Heart Failure: Combination Treatment Strategies

Transcription

1 Heart Failure: Combination Treatment Strategies M. McDonald MD, FRCP State of the Heart Symposium May 28, 2011

2 None Disclosures

3 Case 69 F, prior MIs (LV ejection fraction 25%), HTN No demonstrable ischemia Admitted for worsening heart failure earlier this year Likely due to running out of medicine Medications re-initiated and titrated Received an implantable defibrillator (ICD) Currently, mild SOBOE, able to walk 4 blocks on the level surface, weight stable, no orthopnea Labwork within normal limits

4 Case Medications ASA, atorvastatin Ramipril 5 mg bid Bisoprolol 10 mg/d Digoxin mg/d Furosemide 40 mg/d Is there an opportunity to prevent recurrent hospitalization and improve survival? Role for an angiotensin receptor blocker? Role for an aldosterone antagonist? How should this patient be monitored?

5 The Problem Burden of illness Outline The Paradigms Pharmacologic therapy to improve survival in HF Earlier might be better The Prospects Aldosterone blockade in mild HF The Practicalities Applying new evidence to clinical practice

6 Impact Increasing burden of disease Lifetime incidence ~ 20% Currently > 500,000 Canadians afflicted with HF 50,000 new cases per year The median survival for heart failure patients 2.1 years One year mortality after diagnosis between 25-40% Naylor et al, ICES 1999 Lloyd-Jones et al, Circulation 2002

7 Heart Failure: Who Cares? HF treated solely by GPs = 50% HF treated by GP and specialists = 42% Tu Can J Cardiol 2004; Ezekowitz et al CMAJ 2005

8 % of population >65 yrs old Canada s Aging Population The baby boomers 25 Age: 65 yrs and over

9 The Problem Burden of illness Outline The Paradigms Pharmacologic therapy to improve survival in HF Earlier might be better The Prospects Aldosterone blockade in mild HF The Practicalities Applying new evidence to clinical practice

10 Neurohumoral activation is a central mechanism of progressive HF Myocardial insult LV dysfunction Neurohormonal Activation Progressive LV Remodeling Initially supports the circulation enhanced Na/H2O retention, vasoconstriction Ultimately highly negative impact - myocyte necrosis, fibrosis, progressive remodelling

11 Effects of Remodelling Normal Remodelled - Macro Remodelled - Micro

12 Neurohumoral activation is a central mechanism of progressive HF Myocardial insult LV dysfunction Neurohormonal Activation X Progressive LV Remodeling ACEi/ARB Beta blockers Aldosterone blockade

13 Renin-Angiotensin-Aldosterone system in heart failure Angiotensinogen Angiotensin I Renin ACE ACE Inhibitors Bradykinin Angiotensin receptor blockers X Angiotensin II Inactive peptides Reduced NO and vasodilating PGs AT1 Receptor stimulation Aldosterone Release Aldosteron X e Antagonist Vasoconstriction, Na retention, myocyte hypertrophy and apoptosis, s endothelial dysfunction, sympathetic activation, free radical generation, etc

14 1. Aldosterone blockade in severe chronic HF: RALES trial Pitt et al, N Engl J Med, pts, NYHA III or IV LVEF 35% Treated with ACEi, diuretic 75% on digoxin 10% on beta blocker Creat < 221μmol/L key results: 36% reduction in HF death 29% reduction in sudden death 30% reduction in HF hospitalizatio 10% gynecomastia on rx 2% hyperkalemia

15 Death 2. Aldosterone blockade in acute MI with HF: EPHESUS trial 6642 pts, MI < 2 weeks LVEF 40%, HF or diabete 85% on ACEi/ARB, diuretic 75% on beta blocker Creat < 221μmol/L key results: 15% reduction in death 13% reduction in CV death or hospitalization 5.5% hyperkalemia Pitt et al, N Engl J Med 2003

16 Towards optimal medical therapy Drugs that improve symptoms Furosemide Nitrates Digoxin Inotropes Drugs that improve survival ACE-inhibitors/ARBs Beta blockers Aldosterone antagonists All patients with EF <40% should be treated with an ACE-I and a beta-blocker, unless contraindicated Patients with LVEF 30% and symptoms despite optimized other therapies should be on spironolactone

