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Change from baseline in serum K+ with ZS-9 in patients with chronic kidney disease treated for hyperkalemia
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Abstracts / Journal of the American Society of Hypertension 8(4S) (2014) e67–e74
Keywords: Central aortic blood pressure; Aortic augmentation pressure; Olmesartan; Telmisartan P-105 Change from baseline in serum K+ with ZS-9 in patients with chronic kidney disease treated for hyperkalemia Bhupinder Singh,y,3 Stephen R. Ash,2 Philip Lavin,1 Alex Yang,4 Henrik S. Rasmussen.5 1Boston Biostatistics Research Foundation, Framingham, MA, United States; 2Indiana University Health Arnett, Lafayette, IN, United States; 3Southwest Clinical Research Institute, Tempe, AZ, United States; 4Xelay Acumen, Belmont, CA, United States; 5ZS Pharma, Coppell, TX, United States Hyperkalemia is associated with significant mortality and often leads to a reduction in dose or cessation of renin-angiotensin-aldosterone (RAAS) inhibitors, a drug class that has proven cardio- and reno-protective effects. Yet use of sodium polystyrene sulfonate (SPS), the only drug approved in the U.S. for the treatment of hyperkalemia, is limited by poor patient tolerability and an increased incidence of gastrointestinal-related adverse events, including nausea and diarrhea. ZS-9 is a nonsystemic, selective cation exchanger designed to entrap excess potassium (K+). In a Phase 2 trial in 90 patients with chronic kidney disease (CKD) and hyperkalemia, the primary efficacy endpoint was met in the two higher dose cohorts vs placebo, with generally similar safety (Ash et al. ASN 2013). Here we present the change in serum K+ from baseline during the initial 48 hours of treatment for the highest-dose cohort vs placebo. Eligible patients (estimated glomerular filtration rate: 30-60 mL/min/1.73 m2; serum K+: 5-6 mEq/L) received ZS-9 10g (N¼24) or placebo (N¼30) as an oral suspension 3X daily for an initial 2 days (and up to 2 more days if serum K+ 5.0 mEq/L), with regular meals (8am, 12pm, 6pm) as in-patients. Serum K+ was measured 0.5 hour, 1 hour, and 2 hours after the 1st dose and 4 hours after all doses. RAAS inhibitors were continued during the study. Mean baseline serum K+ was 5.1 mEq/L for ZS-9 10g and placebo. The majority of patients (placebo, 60%; ZS-9 10g, 83%) were on RAAS inhibitors. No patient on ZS- 9 10g required treatment beyond the initial 48 hours. There was a substantially greater decrease from baseline in serum K+ for ZS-9 10g vs placebo at all time points measured during the initial 48-hour treatment period. Serum K+ reductions with ZS-9 10g were significantly different from placebo as early as 1 hour after the first dose (-0.11 vs +0.12 mEq/L; p<0.05) and between hours 28-48 (p0.001; Figure). The mean maximal change from baseline (-0.92 mEq/L) was achieved at 38 hours, 4 hours after the last dose of ZS-9 10g (p<0.001). Overall there was a low rate of adverse events; nausea and vomiting were reported in 1 (3%) patient each on placebo and in 2 (8%) and 3 (13%) patients on
ZS-9 10g. ZS-9 rapidly and robustly reduced serum K+ from baseline in CKD patients with hyperkalemia, the majority of whom were on RAAS inhibitors for end-organ protection. Keywords: Hyperkalemia; ZS-9; Serum Potassium; Renin-AngiotensinAldosterone Inhibitors P-106 Differences in cardiovascular reactivity to mental stress in athletes vs. sedentary subjects Roberto A. Ingaramo, Carlos A. Lopez, Marcela Torrent. Hypertension Center and Cardiovascular Disease, Trelew, Argentina The exaggerated cardiovascular reactivity (CVR) to mental stress (MS) is associated with increased risk of hypertension (HBP), carotid atherosclerosis and increased left ventricular mass, among others. Aerobic exercise improves autonomic control of the heart and reduces the CVR during MS and the recovery after stress. The aim of the study was to assess if a group of trained subjects would face MS situations to advantage with regard to one group of sedentary ones, which could be reflected in a lower CVR and faster recovery post-stress. In order to this we studied 20 young healthy normotensive subjects separated into 2 groups (G). The G1 was composed of 10 athletes (long distance runners), 6 men, mean age 19.2 4.9 years and the G2 of 10 physically untrained students, 6 men, mean age 18.4 2.1 years. In the early hours of the morning, all fasting patients underwent a computerized version of the Stroop