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Discontinuation of RAAS Inhibition in Children with Advanced CKD.
van den Belt, SM, Heerspink, HJL, Kirchner, M, Gracchi, V, Thurn-Valsassina, D, Bayazit, AK, Niemirska, A, Canpolat, N, Kaplan Bulut, I, Azukaitis, K, et al
Clinical journal of the American Society of Nephrology : CJASN. 2020;(5):625-632
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Abstract
BACKGROUND AND OBJECTIVES Although renin-angiotensin-aldosterone system inhibition (RAASi) is a cornerstone in the treatment of children with CKD, it is sometimes discontinued when kidney function declines. We studied the reasons of RAASi discontinuation and associations between RAASi discontinuation and important risk markers of CKD progression and on eGFR decline in the Cardiovascular Comorbidity in Children with CKD study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this study, 69 children with CKD (67% male, mean age 13.7 years, mean eGFR 27 ml/min per 1.73 m2) who discontinued RAASi during prospective follow-up were included. Initial change in BP, albuminuria, and potassium after discontinuation were assessed (median time 6 months). Rate of eGFR decline (eGFR slope) during a median of 1.9 years before and 1.2 years after discontinuation were estimated using linear mixed effects modeling. RESULTS Physician-reported reasons for RAASi discontinuation were increase in serum creatinine, hyperkalemia, and symptomatic hypotension. After discontinuation of RAASi, BP and albuminuria increased, whereas potassium decreased. eGFR declined more rapidly after discontinuation of RAASi (-3.9 ml/min per 1.73 m2 per year; 95% confidence interval, -5.1 to -2.6) compared with the slope during RAASi treatment (-1.5 ml/min per 1.73 m2 per year; 95% confidence interval, -2.4 to -0.6; P=0.005). In contrast, no change in eGFR slope was observed in a matched control cohort of patients in whom RAASi was continued. CONCLUSIONS Discontinuation of RAASi in children with CKD is associated with an acceleration of kidney function decline, even in advanced CKD.
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Kidney Function and Potassium Monitoring After Initiation of Renin-Angiotensin-Aldosterone System Blockade Therapy and Outcomes in 2 North American Populations.
Parikh, RV, Nash, DM, Brimble, KS, Markle-Reid, M, Tan, TC, McArthur, E, Khoshniat-Rad, F, Sood, MM, Zheng, S, Pravoverov, L, et al
Circulation. Cardiovascular quality and outcomes. 2020;(9):e006415
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BACKGROUND Clinical practice guidelines recommend routine kidney function and serum potassium testing within 30 days of initiating ACE (angiotensin-converting enzyme) inhibitor or angiotensin II receptor blocker therapy. However, evidence is lacking about whether follow-up testing reduces therapy-related adverse outcomes. METHODS AND RESULTS We conducted 2 population-based retrospective cohort studies in Kaiser Permanente Northern California and Ontario, Canada. Patients with outpatient serum creatinine and potassium tests in the 30 days after starting ACE inhibitor or angiotensin II receptor blocker therapy were matched 1:1 to patients without follow-up tests. We evaluated the association of follow-up testing with 30-day all-cause mortality and hospitalization with acute kidney injury or hyperkalemia using Cox regression. We also developed and externally validated a risk score to identify patients at risk of having abnormally high serum creatinine and potassium values in follow-up. We identified 75 251 matched pairs initiating ACE inhibitor or angiotensin II receptor blocker therapy between January 1, 2007, and December 31, 2017, in Kaiser Permanente Northern California. Follow-up testing was not significantly associated with 30-day all-cause mortality in Kaiser Permanente Northern California (hazard ratio, 0.75 [95% CI, 0.54-1.06]) and was associated with higher mortality in 84 905 matched pairs in Ontario (hazard ratio, 1.32 [95% CI, 1.07-1.62]). In Kaiser Permanente Northern California, follow-up testing was significantly associated with higher rates of hospitalization with acute kidney injury (hazard ratio, 1.66 [95% CI, 1.10-2.22]) and hyperkalemia (hazard ratio, 3.36 [95% CI, 1.08-10.41]), as was observed in Ontario. The risk score for abnormal potassium provided good discrimination (area under the curve [AUC], 0.75) and excellent calibration of predicted risks, while the risk score for abnormal serum creatinine provided moderate discrimination (AUC, 0.62) but excellent calibration. CONCLUSIONS Routine laboratory monitoring after ACE inhibitor or angiotensin II receptor blocker initiation was not associated with a lower risk of 30-day mortality. We identified patient subgroups in which targeted testing may be effective in identifying therapy-related changes in serum potassium or kidney function.
