Faiez Zannad. Institut Lorrain du Coeur et des Vaisseaux. CIC - Inserm

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1 Faiez Zannad Institut Lorrain du Coeur et des Vaisseaux CIC - Inserm

2 Disclosure Faiez Zannad Grants BG Medicine, Roche Diagnostics. Consultant/Steering committees/event committees/ Data safety Monitoring Boards: Biotronik, Boston Scientific, CVCT, Novartis, Pfizer, Resmed, Servier, Takeda

3 Aldosterone/MRA The complete picture?

4 HF with LV systolic dysfunction. What level of evidence? External validity Consistency with the results of other MRA trials Internal validity Magnitude of effect. Level of statistical significance Consistency of effect on all secondary endpoints Consistency of benefit/risk ratio across a large variety of pre-specified subgroups

5 Mineralocorticoid Receptor Antagonists (MRAs) in Heart Failure Survival 30% RR, P < Total Mortality 15% RR, P= Spironolactone 20 Placebo Placebo 10 Eplerenone Months Months RALES (LVSD, CHF severe symptoms) Pitt B, Zannad F, Remme WJ, et al. N Engl J Med EPHESUS (LVSD + HF after MI) Pitt B, Remme W, Zannad F, et al. N Engl J Med. 2003

6 Main features of MRA major trials Drug Dates RALES EPHESUS EMPHASIS-HF Spironolactone 1999 Eplerenone 2003 Eplerenone 2011 Conc. BB 11% 75% 86.9% N Pts ICD/CRT-D None /8.8% LVEF 25% 33% 26% NYHA III-IV NA II 1y Mortality (Pcb) 27.3% 13.7% 7.1% Drug dose mg mg mg All deaths -30% (p<0.001) -25% (p=0.008) -24% (p=0.008) HF Hospital -35% (p<0.001) 15% (p=0.003) -42% (p<0.0001)

7 Primary Endpoint: Cumulative K-M Rate (%) EPHESUS: Primary Endpoint Cardiovascular Death or HF Hospitalization HR [95% CI] = 0.63 [0.54, 0.74] P < (25.9) Placebo Eplerenone 249 (18.3) No. at Risk Years from Randomization Placebo Eplerenone *Unadjusted HR 0.66; 0.56, 0.78; p< Zannad F et al. NEJM 2010

8 Internal validity Endpoints The efficacy of eplerenone was Substantial and consistent across a wide range of secondary endpoints NNT - 37% CV death or HF hospitalization. - 24% All cause death - 23% All cause hospitalization - 42% HF hospitalization To prevent one patient experiencing the primary endpoint, per year of follow up, is 19 To postpone one death, per year of follow up, is 51

9 Pitt B et al. ESC 2011 Age <75 Age 75 Outcome Eplerenone Placebo p-value Serum K+>5.5 mmol/l 40/322 (12.4) 21/318 (6.6) 0.02 Serum K+>6.0 mmol/l 7/322 (2.2) 4/318 (1.3) 0.55 treatment discontinuation Hyper K 3/330 (0.9) 3/327 (0.9) 1.00 Hospitalization for WRF 5/330 (1.5) 3/327 (0.9) 0.52

10 Pitt B et al. ESC 2011 History of Diabetes No History of Diabetes Outcome Eplerenone Placebo p-value Serum K+>5.5 mmol/l 63/447 (14.1) 33/387 (8.5) 0.01 Serum K+>6.0 mmol/l 17/447 (3.8) 8/387 (2.1) 0.16 treatment discontinuation Hyper K 9/459 (2.0) 3/400 (0.8) 0.15 Hospitalization for WRF 5/459 (1.1) 7/400 (1.8) 0.39

11 Pitt B et al. ESC 2011 egfr<60 egfr 60 Outcome Eplerenone Placebo p-value Serum K+>5.5 mmol/l 70/422 (16.6) 43/461 (9.3) Serum K+>6.0 mmol/l 8/422 (1.9) 15/461 (3.3) 0.29 treatment discontinuation Hyper K 5/439 (1.1) 10/473 (2.1) 0.30 Hospitalization for WRF 5/439 (1.1) 8/473 (1.7) 0.32