17 Ultimately, HF is a progressive disease ACC/AHA Stage A High risk, no symptoms NYHA Class I No symptoms INTERMACS LEVEL Stage B Structural disease No symptoms Class II Limited with activity Stage C Symptomatic Stage D Refractory symptoms Very advanced HF Class III Class IV Limited with less than Severely limited ordinary activity any activity worsens symptoms Walking wounded Housebound Frequent hospitalizations Inotrope dependent Sliding on inotropes Crash and burn Disease Trajectory

18 Progression to Symptomatic HF: Worsening Prognosis Ø Progression to overt HF associated with > 5-fold mortality risk Ø Rate of progression from Stage B to Stage C unknown (~ 6%/yr) Wang et al, Circulation 2003 Ammar et al, Circulation 200

19 LV dysfunction Natural History 100 AHA Stage A AHA Stage B Mechanism of death 40% SCD 40% CHF 20% Other % Survival 0 Annual Mortality <5% 10% 20-30% 30-80% AHA Classification Risk Factor Asymptomatic Mild Moderate Severe Time

20 LV dysfunction Can we alter the natural history? AHA Stage A AHA Stage B Mechanism of death 40% SCD 40% CHF 20% Other 100 % Survival 0 Annual Mortality <5% 10% 20-30% 30-80% AHA Classification Risk Factor Asymptomatic Mild Moderate Severe Time

21 Last Decade of Drug Therapy in Disappointments Phosphodiesterase inhibitors OPTIME-CHF, 2002 Calcium sensitization SURVIVE, 2007 HF Winners (the RAAS inhibitors.still) ARBs CHARM Programme, 2003 Vasopressin antagonists EVEREST, 2007 Adenosine antagonists PROTECT, 2009 Naturetic peptides? Aldosterone antagonists RALES, 1999 EPHESUS, 2003 EMPHASIS, 2010

22 HF Therapy Timeline rise of the machines 200AD

23 Managing patients with HF: What the average HF patient looks like Age 75 years Female 52% Hypertension 72% Diabetes 44% Atrial fibrillation 31% COPD 31% Chronic kidney disease 30% Gheorghiade, Eur Heart J, 2005

24 VAD, Transplant, Tailored therapy 25,000-50,000 Advanced HF 500,000 with HF diagnosis Neurohormonal blockade 180 transplants 60 VADs CRT pacemaker, ICD Digoxin, Diuretics Aldosterone antagonist ACEi, Beta blocker Lifestyle intervention Risk factor control

25 The Problem Burden of illness Outline The Paradigms Pharmacologic therapy to improve survival in HF Earlier might be better The Prospects Aldosterone blockade in mild HF The Practicalities Applying new evidence to clinical practice

26 3. Expanding the role of aldosterone antagonists in mild HF: EMPHASIS, 2010 >2700 patients, NYHA Class II, LVEF <30% Randomized to eplerenone vs placebo Median f/u 21months Primary outcome was CV mortality or HF hospitalization

27 3.Expanding the role of aldosterone antagonist in mild HF: EMPHASIS, 2010 The Cost: increased rates of hyperkalemia (8% vs 4%) No increased risk of renal failure or gynecomastia Zannad et al, N Engl J Med, 2010

28 Aldosterone antagonism is winning Aldosterone escapes effects of ACE inhibition stimulated by ATII and K+ Decreased hepatic clearance Pleiotropic effects of aldo excess Na retention, K losses endothelial dysfunction Baroreceptor dysfunction collagen turnover and tissue fibrosis Unanswered questions: Safety in a real world setting Spironolactone versus epleronone Role of aldosterone antagonism

29 The Problem Burden of illness Outline The Paradigms Pharmacologic therapy to improve survival in HF Earlier might be better The Prospects Aldosterone blockade in mild HF The Practicalities Applying new evidence to clinical practice

30 Application of aldosterone blockade Recognize that aldosterone blockade is underutilized (get with the guidelines) Recognize that careful attention needs to be paid to patients included in trials Example: Patients with creatinine >220 were excluded from clinical trials

31 Medical Therapy: Practical Tips All meds should be titrated to therapeutic dose (some is good more is better) Renal function, electrolytes should be monitored when titrating ACEi or spironolactone ~30% rise in creatinine may be expected with ACEi Check creatinine and K+ 1 week after any changes Combination ACEi, ARB and spironolactone should be avoided Elderly may be more vulnerable