Post MI Heart Failure with Left Ventricular Dysfunction Management and Aldosterone Blockade Alain Wajman M.D., Cardiologist Prat Hosp. Clin. Spe Rothschild Hospital APHP, Paris

Heart Failure One-year mortality Disease with the highest prevalence in the next decade 50% of elderly (age 70 - 80) 50%: ischaemic heart disease (post MI and LVD) High costs for public health Prognosis: poor but improving One-year mortality 5% NYHA class I 25-30% NYHA class IV

Ventricular REMODELING After Acute Infarction Figure 2. Ventricular Remodeling after Infarction (Panel A) and in Diastolic and Systolic Heart Failure (Panel B). At the time of an acute myocardial infarction -- in this case, an apical infarction -- there is no clinically significant change in overall ventricular geometry (Panel A). Within hours to days, the area of myocardium affected by the infarction begins to expand and become thinner. Within days to months, global remodeling can occur, resulting in overall ventricular dilatation, decreased systolic function, mitral-valve dysfunction, and the formation of an aneurysm. The classic ventricular remodeling that occurs with hypertensive heart disease (middle of Panel B) results in a normal-sized left ventricular cavity with thickened ventricular walls (concentric left ventricular hypertrophy) and preserved systolic function. There may be some thickening of the mitral-valve apparatus. In contrast, the classic remodeling that occurs with dilated cardiomyopathy (right side of Panel B) results in a globular shape of the heart, a thinning of the left ventricular walls, an overall decrease in systolic function, and distortion of the mitral-valve apparatus, leading to mitral regurgitation. Jessup M and Brozena S. N Engl J Med 2003;348:2007-2018

Neurohormonal changes: VC > VD Vasodilation / Antiproliferative substances: Natriuretic peptides Bradykinines NO Adrenomedulline Vasoconstriction: Noradrenaline Renin Angiotensine System Endothelin Arginin Vasopressin Cytokines

Targets for Heart Failure Treatment Diuretics ACE I, AIIRAs Beta-blockers Anti-aldosterone Antiarrhytmics CCBs AIIRAs Antiplatelets Anticoagulants Statins? Figure 1. Primary Targets of Treatment in Heart Failure. Treatment options for patients with heart failure affect the pathophysiological mechanisms that are stimulated in heart failure. Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers decrease afterload by interfering with the renin-angiotensin-aldosterone system, resulting in peripheral vasodilatation. They also affect left ventricular hypertrophy, remodeling, and renal blood flow. Aldosterone production by the adrenal glands is increased in heart failure. It stimulates renal sodium retention and potassium excretion and promotes ventricular and vascular hypertrophy. Aldosterone antagonists counteract the many effects of aldosterone. Diuretics decrease preload by stimulating natriuresis in the kidneys. Digoxin affects the Na+/K+-ATPase pump in the myocardial cell, increasing contractility. Inotropes such as dobutamine and milrinone increase myocardial contractility. Beta-blockers inhibit the sympathetic nervous system and adrenergic receptors. They slow the heart rate, decrease blood pressure, and have a direct beneficial effect on the myocardium, enhancing reverse remodeling. Selected agents that also block the alpha-adrenergic receptors can cause vasodilatation. Vasodilator therapy such as combination therapy with hydralazine and isosorbide dinitrate decreases afterload by counteracting peripheral vasoconstriction. Cardiac resynchronization therapy with biventricular pacing improves left ventricular function and favors reverse remodeling. Nesiritide (brain natriuretic peptide) decreases preload by stimulating diuresis and decreases afterload by vasodilatation. Exercise improves peripheral blood flow by eventually counteracting peripheral vasoconstriction. It also improves skeletal-muscle physiology. Jessup M and Brozena S. N Engl J Med 2003;348:2007-2018

Severity of Systolic Heart Failure And Therapeutic Options Figure 3. Stages of Heart Failure and Treatment Options for Systolic Heart Failure. Patients with stage A heart failure are at high risk for heart failure but do not have structural heart disease or symptoms of heart failure. This group includes patients with hypertension, diabetes, coronary artery disease, previous exposure to cardiotoxic drugs, or a family history of cardiomyopathy. Patients with stage B heart failure have structural heart disease but have no symptoms of heart failure. This group includes patients with left ventricular hypertrophy, previous myocardial infarction, left ventricular systolic dysfunction, or valvular heart disease, all of whom would be considered to have New York Heart Association (NYHA) class I symptoms. Patients with stage C heart failure have known structural heart disease and current or previous symptoms of heart failure. Their symptoms may be classified as NYHA class I, II, III, or IV. Patients with stage D heart failure have refractory symptoms of heart failure at rest despite maximal medical therapy, are hospitalized, and require specialized interventions or hospice care. All such patients would be considered to have NYHA class IV symptoms. ACE denotes angiotensin-converting enzyme, ARB angiotensin-receptor blocker, and VAD ventricular assist device. Jessup M and Brozena S. N Engl J Med 2003;348:2007-2018

Diuretics in Post MI HF with LVD Always mandatory, ++++ if congestion Natriuretics Furosemide: 40-60 mg IV, 40 to 250 mg/d Renal vasodilation Hyponatremia Hypokalemia Alkalosis Hyperuricemia Hypertriglyceridemia

