| 1. |
- Bangalore, Sripal, et al.
(författare)
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Management of Coronary Disease in Patients with Advanced Kidney Disease.
- 2020
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 382:17, s. 1608-1618
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Clinical trials that have assessed the effect of revascularization in patients with stable coronary disease have routinely excluded those with advanced chronic kidney disease.METHODS: We randomly assigned 777 patients with advanced kidney disease and moderate or severe ischemia on stress testing to be treated with an initial invasive strategy consisting of coronary angiography and revascularization (if appropriate) added to medical therapy or an initial conservative strategy consisting of medical therapy alone and angiography reserved for those in whom medical therapy had failed. The primary outcome was a composite of death or nonfatal myocardial infarction. A key secondary outcome was a composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest.RESULTS: At a median follow-up of 2.2 years, a primary outcome event had occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36.4% vs. 36.7%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P = 0.95). Results for the key secondary outcome were similar (38.5% vs. 39.7%; hazard ratio, 1.01; 95% CI, 0.79 to 1.29). The invasive strategy was associated with a higher incidence of stroke than the conservative strategy (hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P = 0.004) and with a higher incidence of death or initiation of dialysis (hazard ratio, 1.48; 95% CI, 1.04 to 2.11; P = 0.03).CONCLUSIONS: Among patients with stable coronary disease, advanced chronic kidney disease, and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).
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| 2. |
- Koury, Mark J., et al.
(författare)
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Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease
- 2022
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Ingår i: American Journal of Hematology. - : John Wiley & Sons. - 0361-8609 .- 1096-8652. ; 97:9, s. 1178-1188
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Tidskriftsartikel (refereegranskat)abstract
- Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non–dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.
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| 3. |
- Spertus, John A, et al.
(författare)
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Health Status after Invasive or Conservative Care in Coronary and Advanced Kidney Disease.
- 2020
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 382:17, s. 1619-1628
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In the ISCHEMIA-CKD trial, the primary analysis showed no significant difference in the risk of death or myocardial infarction with initial angiography and revascularization plus guideline-based medical therapy (invasive strategy) as compared with guideline-based medical therapy alone (conservative strategy) in participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease (an estimated glomerular filtration rate of <30 ml per minute per 1.73 m2 or receipt of dialysis). A secondary objective of the trial was to assess angina-related health status.METHODS: We assessed health status with the Seattle Angina Questionnaire (SAQ) before randomization and at 1.5, 3, and 6 months and every 6 months thereafter. The primary outcome of this analysis was the SAQ Summary score (ranging from 0 to 100, with higher scores indicating less frequent angina and better function and quality of life). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate the treatment effect with the invasive strategy.RESULTS: Health status was assessed in 705 of 777 participants. Nearly half the participants (49%) had had no angina during the month before randomization. At 3 months, the estimated mean difference between the invasive-strategy group and the conservative-strategy group in the SAQ Summary score was 2.1 points (95% credible interval, -0.4 to 4.6), a result that favored the invasive strategy. The mean difference in score at 3 months was largest among participants with daily or weekly angina at baseline (10.1 points; 95% credible interval, 0.0 to 19.9), smaller among those with monthly angina at baseline (2.2 points; 95% credible interval, -2.0 to 6.2), and nearly absent among those without angina at baseline (0.6 points; 95% credible interval, -1.9 to 3.3). By 6 months, the between-group difference in the overall trial population was attenuated (0.5 points; 95% credible interval, -2.2 to 3.4).CONCLUSIONS: Participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease did not have substantial or sustained benefits with regard to angina-related health status with an initially invasive strategy as compared with a conservative strategy. (Funded by the National Heart, Lung, and Blood Institute; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).
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| 4. |
- Stanifer, John W., et al.
