Evidence Based Approach In Congestive Heart Failure

Evidence-based medicine: The CHF trials

Moises Auron MD Department of Hospital Medicine Cleveland Clinic Foundation September 21, 2007.

Objectives 





Recognize the evidence supporting the current approach to Chronic Heart Failure (CHF) treatment as an important factor to decrease mortality and improve survival. Review each of the most important trials for pharmacologic therapy of CHF. Review the current alternatives for treatment of CHF in children.

Epidemiology ≈ 5 million Americans with chronic age 40, lifetime risk of



Prevalence heart failure; at developing HF is 20%



Incidence

550,000 new cases/year



Morbidity rose from cause of

1,099,000 hospital discharges (2004) – 399,000 (1979); Most frequent hospitalization in elderly



Mortality deaths/year

Causes



Cost Medicare discharge

or

contributes

to

286,000

$33.2 billion (2007); $5,912 per (2001)

- AHA: Heart Disease and Stroke Statistics - 2007 Update. Circulation. 2007; 115. - Circulation 2004;109:2685–2691.

Cardiorenal Model of HF (1940-1960)

Amer. J Cardiol 1993; 71: 3C-11C

Cardiorenal Model of HF (1940-1960) 



Diuretic s Digitalis

Amer. J. Cardiol. 1993;71:3C-11C

Cardiocirculatory Model of HF (1960 – 1990)

Amer. J Cardiol 1993; 71: 3C-11C

Cardiocirculatory Model of HF (1960 – 1990)  Vasodilators 



V-HeFT 1 (Hydralazine + Nitrate)

Inotropic agents

Amer. J. Cardiol. 1993;71:3C-11C



Initial insights: Vasodilators in Heart Failure

Rationale for use of organic nitrates and hydralazine in combination: complementary "nitroprusside-like" hemodynamic effect Predominant venodilatory action of organic nitrates  Arterial-dilatory effect of hydralazine.  This combination leads to a significant improvement in cardiac function, with a concomitant reduction in right and left Am J Cardiol. 2005 Oct ventricular filling10;96(7B):37i-43i. pressures and 

VHeFT-I (Vasodilator-Heart Failure Trial) African-american White patients

patients

Hydralazine (300 mg) + Isosorbide dinitrate (160 mg) vs. Prazosin (20 mg) vs. Placebo

N = 642 (male) – on Digoxin and diuretics

NEJM. 1986 Jun 12;314(24):1547-52 J Card Fail. 1999; 5(3):178-87

VHeFT-II (Vasodilator-Heart Failure Trial)  



804 men Hydralazine (300 mg) + Isosorbide dinitrate (160 mg) (ISDN-H) vs. Enalapril (20 mg). Decrease in mortality after 2 years Enalapril group (18%) vs. ISDN-H group (25%)  28% reduction in mortality. (P=0.016) 



African-American population benefit more N Engl J Med. 1991;325:303from ISDN-H 310.

VHeFT-II (Vasodilator-Heart Failure Trial)

J Card Fail. 1999; 5(3):178-87

Vasodilators in Heart Failure 



 

V-HeFT I showed improvements in LVEF, exercise tolerance, and survival in patients treated with isosorbide dinitrate and hydralzaine compared with placebo. Retrospective analysis of V-HeFT I and V-HeFT II showed that the benefit of this combination was seen mainly in African Americans. This observation led to the African American Heart Failure Trial (A-HeFT). Concomitant use of hydralazine with a nitrate, both in an animal model and in patients with CHF, has been shown to prevent the development of nitrate tolerance and Am maintain the Oct favorable J Cardiol. 2005 hemodynamic effect of nitrates. 10;96(7B):37i-43i.

Vasodilators in Heart Failure: Hydralazine and Isosorbide

NEJM. 2004; 351(20): 2112-

AHeF-T (African-American Heart Failure Trial)

NEJM 2004; 351 (20): 2049-57 -Am J Cardiol 2005; 96 (suppl): 44i– 48i

AHeF-T (African-American Heart Failure Trial) 

Compared with V-HeFT  H+I

added to conventional CHF treatment.



