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Risk of hyperkalemia (HK) limits the use of RAAS inhibitors (RAASi) in pts with congestive heart failure (CHF), chronic kidney disease (CKD), or diabetes. ZS-9, a nonabsorbed cation exchanger designed to preferentially entrap K + in the GI tract, significantly reduced serum K + vs placebo (PBO) over 48 hours with low rates of adverse events in CKD patients with hyperkalemia. A pre-specified subgroup analysis was conducted with CHF patients from a large Phase 3 trial of ZS-9 for HK. Pts (N=753) with K + 5.0-6.5 mmol/L were randomized (1:1:1:1:1) to ZS-9 (1.25, 2.5, 5 or 10 g) or PBO orally 3х daily for 48 hr (acute phase). At the end of this phase, pts with K + 3.5-5.0 mmol/L (n=542) were randomized 1:1 to the same ZS-9 acute phase dose or PBO once daily (QD) on Days 3-15 (extended phase); patients initially on PBO were randomized to 1.25 or 2.5g ZS-9 QD. RAASi were kept constant during the study. Serum K + in CHF pts treated with the highest ZS-9 dose (10g) was compared to PBO with an unpaired t-test. Among 753 pts, 300 (40%) had CHF at baseline (per investigator assessment), of whom 72% were on RAASi. Mean baseline K + was 5.3 mmol/L in the CHF pts. CHF pts who entered the Extended Phase (n=204) either remained on ZS-9 10g (n=26) or switched to PBO (n=23). The extended phase baseline K + was similar between groups (4.4 vs 4.5 mmol/L) and to the overall group (4.5 mmol/L ZS-9 [n=63] vs 4.4 mmol/L PBO [n=61]). On Day 15, mean K + for CHF patients on ZS-9 10g was 4.5 mmol/L vs 5.0 mmol/L for PBO (P=0.002; Fig). ZS-9 10g once daily maintained mean serum K +

Introduction: RAAS inhibitors (RAASi) are limited by hyperkalemia (HK; serum K + >5.0 mEq/L), a mortality risk factor in patients (pts) with heart failure (HF) and chronic kidney disease (CKD). Sodium zirconium cyclosilicate (ZS-9) is a nonabsorbed cation exchanger that selectively traps potassium (K + ) in the gut. ZS-9 was well tolerated and acutely reduced and maintained K + in HK pts in a Phase 3 study. We report acute phase efficacy of ZS-9 vs placebo (PBO) across prespecified subgroups of baseline (BL) K + , eGFR, HF, CKD, diabetes mellitus (DM), and RAASi use. Methods: Pts (N=753) with serum K+ 5.0-6.5 mEq/L were randomized (1:1:1:1:1) to ZS-9 (1.25, 2.5, 5 or 10g) or PBO orally 3X/day for 48 hr, after which pts with K + ≤4.9 mEq/L (n=542) were switched to ZS-9 or PBO 1x/day on Days 3-14. RAASi was kept constant. Mean serum K + (95% CIs) was recorded at BL and 48 hr. Differences between groups were compared by unpaired t-test. Results: Prevalence of subgroups were CKD 60%, HF 41% and DM 58%; 2/3 of pts were on RAASi. ZS-9 10g (n=158) vs PBO (n=143) is presented. Mean BL K + was 5.3 mEq/L in both groups. Mean change in K + at 48 hr was -0.73 mEq/L and -0.25 mEq/L in ZS-9 10g and PBO groups, respectively (p Pts with starting K + >5.5 mEq/L had the largest decline in K + with 10g ZS-9 (-1.1 mEq/L vs -0.4 mEq/L PBO; p Conclusions: ZS-9 was well tolerated and achieved normokalemia in all prespecified subgroups of HK pts with CKD, HF, DM and on RAASi and may potentially permit optimal cardiorenal protection by life-saving RAASi.

Renal function was observed retrospectively in a population of 228 adults who underwent a cardiac allograft at the University of Pittsburgh from June 1980 through June 1987, survived a minimum of one year, and received cyclosporine. Renal function was determined by serial measurement of serum creatinine concentration. Serum creatinine rose from 1.2 +/- 0.0 mg/dl at time of hospital discharge to 2.0 +/- 0.0 mg/dl at two and four years and 3.3 +/- 0.1 mg/dl at seven years. The fall in renal function was biphasic, with a rapid decline (reciprocal creatinine slope -0.018 dl/mg-mo) through 24 months and a slower decline thereafter -0.0036 dl/mg/month). This occurred despite a progressive decrease in cyclosporine levels from 668 +/- 23 ng/ml (whole blood RIA) to 380 +/- 12 ng/ml at seven years. Three of 222 patients (1.6%) developed end-stage renal disease within 18 months of initiation of cyclosporine therapy. Only one additional patient of 26 followed through 54 months (3.8%) developed end-stage disease thereafter. The decline in renal function seen with cyclosporine is rapid in the first 18 months, with a slower but continuing decline seen with later follow up. At least in heart transplantation, the risk of end-stage renal disease is significant, but not prohibitive.