Heart Failure 2012: The Update WELCOME. Steven R. Goldsmith, M.D.

Transcription

1 Heart Failure 2012: The Update WELCOME Steven R. Goldsmith, M.D. Professor of Medicine, University of Minnesota Director, Heart Failure Program, Hennepin County Medical Center Director, MN Heart Failure Consortium

2 The Minnesota Heart Failure Consortium 2002: founded to foster inter-institutional research and education relating to heart failure in MN : RAPID and other trials successfully completed 2006: Awarded one of the 8 original RCCs in the NIH HF Network, Drs. Bart and Goldsmith develop the CARRESS trial for the Network

3 NIH Heart Failure Network

4 The Minnesota Heart Failure Consortium 2002: founded to foster inter-institutional research and education relating to heart failure in MN : RAPID and other trials successfully completed 2006: Awarded one of the 8 original RCCs in the NIH HF Network, Drs. Bart and Goldsmith develop the CARRESS trial for the Network 2010: Recognized as the RCC with the best combination of enrollment and endpoint completion across all Network studies 2011: DOSE Trial published from the NIH HF NETWORK

5 Original Article Diuretic Strategies in Patients with Acute Decompensated Heart Failure G. Michael Felker, M.D., M.H.S., Kerry L. Lee, Ph.D., David A. Bull, M.D., Margaret M. Redfield, M.D., Lynne W. Stevenson, M.D., Steven R. Goldsmith, M.D., Martin M. LeWinter, M.D., Anita Deswal, M.D., M.P.H., Jean L. Rouleau, M.D., Elizabeth O. Ofili, M.D., M.P.H., Kevin J. Anstrom, Ph.D., Adrian F. Hernandez, M.D., Steven E. McNulty, M.S., Eric J. Velazquez, M.D., Abdallah G. Kfoury, M.D., Horng H. Chen, M.B., B.Ch., Michael M. Givertz, M.D., Marc J. Semigran, M.D., Bradley A. Bart, M.D., Alice M. Mascette, M.D., Eugene Braunwald, M.D., Christopher M. O'Connor, M.D., for the NHLBI Heart Failure Clinical Research Network N Engl J Med Volume 364(9): March 3, 2011

6 The Minnesota Heart Failure Consortium 2002: founded to foster inter-institutional research and education relating to heart failure in MN : RAPID and other trials successfully completed 2006: Awarded one of the 8 original RCCs in the NIH HF Network, Drs. Bart and Goldsmith develop CARRESS Trial for the Network 2010: Recognized as the RCC with the best combination of enrollment and endpoint completion across all Network studies 2011: DOSE trial published from the NIH NETWORK 2012: CARRESS trial, led by Drs. Bart and Goldsmith, completed and published

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8 General Facts 5 million Americans affected in US. Leading cause of hospitalization for Americans >65 years old. Causes or contributes to 250,000 deaths/year in US. Costs in excess of 30 billion dollars. Only major cardiovascular disorder rising in incidence and prevalence (aging population, better survival post MI).

9 HF: Causes and Treatment Mechanical problems (ie valvular diseases) - require mechanical solutions. Ischemia - requires targeted treatment. HF with preserved EF accounts for more than half of all HF, but there is little information to guide the treatment. The evidence base for treating HF is confined to patients with symptomatic or asymptomatic left ventricular dysfunction associated with a low ejection fraction.

10 CHF: Historical Paradigms Congestion Sodium retention/edema Hemodynamics Cardiac pump function/loading conditions

11 Treatment Goals: Historical Paradigms if the problem is congestion, a poor pump and abnormal loading conditions, decrease the congestion, support the pump and improve the loading conditions Diuretics Inotropes Venodilators Arterial vasodilators

12 Survival Until FS <0.16 Effect of Furosemide on Mortality in Experimental Heart Failure Placebo Furosemide Days of Pacing N=16 for both groups. P=.038 from log-rank statistics. McCurley et al. J Am Coll Cardiol. 2004;44:

13 Inotropes and Outcomes in Heart Failure Drug Follow-Up Period Results Milrinone 6 mos Mortality (34%) Ibopamine 6 mos Mortality (21%) Vesnarinone 1 year Mortality (26%)

14 Vasodilators in Heart Failure Rationale: acutely, the use of nitroprusside, hydralazine, isosorbide dinitrate, and prazosin improves hemodynamics in acute and chronic HF. The general mechanism was felt to be unloading of the left ventricle.