(författare)
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Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease
- 2020
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Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 141:17, s. 1384-1392
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Tidskriftsartikel (refereegranskat)abstract
- Background: Compared with the general population, patients with advanced chronic kidney disease have a >10-fold higher burden of atrial fibrillation. Limited data are available guiding the use of nonvitamin K antagonist oral anticoagulants in this population.Methods: We compared the safety of apixaban with warfarin in 269 patients with atrial fibrillation and advanced chronic kidney disease (defined as creatinine clearance [CrCl] 25 to 30 mL/min) enrolled in the ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). Cox proportional models were used to estimate hazard ratios for major bleeding and major or clinically relevant nonmajor bleeding. We characterized the pharmacokinetic profile of apixaban by assessing differences in exposure using nonlinear mixed effects models.Results: Among patients with CrCl 25 to 30 mL/min, apixaban caused less major bleeding (hazard ratio, 0.34 [95% CI, 0.14-0.80]) and major or clinically relevant nonmajor bleeding (hazard ratio, 0.35 [95% CI, 0.17-0.72]) compared with warfarin. Patients with CrCl 25 to 30 mL/min randomized to apixaban demonstrated a trend toward lower rates of major bleeding when compared with those with CrCl >30 mL/min (P interaction=0.08) and major or clinically relevant nonmajor bleeding (P interaction=0.05). Median daily steady-state areas under the curve for apixaban 5 mg twice daily were 5512 ng/(mL center dot h) and 3406 ng/(mL center dot h) for patients with CrCl 25 to 30 mL/min or >30 mL/min, respectively. For apixaban 2.5 mg twice daily, the median exposure was 2780 ng/(mL center dot h) for patients with CrCl 25 to 30 mL/min. The area under the curve values for patients with CrCl 25 to 30 mL/min fell within the ranges demonstrated for patients with CrCl >30 mL/min.Conclusions: Among patients with atrial fibrillation and CrCl 25 to 30 mL/min, apixaban caused less bleeding than warfarin, with even greater reductions in bleeding than in patients with CrCl >30 mL/min. We observed substantial overlap in the range of exposure to apixaban 5 mg twice daily for patients with or without advanced chronic kidney disease, supporting conventional dosing in patients with CrCl 25 to 30 mL/min. Randomized, controlled studies evaluating the safety and efficacy of apixaban are urgently needed in patients with advanced chronic kidney disease, including those receiving dialysis.
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| 5. |
- Heerspink, Hiddo J L, et al.
(författare)
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A pre-specified analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial on the incidence of abrupt declines in kidney function.
- 2022
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Ingår i: Kidney international. - : Elsevier BV. - 1523-1755 .- 0085-2538. ; 101:1, s. 174-184
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Tidskriftsartikel (refereegranskat)abstract
- This pre-specified analysis of DAPA-CKD assessed the impact of sodium-glucose cotransporter 2 inhibition on abrupt declines in kidney function in high-risk patients based on having chronic kidney disease (CKD) and substantial albuminuria. DAPA-CKD was a randomized, double-blind, placebo-controlled trial that had a median follow-up of 2.4 years. Adults with CKD (urinary albumin-to-creatinine ratio 200-5000 mg/g and estimated glomerular filtration rate 25-75 mL/min/1.73m2) were randomized to dapagliflozin 10 mg/day matched to placebo (2152 individuals each). An abrupt decline in kidney function was defined as a pre-specified endpoint of doubling of serum creatinine between two subsequent study visits. We also assessed a post-hoc analysis of investigator-reported acute kidney injury-related serious adverse events. Doubling of serum creatinine between two subsequent visits (median time-interval 100 days) occurred in 63 (2.9%) and 91 (4.2%) participants in the dapagliflozin and placebo groups, respectively (hazard ratio 0.68 [95% confidence interval 0.49, 0.94]). Accounting for the competing risk of mortality did not alter our findings. There was no heterogeneity in the effect of dapagliflozin on abrupt declines in kidney function based on baseline subgroups. Acute kidney injury-related serious adverse events were not significantly different and occurred in 52 (2.5%) and 69 (3.2%) participants in the dapagliflozin and placebo groups, respectively (0.77 [0.54, 1.10]). Thus, in patients with CKD and substantial albuminuria, dapagliflozin reduced the risk of abrupt declines in kidney function.
