kidney disease: Balancing the benefits and risks Patrick Rossignol, - - PowerPoint PPT Presentation

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

Zannad F & Rossignol P. Circulation. 2018; 138:929-44; Rossignol et al. Lancet. 2019;393:1034-44

• RAAS inhibition proven to

−

CKD: preserve kidney function and delay the progression to end-stage renal disease (ESRD)

−

HF: reduce all-cause mortality

Hyperkalemia and RAAS inhibition: Dilemmas in the management of cardio-renal patients

RAAS inhibition

Proteinuria Hypertension (HTN) Hyperkalemia

Be Better renal l outcomes with ith hig igher dose ses of f ACE CEi/ARB

Renin Inhibitors ACE Inhibitors ARBs ARNi MRAs K Retention Na/Water Uptake

Hyperkalemia is an inherent risk in the treatment of HF with RAAS Inhibitors

Angiotensin I AT1 Receptor Angiotensin II Aldosterone Production Mineralocorticoid Receptor Angiotensinogen

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

Zannad F & Rossignol P. Circulation. 2018; 138:929-44; Rossignol et al. Lancet. 2019;393:1034-44

• RAAS inhibition proven to

−

CKD: preserve kidney function and delay the progression to end-stage renal disease (ESRD)

−

HF: reduce all-cause mortality

Hyperkalemia and RAAS inhibition: Dilemmas in the management of cardio-renal patients

RAAS inhibition

Proteinuria Hypertension (HTN) Hyperkalemia

• 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

HK, hyperkalemia; sK+, serum potassium; UK, United Kingdom. Rossignol et al. ERA-EDTA 2018, HFA 2018 posters

• 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

Recurrent hyperkalaemia management and use of RAASi therapy A European multinational targeted chart review

9 Parameter n Values Age, years, mean (SD) 1457 66.2 (12.43) Men, n (%) 936 64.2% BMI, kg/m2, mean (SD) 1457 27.4 (4.60) Serum potassium, mEq/L, mean (SD) 1331 5.9 (0.78) Patient characteristics at HK1

BMI = body mass index; HK = hyperkalaemia; HK1 = first hyperkalaemic episode; SD = standard deviation.

Patient Characteristics at HK1

Patient Characteristics at HK1 – Cont.

10

Parameter n Values

Comorbidities Heart failure, n (%) 587 40.3% NYHA class, n (%) 587 I 38 6.5% II 315 53.7% III 225 38.3% IV 9 1.5% LVEF, n (%) 1311 <30% 74 5.6% 30-40% 259 19.8% 41-49% 284 21.7% 50-75% 421 32.1% >75% 16 1.2% Not done 257 19.6%

Parameter n Values

Diabetes, n (%) 520 35.7% Hypertension, n (%) 1047 71.9% Blood pressure, mmHg, mean (SD) Systolic 1357 143.2 (18.88) Diastolic 1355 83.4 (13.21) CKD, n (%) 996 68.4% CKD stage, n (%) 995 1 63 6.3% 2 237 23.8% 3 445 44.7% 4 216 21.7% 5 (not on dialysis) 34 3.4%

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

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

• The proportion of patients receiving RAASi was significantly lower in HK2

than in HK1, for all classes of medication

60.5 40.7 19.4 12.1 51.7 33.7 17.0 8.0 10 20 30 40 50 60 70 80 90 100 Any RAASi ACEis ARBs MRAs % of patients with prescription HK1 HK2

** *** *** ***

Utilization of health care resources

CV, cardiovascular; HK, hyperkalemia Rossignol et al. ERA-EDTA 2018, HFA 2018 posters

• 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

36.8 21.1 14.7 36.9 3.9 10 20 30 40 50 60 70 80 90 100 % of patients

Proportion of patients with resource utilization (N = 1457 patients)

37.1 30.7 10 20 30 40 50 60 70 80 90 100 % of stationary hospitalizations

Proportion of stationary hospitalizations (N = 326 hospitalizations)

121 hosp. 100 hosp.

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

• RAAS inhibition proven to
• CKD: preserve kidney function and

delay the progression to end-stage renal disease (ESRD)

• HF: reduce all-cause mortality

RAAS inhibition

Proteinuria Hypertension (HTN) Hyperkalemia

Window of opportunity for potassium-binders ?

