DECLARATION OF CONFLICT OF INTEREST

DECLARATION OF CONFLICT OF INTEREST

TAKE HOME MESSAGES FROM RECENT HEART FAILURE CLINICAL TRIALS How to use aldosterone blockers? Faiez Zannad INSERM, U961 and Clinical Investigation Center CHU, Heart Failure and Hypertension Unit, Institut Lorrain du Coeur et des Vaisseaux University Henri Poincaré Nancy, France

TAKE HOME MESSAGES FROM RECENT HEART FAILURE CLINICAL TRIALS How to use Mineralocorticoid Receptor Antagonists (MRAs)? Faiez Zannad INSERM, U961 and Clinical Investigation Center CHU, Heart Failure and Hypertension Unit, Institut Lorrain du Coeur et des Vaisseaux University Henri Poincaré Nancy, France

Disclosures Dr Zannad reports receiving Speaker/consultant honoraria from Alere, AstraZeneca, BG Medicine, Boston Scientific, Novartis, Pfizer, Resmed, Servier and Takeda.

MRAs in clinical practice Why? When to use? When Not to use? How? (Dosing, Safety) Which one? Class effect.

Aldosterone/MR antagonists beneficial across the spectrum of severity 1.00 Survival 30% RR, P < 0.001 Total Mortality 15% RR, P=0.008 0.90 0.80 Spironolactone 20 Placebo 0.70 Eplerenone 0.60 0.50 Placebo 10 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

Probability of survival Probability of survival Aldosterone/MR antagonists beneficial across the spectrum of severity RALES 1663 NYHA class III/IV patients 95% ACE-I/10% β-blocker EMPHASIS-HF 2737 NYHA class II patients 93% ACE-I or ARB/87% β-blocker 1.00 0.90 0.80 1.00 0.90 0.80 Placebo Eplerenone 0.70 0.60 Placebo Spironolactone 0.70 0.60 0.50 0.00 RRR (95% CI) 30 (18-40)% P < 0.001 0 1 2 3 Years from randomization 0.50 0.00 RRR (95% CI) 22 (5-36)% P = 0.0139 0 1 2 3 Years from randomization Pitt B, et al. N Engl J Med. 1999;341:709-717. Zannad F, et al. N Engl J Med. 2010;364:11-21.

1 year mortality (%) Opitimization of Neurohumoral blockade Systolic heart failure. Moderate to severe symptoms. 35 30 25 20 CONSENSUS 1987 35 25 27.3 RALES 1999 21 COPERNICUS 2001 19.7 15 12.8 10 5 0 NO ACE inhib. ACE inhib. Pitt B, et al. N Engl J Med. 1999;341:709-717. Packer M, et al. N Engl J Med. 2001;344:1651-1658. ACE inhib. ACE inhib. Aldo. antag. ACE inhib. ACE inhib. Aldo. antag. Aldo. antag Beta-blocker

Death at 1year (%) Opitimization of Neurohumoral blockade in systolic heart failure. Mild symptoms. 18 16 14 12 10 8 6 4 2 0 SOLVD-T 1991 15,6 12,4 CIBIS + MERIT-HF 1999 11,9 7,8 ACE inhib ACE inhib. ACE inhib. Beta-blocker The SOLVD Investigators. N Engl J Med.. 1991;325:293-302. CIBIS II. Lancet. 1999;353:9-13. MERIT-HF. Lancet. 1999;353:2001-2007. Zannad F, et al. N Engl J Med. 2011;364:11-21. EMPHASIS-HF 2011 7.1 ACE inhib. Beta-blocker 6.1 ACE inhib. Beta-blocker MRA

CV death or hospitalisation (%) CV death or hospitalisation (%) Which drug to add next to an ACE inhibitor and beta-blocker? CHARM-Added 2548 mainly NYHA class III patients 100% ACE-I/55% β-blocker/17% MRA EMPHASIS-HF 2737 NYHA class II patients 93% ACE-I or ARB/87% β-blocker 50 50 40 40 30 Placebo 30 Placebo 20 Candesartan 20 Eplerenone 10 RRR 15 (4-25)% P=0.011 10 RRR 37 (26-46)% P<0.001 0 0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 0 0.5 1.0 1.5 2.0 2.5 3.0 Time since randomization (years) Time since randomization (years) McMurray, et al. Lancet. 2003;362:767-71. Zannad F, et al. N Engl J Med. 2010;364:11-21.