Post-Hoc analysis  Beta-blocker

AA.

increases survival in Congest H Fail. 2004; 10(1):34-7

Neurohormonal Model of HF (1980 – present) 

Heart failure progressed:

developed

and

 Endogenous

neurohormonal systems activated by the initial injury to the heart  Deleterious

effects on the heart and

circulation  Independent of the hemodynamic Amer J Cardiol 1993; 71: 3C-11C status of the patient.

Neurohumoral modification in HF 



 Natriuretic Renin-angiotensinpeptides aldosterone system  Sympathetic nervous Cytokines  Endothelin system 





Norepinephrine

Vasodilators   

Bradykinin Nitric oxide Prostaglandins



 

Tumor necrosis factor Interleukins

Vasopressin Matrix metalloproteinases NEJM. 2003; 348 (20): 200718. NEJM. 1999; 341(8): 577-585.

From: Shrier, R. U. Colorado.

Neurohormonal Model of Heart Failure

Shah M et al. Rev Cardiovasc Med. 2001; 2 (suppl 2): S2–S6

Renin – Angiotensin – Aldosterone System

Modified from Swedberg K. ESC –Heart Failure Lisbon 2005.

Catecholamines in Heart Failure

Am J Cardiol. 1984; 54: 783-6

Relationship between plasma NE and survival in Heart Failure

NEJM. 1984: 311: 819823.

Cathecolamines 

Stimulation of RAAS  further increase in sympathetic activation.  Enhanced sodium and water retention, potassium loss, peripheral vasoconstriction, and oxidative tissue stress.

NEJM. 1999; 341(8): 577-585. Congest Heart Fail. 2002 SepOct;8(5):262-9;

Cathecolamines 

Circulating catecholamines adversely affect cardiac structure and function.  Desensitization (via G-protein uncoupling) and down-regulation of β 1adrenergic receptors  Myocardial ischemia  Enhanced cardiomyocyte necrosis  Apoptosis.  Induce and potentiate cardiac arrhythmias mediated predominantly through β2-adrenergic receptor stimulation.

Cardiac remodeling 

Angiotensin II, aldosterone, and catecholamines also function as growth factors in paracrine fashion.  Fibroblast activation and the induction of myocyte hypertrophy.  Increase in overall ventricular muscle mass and fibrous tissue.

Consequences of Neurohormonal Activation 

  

Maladaptive hypertrophy  energy starvation  necrosis Apoptosis Increased interstitial fibrosis Myocyte elongation  progressive dilatation of the ventricle CARDIAC REMODELING Katz, AM. Heart Failure. Lippincott Williams & Wilkins, 2000

Alterations in Myocyte Morphology with Ventricular Dysfunction

Katz, AM. Heart Failure. Lippincott Williams & Wilkins, 2000 NEJM. 2003; 348: 2007-18.

Cardiac hypertrophy

From: Tornoci L. Semmelweis U.

N = 253 NYHA IV on diuretics and digoxin Enalapril 20 mg BID vs Placebo

Probability of death

CONSENSUS: Cooperative North Scandinavian Enalapril Survival Study

NEJM 1987; 316: 1429–35.

ACEI Trials

Adapted from Yan AT, et al. Ann Intern Med. 2005; 142: 132-145

ACEI Trials 

 

  

CONSENSUS = Cooperative North Scandinavian Enalapril Survival Study SOLV-D = Studies of Left Ventricular Dysfunction ATLAS = Assessment of Treatment with Lisinopril And Survival Trial SAVE = Survival and Ventricular Enlargement AIRE = Acute Infarction Ramipril Efficacy TRACE = Trandolapril Cardiac Evaluation - NEJM 1987; 316: 1429-35. - Eur Heart J. 1999; 20(2):136-9. - NEJM. 1991; 325: 293-302. - NEJM. 1992; 327: 685-91. - Circulation 1999 Dec 7; 100(23):2312-8. - Eur Heart J 2000 Dec; 21(23):1967-78. - NEJM. 1992;327:669-77. - NEJM. 1995; 333: 1670-6. - Lancet. 1993; 342: 821-8.

ACE Inhibitors in HF  

Mortality ↓ 20%–25% (P< 0.001) Death plus hospitalization ↓ 30%–35% HOWEVER…..