Hyperkalemia and RAAS inhibition: Dilemmas in the management of cardio-renal patients

• The PATHWAY-2 study2 excluded patients with an eGFR <45 mL/min/1.73

m2, 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

• 1. Williams B, et al. Eur Heart J. 2018;39:3021-3104; 2. Williams B, et al. Lancet. 2015;386:2059-2068.

Does patiromer enable through prevention of hyperkalaemia a persistent use of spironolactone?

Background: 2018 ESC/ESH Guidelines for the Management

• f Arterial Hypertension1

AMBER: study design

*To ensure eligibility criteria, stable medication, and competent use of HBP monitor. †For patients who meet all inclusion criteria, 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

Additional antihypertensive medication as needed Spironolactone + blinded patiromer Spironolactone + blinded placebo DAY 1: start spironolactone 25 mg QD, 8.4 g/day patiromer or placebo Screening/run-in up to 4 weeks* Visit: S1 S2 S3 S4/ BL† Double-blind treatment period 12 weeks Wk1 Wk2 Wk3 Wk4 Wk6 Wk8 Wk10 Wk12 Safety follow-up 2 weeks F/U

CKD patients with RHTN

• Systolic AOBP 135–160 mm Hg
• eGFR 25–45 mL/min/1.73m2
• Serum K+ 4.3–5.1 mEq/L

Randomization‡

Study endpoints

Agarwal R et al. Am J Nephrol. 2018;48:172-80

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

A RandoMized, Double-Blind, Placebo-Controlled, Parallel Group Study of Patiromer for the Enablement of Spironolactone Use for Blood PrEssure Control in Patients with Resistant Hypertension and Chronic Kidney Disease: Evaluation of Safety and Efficacy (AMBER)

Rajiv Agarwal,1 Patrick Rossignol,2 Alain Romero,3 Dahlia Garza,3 Martha R. Mayo,3 Suzette Warren,3 Jia Ma,3 William B. White,4 Bryan Williams5

1Indiana University School of Medicine, Indianapolis, IN; 2University of Lorraine and FCRIN INI-CRCT, Nancy, France; 3Relypsa,

Inc., a Vifor Pharma Group Company, Redwood City, CA; 4University of Connecticut School of Medicine, Farmington, CT;

5University College London, London, UK.

A RandoMized, Double-Blind, Placebo-Controlled, Parallel Group Study of Patiromer for the Enablement of Spironolactone Use for Blood PrEssure Control in Patients with Resistant Hypertension and Chronic Kidney Disease: Evaluation of Safety and Efficacy (AMBER)

Rajiv Agarwal,1 Patrick Rossignol,2 Alain Romero,3 Dahlia Garza,3 Martha R. Mayo,3 Suzette Warren,3 Jia Ma,3 William B. White,4 Bryan Williams5

1Indiana University School of Medicine, Indianapolis, IN; 2University of Lorraine and FCRIN INI-CRCT, Nancy, France; 3Relypsa,

Inc., a Vifor Pharma Group Company, Redwood City, CA; 4University of Connecticut School of Medicine, Farmington, CT;

5University College London, London, UK.

Baseline characteristics of randomised patients

Characteristic Spironolactone + Placebo (n=148) Spironolactone + Patiromer (n=147) Age, mean years 69 68 65, % 70% 67% Male, % 52% 52% Systolic AOBP, mean mmHg 145 143 Diabetes mellitus, % 49% 50% History of heart failure, % 47% 43% eGFR, mean mL/min/1.73 m2 36 35 Stage 4 CKD, % 21% 23% Stage 3B CKD, % 79% 73%

• No. of antihypertensive meds, mean

3.6 3.7

Primary endpoint: Patients who remained on spironolactone at week 12

Patients Who Remained on Spironolactone at Week 12, % (95% CI)

LS mean (95% CI) difference between groups: 20% (95% CI 10, 29)

P<0.0001

n/N =

In advanced CKD with resistant hypertension, patiromer enables a more persistent use of spironolactone

Time to discontinuation of spironolactone

*Patients who completed 12 weeks of study treatment and had not had any event are censored at Week 12. ITT, intent-to-treat.

