RAAS inhibition in patients with kidney disease: Balancing the benefits and risks Patrick Rossignol, MD Nancy, France June 15, 2019 - Budapest, Hungary
RAAS in inhibition in in patients wit ith kid idney dis isease: Bala lancing the benefits and ri risks Patrick Rossignol, MD, PhD University of Lorraine Nancy, France
Hyperkalemia and RAAS inhibition: Dilemmas in the management of cardio-renal patients RAAS inhibition proven to • Hypertension CKD: preserve kidney function (HTN) − and delay the progression to end-stage renal disease (ESRD) Proteinuria Hyperkalemia HF: reduce all-cause mortality − RAAS inhibition Zannad F & Rossignol P. Circulation . 2018; 138:929-44; Rossignol et al. Lancet. 2019;393:1034-44
Be Better renal l outcomes with ith hig igher dose ses of f ACE CEi/ARB
Treatment with ith Renin in-Angio iotensin in-Ald ldosterone System (R (RAAS) ) In Inhib ibit itors Reduce Water and So Sodiu ium, , Bu But In Increase Potassiu ium Hyperkalemia is an inherent risk in the treatment of Angiotensinogen Renin Inhibitors HF with RAAS Inhibitors Angiotensin I ACE Inhibitors K Retention Angiotensin II Na/Water Uptake Mineralocorticoid Receptor ARBs ARNi AT1 Receptor MRAs Aldosterone Production
Hyperkalemia and RAAS inhibition: Dilemmas in the management of cardio-renal patients RAAS inhibition proven to • Hypertension CKD: preserve kidney function (HTN) − and delay the progression to end-stage renal disease (ESRD) Proteinuria Hyperkalemia HF: reduce all-cause mortality − RAAS inhibition Zannad F & Rossignol P. Circulation . 2018; 138:929-44; Rossignol et al. Lancet. 2019;393:1034-44
• an individual-level data meta-analysis of 27 international cohorts [10 general population, 7 high cardiovascular risk, and 10 CKD ] • 1 217 986 participants followed up for a mean of 6.9 years
̶ ̶ ̶ ̶ Recurrent hyperkalaemia management and use of RAASi therapy A European multinational targeted chart review Objective: Describe management of recurrent HK (≥2 episodes of sK + ≥5.5 mEq/L/year) and related • healthcare resource utilization in routine clinical practice across Europe • Study design: A targeted retrospective chart review was conducted in France, Germany, Italy, Spain and the UK, between June and September 2016 • Participants: Cardiologists and nephrologists with ≥3 years of experience, seeing on average ≥5 patients with HK per month who were part of a global panel. A total of 568 physicians (44.5% nephrologists, 55.5% cardiologists), entered data from 1457 patients • Medical records: Data were included from the following patients: Men and women, 18 years of age or older ≥2 HK episodes ( sK + ≥5.5 mEq/L) within 12 months starting with the 1st HK episode Not on dialysis Data not older than 5 years HK, hyperkalemia; sK + , serum potassium; UK, United Kingdom. Rossignol et al. ERA-EDTA 2018, HFA 2018 posters
9 Patient Characteristics at HK1 Patient characteristics at HK1 Parameter n Values Age, years, mean (SD) 1457 66.2 (12.43) Men, n (%) 936 64.2% BMI, kg/m 2 , mean (SD) 1457 27.4 (4.60) Serum potassium, mEq/L, mean (SD) 1331 5.9 (0.78) BMI = body mass index; HK = hyperkalaemia; HK1 = first hyperkalaemic episode ; SD = standard deviation.
10 Patient Characteristics at HK1 – Cont . Parameter n Values Parameter n Values Comorbidities Diabetes, n (%) 520 35.7% Heart failure, n (%) 587 40.3% Hypertension, n (%) 1047 71.9% NYHA class, n (%) 587 Blood pressure, mmHg, mean (SD) I 38 6.5% Systolic 1357 143.2 (18.88) II 315 53.7% Diastolic 1355 83.4 (13.21) III 225 38.3% CKD, n (%) 996 68.4% IV 9 1.5% CKD stage, n (%) 995 LVEF, n (%) 1311 <30% 74 5.6% 1 63 6.3% 30-40% 259 19.8% 2 237 23.8% 41-49% 284 21.7% 3 445 44.7% 50-75% 421 32.1% 4 216 21.7% >75% 16 1.2% 5 (not on dialysis) 34 3.4% Not done 257 19.6% CKD = chronic kidney disease; HK = hyperkalaemia; HK1 = first hyperkalaemic episode; LVEF = left ventricle ejection fraction; NYHA = New York Heart Association; SD = standard deviation.