 

~ 50% will still die within 5 years 30% may be rehospitalized for CHF within three months

- JAMA. 1995;273:1450–1456 - AHA. 2001 Heart and Stroke Statistical Update. 20 - Am J Cardiol. 1999;83(Suppl 2A):1A–39A.

Sir James Black  

Nobel Prize 1988 Discovery of Betablockers (Propranolol)

  



 

Potential effects of βblockers in cardiac remodeling 

↓ Heart rate ↓ VO2 Modulation of βreceptors Protection from catecholamine toxicity ↓ RAAS Anti-ischemic and anti-arrhythmic effect

Improvement in synthesis of myocardial proteins  Peripheral vasodilation  Decrease of heart work  Antioxidant action  Anti-inflammatory Eur Rev Med Pharmacol Sci. 2002; 6: action 115-126.

MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in CHF). N = 3991 NYHA II-IV

34% P=0.00 62

Lancet 1999; 353 (9169):2001-7.

MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in CHF).



Post-hoc analysis in NYHA IV (n=795)

Number of hospital days: 15 vs. 26 

J Am Coll Cardiol. 2001; 38:932.

COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival)

N = 2289 NYHA III-IV

35% (P = 0.0014)

Carvedilol 25 mg BID vs. Placebo NEJM 2001; 344(22): 1651-8.

COMET (Carvedilol or Metoprolol European Trial) 6% P= 0.017

Carvedilol 25 mg BID vs. Metoprolol tartrate 50 mg BID

N = 3029 NYHA II-IV

Lancet 2003; 362(9377):7-13.

Beta-Blockers: Trials MERIT (12 mos)

Metoprolol succinate 200 mg Qday vs. placebo

All-cause mortality

Overall ↓ in mortality 34% (P = 0.0062)

CIBIS II (16 mos)

Bisoprolol 10 mg/d vs. placebo

All-cause mortality

Early termination; ↓ in mortality 32% (P< 0.001)

COPERNICUS (10.4 mos)

Carvedilol 25 mg BID vs. placebo

All-cause mortality

COMET (58 mos)

Carvedilol 25 mg BID vs. Metoprolol tartrate 50 mg BID

All-cause mortality

↓ in overall mortality 35% (P = 0.0014). Not worsening HF when initiating Rx. Absolute risk ↓ 6% favor carvedilol (P= 0.0017)

US Carvedilol (6 mos)

Carvedilol 25 – 50 mg BID vs. placebo

All cause mortality, exercise tolerance, QOL.

BEST (24 mos)

Bucindolol 50 – 100 mg BID vs. placebo

All cause mortality

Early termination. ↓ in mortality rate 38% (P < 0.001)

No difference (P= 0.16) Benefit in non-black patients Adapted from Yan AT, et al. Ann Intern Med. 2005; 142: 132-145

Beta-Blockers: Trials       

MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in CHF CIBIS: Cardiac Insufficiency Bisoprolol Study COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival COMET: Carvedilol or Metoprolol European Trial United States Carvedilol Heart Failure Study Group BEST: Beta-blocker Evaluation of Survival Trial (Bucindolol) CAPRICORN: Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction

Lancet 1999; 353 (9169):2001-7. J Am Coll Cardiol. 2001; 38:932. Lancet 1999 Jan 2;353(9146):9-13. Am Heart J 2002 Feb;143(2):301-7. Eur Heart J 2001 Jun; 22(12):102131. NEJM 2001; 344(22): 1651-8. Circulation 2002; 106(17):2194-9. Lancet 2003; 362(9377):7-13. Circulation 1996; 94:2793-9. Circulation 1996; 94:2800-6. Circulation 1996; 94:2807-16. NEJM 1996; 334:1349-55. Lancet. 2001;357:1385-90. NEJM 2001; 344(22):1659-67

Not all Beta Blocker are the Same!!!  