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A pilot double-blind randomized placebo-controlled crossover pharmacodynamic study of the centrally active aminopeptidase A inhibitor, firibastat, in hypertension.
Azizi, M, Courand, PY, Denolle, T, Delsart, P, Zhygalina, V, Amar, L, Lantelme, P, Mounier-Vehier, C, De Mota, N, Balavoine, F, et al
Journal of hypertension. 2019;(8):1722-1728
Abstract
OBJECTIVES We conducted a pilot multicenter double-blind randomized placebo-controlled crossover pharmacodynamic study to evaluate the blood pressure (BP) and the hormonal effects of firibastat, a first-in-class aminopeptidase A inhibitor prodrug, in patients with hypertension. METHODS Thirty-four patients with daytime ambulatory BP of at least 135/85 mmHg and less than 170/105 mmHg, after a 2-week run-in period were randomly assigned to receive either firibastat (250 mg b.i.d. for 1 week uptitrated to 500 mg b.i.d. for 3 weeks) and then placebo for 4 weeks each or vice versa, with a 2-week washout period on placebo. RESULTS At 4 weeks, daytime ambulatory systolic BP (SBP) decreased by 2.7 mmHg (95% confidence interval -6.5 to +1.1 mmHg) with firibastat versus placebo (P = 0.157). Office SBP decreased by 4.7 mmHg (95% confidence interval -11.1 to +1.8 mmHg) with firibastat versus placebo (P = 0.151). However, more the basal daytime ambulatory SBP was elevated, more the firibastat-induced BP decrease was marked. Firibastat did not influence 24h-ambulatory heart rate. Firibastat had no effect on plasma renin, aldosterone, apelin and copeptin concentrations. No major adverse events occurred. There was one episode of reversible skin allergy with facial edema. CONCLUSION In patients with hypertension, a 4-week treatment with firibastat, tended to decrease daytime SBP relative to placebo. Firibastat did not modify the activity of the systemic renin-angiotensin system These results have justified designing a larger, powered trial of longer duration to fully assess its safety and effectiveness. CLINICAL TRIAL REGISTRATION http://www.clinicaltrials.gov. NCT02322450.
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Implications of renin-angiotensin-system blocker discontinuation in acute decompensated heart failure with systolic dysfunction.
Darden, D, Drazner, MH, Mullens, W, Dupont, M, Tang, WHW, Grodin, JL
Clinical cardiology. 2019;(10):1010-1018
Abstract
BACKGROUND Renin-angiotensin-system blockers (RASB) improve clinical outcomes in patients with chronic heart failure with reduced fraction; however, there remains ambiguity whether RASB therapy should be continued during the treatment of acute decompensated heart failure (ADHF). HYPOTHESIS In comparison to patients with RASB use, RASB discontinuation in ADHF will be associated with worsening renal function, hypotension, and adverse long-term clinical outcomes. METHODS Patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization (ESCAPE) trial were separated into four groups based on RASB use at baseline and discharge: continuation (n = 316), discontinuation (n = 21), initiation (n = 42), and nonuse (n = 23). Post-discharge outcomes were validated in an independent ADHF cohort admitted to the Cleveland Clinic (n = 253). RESULTS RASB discontinuation and nonuse were associated with higher serial creatinine and blood urea nitrogen levels than RASB continuation or initiation (P < .001 for both), but not with serial potassium and systolic blood pressure measurements. No other clinical parameter changes were significant. In comparison to RASB continuation, RASB discontinuation and nonuse was associated with ~75% increased risk of a 180-day composite of death, transplant, or rehospitalization (HR 1.87, 95% CI 1.09-3.20, P = 0.02 and HR 1.72, CI 1.04-2.82, P = .03, respectively). Post-discharge outcomes were similar in the validation cohort. CONCLUSION Compared to RASB continuation, RASB discontinuation and nonuse were associated with higher baseline and serial creatinine levels during treatment for ADHF, but not with changes in SBP and potassium levels. Furthermore, RASB discontinuation and nonuse in ADHF were associated with an increased risk of adverse clinical outcomes.