color word conflict stress test and a mental arithmetic test. Blood pressure (BP) and heart rate (HR) were measured at baseline and every 5 minutes (total10 min.) during the test and 5 minutes after it. Moreover, plasma catecholamine levels were measured before and after stress. The results were analyzed using the t test, the MANOVA and Bonferroni test. A level of p < 0.05 was considered statistically significant. During MS and at the end of it, HR, systolic (SBP) and diastolic (DBP) BP were higher in G1, although these differences were not significant (0.11, 0.43 and 0.09 respectively). We did not observe hyper- reactors. The DBP in the G2 was significantly lower at rest while the increase of catecholamines in the same group was significantly higher with respect to G1 in the MS. The behavior of the HR and BP in the G1 could be interpreted as a better and faster cardiovascular adaptive process by physical training, while lower catecholamine release, a better cardiovascular adjustment to MS. Subjects with high athletic training would be less reactive to mental stress, which could be a protective factor against its future adverse cardiovascular effects. Keywords: Blood prtesure; Mental stress; Athletes; Sedentary P-107 Effects of amlodipine on cardiovascular outcomes in hypertension clinical trials: traditional and network meta-analyses Willilam J. Elliott,1 Peter M. Meyer.2 1Pacific Northwest University of Health Sciences, Yakima, WA, United States; 2RUSH Medical College, Chicago, IL, United States Although the FDA has approved a statement that ‘‘lowering blood pressure reduces the risk of adverse cardiovascular outcomes,’’ only a few individual antihypertensive agents have been used in outcomes-based clinical trials, typically against several different comparators. To estimate the cardiovascular effects of amlodipine, traditional, fixed-effects meta-analyses were performed, using data from 11 clinical trials (FACET, PREVENT, IDNT, AASK, ALLHAT, VALUE, ACCOMPLISH, ASCOT, CASE-J, VART, Nagoya Heart Study) involving 36,831 subjects randomized to amlodipine, compared to 52,937 randomized to another regimen in these trials. In an attempt to identify and minimize inhomogeneity among all comparators, network meta-analyses were also performed, using data from PREVENT and 69 other trials that randomized 312,520 subjects to
Abstracts / Journal of the American Society of Hypertension 8(4S) (2014) e67–e74
Keywords: Central aortic blood pressure; Aortic augmentation pressure; Olmesartan; Telmisartan P-105 Change from baseline in serum K+ with ZS-9 in patients with chronic kidney disease treated for hyperkalemia Bhupinder Singh,y,3 Stephen R. Ash,2 Philip Lavin,1 Alex Yang,4 Henrik S. Rasmussen.5 1Boston Biostatistics Research Foundation, Framingham, MA, United States; 2Indiana University Health Arnett, Lafayette, IN, United States; 3Southwest Clinical Research Institute, Tempe, AZ, United States; 4Xelay Acumen, Belmont, CA, United States; 5ZS Pharma, Coppell, TX, United States Hyperkalemia is associated with significant mortality and often leads to a reduction in dose or cessation of renin-angiotensin-aldosterone (RAAS) inhibitors, a drug class that has proven cardio- and reno-protective effects. Yet use of sodium polystyrene sulfonate (SPS), the only drug approved in the U.S. for the treatment of hyperkalemia, is limited by poor patient tolerability and an increased incidence of gastrointestinal-related adverse events, including nausea and diarrhea. ZS-9 is a nonsystemic, selective cation exchanger designed to entrap excess potassium (K+). In a Phase 2 trial in 90 patients with chronic kidney disease (CKD) and hyperkalemia, the primary efficacy endpoint was met in the two higher dose cohorts vs placebo, with generally similar safety (Ash et al. ASN 2013). Here we present the change in serum K+ from baseline during the initial 48 hours of treatment for the highest-dose cohort vs placebo. Eligible patients (estimated glomerular filtration rate: 30-60 mL/min/1.73 m2; serum K+: 5-6 mEq/L) received ZS-9 10g (N¼24) or placebo (N¼30) as an oral suspension 3X daily for an initial 2 days (and up to 2 more days if serum K+ 5.0 mEq/L), with regular meals (8am, 12pm, 6pm) as in-patients. Serum K+ was measured 0.5 hour, 1 hour, and 2 hours after the 1st dose and 4 hours after all doses. RAAS inhibitors were continued during the study. Mean baseline serum K+ was 5.1 mEq/L for ZS-9 10g and placebo. The majority of patients (placebo, 60%; ZS-9 