RAASi prescription • The proportion of patients receiving RAASi was significantly lower in HK2 than in HK1, for all classes of medication 100 % of patients with prescription 90 80 HK1 HK2 70 *** 60.5 60 51.7 50 *** 40.7 40 33.7 ** 30 *** 19.4 17.0 20 12.1 8.0 10 0 Any RAASi ACEis ARBs MRAs Significant difference from HK1: **p<0.01,***p<0.001. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; HK1/HK2, first/second hyperkalaemia episode; MRA, mineralocorticoid receptor antagonist; RAASi, renin-angiotensin-aldosterone system inhibitor Rossignol et al. ERA-EDTA 2018, HFA 2018 posters
Utilization of health care resources • A total of 326 hospitalizations due to recurrent HK or underlying comorbidities were documented for 307 patients (21.1% of all patients) • Only 36.8% of patients had no documented health care resource utilization Proportion of stationary hospitalizations Proportion of patients with resource utilization (N = 326 hospitalizations) (N = 1457 patients) % of stationary hospitalizations 100 100 90 90 80 % of patients 80 70 60 70 50 60 36.8 36.9 40 50 30 21.1 37.1 40 20 14.7 30.7 10 30 3.9 0 20 121 hosp. 100 hosp. 10 0 CV, cardiovascular; HK, hyperkalemia Rossignol et al. ERA-EDTA 2018, HFA 2018 posters
Conclusions • In this study population, RAASi discontinuation was a prominent approach, with a lower proportion of patients with a RAASi prescription in HK2 than in HK1 • Among the 326 documented hospitalizations, 121 (37.1%) were due to HK • More effective HK management and mitigation strategies are needed ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; HFrEF, heart failure with reduce ejection fraction; HK, hyperkalemia; HK1/HK2, first/second hyperkalemic episode; MRA, mineralocorticoid receptor antagonist; RAASi, renin-angiotensin-aldosterone system inhibitor Rossignol et al. ERA-EDTA, HFA 2018 posters
Hyperkalemia and RAAS inhibition: Dilemmas in the management of cardio-renal patients • RAAS inhibition proven to Hypertension (HTN) • CKD: preserve kidney function and delay the progression to end-stage Proteinuria Hyperkalemia renal disease (ESRD) • HF: reduce all-cause mortality Window of opportunity for potassium-binders ? RAAS inhibition
Background: 2018 ESC/ESH Guidelines for the Management of Arterial Hypertension 1 • The PATHWAY-2 study 2 excluded patients with an eGFR <45 mL/min/1.73 m 2 , as have previous studies; thus, there are no data on the safety profile of spironolactone in patients with resistant HTN and an eGFR <45 mL/min • External validity? • AMBER trial aims: in patients with advanced CKD with resistant hypertension Does patiromer enable through prevention of hyperkalaemia a persistent use of spironolactone? 1. Williams B, et al. Eur Heart J . 2018;39:3021-3104; 2. Williams B, et al. Lancet . 2015;386:2059-2068 .
AMBER: study design Spironolactone + Randomization ‡ blinded patiromer CKD patients with RHTN • Systolic AOBP 135 – 160 mm Hg Additional antihypertensive medication as needed • eGFR 25 – 45 mL/min/1.73m 2 Serum K + 4.3 – 5.1 mEq/L • Spironolactone + blinded placebo DAY 1: start spironolactone 25 mg QD, 8.4 g/day patiromer or placebo Visit: S1 S2 S3 S4/ Wk1 Wk2 Wk3 Wk4 Wk6 Wk8 Wk10 Wk12 F/U BL † Screening/run-in Double-blind treatment period Safety follow-up up to 4 weeks* 12 weeks 2 weeks *To ensure eligibility criteria, stable medication, and competent use of HBP monitor. †For patients who meet all inclusion cr iteria, this visit becomes the Randomization/Baseline Visit (Day 0). ‡Stratified by local K+ (4.3– <4.7 vs. 4.7 – 5.1) and history of diabetes. AOBP, automated office blood pressure; HBP, home blood pressure; RHTN, resistant hypertension; K+, potassium. Agarwal R et al. Am J Nephrol. 2018;48:172-180
Study endpoints Primary Between-group difference in proportion of subjects remaining on spironolactone at Week 12 Secondary Between-group difference in change from Baseline to Week 12 in SBP by AOBP Agarwal R et al. Am J Nephrol. 2018;48:172-80
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