RAAS inhibition in heart failure: Cornerstone of therapy & - - PowerPoint PPT Presentation

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RAAS inhibition in heart failure: Cornerstone of therapy & - - PowerPoint PPT Presentation

Apr 10, 2023 265 likes •629 views

CIC-P Nancy Optimizing RAAS inhibition in Heart Failure: Novel treatment considerations for the management of hyperkalemia RAAS inhibition in heart failure: Cornerstone of therapy & potassium homeostasis Faiez Zannad Inserm, Universit

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CIC-P Nancy

RAAS inhibition in heart failure: Cornerstone of therapy & potassium homeostasis

Faiez Zannad

Inserm, Université de Lorraine, Institut Lorrain du Coeur et des Vaisseaux Clinical Investigation Center & Hypertension and Heart Failure Unit

Optimizing RAAS inhibition in Heart Failure: Novel treatment considerations for the management of hyperkalemia

DGOS

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Eur Heart J. 2016 May 20. http://dx.doi.org/10.1093/eurheartj/ehw128

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EORP – HF Long term registry

Frequency of not taking HF life saving therapies in « eligible » patients with EF < 40%

Courtesy, Maggioni A, ESC Eurobservational 2015

9% 7.3% 32.3%

ACEi or ARBs Beta-blockers MRAs

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ESC HF Registry

Under-use of life saving therapy

European Journal of Heart Failure (2013) 15, 1173–1184

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European Journal of Heart Failure (2013) 15, 1173–1184

ESC HF Registry

Under-use of life saving therapy

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ESC HF Registry

Under-dosing of life-saving therapy

European Journal of Heart Failure (2013) 15, 1173–1184

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European Journal of Heart Failure (2013) 15, 1173–1184

ESC HF Registry

Under-dosing of life-saving therapy

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IMPROVE-HF Registry

Under-dosing of life-saving therapy

Congest Heart Fail. 2012;18:9–17.

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Congest Heart Fail. 2012;18:9–17.

IMPROVE-HF Registry

Under-dosing of life-saving therapy

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Reasons for not Prescribing a RAAS Blocker

Reason N (%) No reasona 132 (58.7) AKI 29 (12.9) Hyperkalemia 23 (10.2) Hypotension 14 (6.2) Allergyb 9 (4.0) D/C 5 (2.2) Not indicatedc 4 (1.8) Advanced CKD 4 (1.8) Renal artery stenosis 2 (0.9) Otherd 3 (1.3) Total 225

aNo documented reason found. bAllergy: angioedema, hand paresthesia, hives, cough and dizziness. cProvider documented that RAS blockade was not indicated for the patient. dOther: side effects, dizziness and pregnancy.

AKI=acute kidney injury; CKD=chronic kidney disease; D/C=discontinued by another physician. Shirazian S,. Am J Med Sci. 2015;349(6):510-15.

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RAASi and HF Mortality

Edner M, Benson L, Dahlström U, Lund LH. Eur Heart J. 2015. Epub ahead of print.

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No RAAS inhibitor therapy at discharge doubles the 30-d risk of death +readmission

(disregarding LVEF)

Di Tano G, EJHF May 2015

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CIC-P Nancy Severe Renal Insufficiency NO Severe Renal Insufficiency

Overall survival was much worse in the severe renal insufficiency cohort, but the risk reduction was similar in the severe renal insufficiency-matched cohort (A, HR 0.76) and non-severe renal insufficiency-matched cohort (B, HR 0.79).

In HF with Severe Renal Insufficiency: Use of RAS Antagonists was Associated with Lower All-Cause Mortality

Edner M, Benson L, Dahlström U, Lund LH. Eur Heart J. 2015. Epub ahead of print.

No RAS Use 602 249 132 81 44 23 Ras Use 602 287 184 109 58 35 No RAS Use 808 305 162 98 52 27 Ras Use 1602 874 567 339 207 116 No at Risk Matched Cohort Overall Cohort No RAS Use 1545 928 658 447 306 199 Ras Use 1545 1035 734 503 343 232 No RAS Use 1574 939 664 452 309 200 Ras Use 20299 15783 12047 9092 6427 4191 No at Risk Matched Cohort Overall Cohort

HR 0.76 HR 0.79

100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 Years Since Inclusion

Survival Proportion

100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 Years Since Inclusion

Survival Proportion

RAS, overall RAS, matched No RAS, overall No RAS, matched RAS, overall RAS, matched No RAS, overall No RAS, matched

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Am J Manag Care. 2015;21:S212-S220

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Distribution of RAAS Inhibitor Dose Levels by Comorbidity Group

Am J Manag Care. 2015;21:S212-S220

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Among Patients on RAAS Inhibitor at Submaximum Dose

Am J Manag Care. 2015;21:S212-S220

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Percent Mortality by Prior RAAS Inhibitor Dose

Am J Manag Care. 2015;21:S212-S220

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Renin Inhibitors ACE Inhibitors ARBs MRAs K Retention Na/Water Uptake Hyperkalemia is an inherent risk in the treatment of HF with any RAAS Inhibitor Angiotensin I AT1 Receptor Angiotensin II Aldosterone Production Mineralcorticoid Receptor Angiotensinogen

Treatment with Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors Reduces Water and Sodium, But Increases Potassium

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  • A. Reductions in eGFR>20%
  • B. hyperkalemia >5.0mmol/L
  • C. hyperkalemia >5.5 mmol/L

Multiple occurrences of WRF and HK

  • P. Rossignol et al. Int J Cardiol 2014
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RALES - Potassium levels during the study by treatment.