  

BEST Trial (Bucindolol) COMET Trial (Metoprolol Tartrate vs Carvedilol) Atenolol - not proven in heart failure Labetalol – not proven in heart failure Metoprolol Tartrate – no trials showing increased survival compared to placebo

Treatment Strategies

Amer. J. Cardiol. 1993;71:3C-11C

Neurohormones in HF: Aldosterone  





↑ 20-fold in CHF Aldosterone escape phenomenon As well secretion can be independent of [AT II] Extraadrenal production 

Endothelial cells

NEJM. 1999; 341(8): 577-585.  Vascular smooth Int J Clin Pract. 2006 muscle in the heart Jul;60(7):835-46. NEJM. 2001 345(23): and Dec; blood vessels

Neurohormones in HF: Aldosterone

NEJM. 1999; 341(8): 577-585. Int J Clin Pract. 2006 Jul;60(7):835-46. NEJM. 2001 Dec; 345(23):

RALES (Randomized Aldactone® Evaluation Study) N = 1664 Class IV or class III (EF < 35%) with hx. < 6 mos of class IV CHF Spironolacton e 25 mg/d vs. placebo 34% (P = 0.001)

- Am J Cardiol 1996 Oct 15; 78(8):902-7. - NEJM 1999; Sep 2; 341(10):709-17. - NEJM 2003; Apr 3;

EPHESUS (Eplerenone In Heart Failure Post Acute Myocardial Infarction) N= 6642 MI < 2 wk; EF < 40% with evidence of HF and/or DM. Eplerenone 50 mg/d vs. placebo

NEJM 2003; Apr 3; 348(14):1309-21.

Spironolactone in Heart Failure 

ACC/AHA guidelines - Spironolactone 2550 mg-day in:   



NYHA IV Creatinine < 2.5 mg/dL Serum potassium < 5 mEq/L.

Endocrine side effects: gynecomastia, breast pain, menstrual irregularities, impotence, and decreased libido 

Non-selective binding to androgen and progesterone receptors. - Am J Cardiol 1996 Oct 15; 78(8):902-7. - NEJM 1999; Sep 2;

Neurohormones in HF: Angiotensin II   

High mortality in CHF patients despite being on ACEI and BB Potent vasoconstrictor and growth-stimulating hormone May contribute to the impairment of left ventricular function and the progression of heart failure:   



Physiologically active levels in patient on ACEI 



increased impedance of left ventricular emptying adverse long-term structural effects on the heart and vasculature activation of other neurohormones (NE, ET1, aldosterone) NEJM. 1999; 341(8): 577-585.

NEJM. 1999; 341(8): 577-585. Incomplete supression of ATII production ACC/AHA Heart Failure Guidelines

2005. Intolerance to ACEI (cough due to increase in

Angiotensin II Receptor Blockage: Trials ELITE II (18.5 mos) Val-HeFT (23 mos)

CHARMAdded (41 mos) CHARM – Alternativ e (33.7 mos)

N = 3152 Age > 60 y/o NYHA II-IV EF 40% N =<5010 NYHA II-IV EF < 40%; LV dilatation N = 2548 NYHA II-IV EF < 40% On ACEI N = 2028 NYHA II-IV EF < 40% Intolerance to ACEI

Losartan 50 mg/d vs. Captopril 50 mg TID.

All-cause mortality

No superiority of one agent vs. other (P = 0.16)

Valsartan 160 mg BID vs. Placebo

All-cause mortality; mortality or cardiac arrest or hospitalization for HF

Candesartan 32 mg/d vs. placebo

CV death or hospitalization for heart failure

Candesartan 32 mg/d vs. placebo

CV death or hospitalization for heart failure

Similar mortality (P > 0.2) Absolute risk ↓3.3% (P<0.002) in composite end-point. (Decreased Absolute risk ↓ 4% admissions) (P=0.011) ↑ LVID ↓EF  ↑ Trend Benefittoward lower allcause mortality (P= 0.086) Absolute risk ↓ 7% (P<0.001) Trend toward lower allcause mortality (P= 0.11)

Adapted from Yan AT, et al. Ann Intern Med. 2005; 142: 132-145

Angiotensin II Receptor Blockage: Trials   

ELITE: Evaluation of Losartan in the Elderly Val-HeFT: Valsartan heart failure trial CHARM: Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Lancet. 1997;349: 747-52.