12 Pitt B et al. ESC 2011 SBP < Median (123 mmhg) SBP Median (123 mmhg) Outcome Eplerenone Placebo p-value Serum K+>5.5 mmol/l 72/658 (10.9) 48/660 (7.3) 0.02 Serum K+>6.0 mmol/l 14/658 (2.1) 16/660 (2.4) 0.85 treatment discontinuation Hyper K 8/669 (1.2) 5/683 (0.7) 0.42 Hospitalization for WRF 3/669 (0.4) 5/683 (0.7) 0.44

13 Krum H et al. AHA 2011 Receiving >= 50% Target Dose of ACE Inhibitors (or ARB) and >= 50% Target Dose of Beta-Blockers: No vs. Yes Received Both >=50% Target Dose No Received Both >=50% Target Dose Yes HF Hospitalization / CV Death Cumulative K-M Rate (%) HR [95% CI] = [0.567, 0.817] P < Placebo 278 (27.6%) Eplerenone 198 (19.9%) HF Hospitalization / CV Death Cumulative K-M Rate (%) HR [95% CI] = [0.416, 0.844] P = Placebo 78 (21.4%) Eplerenone 51 (13.7%) Years from Randomization No. at Risk Placebo Eplerenone Years from Randomization No. at Risk Placebo Eplerenon

14 Internal validity Subgroups The efficacy and safety of eplerenone was relatively consistent irrespective of dose of background drug therapy, even in patients taking optimal high-dose ACEi/ARBs and BB relatively constant across a number of pre-specified subgroups and more specifically in patients at risk, i.e. Elderly Low egfr ( > 30 ml/min) Diabetes BP below median

15 Safety - Potassium related issues Zannad F et al. NEJM 2010

16 Treatment with Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors Reduces Water and Sodium, But Increases Potassium Renin Inhibitors Angiotensin I ACE Inhibitors Angiotensin II ARBs Angiotensinogen K Retention Na/Water Uptake Hyperkalemia is an inherent risk in the treatment of HF with any RAAS Inhibitor Mineralcorticoid Receptor AT1 Receptor Aldosterone Production MRAs

17 K recommendations Discontinue drugs that interfere with renal K secretion No NSAIDs, COX2 inhibitors, herbal preparations, salt substitutes that contain potassium Use low-potassium diet Monitor K+ and egfr after initiation at 1 Week, 1 month and then every 4 months. Optimise dosing Do not initiate if egfr < 30ml/min or K > 5.0 Half the dose if egfr < 60 ml/min and if K is 5.5 to 5.9 mmol/l Withhold drug if K> 6.0 mmol/l Remeasure K within 72 hours after dose reduction or drug withdrawal Restart only if K < 5.0 mmol per liter.

18 Hyperkalemia with MRA therapy Caution in extrapolating benefit/risk of eplerenone (25-50 mg) in Emphasis-HF to that of spironolactone ( mg) in RALES The fear of inducing hyperkalemia should not limit the initiation or increase in dose of eplerenone in patients with HF Hyperkalemia is predictable, preventable and manageable Beneficial effects of MRAs override adverse effects

19 Mc Murray J et al EHJ 2012 Pharmacological treatments indicated in potentially all patients with symptomatic (NYHA functional class II IV) systolic HF Recommendations Class a Level b Ref. c An ACE inhibitor is recommended for all patients with an EF 40% to reduce the risk of HF hospitalization and the risk of premature death. I A SOLVD CONSENSUS ATLAS A beta-blocker is recommended in addition to an ACE inhibitor (or ARB if ACE inhibitor not tolerated) for all patients with an EF 40% to reduce the risk of HF hospitalization and the risk of premature death. An MRA is recommended for all patients with persisting symptoms (NYHA class II IV) and an EF 35% despite treatment with an ACE inhibitor (or ARB) to reduce the risk of HF hospitalization and the risk of premature death. I A CIBIS I A MERIT Carvedillol Copernicus SENIORS RALES EPHESUS EMPHASISS

20 What else? ACS HFPEF Acute HF Prevention

21 Cumulative survival rate (%) Admission aldosterone level and survival in patients undergoing primary PCI for STEMI Quartile 1 (lowest) Quartile 2 Quartile Quartile 4 (highest) 75 Log-rank p= Days Beygui F et al. Circulation 2006