Changing practice All symptomatic patients with low EF (With egfr > 30 ml/min and K <5.5 meq/l) + LBBB

Target population All patients with LVSD except patients with CKD (egfr < 40-30 ml/min), excluded from trials and contra-indicated Patients with hyperkalemia (K+ > 5mEq/ml) Patients on potassium sparing agents or potassium supplements

When to initiate? CHF patients with stable conditions AHF post dischage when renal function has stabilized Acute MI + LVSD and HF as soon as possible after the 3rd day (the earlier the better)

EPHESUS: All-cause mortality EPHESUS Early initiation Late initiation

How to use? The evidence Target patient population Dosing Safety Class effect?

Dose-Finding in RALES Pmol/L 100 Nt-ANF 0-100 - 200-300 - 400 Pcb 12.5 25 50 75 Spironolactone (mg)

Treatment with 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 RAAS Inhibitors Mineralcorticoid Receptor AT1 Receptor Aldosterone Production Mineralocorticoid Receptor Antagonists (MRA)

Hyperkalemia with MRAs in Real Life HF Therapy Canada In-Hospital death from hyperkalemia before & after RALES publication Juurlink et al, NEJM 2004

Juurlink et al, NEJM 2004 Patients had frequently renal dysfunction Creatinine levels 1.8 to 2.0 mg per deciliter [159 to 176 μmol per liter]) RALES : 1.2 mg per deciliter (106 μmol per liter) Doses of spiro were higher than in RALES Many patients took potassium supplements or other hyerkamemic drugs Follow-up also was less vigorous than that in the clinical trial.

BMJ 2010;340:c1768 doi:10.1136/bmj.c1768

RAAS inhibition may be associated to serious adverse effects ONLY when used inappropriately In patients with or at risk of hyperkalemia or renal failure Beyond approved indications Without proper monitoring At doses exceeding the «safe» dose range

RAAS antagonists and Hyperkalemia How frequent? How to predict? How to prevent? How to manage?

Incidence (%) Incidence of hyperkalemia K+ >6.0 mmol/l Placebo Eplerenone Spironolactone P<.001 P=.002 6 4 5.5% 3.9% NS 2 1.7% 1.2% 2.5% 1.9% 0 RALES EPHESUS EMPHASIS-HF

EMPHASIS-HF Potassium Safety Outcome Patients with an adverse event leading to drug withdrawal no. (%) Eplerenone (N=1360) Placebo (N=1373) P Value Hyperkalemia (investigator reported AE) Hyperkalemia leading to drug discontinuation 109 (8) 50 (3.7) <0.001 15 (1.1) 12 (0.9) 0.57 Serum K+ > 5.5 mmol/l 158 (11.8) 96 (7.2) <0.001 Serum K+ > 6.0 mmol/l 33 (2.5) 25 (1.9) 0.29 Hospitalization for hyperkalemia (adjudicated) 4 (0.3) 3 (0.2) 0.85

CHARM Potassium Safety Study Candesartan Placebo Odds ratio CHARM Alternative CHARM Preserved CHARM Added CHARM Overall 4.0% 1.5% 2.7 3.3% 1.2% 3.1 8.4 % 2.9% 2.8 5.2% 1.8% 2.9 Based on investigator s assessment of clinically important hyperkalemia Source: Desai et al, J Am Coll Cardiol 2007

Selected Adverse Events Rate / 100 person-years 8 7 All AEs 7.12 8 7 Resulting in Discontinuation of Study Drug 6 * p <.001 6 5 ** p =.002 4.73 5 4 3 2 2.79 2.92 1.87 2.07 4 3 2 1 0 Hyperkalemia * Hypotension ** Renal Impairment * 1 0 0.12 0.05 0.26 0.22 0.65 0.49 Hyperkalemia Hypotension Renal Impairment Losartan 150 mg (n=1912) Losartan 50 mg (n=1905) Konstam MA et al, Lancet 2009; 374: 1840 48 17

Mineralocorticoid-antagonists and Hyperkalemia How frequent? How to predict? How to prevent? How to manage?

Risk Factors for Hyperkalemia Stepwise logistic regression identified 3 independent risk factors for K : Baseline K + Baseline creatinine clearance History of diabetes None was associated with a significant differential adverse effect of intervention vs. placebo for outcome

EMPHASIS - Cumulative rate of Worsening Renal Function (egfr> 20% decrease) without hyperkalemia (K>5.5 mmol/l) (%) 60 50 40 30 HR [95% CI] = 1.218 [1.044, 1.422] P = 0.0118 Eplerenone Placebo 20 10 0 0 6 12 18 24 30 36 42 48 Months from Randomization

EMPHASIS Cumulative rate Hyperkalemia (K>5.5 mmol/l) With WRF without WRF (egfr> 20% decrease) (egfr> 20% decrease) 15 HR [95% CI] = 1.494 [1.065, 2.094] P = 0.0191 Eplerenone 15 HR [95% CI] = 1.964 [1.287, 2.996] P = 0.0014 10 10 Eplerenone Placebo 5 5 Placebo 0 0 6 12 18 24 30 36 42 48 Months from Randomization 0 0 6 12 18 24 30 36 42 48 Months from Randomization