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Renin Angiotensin Aldosterone System Blockades Does Not Protect Residual Renal Function in Patients with Hemodialysis at 1 Year After Dialysis Initiation: A Prospective Observational Cohort Study.
Yoo, KD, Kim, CT, Kwon, S, Lee, J, Oh, YK, Kang, SW, Yang, CW, Kim, YL, Kim, YS, Lim, CS, et al
Scientific reports. 2019;(1):18103
Abstract
The beneficial effects of renin angiotensin aldosterone system (RAAS) blockade on residual renal function (RRF) in patients who have just initiated hemodialysis (HD) have been inconclusive. In this study, 935 patients with incident HD from a nationwide prospective observational cohort in Korea were included for analysis. The primary outcome showed that RRF as demonstrated by urine volume changes over 0, 3, and 12 months differed between the RAAS blockade and control groups. Mixed-effects linear regression was used to compare RRF between the groups. Patients in the RAAS group had a greater proportion of higher urine volume at study enrollment compared to the control group, but there was no difference in baseline characteristics, heart function, and dialysis-related indices. After adjusting for confounding factors, the RAAS group did not provide a significant benefit to RRF in a mixed-effects linear regression (p = 0.51). Male gender, high Charlson comorbidity index, diuretic use, and high weekly ultrafiltration volume were associated with faster decline in RRF. The RAAS group failed to provide a protective effect for the development of anuria 1 year after initiating dialysis based on the multivariate logistic regression (OR 0.73 95% CI 0.25-2.13, p = 0.57). In Korean patients with incident HD, RAAS blockade did not provide a protective effect for RRF after 1 year. Further research is needed to clarify the optimal treatment for preserving RRF in HD patients.
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Effect of Patiromer in Hyperkalemic Patients Taking and Not Taking RAAS Inhibitors.
Kloner, RA, Gross, C, Yuan, J, Conrad, A, Pergola, PE
Journal of cardiovascular pharmacology and therapeutics. 2018;(6):524-531
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INTRODUCTION Hyperkalemia (potassium >5.0 mEq/L) affects heart failure patients with renal disease regardless of the use of renin-angiotensin-aldosterone system inhibitors (RAASi). The open-label TOURMALINE study showed that patiromer, a sodium-free, nonabsorbed potassium binder, lowers serum potassium of hyperkalemic patients similarly when given with or without food; unlike prior studies, patients were not required to be taking RAASi. We conducted post hoc analyses to provide the first report of patiromer in patients not taking RAASi. METHODS Hyperkalemic patients received patiromer, 8.4 g/d to start, adjusted to achieve and maintain serum potassium of 3.8 to 5.0 mEq/L. If taking RAASi, stable doses were required. The primary end point was the proportion of patients with serum potassium 3.8 to 5.0 mEq/L at week 3 or 4. This analysis presents data by patients taking or not taking RAASi. RESULTS Demographics and baseline characteristics were similar in patients taking (n = 67) and not taking RAASi (n = 45). Baseline mean (SD) serum potassium was 5.37 (0.37) mEq/L and 5.42 (0.43) mEq/L in patients taking and not taking RAASi, respectively. Mean (SD) daily patiromer doses were similar (10.7 [3.2] and 11.5 [4.0] g, respectively). The primary end point was achieved in 85% (95% confidence interval [CI]: 74-93) of patients taking RAASi and in 84% (95% CI: 71-94) of patients not taking RAASi. From baseline to week 4, the mean (SE) change in serum potassium was -0.67 (0.08) mEq/L in patients taking RAASi and -0.56 (0.10) mEq/L in patients not taking RAASi (both P < .0001 vs baseline, P = nonsignificant between groups). Adverse events were reported in 26 (39%) patients taking RAASi and 25 (54%) not taking RAASi; the most common adverse event was diarrhea (2% and 11%, respectively; no cases were severe). Five patients (2 taking RAASi) reported 6 serious adverse events; none considered related to patiromer. CONCLUSIONS Patiromer was effective and generally well-tolerated for hyperkalemia treatment, whether or not patients were taking RAAS inhibitors.
