Combination of renin-angiotensinaldosterone system inhibitors how to choose? Karl Swedberg Professor of Medicine Sahlgrenska Academy University of Gothenburg karl.swedberg@gu.se
Disclosures Research grants and honoraria from Amgen, Servier, Astrazeneca, Novartis, Pfizer Consultant: Roche
Target organs for the RAAS
Renin-Angiotensin Aldosterone System Angiotensinogen renin Non-ACE Pathways (e.g., chymase) Angiotensin I Vasoconstriction Cell growth Na/H 2 O retention Sympathetic activation Aldosterone AT 1 Angiotensin II ACE AT 2 Cough, Angioedema Benefits? Bradykinin Inactive Fragments Vasodilation Antiproliferation (kinins)
CONSENSUS Mortality 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 253 patients in NYHA class IV Randomized to placebo/enalapril From first patient to end of study 20 month 118 deaths Placebo Enalapril p=0.002 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Year Consensus trial study group NEJM 1987
CONSENSUS 10-Year Follow-Up All Randomized Patients, Original and Follow-Up Mortality 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 p=0.008 Placebo Enalapril 1 2 3 4 5 6 7 8 9 10 11 Year Swedberg et al EHJ 1999
ESC HF Guidelines 2012
ESC HF Guidelines 2012 Three neurohumoral antagonists an ACE inhibitor [or angiotensin receptor blocker (ARB)], a betablocker, and an MRA are fundamentally important in modifying the course of systolic HF and should at least be considered in every patient.
Combination of blockers It is important to plan for a combination of neurohormonal blockers already at treatment start. The plan should be outlined and agreed on together with the patient The order of additional blockers are dependent on blood pressure, heart rate and renal function
Trade-offs? Side-effects Hemodynamic hypotension, heart rate Renal dysfunction
Angiotensin Receptor Blockers (ARBs) as RAAS-blocker
CHARM Programme 3 component trials (N=7601) comparing candesartan to placebo in patients with symptomatic heart failure CHARM Alternative n=2028 LVEF 40% ACE inhibitor intolerant CHARM Added n=2548 LVEF 40% ACE inhibitor treated CHARM Preserved n=3025 LVEF >40% ACE inhibitor treated/not treated Primary outcome for each trial: CV death or CHF hospitalization Primary outcome for Overall Programme: All-cause death 12
Study Design Dose-titration and visit schedule 16 mg 8 mg 32 mg 4 mg 16 mg 8 mg 32 mg Candesartan/ matching placebo once daily Time 0 w 2 w 4 w 6 w 6 m Visit 1 2 3 4 5 Every 4 months until study end 31 March 2003 13
Class-effect or dose dependant?
JAMA 2012:307;1506
Survival and Follow-up of Candesartan and Losartan Users With Heart Failure Svanström et al JAMA 2012
All-Cause Mortality in Candesartan and Losartan Users With Heart Failure Svanström et al JAMA 2012
ESC HF Guidelines 2012
Renin-Angiotensin-Aldosteron System Angiotensinogen Renin Non-ACE Pathways (tonin, chymase, CAGE) Angiotensin I Vasoconstriction Cell growth Na/H 2 0 retention Sympathetic activation Aldosterone AT 1 ACE Angiotensin II cough vasodilation platelet agg ischemia + inotropic Bradykinin B 2, NO Inactive Fragments AT 2 Vasodilation Antiproliferatio n (kinins)
Randomized Aldactone Evaluation Study (RALES) 1663 pts with LVEF< 35% NYHA III-IV (class IV within 6 months) Probability of survival 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 Placebo Spironolactone 0.00 0 3 6 9 12 15 18 21 24 27 30 33 36 p<0.001 Months Pitt et al N Engl J Med 1999
Inclusion Criteria Inclusion > 55 years of age NYHA functional class II Ejection fraction < 30% (or, if between 30% and 35%, QRS >130 msec) Treated with the recommended or maximally tolerated dose of ACE inhibitor (or an ARB or both) and a beta-blocker (unless contraindicated). Exclusion Serum potassium > 5.0 mmol/l egfr < 30 ml/min/1.73 m 2
Baseline Therapy Characteristic Eplerenone (N=1364) Placebo (N=1373) Implantable cardioverter defibrillator (ICD) 178 (13.0) 184 (13.4) Cardiac resynchronization therapy (CRT-P) 38 (2.8) 22 (1.6) CRT-D 74 (5.4) 99 (7.2) Diuretic 1150 (84.3) 1176 (85.7) ACE inhibitor or angiotensin-receptor blocker or both 1282 (94.0) 1275 (92.9) Beta-blocker 1181 (86.6) 1193 (86.9) Digitalis glycosides 363 (26.6) 377 (27.5) Antiarrhythmic drug 196 (14.4) 192 (14.0) Antithrombotic drug (antiplatelet or oral anticoagulant) 1205 (88.3) 1214 (88.4) Lipid-lowering agent 857 (62.8) 856 (62.3)
Primary Endpoint Cardiovascular Death or Hospitalization for HF -37%
Mortality From Any Cause -24% *Unadjusted HR, 0.78; 0.64, 0.95; p=0.01
Safety (Investigator reported events)
Safety (Investigator reported events)
ESC HF Guidelines 2012
Side-effects
Adding ARB to ACE-I According to Baseline Use of Beta-Blocker and Spironolactone Events Events Group n placebo candesartan CV mortality or CHF hospitalisation ACE-i, no spiro, no β-blocker 936 218/475 194/451 ACE-i, no spiro, + β-blocker 1175 223/582 184/593 ACE-i, spiro, no β-blocker 199 46/86 66/113 ACE-i, spiro, + β-blocker 238 51/129 39/109 All patients 5482 538/1272 483/1276 All-cause mortality ACE-i, no spiro, no β-blocker 936 173/475 156/451 ACE-i, no spiro, + β-blocker 1175 151/582 148/593 ACE-i, spiro, no β-blocker 199 44/86 46/113 ACE-i, spiro, + β-blocker 238 44/129 27/109 All patients 2548 412/1272 377/1276 Placebo better Ca 0.4 0.5 0.6 0.7 0.8 0.9 0 1.1 1.2 1.3 1.4 1.5 1.6 Hazard ratio (95% CI) Weir RA et al. Eur J Heart Fail 2008;10:157-63
Impact of Candesartan on Hyperkalemia Risk in CHARM-Overall, by Subgroups Desai, A. S. et al. J Am Coll Cardiol 2007;50:1959-1966 Copyright 2007 American College of Cardiology Foundation. Restrictions may apply.
ESC HF Guidelines 2012
Spironolactone or Eplerenone?
Dosing of spironolactone and eplerenone Starting dose (mg) Target dose (mg) Eplerenone 25 od 50 od Spironolactone 25 od 25-50 od
Comparative Pharmacokinetics of Eplerenone and Spironolactone Spironolactone Eplerenone Bioavailability ordinarily 60% 70% enhanced by food intake by almost 100% 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
Gynecomastia in RALES 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.
Conclusions For the treatment of symptomatic systolic heart failure, a combination of neurohormonal blockers should be considered in all patients. For RAS-blockade, an ACE-inhibitor (or an ARB when ACEI-intolerance) and a MRA should be used The treatment plan should be discussed with the patient when treatment starts. Monitoring of renal function and for hyperkalemia should always be done when initiating these combinations