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| 6. |
- Heerspink, Hiddo J L, et al.
(författare)
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Effects of dapagliflozin on mortality in patients with chronic kidney disease : a pre-specified analysis from the DAPA-CKD randomized controlled trial.
- 2021
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 42:13, s. 1216-1227
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Heerspink, Hiddo J L, et al.
(författare)
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Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial.
- 2020
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Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 35:2, s. 274-282
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recent cardiovascular outcome trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease (CKD) in patients with type 2 diabetes at high cardiovascular risk. Whether these benefits extend to CKD patients without type 2 diabetes or cardiovascular disease is unknown. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) will assess the effect of the SGLT2 inhibitor dapagliflozin on renal and cardiovascular events in a broad range of patients with CKD with and without diabetes.METHODS: DAPA-CKD is a randomized, double-blind, placebo-controlled, trial in which ∼4300 patients with CKD Stages 2-4 and elevated urinary albumin excretion will be enrolled. The vast majority will be receiving a maximum tolerated dose of a renin-angiotensin system inhibitor at enrolment.RESULTS: After a screening assessment, eligible patients with a urinary albumin:creatinine ratio ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 are randomly assigned to placebo or dapagliflozin 10 mg/day. Enrolment is monitored to ensure that at least 30% of patients do not have diabetes and that no more than 10% have an eGFR >60 mL/min/1.73 m2. The primary endpoint is a composite of a sustained decline in eGFR of ≥50%, end-stage renal disease, renal death or cardiovascular death. The trial will conclude when 681 primary renal events have occurred, providing 90% power to detect a 22% relative risk reduction (α level of 0.05).CONCLUSION: DAPA-CKD will determine whether the SGLT2 inhibitor dapagliflozin, added to guideline-recommended therapies, safely reduces the rate of renal and cardiovascular events in patients across multiple CKD stages with and without diabetes.
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| 8. |
- McMurray, John J. V., et al.
(författare)
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Effect of Dapagliflozin on Clinical Outcomes in Patients with Chronic Kidney Disease, With and Without Cardiovascular Disease
- 2021
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Ingår i: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 143:5, s. 438-448
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Tidskriftsartikel (refereegranskat)abstract
- Background:Dapagliflozin reduces the risk of end-stage renal disease in patients with chronic kidney disease. We examined the relative risk of cardiovascular and renal events in these patients and the effect of dapagliflozin on either type of event, taking account of history of cardiovascular disease.Methods:In the DAPA-CKD trial (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), 4304 participants with chronic kidney disease were randomly assigned to dapagliflozin 10 mg once daily or placebo. The primary end point was a composite of sustained decline in estimated glomerular filtration rate ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The secondary end points were a kidney composite outcome (primary end point, minus cardiovascular death), the composite of hospitalization for heart failure or cardiovascular death, and all-cause death. In a prespecified subgroup analysis, we divided patients into primary and secondary prevention subgroups according to history of cardiovascular disease.Results:Secondary prevention patients (n=1610; 37.4%) were older, were more often male, had a higher blood pressure and body mass index, and were more likely to have diabetes. Mean estimated glomerular filtration rate and median urinary albumin-to-creatinine ratio were similar in the primary and secondary prevention groups. The rates of adverse cardiovascular outcomes were higher in the secondary prevention group, but kidney failure occurred at the same rate in the primary and secondary prevention groups. Dapagliflozin reduced the risk of the primary composite outcome to a similar extent in both the primary (hazard ratio, 0.61 [95% CI, 0.48–0.78]) and secondary (0.61 [0.47–0.79]) prevention groups (P-interaction=0.90). This was also true for the composite of heart failure hospitalization or cardiovascular death (0.67 [0.40–1.13] versus 0.70 [0.52–0.94], respectively; P-interaction=0.88), and all-cause mortality (0.63 [0.41–0.98] versus 0.70 [0.51–0.95], respectively; P-interaction=0.71). Rates of adverse events were low overall and did not differ between patients with and without cardiovascular disease.Conclusions:Dapagliflozin reduced the risk of kidney failure, death from cardiovascular causes or hospitalization for heart failure, and prolonged survival in people with chronic kidney disease, with or without type 2 diabetes, independently of the presence of concomitant cardiovascular disease.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036150.