Lancet. 2000;355: 1582-7. NEJM 2001 Dec 6; 345(23):1667-75. Circulation 2002 Nov 5; 106(19):2454-8. J Am Coll Cardiol 2004 Jun 2; 43(11):2022-7. Lancet 2003; Sep 6; 362(9386):759-66. Lancet 2003; Sep 6; 362(9386):767-71. Circulation 2004 Oct 12; 110(15):2180-3.

Summary of Major Therapeutic Options for Systolic Heart Failure

2005 ACC/AHA Guidelines.

Electrical consequences of heart failure

www.HRSonline.org/professional_education/learning_cate gories/articles

COMPANION (35 mo)

CARE – HF (29.4 mo)

MADIT (27 mo)

MADIT II (20 mo) SCD-HeFT (45 mo)

Electrical therapy of CHF: Trials N = 1520 NYHA III-IV EF < 35%, stable QRS=120 msec PR>150 msec

1:2:2 ratio -Medical Rx -Medical Rx + PM -Medical Rx + PM/ICD

All-cause mortality of hospitalization

N = 813 NYHA III-IV EF< 35% Cardiac dysynchrony N = 156 NYHA I-III; prior MI EF < 35%; Documented VT; inducible N = 1232 VT

Medical Rx vs. BiV pacing

Time to death (all-cause) or hospitalization (CV)

EF < 30%; Prior MI N = 2521 NYHA II-III EF < 35%

Medical Rx vs. ICD

All-cause mortality

↓ composite end-point 20% (P= 0.015 and 0.011) Improvement in NYHA, 6 min. walk distance, ↓ composite and SBP. 29% end-point (P< 0.001) 33% ↓ mortality (P <0.002) ↑ 7% at 18 ↓ LVEF overall mo mortality 61% (P= 0.009)

3:2 ratio ICD vs. Medical Rx

All-cause mortality

1:1:1 Medical Rx + placebo; Medical Rx + amiodarone; Medical Rx + ICD

All-cause mortality

↓ in overall mortality 28% (P = 0.016) Amiodarone=pla cebo ICD ↓ absolute risk 7.2% in mortality (P= 0.007)

Electrical therapy in CHF: Trials 







COMPANION: Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure CARE-HF: Cardiac resynchronization in Heart Failure SCD-HeFT: Sudden Cardiac Death in Heart Failure Trial MADIT: Multicenter Automatic Defibrillator Implantation Trial NEJM 2004 May 20; 350(21):2140-50. NEJM. 2005 Apr 14; 352(15):1539-49. NEJM 2005 Jan 20; 352(3):225-37. NEJM. 1996 Dec 26; 335 (26): 1933-40. NEJM. 2002 Mar 21; 346(12):877-83. JACC. 2004; 43(8): 1459-65

Stages of Heart Failure and Treatment options

NEJM 2003; 348 (20): 2007-18.

Other research endeavors in CHF   

Stem cell transplantation Ultrafiltration (UNLOAD) - Completed Vasopressin antagonists   



Thyroid hormone analog 

  

Acute and Chronic Therapeutic Impact of Vasopressin 2 Antagonist in Congestive Heart Failure (ACTIV in CHF) SALT (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2) - Completed EVEREST (3,5- diiodothyropropionic acid [DITPA])

Endothelin receptors antagonists Neutral endopeptidase inhibitors Metalloproteinases inhibitors Pediatr Cardiol. 2006 Sep-Oct; 27(5): 533-51.

Vasopressin stimulation Low cardiac output

Activation of the carotid sinus and aortic arch baroreceptor ↑ADH

V2 receptor (coll.tubule 1A receptor (vascular smooth muscle) Thirst.

rease in systemic vascular resistance crease ↓Na

Water retention

Hyponatremia in HF N = 203 Na > 137 = 373 d Na < 137 = 164 d

Lee WH, Packer M. Circulation. 1986; 73(2): 257-267.

Vasopressin antagonists 



V1A receptor blockage  reduction in SVR  afterload reduction  improve myocardial fx V2 receptor blockage  increased free water excretion  correction of hyponatremia and volume overload

J Am Coll Cardiol 2005 Nov

Tolvaptan investigators

Circulation. 2003;107:2690-2696.