15 V-HeFT Mortality Study In Congestive Heart Failure

16 Other Failures of Vasodilator Therapy in CHF Prostacyclin Hydralazine (as monotherapy) Flosequinan Amlodipine

17 Congestive Heart Failure: Neurohormonal Imbalances Newer Paradigm Focus shifts to cellular/molecular processes Hypertrophy/remodeling Bioenergetic abnormalities Oxidative stress Apoptosis

18 Mechanisms of Disease Progression Load Dependent (old paradigms) Systolic and diastolic wall stress Preload and afterload Load Independent (new paradigm) Inappropriate hypertrophy, bioenergetic changes, inflammation, apoptosis

19 Ventricular Remodeling A dynamic process in which the LV undergoes structural changes characterized by dilatation, hypertrophy, fibrosis and altered shape. Develops in response to injury and/or increased load. Often continues under systemic neurohormonal and poorly understood local influences after initiating event has resolved. Leads to progressive systolic and diastolic dysfunction. Essentially perfect correlation between changes in LV volumes/ef and outcome in CHF therapeutic trials.

20 Apoptosis Pathways of Cardiac Remodeling ATII-R/ET-IR 1 - AR OX rad JAK STAT ras raf PLC G-Protein DAG IP 3 camp ATP NFΚB PK Ca++ CREB MAPK Transcriptional Activation Cardiac Remodeling

21 Neurohormonal Imbalance and Disease Progression Aggravation of loading conditions which in turn aggravates systolic and diastolic wall stress, furthering the remodeling process. Direct activation of maladaptive genetic programs contributing to hypertrophy, abnormal calcium handling, fibrosis and cell death (apoptosis). Direct myocardial cell toxicity (norepinephrine).

22 ET A Vasoconstriction ET B Vasodilation Natriuretic Peptides Na + loss Renin inhibition Sympathetic inhibition Vasodilation Endothelin AVP Release Myocardial Injury Renin Release V 1 Receptors Inotropic stimulation Myocardial hypertrophy V 2 Receptors H 2 O retention Diastolic wall stress Sympathetic Stimulation Alpha Hypertrophy Vasoconstriction Na + retention Beta Myocardial toxicity Receptor down regulation Arrhythmia Renin release A-II Aldosterone Na + retention Myocardial fibrosis Vasoconstriction Hypertrophy Reflex resetting Sympathetic stimulation

23 Success With Neurohormonally Directed Therapy Interference with the renin-angiotensinaldosterone system (RAAS) Angiotensin converting enzyme inhibition (ACEI) Angiotensin II receptor blockade (ARB) Aldosterone antagonism Interference with the sympathetic nervous system Beta adrenergic blockade Combined alpha and beta adrenergic blockade

24 Outcomes in CHF vs year mortality rate in stable patients on diuretics and digoxin only, NYHA functional class 2 or 3: 20% VHEFT 1 1 year mortality rate in stable patients, NYHA functional class 2 or 3, on ACEI or ARB plus beta blockade: 5-6% VALHEFT, CHARM

25 The Renin-Angiotensin Aldosterone System Chymase CAGE Angiotensinogen Angiotensin I Angiotensin II AT 1 -receptor ARB X Renin Inhibition Beta-blockade ACE Inhibition Bradykinin NO Vasoconstriction Afterload Cell growth Hypertrophy Fibrosis X Aldosterone X X Sympathetic activation AVP Na + retention, K + loss X = Aldo antagonists

26 Effect of ACE Inhibitors on Mortality Reduction in Patients With Heart Failure Mortality Trial ACEI Controls RR (95% CI) Chronic CHF CONSENSUS I SOLVD (Treatment) SOLVD (Prevention) 39% 54% 0.56 ( ) 35% 40% 0.82 ( ) 15% 16% 0.92 ( ) Post MI SAVE AIRE TRACE 20% 25% 0.81 ( ) 17% 23% 0.73 ( ) 35% 42% 0.78 ( ) SMILE 5% 6.5% 0.75 ( ) Average 21% 25%