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| 9. |
- Nilsson, Erik, 1975-, et al.
(författare)
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Testosterone concentrations andoutcomes in hemodialysis patients of the EVOLVE trial
- 2023
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Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press. - 0931-0509 .- 1460-2385. ; 38:6, s. 1519-1527
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hypogonadism is common in end-stage kidney disease and may contribute to morbidity and mortality.METHODS: Using data from the randomized controlled EVOLVE trial of cinacalcet, we analyzed the associations of total testosterone, free testosterone, and sex-hormone binding globulin (SHBG) serum concentrations with mortality and major cardiovascular events in 1692 men and 1059 women receiving hemodialysis. We also describe the effect of cinacalcet treatment on serum concentrations of testosterone.RESULTS: Among men, lower serum free testosterone (OR 0.18 95%, CI 0.04-0.82, p = 0.026) and higher SHBG (OR 1.05 per 10 nmol/L, 95% CI 1.01-1.10, p = 0.012), but not total testosterone, were associated with higher risk of death or cardiovascular event. Only SHBG was associated with all-cause mortality (OR 1.07 per 10 nmol/L, 95% CI 1.02-1.12, p = 0.0073). Among women, neither total- or free testosterone, nor SHBG were associated with outcomes. We found no statistically significant effect of cinacalcet treatment on SHBG, free- or total testosterone.CONCLUSIONS: Lower free testosterone and higher SHBG in serum are associated with higher risk of death or cardiovascular event in men undergoing chronic hemodialysis.
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| 10. |
- Toto, Robert D., et al.
(författare)
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Correction of hypomagnesemia by dapagliflozin in patients with type 2 diabetes : A post hoc analysis of 10 randomized, placebo-controlled trials
- 2019
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Ingår i: Journal of diabetes and its complications. - : Elsevier. - 1056-8727 .- 1873-460X. ; 33:10
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Hypomagnesemia (serum magnesium [Mg] <0.74 mmol/L [<1.8 mg/dL]) is commonly observed in patients with type 2 diabetes (T2D). This study investigated the effect of treatment with dapagliflozin 10 mg on Mg concentrations in patients with T2D. Methods: In this post hoc analysis, we used pooled data from 10 placebo-controlled studies of dapagliflozin over 24 weeks of treatment in patients with T2D. We evaluated the change in Mg in patients receiving dapagliflozin vs. placebo overall, and in subgroups with baseline hypomagnesemia and normal/hypermagnesemia (≥0.74 mmol/L [≥1.8 mg/dL]). We determined the proportion of patients with baseline hypomagnesemia who achieved Mg ≥0.74 mmol/L (≥1.8 mg/dL). Results: A total of 4398 patients with T2D were included. The mean change from baseline to week 24 in Mg was significantly larger with dapagliflozin vs. placebo; difference, 0.06 mmol/L (95% confidence interval [CI]: 0.05, 0.06). The proportion of patients with Mg within the population reference range after 24 weeks of treatment was significantly higher with dapagliflozin vs. placebo; difference, 47.8% (95% CI: 41.4, 53.9). The proportion of patients displaying hypermagnesemia did not increase with dapagliflozin treatment. Conclusions: Treatment with dapagliflozin 10 mg resulted in correction of Mg concentrations in patients with T2D and hypomagnesemia.
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