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Potassium and the use of renin-angiotensin-aldosterone system inhibitors in heart failure with reduced ejection fraction: data from BIOSTAT-CHF.
Beusekamp, JC, Tromp, J, van der Wal, HH, Anker, SD, Cleland, JG, Dickstein, K, Filippatos, G, van der Harst, P, Hillege, HL, Lang, CC, et al
European journal of heart failure. 2018;(5):923-930
Abstract
BACKGROUND Hyperkalaemia is a common co-morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Whether it affects the use of renin-angiotensin-aldosterone system inhibitors and thereby negatively impacts outcome is unknown. Therefore, we investigated the association between potassium and uptitration of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and its association with outcome. METHODS AND RESULTS Out of 2516 patients from the BIOSTAT-CHF study, potassium levels were available in 1666 patients with HFrEF. These patients were sub-optimally treated with ACEi/ARB or beta-blockers and were anticipated and encouraged to be uptitrated. Potassium levels were available at inclusion and at 9 months. Outcome was a composite of all-cause mortality and heart failure hospitalization at 2 years. Patients' mean age was 67 ± 12 years and 77% were male. At baseline, median serum potassium was 4.3 (interquartile range 3.9-4.6) mEq/L. After 9 months, 401 (24.1%) patients were successfully uptitrated with ACEi/ARB. During this period, mean serum potassium increased by 0.16 ± 0.66 mEq/L (P < 0.001). Baseline potassium was an independent predictor of lower ACEi/ARB dosage achieved [odds ratio 0.70; 95% confidence interval (CI) 0.51-0.98]. An increase in potassium was not associated with adverse outcomes (hazard ratio 1.15; 95% CI 0.86-1.53). No interaction on outcome was found between baseline potassium, potassium increase during uptitration, or potassium at 9 months and increased dosage of ACEi/ARB (Pinteraction > 0.5 for all). CONCLUSION Higher potassium levels are an independent predictor of enduring lower dosages of ACEi/ARB. Higher potassium levels do not attenuate the beneficial effects of ACEi/ARB uptitration.
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Probucol in Albuminuric Type 2 Diabetes Mellitus Patients on Renin-Angiotensin System Blockade: A 16-Week, Randomized, Double-Blind, Placebo-Controlled Trial.
Jin, SM, Han, KA, Yu, JM, Sohn, TS, Choi, SH, Chung, CH, Park, IeB, Rhee, EJ, Baik, SH, Park, TS, et al
Arteriosclerosis, thrombosis, and vascular biology. 2016;(10):2108-14
Abstract
OBJECTIVE To determine the effect of probucol on urine albumin excretion in type 2 diabetes mellitus patients with albuminuria using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. APPROACH AND RESULTS This was a 16-week, phase II, randomized, placebo-controlled, parallel-group study in type 2 diabetes mellitus patients with a urinary albumin/creatinine ratio of ≥300 mg/g using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, conducted in 17 tertiary referral hospitals. Eligible patients were randomized to probucol 250 mg/d (n=44), probucol 500 mg/d (n=41), and placebo (n=41) groups in a ratio of 1:1:1 after block randomization procedures, keeping the treatment assignment blinded to the investigators, patients, and study assistants. The primary end point was change in the geometric mean of urinary albumin/creatinine ratio from baseline to week 16 (ClinicalTrials.gov identifier NCT01726816). The study was started on November 8, 2012, and completed on March 24, 2014. The least squares mean change±SE from baseline in urinary albumin/creatinine ratio at week 16 was -7.2±639.5 mg/g in the probucol 250 mg/d group (n=43; P=0.2077 versus placebo group), 9.3±587.4 mg/g in the probucol 500 mg/d group (n=40; P=0.1975 versus placebo group), and 259.0±969.1 mg/g in the placebo group (n=41). Although the majority of subjects were on statins, probucol treatment significantly lowered total cholesterol and low-density lipoprotein cholesterol levels. QT prolongation occurred in one and two subjects in control and probucol 250 mg/d groups, respectively. CONCLUSIONS Four months of probucol up to 500 mg/d failed to reduce urinary albumin excretion.
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Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers.