12 10 8 6 4 2 3 1 Baseline Study Week 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Proportion with Event Log-rank P=0.0001 Circles indicate censored observations* Spironolactone + placebo Spironolactone + patiromer

ITT Population

• No. at risk

Spironolactone + placebo Spironolactone + patiromer 148 147 146 146 142 143 136 140 130 145 124 133 113 133 106 127 98 126

Cumulative dose of spironolactone

LS, least squares

Mean (SE) Cumulative Dose

• f Spironolactone, mg

LS mean (95% CI) difference between groups: 385 mg (95% CI: 140, 629) P=0.0021 2581 2942 500 1.000 1.500 2.000 2.500 3.000 Placebo n=148 Patiromer n=147

Time to Serum K+ ≥5.5 mEq/L

*Patients who did not have any event are censored on the last date with serum K+ assessment.

• No. at risk

Spironolactone + placebo Spironolactone + patiromer 148 147 146 146 142 143 136 140 130 145 124 133 113 133 106 127 98 126

12 10 8 6 4 2 3 1 Baseline Study Week 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Proportion with Event

ITT Population

Circles indicate censored observations* Spironolactone + placebo Spironolactone + patiromer Log-rank P0.0001

Change from baseline to week 12: systolic AOBP

125 130 135 140 145 150

LS mean (95% CI) between-group difference in change from baseline: –1.0 mmHg (–4.4, 2.4), P=0.58 LS mean change from baseline –10.8 P<0.001 Spironolactone + Placebo Baseline (n=148) Week 12 (n=141) –11.7 P<0.001 Spironolactone + Patiromer Baseline (n=147) Week 12 (n=144) Mean (SE) Systolic AOBP (mmHg)

Systolic AOBP over time and spironolactone/metabolite detection

*Measurable spironolactone level or detectable metabolite (7 alpha-thiomethyl spironolactone or canrenone). N=71 for analysis (placebo, 50; patiromer, 21); data for weeks 5-10+ post-last dose are not shown due to small sample sizes. This was an exploratory analysis.

125 130 135 140 145 150 155 160 Spironolactone + placebo Spironolactone + patiromer Screening On-Study Follow-Up Mean (SE) Systolic AOBP (mmHg) S1 S2 S3 BL 1 2 3 4 6 8 10 12 F/U Study Week

Systolic AOBP Over Time

Week after last spironolactone dose

• No. (%) of Patients

Spironolactone + Placebo Spironolactone + Patiromer Total 1 14/16 (88%) 6/7 (86%) 87% 2 11/14 (79%) 1/2 (50%) 75% 3 3/5 (60%) 1/6 (17%) 36% 4 1/10 (10%) 1/5 (20%) 13%

Spironolactone/Metabolite Detection

Observed patients Spiro + PBO 148 148 148 148 147 147 145 145 144 142 139 141 136 Spiro + PAT 147 147 147 147 147 147 146 145 144 144 143 144 142

Adverse event summary

Data are percent of patients with at least one event; each patient is counted only once for each adverse event. *None were considered related to study drug in the opinion of the investigator. In the spironolactone + placebo group, one serious adverse event occurred in each of 4 patients (renal colic, renal failure, hypersensitivity, and aortic rupture [the adverse event leading to death]); in the spironolactone + patiromer group, one serious adverse event occurred in one patient (humerus fracture). †In at least 5% of patients in either treatment group; results are presented in descending order in either treatment group and then in alphabetical order.

Spironolactone + Placebo (n=148) Spironolactone + Patiromer (n=147) Adverse events 53% 56% Severe adverse events 2% 1% Serious adverse events* 3% 1% Adverse event leading to study treatment discontinuation 14% 7% Hyperkalemia 7% 1% Adverse event leading to death 1% Most common adverse events† Hyperkalemia or blood potassium increased 9% 6% Renal impairment 7% 9% Headache 7% 6% Diarrhea 5% 6% Hypotension 4% 6%

Conclusions

In advanced CKD with resistant hypertension, patiromer enables more persistent use of spironolactone. Among patients treated with placebo, 2 out of 3 developed

• hyperkalemia. Patiromer reduced this risk by half.

Conclusions

Spironolactone use associates with 11–12 mmHg reduction in systolic BP. Change in systolic BP between groups was similar Patiromer use allows more spironolactone use: 385 mg more over 12 weeks Patiromer’s safety profile was consistent with previous reports