EMPHASIS Prognostic significance of Hyperkalemia, mainly driven by assocition with worsening renal function (CV death/or HF hosp) HR CI P K>5.5 mmol/l (without egfr> 20% decrease) K>5.5 mmol/l (with egfr> 20% decrease) 1.2 0.3-3.9 0.7 3.4 1.1-10.6 0.03

Approach to Patients at Risk for Hyperkalemia Caused by RAAS Inhibitors 1. Estimate egfr 1. use low dose if < 60 ml/min 2. Do not use if egfr >30ml/min 2. Discontinue drugs that interfere with renal K secretion 3. Inquire about and discontinue use of herbal preparations, and NSAIDs including selective COX2 inhibitors 4. Prescribe low-potassium diet, inquire about use of salt substitutes that contain potassium 5. Prescribe thiazide or loop diuretics (loop diuretics necessary when estimated glomerular filtration rate is <30 ml/min) 6. Monitor K+ and egfr and optimise dosing

Mineralocorticoid-antagonists and Hyperkalemia How frequent? How to predict? How to prevent? How to manage?

K recommendations Do not initiate if K > 5.0 Evaluate K after initiation at 1 Week, 1 month and then every 4 months. Half the dose 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.

Some potassium sparing may be 14 12 10 beneficial? Patients 8 1.6% absolute increase Eplerenone (%) P = 0.002 Placebo 6 4 2 0 Serious Hyperkalemia (K + 6.0 meq/l) 4.7% absolute decrease P < 0.001 Hypokalemia (K + 3.5 meq/l)

Conclusions on Hyperkalemia in RAAS Inhibition The fear of inducing hyperkalemia should not limit the initiation or increase in dose of ACE-Is, ARBs, DRIs and Aldosterone Blockers in patients with HF The risk of hyperkalemia is mainly driven by worsening renal function Hyperkalemia is predictable, preventable and manageable Beneficial effects of RAAS inhibition override adverse effects

Spironolactone or Eplerenone? The level of evidence Risk/benefit Differing pharmacokinetics Differing pharmacodynamics

Main features of MRA major trials Drug Dates Concomitant Beta Blockers RALES EPHESUS EMPHASIS-HF Spironolactone 1999 Eplerenone 2003 Eplerenone 2011 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 One year Mortality (Pcb) 27.3% 13.7% 7.1% Drug dose Spiro 25-50 mg Eple 25-50 mg Eple 25-50 mg RR All cause death 0.70 (0.60 0.82) <0.001 RR HF Hospital 0.65 (0.54 0.77) <0.001 0.85 (0.75-0.96) 0.008 0.85 (0.74-0.99) 0.003 0.76 (0.62, 0.93) 0.008 0.58 (0.47, 0.70) <0.0001

Comparative Pharmacokinetics of Eplerenone and Spironolactone Bioavailability Spironolactone ordinarily 60% 70% enhanced by food intake by almost 100% Eplerenone Unknown. Absorption approaches 100% and is not influenced by food Protein Binding >90% 50% with binding to 1 -acid glycoproteins Active Metabolites Half-life (hours) Yes sulfur-containing products Spironolactone = 1.4 Active metabolites = 13 24 No 4 6

Patients (%) Hyperkalemia in Phase III HTN Database Excluding Study-021 (Diabetics with Proteinuria) 9 8 7 6 5 4 3 2 1 0 Maximum Potassium >5.5 mmol/l Verified Potassium >5.5 mmol/l Spironolactone (N=119) Eplerenone monotherapy (N=1748) Maximum Potassium 6.0 mmol/l Note: Includes studies 010, 015, 016, 017, 018, 019, 020, 021, 022, 023, 024, 026, and 049

Spironolactone Induces Gynecomastia in HF Patients vs. No excess Gynecomastia with Eplerenone over Placebo 15 P < 0.001 Gynecomastia or Breast Pain (Males) (%) 10 5 10 1 0 Placebo Spironolactone Pitt B et al. N Engl J Med. 1999;341:709-17.

Spironolactone Spironolactone The but rise not in HbA1c but not was eplerneone correlated to eplerneone raised worsened the rise in HbA1c Cortisol Cortisol Am Heart J 2010;160:915-21.

Ach Control Spironolactone No Ach Diabetologia (2004) 47:1687 1694

Do you believe in class effect? Felis Catus Felis Catus Felis rufus Panthera leo Panthera pardus Panthera tigris