Vardeny O et al. Circ Heart Fail. 2014;7:573-579

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RALES

Mortality in the spironolactone group based on time-varying maximum potassium level when compared with a referent participant on placebo who never experienced potassium levels ≥5.0 mEq/L, adjusting for age, estimated glomerular filtration rate, baseline potassium, and diabetes mellitus.

Vardeny O et al. Circ Heart Fail. 2014;7:573-579

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RALES

Rates of death after visit 2 (4 weeks) by treatment, based on serum potassium levels at visit 2.

Vardeny O et al. Circ Heart Fail. 2014;7:573-579

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CONCLUSIONS

In HFrEF patients receiving optimal therapy, WRF and HK (>5.5 mmol/L only) were interrelated, were more frequent when eplerenone was added, but their occurence did not eliminate the survival benefit of eplerenone.

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Guidelines for Follow-Up (Patients Monitored) after One Week, One Month, and Every Four Months Thereafter Eplerenone Dose Potassium 5.5 to 5.9 mmol/L at any follow-up time point Decrease the dose of study drug Potassium ≥6 mmol/L at any follow-up time point Withhold study drug and restart only if potassium (remeasured within 72 hours) was < 5 mmol/L

A critical dynamic management : Eplerenone titration algorithm used in EMPHASIS-HF

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pharmacoepidemiology and drug safety 2007; 16: 55–64

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Congestion: plasma volume variations Kidney function : Creatinine Cardiorenal toxicity : Potassium

Optimize Medications : beta-blockers, Renin angiotensin aldosterone inhibitors, diuretics

A Therapeutic algorithm for a dynamic management of the disease (DSS) Point Of Care device,

  • minimally invasive
  • Remote monitoring

enabled.

Refining Disease management with Telemedicine

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Algorithmic decision support system (DSS)

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Are potassium binders part of the solution?

Working hypothesis:

  • New potassium binders might be used preventively to enable

RAASi use and maximal dosing in patients with a history of hyperkalemia due to RAASi or who are suspected to be at high- risk for developing hyperkalemia after RAASi initiation.

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BIOSTAT-HF

496 patients discharged from HFH with

  • LVEF<35%
  • <50%
  • ptimal

dose

  • f

ACEi/ARBs, and/or MRA therapy

  • And one or more of the following

– Age>75 years – eGFR<50 – Diabetes

80 % 20 % 63 % 9 % Courtesy Adriaan Voors Survived and not readmitted 6 months post-discharge Survived not readmitted and on > 50% dose

  • f RAASi
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Placebo

Randomized Double blind N= 310

6 months FU

Potassium Binder LVEF<35%, within month post discharge from a HHF No ACEi/ARB or no MRA or at doses < 50% of guideline target doses at risk of developing hyperkalemia (documented history of hyperkalemia, or age > 75 years, or eGFR < 50 ml/min or diabetes)

Event free surival and on optimal RAASi therapy (alive,

not re-hopsitalized and on optimal therapy of ACE i/ARB and MRAs i.e: at doses > 50% of guideline target doses (Doubling from 10 to 20%)

Potassium binders to optimise RAASi therapy

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Summary (1/2)

  • Concerns about inducing worsening renal function or

hyperkalemia lead clinicians to avoid RAASi initiation or dose titration in patients with HFrEF, with or without existing CKD.

  • When hyperkalemia occurs, RAASi doses are either

reduced or these drugs are discontinued.

  • Importantly, when hyperkalemia occurred within large

RAASi outcome trials, the clinical benefit associated with the RAASi was not hindered

  • Serum potassium monitoring and algorithm-based RAASi

dosing are associated with a lower risk of developing hyperkalemia.

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Summary (2/2)

  • Maximizing the chances of initiating, maintaining and
  • ptimising dosing of RAAS inhibitor life-saving therapy

can be obtained by

– Understanding the mechanism of action of RAASi – Predicting and preventing hyperkalemia and worsening renal function – frequent monitoring of K+ and creatinine.

  • Should hyperkalemia occur, prompt recognition and

management can optimize clinical outcome.

  • The role of new potassium binders in helping maximise

RAAS therapy in HF is to be investigated.