best possible]). Results Of 631 randomized patients (mean age, 65.0 years; men, 63.4%; mean eGFR, 43 mL/min/1.73 m²; median urine albumin, 123 mg/d), 12 died (hydration group [n = 5]; control group [n = 7]). Among 590 survivors with 1-year follow-up measurements (95% of 619), the mean change in 24-hour urine volume was 0.6 L per day higher in the hydration group (95% CI, 0.5 to 0.7; P < .001). The mean change in eGFR was −2.2 mL/min/1.73 m² in the hydration group and −1.9 mL/min/1.73 m² in the control group (adjusted between-group difference, −0.3 mL/min/1.73 m² [95% CI, −1.8 to 1.2; P = .74]). The mean between-group differences (hydration vs control) in secondary outcomes were as follows: plasma copeptin, −2.2 pmol/L (95% CI, −3.9 to −0.5; P = .01); creatinine clearance, 3.6 mL/min/1.73 m² (95% CI, 0.8 to 6.4; P = .01); urine albumin, 7 mg per day (95% CI, −4 to 51; P = .11); and quality of health, 0.2 points (95% CI, −0.3 to 0.3; P = .22). Conclusions and Relevance Among adults with chronic kidney disease, coaching to increase water intake compared with coaching to maintain the same water intake did not significantly slow the decline in kidney function after 1 year. However, the study may have been underpowered to detect a clinically important difference. Trial Registration clinicaltrials.gov Identifier: NCT01766687.