Tolvaptan investigators

Circulation. 2003;107:2690-2696.

ACTIV Trial N = 319 LVEF < 40% NYHA III-IV

- 1.6

- 2.8

JAMA. 2004;291:1963-1971

EVEREST     

 

N= 4133 patients LVEF < 40 % Randomly assigned to tolvaptan (30 mg/day) vs. placebo Minimum of 60 days. The primary end point was a composite score of changes from baseline in patient-assessed global clinical status and body weight at day 7 or discharge Secondary end points included patient-assessed changes in dyspnea at day 1, global clinical status at day 7 or discharge, body weight at days 1 and 7 or discharge, and peripheral edema at day 7 or discharge for patients manifesting

EVEREST 

EVEREST Clinical Status  Weight loss -day 1- (1.7 - 1.8 vs. 1.0 kg placebo) - P <0.001.  Weight loss -day 7 or D/C- (3.3-3.8 vs. 2.7-2.8 kg placebo) - P <0.001. 



Dyspnea - improvement at day one (72-77% vs. 6571%placebo) – P <0.001.

EVEREST Outcome 



Median follow up - 10 months - no difference in all cause mortality or in a combined endpoint of cardiovascular death or HF hospitalization. Baseline Na < 134 mEq/L  Tolvaptan ↑ Na at seven days or D/C (5.5 vs. 1.9 mEq/L placebo) JAMA. 2007 Mar 28;297(12):1319-31. JAMA. 2007 Mar 28;297(12):1332-43.

Nesiritide    

 

Decreases PCWP -6 to -10 mmHg vs 2 mmHg placebo. Improved clinical status (60 and 67 % vs. 14 % placebo). No difference when compared to intravenous nitroglycerin. Pooled analysis 3 RCT (N = 862) comparing nesiritide with noninotropic vasodilator therapy  increase in 30-day mortality among patients receiving nesiritide (7.2 vs. 4 %, P = 0.059). Less likely to provoke ventricular arrhythmias (vs. dobutamine) N Engl J Med 2000 Jul 27;343(4):246-53 Does not reduce the length of2002 stay to JAMA Marcompared 27;287(12):1531-40 Heart J. 2006 Dec;152(6):1084-90 dobutamine, but…. lowerAm readmission rate for

Nesiritide  





 

Initial iv bolus of 2 mcg/kg, followed by a continuous infusion of 0.01 mcg/kg/min Dose is increased if, after 3 to 24 hours, to target the desired therapeutic response:  increase in urine output  symptomatic improvement  reduction in cardiac filling pressures Infusion is usually increased by 0.005 mcg/kg/min, preceded by a bolus of 1 mcg/kg, up to a maximum of 0.03 mcg/kg/min. If hypotension occurs, the infusion should be discontinued and restarted when the blood pressure has stabilized, at a 30% lower dose without bolus. Continue iv diuretics ACE inhibitors can be given in combination with nesiritide – if hypotension use ACEI rather nesiritide Clev than Clin J Med 2002 Mar;69(3):252-6

Caveats







Age  Most trials include people 10 years younger than in general population EF  Little evidence for efficacy in patients with near-normal EF Gender  Few women have been included in trials

Semin Cardiothorac Vasc Anesthesia. 10 (3); Sept 2006: 242-245

Caveats 

Devices: 

Inclusion criteria EF < 35%  QRS width > 120 ms. 

Actual EF in the population studied is < 25%  Actual mean QRS is 150 ms. 

Semin Cardiothorac Vasc Anesthesia. 10 (3); Sept 2006: 242-245

Caveats 





Redefinition of the primary variable after unblinding is considered unacceptable Post-hoc analysis does not have protection against type I error Additional data-derived analyses on endpoints other than the one defined prospectively as the primary one, might be useful in suggesting hypotheses for further studies. 

the conclusions should not be considered in the same manner as the principal hypothesis of Zanolla L. Eur J Heart Failure. 5 (2003): 717– the study design. 723.

Thank you     

Dr. Shanti Gunawardena. Dr. Mark E. Dunlap. Dr. James C. Pile. Dr. David J. Mansour. Dr. Holly B. Perzy.