27 Cumulative Mortality V-Heft II: Enalapril vs. Hydralazine- ISDN in Mild to Moderate CHF Enalapril 1 yr mortality 33.6% 2 yr mortality 28.2% Sudden death 38% Hydralazine-ISDN Greater in LVEF exercise tolerance Hydralazine-ISND Isosorbide dinitrate Enalapril Months Cohn JN, et al. N Engl J Med 1991;325:

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29 Effects of Therapy on Adrenergic Activation

30 Angiotensin II Receptor Antagonism On theoretical grounds, should be equally effective and likely additive to ACEI. DATA: ARB not superior to ACEI in absence of placebo (ELITE II). DATA: ARB effective in ACEI-intolerant pts (CHARM, placebo controlled). DATA: ARB + ACEI not superior to ACEI on mortality, modest morbidity benefit (VALHEFT, CHARM).

31 Aldosterone Conventional view: sodium/potassium regulation. Newer view: potential role in myocardial hypertrophy/fibrosis, possibly sympathoactivation. Clearly escapes during therapy with ACEI and ARB.

32 Probability of Survival RALES: Spironolactone vs Placebo in Chronic Severe CHF Results Spironolactone Placebo P<0.001 Pitt et al. N Engl J Med. 1999;341(10): Months

33 EPHESUS: Study Design AMI, Rales, LVEF 40%, Standard Therapy Eplerenone mg QD n = 3100 Randomize 3 14 days Post AMI Placebo n = 3100 Primary End Points: All-cause mortality CV mortality + CV hospitalization Secondary End Points: CV mortality CV hospitalizations All-cause mortality + all-cause hospitalizations Other End Points: New onset of atrial fibrillation/flutter NYHA functional class QOL Pitt B et al. Cardiovasc Drugs Ther. 2001;15:79 87.

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35 Aldosterone Antagonism in Chronic Severe HF: A Caveat Since the publication of RALES the death rate from hyperkalemia in chronic HF has skyrocketed (6 studies), probably obviating any statistically predicted clinical benefit from the trials. In chronic severe HF, aldosterone-antagonism HAS NOT been thoroughly tested with beta-adrenergic antagonism, which reduces renin levels and may increase the chance of hyperkalemia. OPINION: The guideline regarding aldosterone antagonism in chronic severe HF is premature, and additional trials are needed. Intensive monitoring is crucial if the therapy is employed.

36 RAAS in CHF Summary ACEI indicated for all patients with EF <40% ARB may be substituted for ACEI intolerant patients ACEI + ARB No mortality benefit (VALHAFT class 2,3 CHF) No mortality benefit (VALIANT post MI) Small morbidity benefit (VALHAFT and CHARM) ACEI + Aldosterone-antagonist Mortality benefit class 3,4 CHF (RALES, only 5% beta blocker use) Mortality benefit post MI EF <40% and CHF (EPHESUS, with beta blockade)

37 Adrenergic System in CHF The Good Provides inotropic support and vasoconstriction when cardiac output fails The Bad Chronic stimulation of both beta 1and alpha 1 receptors is toxic to myocardial cells Chronic sympathetic stimulation aggravates cardiac loading conditions The Ugly. Excess beta adrenergic activity is linked to arrhythmias and sudden death

38 Effects of Adrenergic Activity in Heart Failure CNS sympathetic outflow Cardiac sympathetic activity Sympathetic activity to kidneys + blood vessels 1 - receptors 2 - receptors 1 - receptors Activation of RAS Inotropic support Vasoconstriction Myocardial toxicity Vasoconstriction Sodium retention Disease progression

39 Adrenergic Interventions in CHF Inhibition of adrenergic activity (failed: moxonidine trials). Alpha-adrenergic antagonism (failed: VHEFT 1). Beta- one adrenergic antagonism (mixed results, but successful with adequate doses of long acting metoprolol and bisoprolol). No real data but early failure with mixed beta 1/beta 2 antagonist (propranolol). Combined beta 1/beta2/alpha adrenergic antagonism (success with carvedilol). Combined beta1/beta2 antagonism with additional vasodilation (failed: bucindolol).