22 EPHESUS: All-cause mortality Early initiation Late initiation

23 The ALBATROSS trial AMI (ST+ or ST-) in the first 72hrs potassium canrenoate spironolactone Canrenone IV then Spironolactone Randomized Open label N=1600 control Primary End Point: death, resuscitated cardiac death, VF/VT, indication for defibrillator, heart failure up to 6-month FU clinicaltrials.gov registration number NCT Beygui et al. Am Heart J 2010

24 The REMINDER trial STEMI in the first 24hrs Eplerenone 25-50mg od Randomized Double blind N=612 placebo Primary End Point: CV mortality, re-hospitalisation or extended stay for HF, sustained VT or fibrillation, EF 40% after 1 month or BNP>200pg/ml 6 month FU minimum

25 HF with a LVEF>45% Age 50 years At least 1 hospitalization for HF within 12 months or a BNP>100 pg/ml within 30 days Serum K < 5.0 meq/l Systolic BP < 140 mmhg Placebo (n=2250) 4.5 years Spironolactone mg/day (n=2250) CV death/hospitalization for HF B. Pitt, M. Pfeffer

26 Post MI Low EF CHF Preserved EF CHF Mild Moderate Low EF CHF Severe Low EF AIRE/SAVE PEP-CHF (Perindopril) SOLVD CONSENSUS CAPRICORN SENIORS US Carvedilol MERIT CIBIS SENIORS COPERNICUS OPTIMAAL VALIANT CHARM I-PRESERVE ELITE HEAAL VALHeft CHARM -----? EPHESUS TOPCAT EMPHASIS RALES ASPIRE ATMOSPHERE PARADIGM

27 EVEREST: Aldosterone levels at admission associated with worse long term outcome 36.0% 51.2% 19.0% 22.5% 27.0% 30..5% 40.7% 37.8%

28 Post MI Low EF CHF Preserved EF CHF Mild Moderate Low EF CHF Severe Low EF Acute Worsening Hosp AIRE/SAVE PEP-CHF (Perindopril) SOLVD CONSENSUS -----? CAPRICORN SENIORS US Carvedilol MERIT CIBIS SENIORS COPERNICUS -----? OPTIMAAL VALIANT CHARM I-PRESERVE ELITE HEAAL VALHeft CHARM -----? ? EPHESUS TOPCAT EMPHASIS RALES -----? ASPIRE ATMOSPHERE PARADIGM ASTRONAUT

29 Pathways to heart failure In arterial hypertension: Targets for MRAs? MRA Atrial fibrillation Normal BP Adiposity MRA MetS MRA Coronary atherosclerosis * Metabolic cardiomyopathies Ischemic heart disease MRA MRA Heart Failure LV growth & remodeling MRA Hypertensive heart disease MRA Aortic valve stenosis

30 Prevent HF Post MI Low EF CHF Preserved EF CHF Mild Moderate Low EF CHF Severe Low EF Acute Worsening Hosp HOPE EUROPA AIRE/SAVE PEP-CHF (Perindopril) SOLVD CONSENSUS -----? ? CAPRICORN SENIORS US Carvedilol MERIT CIBIS SENIORS COPERNICUS -----? ONTARGET TRANSCEND OPTIMAAL VALIANT CHARM I-PRESERVE ELITE HEAAL VALHeft CHARM -----? ? ? EPHESUS TOPCAT EMPHASIS RALES -----? ASPIRE ATMOSPHERE PARADIGM ASTRONAUT

31 ALCHEMIST Hemodialysis LVH, or LVEF <40% or diabetes, or history of CV disease Placebo (n=375) Spironolactone mg/j (n=375) MI, hospitalisation for HF, stroke, or CV death QOL, economic evaluation : CIC-EC

32 Future MRAs Genration First Spiro Second Eplerenone Selectivity (sex side effects) potency Cardio/renal effect Antiinflammatory Third Non steroidal Fourth, Non renal

33 Faiez Zannad Institut Lorrain du Coeur et des Vaisseaux CIC - Inserm