Faiez Zannad Institut Lorrain du Coeur et des Vaisseaux CIC - Inserm
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
Aldosterone/MRA The complete picture?
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
Mineralocorticoid Receptor Antagonists (MRAs) in Heart Failure Survival 30% RR, P < 0.001 Total Mortality 15% RR, P=0.008 1.00 0.90 0.80 Spironolactone 20 Placebo 0.70 0.60 0.50 Placebo 10 Eplerenone 0.40 0 6 12 18 24 30 36 Months 0 0 6 12 18 Months 24 30 36 RALES (LVSD, CHF severe symptoms) Pitt B, Zannad F, Remme WJ, et al. N Engl J Med. 1999 EPHESUS (LVSD + HF after MI) Pitt B, Remme W, Zannad F, et al. N Engl J Med. 2003
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 1663 6622 1773 ICD/CRT-D None 0 13.4/8.8% LVEF 25% 33% 26% NYHA III-IV NA II 1y Mortality (Pcb) 27.3% 13.7% 7.1% Drug dose 25-50 mg 25-50 mg 25-50 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)
Primary Endpoint: Cumulative K-M Rate (%) EPHESUS: Primary Endpoint Cardiovascular Death or HF Hospitalization 50 40 30 20 HR [95% CI] = 0.63 [0.54, 0.74] P < 0.0001 356 (25.9) Placebo Eplerenone 249 (18.3) 10 0 0 1 2 3 No. at Risk Years from Randomization Placebo 1373 848 512 199 Eplerenone 1364 925 562 232 *Unadjusted HR 0.66; 0.56, 0.78; p<0.0001 Zannad F et al. NEJM 2010
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
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
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
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) 0.002 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
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
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 60 60 HF Hospitalization / CV Death Cumulative K-M Rate (%) 50 40 30 20 10 HR [95% CI] = 0.681 [0.567, 0.817] P < 0.0001 Placebo 278 (27.6%) Eplerenone 198 (19.9%) HF Hospitalization / CV Death Cumulative K-M Rate (%) 50 40 30 20 10 HR [95% CI] = 0.593 [0.416, 0.844] P = 0.0037 Placebo 78 (21.4%) Eplerenone 51 (13.7%) 0 0 1 2 3 Years from Randomization No. at Risk Placebo 1008 608 365 140 Eplerenone 993 663 396 156 0 0 1 2 3 Years from Randomization No. at Risk Placebo 365 240 147 59 Eplerenon 371 262 166 76
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
Safety - Potassium related issues Zannad F et al. NEJM 2010
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
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.
Hyperkalemia with MRA therapy Caution in extrapolating benefit/risk of eplerenone (25-50 mg) in Emphasis-HF to that of spironolactone (12.5-50 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
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
What else? ACS HFPEF Acute HF Prevention
Cumulative survival rate (%) Admission aldosterone level and survival in patients undergoing primary PCI for STEMI 100 95 90 Quartile 1 (lowest) Quartile 2 Quartile 3 85 80 Quartile 4 (highest) 75 Log-rank p=0.005 70 1 11 21 31 41 51 61 71 81 91 101111121131141151161171181 Days Beygui F et al. Circulation 2006
EPHESUS: All-cause mortality Early initiation Late initiation
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 01059136 Beygui et al. Am Heart J 2010
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
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 15-30-45 mg/day (n=2250) CV death/hospitalization for HF B. Pitt, M. Pfeffer
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
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%
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
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
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
ALCHEMIST Hemodialysis LVH, or LVEF <40% or diabetes, or history of CV disease Placebo (n=375) Spironolactone 12.5-25 mg/j (n=375) MI, hospitalisation for HF, stroke, or CV death QOL, economic evaluation : CIC-EC
Future MRAs Genration First Spiro Second Eplerenone Selectivity (sex side effects) potency Cardio/renal effect Antiinflammatory + ++ + ++ +++ ++ + ++ Third Non steroidal ++++ +++ ++ ++ Fourth, Non renal +++ ++++ +++++
Faiez Zannad Institut Lorrain du Coeur et des Vaisseaux CIC - Inserm