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41 Major Placebo Controlled Trials of Beta-Blockade in Heart Failure Target Mean Dosage HF Patients Follow-up Dosage Achieved Effects on Study Drug Severity (n) (yrs) (mg) (mg/day) Outcomes CIBIS bisoprolol* moderate/ qd 3.8 All-cause mortality Circ severe NS CIBIS-II 3 bisoprolol* moderate/ qd 7.5 All-cause mortality Lancet 1999 severe 34% (P<.0001) MDC metoprolol mild/ qd 108 Death or need for Lancet 1993 tartrate* moderate transplant (primary endpoint) NS MERIT-HF 1 metoprolol mild/ qd 159 All-cause mortality Lancet 1999 succinate moderate 34% (P=.0062) BEST 4 bucindolol* moderate/ All-cause mortality NEJM 2001 severe bid NS US Carvedilol 2 carvedilol mild/ to All-cause mortality NEJM 1996 moderate months bid 65% (P=.0001) COPERNICUS 5 carvedilol* severe bid 37 All-cause mortality NEJM 2001 months 35% (P=.0014) Not a planned end point.

42 MERIT-HF/Relative Risk for Mortality No. of deaths Metoprolol XL better Placebo better Risk reduction Total mortality CV mortality Sudden death Death from HF % 38% 41% 49% Relative risk and 95% CI MERTI-HF Study Group. Lancet. 1999;253:

43 Absolute Change From Baseline LVEF units (%) Beta Blockade and Left Ventricular Remodeling LVEF LV EDV LV ESV 0 * *** *** ml/m ** *** *** *** Metoprolol (n=61) Carvedilol (n=61) 150 HF patients on diuretics, ACE inhibitors, +/- digoxin were randomized to doubleblind treatment; 122 had EF/hemodynamic assessments at baseline and after months of treatment. Metra M et al. Circulation. 2000;102: *P<.05; **P<.01; ***P<.001. Metoprolol tartrate.

44 Myocardial Gene Expression in Dilated Cardiomyopathy Treated with Beta-Blocking Agents Brian D. Lowes, M.D., Edward M. Gilbert, M.D., William T. Abraham, M.D., Wayne A. Minobe, B.S., Patti Larrabee, B.S., Debra Ferguson, M.S., Eugene E. Wolfel, M.D., JoAnn Lindenfeld, M.D., Tatiana Tsvetkova, M.D., Alastair D. Robertson, Ph.D., Robert A. Quaife, M.D., and Michael R. Bristow, M.D., Ph.D. ABSTRACT Background Beta-blocker therapy may improve cardiac function in patients with idiopathic dilated cardiomyopathy. We tested the hypothesis that beta-blocker therapy produces favorable functional effects in dilated cardiomyopathy by altering the expression of myocardial genes that regulate contractility and pathologic hypertrophy. Methods We randomly assigned 53 patients with idiopathic dilated cardiomyopathy to treatment with a -adrenergic receptor blocking agent (metoprolol or carvedilol) or placebo. The amount of messenger RNA (mrna) for contractility-regulating genes (those encoding 1 - and 2 -adrenergic receptors, calcium ATPase in the sarcoplasmic reticulum, and - and -myosin heavy-chain isoforms) and of genes associated with pathologic hypertrophy (-myosin heavy chain and atrial natriuretic peptide) was measured with a quantitative reverse-transcription polymerase chain reaction in total RNA extracted from biopsy specimens of the right ventricular septal endomyocardium. Myocardial levels of -adrenergic receptors were also measured. Measurements were conducted at base line and after six months of treatment, and changes in gene expression were compared with changes in the left ventricular ejection fraction as measured by radionuclide ventriculography. Results Twenty-six of 32 beta-blocker treated patients (those with complete mrna measurements) had an improvement in left ventricular ejection fraction of at least 5 ejection-fraction (EF) units (mean [±SE] increase, 18.8±1.8). As compared with the six beta-blocker treated patients who did not have a response (mean change, a decrease of 2.5±1.8 EF units), those who did have a response had an increase in sarcoplasmic-reticulum calcium ATPase mrna and -myosin heavy chain mrna and a decrease in -myosin heavy chain mrna. The change in sarcoplasmic-reticulum calcium ATPase was not present in the patients in the placebo group who had a spontaneous response. There were no differences between those who had a response and those who did not in terms of the change in mrna or protein expression of -adrenergic receptors. Conclusions In idiopathic dilated cardiomyopathy, functional improvement related to treatment with beta-blockers is associated with changes in myocardial gene expression.