10g, 83%) were on RAAS inhibitors. No patient on ZS- 9 10g required treatment beyond the initial 48 hours. There was a substantially greater decrease from baseline in serum K+ for ZS-9 10g vs placebo at all time points measured during the initial 48-hour treatment period. Serum K+ reductions with ZS-9 10g were significantly different from placebo as early as 1 hour after the first dose (-0.11 vs +0.12 mEq/L; p<0.05) and between hours 28-48 (p0.001; Figure). The mean maximal change from baseline (-0.92 mEq/L) was achieved at 38 hours, 4 hours after the last dose of ZS-9 10g (p<0.001). Overall there was a low rate of adverse events; nausea and vomiting were reported in 1 (3%) patient each on placebo and in 2 (8%) and 3 (13%) patients on
ZS-9 10g. ZS-9 rapidly and robustly reduced serum K+ from baseline in CKD patients with hyperkalemia, the majority of whom were on RAAS inhibitors for end-organ protection. Keywords: Hyperkalemia; ZS-9; Serum Potassium; Renin-AngiotensinAldosterone Inhibitors P-106 Differences in cardiovascular reactivity to mental stress in athletes vs. sedentary subjects Roberto A. Ingaramo, Carlos A. Lopez, Marcela Torrent. Hypertension Center and Cardiovascular Disease, Trelew, Argentina The exaggerated cardiovascular reactivity (CVR) to mental stress (MS) is associated with increased risk of hypertension (HBP), carotid atherosclerosis and increased left ventricular mass, among others. Aerobic exercise improves autonomic control of the heart and reduces the CVR during MS and the recovery after stress. The aim of the study was to assess if a group of trained subjects would face MS situations to advantage with regard to one group of sedentary ones, which could be reflected in a lower CVR and faster recovery post-stress. In order to this we studied 20 young healthy normotensive subjects separated into 2 groups (G). The G1 was composed of 10 athletes (long distance runners), 6 men, mean age 19.2 4.9 years and the G2 of 10 physically untrained students, 6 men, mean age 18.4 2.1 years. In the early hours of the morning, all fasting patients underwent a computerized version of the Stroop color word conflict stress test and a mental arithmetic test. Blood pressure (BP) and heart rate (HR) were measured at baseline and every 5 minutes (total10 min.) during the test and 5 minutes after it. Moreover, plasma catecholamine levels were measured before and after stress. The results were analyzed using the t test, the MANOVA and Bonferroni test. A level of p < 0.05 was considered statistically significant. During MS and at the end of it, HR, systolic (SBP) and diastolic (DBP) BP were higher in G1, although these differences were not significant (0.11, 0.43 and 0.09 respectively). We did not observe hyper- reactors. The DBP in the G2 was significantly lower at rest while the increase of catecholamines in the same group was significantly higher with respect to G1 in the MS. The behavior of the HR and BP in the G1 could be interpreted as a better and faster cardiovascular adaptive process by physical training, while lower catecholamine release, a better cardiovascular adjustment to MS. Subjects with high athletic training would be less reactive to mental stress, which could be a protective factor against its future adverse cardiovascular effects. Keywords: Blood prtesure; Mental stress; Athletes; Sedentary P-107 Effects of amlodipine on cardiovascular outcomes in hypertension clinical trials: traditional and network meta-analyses Willilam J. Elliott,1 Peter M. Meyer.2 1Pacific Northwest University of Health Sciences, Yakima, WA, United States; 2RUSH Medical College, Chicago, IL, United States Although the FDA has approved a statement that ‘‘lowering blood pressure reduces the risk of adverse cardiovascular outcomes,’’ only a few individual antihypertensive agents have been used in outcomes-based clinical trials, typically against several different comparators. To estimate the cardiovascular effects of amlodipine, traditional, fixed-effects meta-analyses were performed, using data from 11 clinical trials (FACET, PREVENT, IDNT, AASK, ALLHAT, VALUE, ACCOMPLISH, ASCOT, CASE-J, VART, Nagoya Heart Study) involving 36,831 subjects randomized to amlodipine, compared to 52,937 randomized to another regimen in these trials. In an attempt to identify and minimize inhomogeneity among all comparators, network meta-analyses were also performed, using data from PREVENT and 69 other trials that randomized 312,520 subjects to