Heerspink, HJ, Johnsson, E, Gause-Nilsson, I, Cain, VA, Sjöström, CD
Diabetes, obesity & metabolism. 2016;(6):590-7
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AIMS: To characterize the effect of dapagliflozin on albuminuria and estimated glomerular filtration rate (eGFR) and to determine whether effects on albuminuria were mediated through changes in glycated haemoblogin (HbA1c), systolic blood pressure (SBP), body weight or eGFR. METHODS We conducted a post hoc analysis of data pooled from two phase III clinical trials in hypertensive patients with type 2 diabetes (T2DM) on stable angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, randomly assigned to dapagliflozin 10 mg/day or matched placebo. This analysis included only patients with microalbuminuria or macroalbuminuria at baseline. RESULTS Patients were randomized to receive dapagliflozin 10 mg (n = 167) or placebo (n = 189). Dapagliflozin resulted in greater 12-week reductions in albuminuria compared with placebo: -33.2% [95% confidence interval (CI) -45.4, -18.2]. The reduction in albuminuria was also present after adjusting for age, sex and changes in HbA1c, SBP, body weight and eGFR: -23.5% (95% CI -37.6, -6.3). There was a decrease in eGFR with dapagliflozin versus placebo that was readily reversed 1 week after last dose. No serious renal-related adverse events were observed in any group. CONCLUSIONS Dapagliflozin was effective in lowering albuminuria in patients with T2DM and hypertension using renin-angiotensin system blockade therapy. Reductions in albuminuria were still present after adjusting for changes in HbA1c, SBP, body weight and eGFR. Dapagliflozin-induced improvements in glycaemic control and reductions in SBP, coupled with other potentially beneficial renal effects, may lead to a reduced long-term renal and cardiovascular risk.
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Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.
Weir, MR, Bakris, GL, Bushinsky, DA, Mayo, MR, Garza, D, Stasiv, Y, Wittes, J, Christ-Schmidt, H, Berman, L, Pitt, B, et al
The New England journal of medicine. 2015;(3):211-21
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BACKGROUND Hyperkalemia increases the risk of death and limits the use of inhibitors of the renin-angiotensin-aldosterone system (RAAS) in high-risk patients. We assessed the safety and efficacy of patiromer, a nonabsorbed potassium binder, in a multicenter, prospective trial. METHODS Patients with chronic kidney disease who were receiving RAAS inhibitors and who had serum potassium levels of 5.1 to less than 6.5 mmol per liter received patiromer (at an initial dose of 4.2 g or 8.4 g twice a day) for 4 weeks (initial treatment phase); the primary efficacy end point was the mean change in the serum potassium level from baseline to week 4. Eligible patients at the end of week 4 (those with a baseline potassium level of 5.5 to <6.5 mmol per liter in whom the level decreased to 3.8 to <5.1 mmol per liter) entered an 8-week randomized withdrawal phase in which they were randomly assigned to continue patiromer or switch to placebo; the primary efficacy end point was the between-group difference in the median change in the serum potassium level over the first 4 weeks of that phase. RESULTS In the initial treatment phase, among 237 patients receiving patiromer who had at least one potassium measurement at a scheduled visit after day 3, the mean (±SE) change in the serum potassium level was -1.01±0.03 mmol per liter (P<0.001). At week 4, 76% (95% confidence interval, 70 to 81) of the patients had reached the target potassium level (3.8 to <5.1 mmol per liter). Subsequently, 107 patients were randomly assigned to patiromer (55 patients) or placebo (52 patients) for the randomized withdrawal phase. The median increase in the potassium level from baseline of that phase was greater with placebo than with patiromer (P<0.001); a recurrence of hyperkalemia (potassium level, ≥5.5 mmol per liter) occurred in 60% of the patients in the placebo group as compared with 15% in the patiromer group through week 8 (P<0.001). Mild-to-moderate constipation was the most common adverse event (in 11% of the patients); hypokalemia occurred in 3%. CONCLUSIONS In patients with chronic kidney disease who were receiving RAAS inhibitors and who had hyperkalemia, patiromer treatment was associated with a decrease in serum potassium levels and, as compared with placebo, a reduction in the recurrence of hyperkalemia. (Funded by Relypsa; OPAL-HK ClinicalTrials.gov number, NCT01810939.).