45 COMET Carvedilol or Metoprolol European Trial Designed to compare the effects of treatment with metoprolol tartrate, a 1 selective beta blocker, to carvedilol, a non-selective blocker with 1 blocking, anti-oxidant, anti-apoptotic and anti-ischemic properties. A randomized head to head comparison in 3000 patients with stable heart failure receiving standard therapy including ACEIs. Designed to continue until 1020 deaths occurred.

46 Primary Endpoint of Mortality Mortality (%) Metoprolol Carvedilol hazard ratio 0.83, 95% CI , p= Number at risk Time (years) Carvedilol Metoprolol

47 Explanations for COMET Greater complexity of adrenergic antagonism with carvedilol. Includes alpha-1 and beta -2 receptor blockade, which may yield greater myocardial protection and modest cardiac sympathoinhibition. Greater beta 1 adrenergic blockade with carvedilol at the doses used. Antioxidant effect of carvedilol. Hemodynamic effects of carvedilol (ie vasodilation).

48 Vascular Events in COMET (Remme et al, JACC, March 2007) MI: carvedilol 69 vs metoprolol 94 (HR.71,p<.03). Unstable angina: carvedilol 56 vs metoprolol 77, (HR.71,p<.05). Fatal MI or Fatal CVA: carvedilol 34 vs 72 metoprolol, (HR.46, p=.0002). Death after nonfatal MI or CVA: carvedilol 61/124 vs106/160 metoprolol, (HR.66, p=.0086).

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51 HFSA 2006 Practice Guideline (7.3, 7.4) Pharmacologic Therapy: Beta Blockers Beta blockers are recommended for symptomatic and asymptomatic patients with an LVEF 40%. Beta blockers should be titrated to doses used in clinical trials (as tolerated during uptitration of other medications, such as ACE inhibitors). Strength of Evidence = A

52 2005 ACC/AHA HF Guidelines Do Not Support a Class Effect Among -Blockers Within drug classes, agents may differ pharmacologically. These pharmacological differences may translate into differences in clinical outcomes. When multiple agents within a class produce discordant results on clinical outcomes, class effect cannot be presumed (eg, -blockers). I IIa IIb III Hunt SA et al. Circulation. 2005;112: Use of 1 of the 3 -blockers proven to reduce mortality (ie bisoprolol, carvedilol, and metoprolol succinate, at doses used in the RCTs) is recommended for all stable patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated

53 Beyond the RAAS and SNS Endothelin antagonism: Failed V2 antagonism: Failed Endopeptidase inhibition: Failed Adding Hydral/Nitrate: Success

54 Beyond the SNS and RAAS Endopeptidase Inhibition + ACEI (increases BNP levels): no benefit compared to ACEI alone. Endothelin antagonism: no benefit. Selective vasopressin V2 antagonism: no mortality/morbidity benefit longterm. Hydralazine ISDN: Survival benefit in African-American patients. Device therapy (defibrillators, biventricular pacing)

55 Vasodilators + Neurohormonal Antagonism: AHEFT AHEFT TRIAL African-American patients with NYHA Class 3 CHF and EF less than 35%, predominantly idiopathic and hypertensive cardiomyopathy,randomized to hydralazine/isosorbide dinitrate or placebo plus standard care. RESULTS 43% reduction in mortality, 33% reduction in hospitalization. QUESTIONS Mechanism of benefit? Can we generalize results? Cohn et al, NEJM 351: , 2004

56 Device Therapy Cardiac resynchronization: improves LV function and survival in appropriate patients with prolonged QRS (CARE HF, MIRACLE, COMPANION). AICDs: Improve survival in most studies, but absolute benefit small in unselected patient population.

57 Ancillary Treatment for CHF Digoxin (no survival effect, possible morbidity reduction). Nitrates (short term studies show benefit on exercise capacity). Disease Management Programs (reduce mortality after ADHF). Exercise.

58 The Future(?) Direct manipulation of transcriptional/translational control of myocyte and fibroblast growth. Myocyte replacement/stem cell transplant/stem cell transformation.

59 Conclusions Our understanding of the fundamental pathophysiologic processes causing heart failure associated with low ventricular ejection fraction has advanced significantly in the past 35 years. Assuming adequate control of arterial blood pressure and intravascular volume, implementation of neurohormonally based therapy has dramatically improved the survival and quality of life for HF patients. Significant challenges remain regarding prevention of HF, the treatment of acute HF, appropriate selection of patients for device therapy, and rescue of the end stage patient.