Beta-blockers in Post MI HF with LVD If EF < 35 % to 40 % Mandatory, start late, 4 to 6 weeks after acute phase …. In combination with ACE I Carvedilol Bisoprolol Metoprolol Nebivolol Start Late, Low, and go Slow Control: HR, BP, Diuresis, Body weight

ACE I or ARBs (AIIRAs) “sartans” in HF with low ejection fraction Candesartan, CHARM trial: 7000 patients with heart failure already receiving an ACE I or intolerant to an ACE I and low EF < 40% Significant mortality and rehospitalization reduction No benefit if EF > 40% Candesartan: 4.8 mg then 16 to 32 mg/d

The Renin-Angiotensin-Aldosterone System Figure 1. The Renin-Angiotensin-Aldosterone System. Angiotensinogen, the precursor of all angiotensin peptides, is synthesized by the liver. In the circulation it is cleaved by renin, which is secreted into the lumen of renal afferent arterioles by juxtaglomerular cells. Renin cleaves four amino acids from angiotensinogen, thereby forming angiotensin I. In turn, angiotensin I is cleaved by angiotensin-converting enzyme (ACE), an enzyme bound to the membrane of endothelial cells, to form angiotensin II. In the zona glomerulosa of the adrenal cortex, angiotensin II stimulates the production of aldosterone. Aldosterone production is also stimulated by potassium, corticotropin, catecholamines (e.g., norepinephrine), and endothelins. Weber K. N Engl J Med 2001;345:1689-1697

Physiologic and Pathophysiologic Effects of Aldosterone on the Kidney and Heart in Relation to Dietary Salt Levels Figure. Physiologic and Pathophysiologic Effects of Aldosterone on the Kidney and Heart in Relation to Dietary Salt Levels. Dluhy R and Williams G. N Engl J Med 2004;351:8-10

Sites of Diuretic Action in the Nephron Figure 1. Sites of Diuretic Action in the Nephron. The percentage of sodium reabsorbed in a given region is indicated in parentheses. "K+-sparing agents" collectively refers to the epithelial sodium-channel inhibitors (e.g., amiloride and triamterene) and mineralocorticoid-receptor antagonists (e.g., spironolactone and eplerenone). Sodium is reabsorbed in the distal tubule and collecting ducts through an aldosterone-sensitive sodium channel and by activation of an ATP-dependent sodium-potassium pump. Through both mechanisms, potassium is secreted into the lumen to preserve electroneutrality. Sodium-channel inhibitors preserve potassium by interfering with the sodium-potassium pump, whereas mineralocorticoid-receptor antagonists spare potassium through their inhibitory effect on aldosterone. NaHCO3 denotes sodium bicarbonate. Ernst M and Moser M. N Engl J Med 2009;361:2153-2164

Extraadrenal Production of Aldosterone by Endothelial and Vascular Smooth-Muscle Cells in an Intramyocardial Coronary Artery Figure 2. Extraadrenal Production of Aldosterone by Endothelial and Vascular Smooth-Muscle Cells in an Intramyocardial Coronary Artery. Modified from Slight et al.23 with the permission of the publisher. Weber K. N Engl J Med 2001;345:1689-1697

Coronary Vascular Remodelling in Hyperaldosteronism in Rats Figure 3. Coronary Vascular Remodeling in Hyperaldosteronism in Rats. Panel A shows a section from a normal heart with a normal intramural coronary artery (a) surrounded by yellow-stained fibrillar collagen. A small amount of collagen is also present between the muscle fibers. In Panel B, a section from the heart of a rat given aldosterone (plus salt) shows marked perivascular fibrosis of coronary vessels (a) and the contiguous interstitial space between muscle fibers. (Sirius red staining and polarized light, x40.)‏ Weber K. N Engl J Med 2001;345:1689-1697

EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Objective To evaluate the effects of eplerenone (a selective aldosterone blocker): on morbidity and mortality in patients with acute myocardial infarction (MI) complicated by left ventricular dysfunction and heart failure Reference Pitt B, Remme W, Zannad F et al. for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309–21.

EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study - TRIAL DESIGN - Design Multicentre, multinational, randomized, double-blind, placebo-controlled Patients 6632 patients 3–14 days after acute MI, who had left ventricular ejection fraction <40% and were receiving optimal treatment, which could include ACE inhibitors, angiotensin receptor blockers, diuretics (other than K+-sparing diuretics) and beta-blockers Follow-up and primary endpoints Primary endpoints: all-cause mortality; death from cardiovascular cause or first hospitalization for cardiovascular event. Mean 16 months follow-up. Treatment Placebo or eplerenone titrated to target dose 50 mg daily

Baseline characteristics EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Baseline characteristics Placebo Eplerenone (n=3313) (n=3319) Age (years) a 64 64 Male (%) 70 72 History Left ventricular ejection fraction (%) a 33 33 Days from MI to randomization a 7.3 7.3 Symptoms of heart failure 90 90 Medications ACE inhibitor or angiotensin-receptor blocker 87 86 Beta-blockers 75 75 Diuretics 61 60 Aspirin 89 88 Statins 47 47 a Mean Pitt et al. N Engl J Med 2003; 348 :1309 – 21.

EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study - RESULTS - Both primary endpoints significantly reduced in eplerenone group compared with placebo: all-cause mortality: 14.4 vs. 16.7% (RR 0.85, P=0.008) death or hospitalization due to cardiovascular event: 26.7 vs. 30.0% (RR 0.87, P=0.002) Significantly fewer hospitalizations for cardiovascular events in eplerenone group, attributable to significant reduction in hospitalizations for heart failure Incidence of gynecomastia in the two groups was similar. Incidence of serious hyperkalemia significantly higher in eplerenone group; serious hypokalemia significantly lower Drug well tolerated as defined by withdrawal rate from trial: only marginally higher with eplerenone

EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study - RESULTS, continued - All-cause mortality Cumulative 40 incidence (%) 30 20 RR=0.85 (95% CI=0.75–0.96) P=0.008 10 Placebo Eplerenone 6 12 18 24 30 36 Months after randomization Pitt et al. N Engl J Med 2003; 348 :1309 – 21.

EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study - RESULTS, continued - Primary and selected secondary endpoints Placebo Eplerenone Relative risk (n=3313) (n=3319) (95% CI) P No. (%) No. (%) or ratio Primary endpoints All-cause mortality 554 (16.7) 478 (14.4) 0.85 (0.75–0.96) 0.008 Cardiovascular death or 993 (30.0) 885 (26.7) 0.87 (0.79–0.95) 0.002 hospitalization for cardiovascular events Secondary endpoints (No.) Hospitalization for cardiovascular events 1004 876 0.87 0.03 Acute MI 269 268 0.99 0.96 Heart failure 618 477 0.77 0.002 Stroke 54 73 1.35 0.11 Ventricular arrhythmia 63 58 0.92 0.69 Pitt et al. N Engl J Med 2003; 348 :1309 – 21.

-15% Deaths from any cause Deaths from CV cause -13% EPHESUS main results -15% Deaths from any cause Deaths from CV cause or hospitalizations -13% Figure 1. Kaplan-Meier Estimates of the Rate of Death from Any Cause (Panel A), the Rate of Death from Cardiovascular Causes or Hospitalization for Cardiovascular Events (Panel B), and the Rate of Sudden Death from Cardiac Causes (Panel C). RR denotes relative risk, and CI confidence interval. Sudden death from cardiac causes -21% Pitt B et al. N Engl J Med 2003;348:1309-1321

EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study - RESULTS, continued - Adverse events Placebo Eplerenone (n=3301) (n=3307) P No. (%) No. (%) Gynecomastia 14 (0.6) 12 (0.5) 0.70 Serious hyperkalemia 126 (3.9) 180 (5.5) 0.002 (serum potassium >6 mmol/L) Serious hypokalemia 424 (13.1) 273 (8.4) <0.001 (serum potassium <3.5 mmol/L) Pitt et al. N Engl J Med 2003; 348 :1309 – 21.

EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study - SUMMARY - In patients with acute myocardial infarction (MI) complicated by left ventricular dysfunction and heart failure, eplerenone: Reduced all-cause mortality, and reduced death or hospitalization due to cardiovascular events Had no effect on the incidence of gynecomastia Increased the incidence of serious hyperkalemia but decreased serious hypokalemia NEJM 2003

Post MI Heart failure with LVD Take-home messages Clinical examination X-ray Cardiac ultrasound (ejection fraction) BNP or NT-Pro BNP Body weight Blood pressure control Repeat ionograms ( Na, K, …) Kidney function Use drugs at the “right dosages” Eplerenone at top of standard treatment (EPHESUS)

International Congress of Medicine for Everyday Practice Questions? ~ Answers!

NT pro-BNP and heart failure HF and AGE HF Probablilty LOW <300 1800 900 450 >75 yrs 50-75yrs <50 yrs ng/l G.Meune 2008

Compensated and Decompensated Heart Failure, as Indicated by the Presence or Absence of Urinary Sodium Retention, Together with Symptoms and Signs of Expanded Intravascular and Extravascular Volume Figure 4. Compensated and Decompensated Heart Failure, as Indicated by the Presence or Absence of Urinary Sodium Retention, Together with Symptoms and Signs of Expanded Intravascular and Extravascular Volume. In compensated heart failure with mild-to-moderate reductions in renal perfusion, natriuretic peptides, such as atrial natriuretic peptide (ANP) released by distended atria, stimulate sodium excretion (decreasing reabsorption, minus sign) so that the urinary sodium:potassium ratio is greater than 1.0. In decompensated heart failure, moderate-to-severe reductions in renal perfusion activate the renin-angiotensin-aldosterone system (RAAS), overriding the action of natriuretic peptides to stimulate nearly complete urinary sodium reabsorption (plus sign), resulting in a urinary sodium:potassium ratio of less than 1.0. Reproduced from Weber and Villarreal74 with the permission of the publisher. Weber K. N Engl J Med 2001;345:1689-1697