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, Université de Lorraine, Institut Lorrain du Coeur et des Vaisseaux Clinical Investigation Center & Hypertension and Heart Failure Unit DGOS
CIC-P Nancy Eur Heart J. 2016 May 20. http://dx.doi.org/10.1093/eurheartj/ehw128
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CIC-P Nancy EORP – HF Long term registry Frequency of not taking HF life saving therapies in « eligible » patients with EF < 40% 32.3% 9% 7.3% MRAs Beta-blockers ACEi or ARBs Courtesy, Maggioni A, ESC Eurobservational 2015
CIC-P Nancy ESC HF Registry Under- use of life saving therapy European Journal of Heart Failure (2013) 15, 1173 – 1184
CIC-P Nancy ESC HF Registry Under- use of life saving therapy European Journal of Heart Failure (2013) 15, 1173 – 1184
CIC-P Nancy ESC HF Registry Under- dosing of life-saving therapy European Journal of Heart Failure (2013) 15, 1173 – 1184
CIC-P Nancy ESC HF Registry Under- dosing of life-saving therapy European Journal of Heart Failure (2013) 15, 1173 – 1184
CIC-P Nancy IMPROVE-HF Registry Under- dosing of life-saving therapy Congest Heart Fail. 2012;18:9 – 17.
CIC-P Nancy IMPROVE-HF Registry Under- dosing of life-saving therapy Congest Heart Fail. 2012;18:9 – 17.
CIC-P Nancy Reasons for not Prescribing a RAAS Blocker Reason N (%) No reason a 132 (58.7) AKI 29 (12.9) Hyperkalemia 23 (10.2) Hypotension 14 (6.2) Allergy b 9 (4.0) D/C 5 (2.2) Not indicated c 4 (1.8) Advanced CKD 4 (1.8) Renal artery stenosis 2 (0.9) Other d 3 (1.3) Total 225 a No documented reason found. b Allergy: angioedema, hand paresthesia, hives, cough and dizziness. c Provider documented that RAS blockade was not indicated for the patient. d Other: 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.
CIC-P Nancy RAASi and HF Mortality Edner M, Benson L, Dahlström U, Lund LH. Eur Heart J. 2015. Epub ahead of print.
CIC-P Nancy No RAAS inhibitor therapy at discharge doubles the 30-d risk of death +readmission (disregarding LVEF) Di Tano G, EJHF May 2015
CIC-P Nancy In HF with Severe Renal Insufficiency: Use of RAS Antagonists was Associated with Lower All-Cause Mortality Severe Renal Insufficiency NO Severe Renal Insufficiency 100 100 90 90 RAS, overall RAS, matched 80 Survival Proportion 80 Survival Proportion No RAS, overall 70 70 No RAS, matched 60 60 50 50 40 40 RAS, overall RAS, matched 30 30 No RAS, overall 20 20 No RAS, matched 10 10 HR 0.76 HR 0.79 0 0 0 1 2 3 4 5 0 1 2 3 4 5 No at Risk No at Risk Years Since Inclusion Years Since Inclusion Matched Cohort Matched Cohort No RAS Use 602 249 132 81 44 23 No RAS Use 1545 928 658 447 306 199 Ras Use 602 287 184 109 58 35 Ras Use 1545 1035 734 503 343 232 Overall Cohort Overall Cohort No RAS Use 808 305 162 98 52 27 No RAS Use 1574 939 664 452 309 200 Ras Use 1602 874 567 339 207 116 Ras Use 20299 15783 12047 9092 6427 4191 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). Edner M, Benson L, Dahlström U, Lund LH. Eur Heart J. 2015. Epub ahead of print.
CIC-P Nancy Am J Manag Care. 2015;21:S212-S220
CIC-P Nancy Distribution of RAAS Inhibitor Dose Levels by Comorbidity Group Am J Manag Care. 2015;21:S212-S220
CIC-P Nancy Among Patients on RAAS Inhibitor at Submaximum Dose Am J Manag Care. 2015;21:S212-S220
CIC-P Nancy Percent Mortality by Prior RAAS Inhibitor Dose Am J Manag Care. 2015;21:S212-S220
CIC-P Nancy Treatment with Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors Reduces Water and Sodium, But Increases Potassium Hyperkalemia is an inherent risk in the treatment of Angiotensinogen Renin Inhibitors HF with any RAAS Inhibitor Angiotensin I ACE Inhibitors K Retention Angiotensin II Na/Water Uptake Mineralcorticoid Receptor ARBs AT1 Receptor MRAs Aldosterone Production
CIC-P Nancy Multiple occurrences of WRF and HK A. Reductions in eGFR>20% C. hyperkalemia >5.5 mmol/L B. hyperkalemia >5.0mmol/L P. Rossignol et al. Int J Cardiol 2014
CIC-P Nancy RALES - Potassium levels during the study by treatment . Vardeny O et al. Circ Heart Fail. 2014;7:573-579
CIC-P Nancy 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
CIC-P Nancy 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
CIC-P Nancy 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.
CIC-P Nancy A critical dynamic management : Eplerenone titration algorithm used in EMPHASIS-HF Guidelines for Follow-Up Eplerenone Dose (Patients Monitored) after One Week, One Month, and Every Four Months Thereafter Potassium 5.5 to 5.9 mmol/L at Decrease the dose of study drug any follow-up time point Potassium ≥6 mmol/L at any Withhold study drug and restart only if potassium follow-up time point (remeasured within 72 hours) was < 5 mmol/L
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CIC-P Nancy pharmacoepidemiology and drug safety 2007; 16: 55 – 64
CIC-P Nancy Refining Disease management with Telemedicine Congestion: plasma volume Point Of Care device, variations • minimally invasive Kidney function : Creatinine • Remote monitoring Cardiorenal toxicity : Potassium enabled . A Therapeutic algorithm for a dynamic management of the disease (DSS) Optimize Medications : beta-blockers, Renin angiotensin aldosterone inhibitors, diuretics
CIC-P Nancy Algorithmic decision support system (DSS)
CIC-P Nancy 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.
CIC-P Nancy BIOSTAT-HF 496 patients discharged from HFH with Survived Survived • LVEF<35% and not not readmitted readmitted • <50% optimal dose of ACEi/ARBs, 80 % and on > 63 % and/or MRA therapy 50% dose of RAASi • And one or more of the following – Age>75 years – eGFR<50 – Diabetes 20 % 9 % 6 months post-discharge Courtesy Adriaan Voors
CIC-P Nancy Potassium binders to optimise RAASi therapy 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) Randomized Potassium Double blind Placebo Binder N= 310 6 months FU 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%)
CIC-P Nancy 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.
CIC-P Nancy Summary (2/2) • Maximizing the chances of initiating, maintaining and optimising 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.
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