Evidence Based Treatment for Heart Failure

Promising Therapies for Heart Failure Gregg C. Fonarow, MD Eliot Corday Professor of Cardiovascular Medicine and Science UCLA Division of Cardiology Director, Ahmanson-UCLA Cardiomyopathy Center Director, UCLA Cardiology Fellowship Training Program Co-Director, UCLA Preventative Cardiology Program Los Angeles, California Background on Heart Failure Population Hospital Group Prevalence Incidence Mortality Discharges Cost Total population  5,000,000 550,000 50% within 5 years 1,000,000 $24.3 billion One of the few major cardiovascular diseases rising in incidence  Over 1 million patients hospitalized this year; 12 million outpatient office visits HF hospitalizations one of largest expenses for CMS1,2   Mortality rates remain very high Heart Association. 2004 Heart and Stroke Statistical Update. Dallas, Texas: American Heart Association; 2002. SA et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult. 2001. 1American 2Hunt Therapies Demonstrated to Reduce Mortality in Heart Failure     ACE Inhibitors Beta Blockers Aldosterone Antagonists ICD – LVEF < 35, Class II or III LVEF <35, QRS >120 ms, Class III or IV  Cardiac Resynchronization + ICD – 1. 2. 3. 4. 5. The CONSENSUS Trial Study Group. N Engl J Med. 1987;316:1429-1435. Packer M et al. N Engl J Med. 1996;334:1349-1355. Pitt B et al. N Engl J Med. 1999;341:709-717. Moss A et al. N Engl J Med. 1996;335:1933-1940. Abraham WT et al. N Engl J Med. 2002;346:1845-1853. New Therapies for Heart Failure      Natriuretic peptides Endothelin antagonists Vasopeptidase inhibitors Cytokine antagonists Statins     Erythropoeitin    External enhanced counter pulsation Cardiac resynchronization therapy Routine use of implantable cardiac defibrillators Ventricular constraint devices Cell transplantation Total artificial heart / permanent LVADs Heart Failure Pathophysiology Myocardial injury Fall in LV performance Activation of RAAS, SNS, ET, and others Myocardial toxicity ANP BNP Peripheral vasoconstriction Hemodynamic alterations Morbidity and mortality Remodeling and progressive worsening of LV function Heart failure symptoms Fonarow GC. Rev Cardiovasc Med. 2001;2:7-12. Beneficial Effects of B-Type Natriuretic Peptide Cardiac Myocyte Hypertrophy Decreased wall stress Fibroblast Hyperplasia Collagen synthesis Peripheral Artery Vasodilation Endothelial function Hypertrophy Improved compliance Coronary Artery Vasodilation Endothelial function Decreased O2 consumption Anti-fibrotic Improved relaxation The Effects of Nesiritide on Neurohormones 900 860 P=0.06 P<0.05 595 496 670 P<0.001 800 700 600 500 400 300 690 Before nesiritide 383 During nesiritide 200 100 0 Norepinephrine (pg/mL)1 Aldosterone (pmol/L)1 Endothelin-1 (pg/dL)2 1. Abraham WT et al. J Card Fail. 1998;4:37-44. 2. Aronson D et al. J Am Coll Cardiol. 2001;37(2 suppl A):148A. Cardiac Fibrosis in Mice Lacking BNP Tamura et al. Proc Natl Acad Sci. 2000;97:4239-4244. ANP Inhibits LV Remodeling in Patients With Acute MI P=0.034(ANOVA) 60 * 120 P=0.034(ANOVA) 60 † P=0.009(ANOVA) LVEDVI (mL/m2) 55 LVEF (%) † 100 LVESVI (mL/m2) 50 ‡ 50 45 40 80 30 60 40 20 Baseline 1 Month Baseline 1 Month Baseline 1 Month Nitroglycerin *P<0.001 †P<0.01 ‡P<0.05 Hayashi M et al. J Am Coll Cardiol. 2001;37:1820-1826. ANP Potential Use of Nesiritide in the Outpatient Management of Advanced HF     Absence of inotropic activity Favorable hemodynamic profile – cGMP-mediated inhibition of vasoconstriction1 – targets CG-A-receptor–rich vascular beds in the heart and kidney Neurohormonal antagonist2 – Reduces aldosterone – Inhibits norepinephrine Antifibrotic3 – Inhibits cardiac fibroblast proliferation – Modulates ventricular remodeling in animal models – Improves cardiac wall elasticity 1. Chen HH, Burnett JC. Curr Cardiol Rep. 2000;2:198-205. 2. Abraham WT et al. J Card Fail. 1998;4:37-44. 3. Tamura N et al. Proc Natl Acad Sci USA. 2000;97:4239-4244. FUSION Trial: Study Design n=70  Group A: Usual long-term cardiac medications (excluding nesiritide); may include inotropic therapy*  Group B: Usual long-term cardiac medications (excluding inotropes) plus serial infusions of nesiritide: • Initial dose (week 1): 0.5 μg/kg bolus plus 0.0025 μg/kg/min infusion • Weeks 2 to 12: adjustable* from half to double the initial dose, 1 to 3 times per week  Group C: Usual long-term cardiac medications (excluding inotropes) plus serial infusions of nesiritide: • Initial dose (Week 1): 1.0 mg/kg bolus plus 0.005 mg/kg/min infusion • Weeks 2 to 12: adjustable* from half to double the initial dose, 1 to 3 times per week N=210 n=70 n=70 *At the investigator’s discretion. Silver MA et al. J Card Fail. 2002;8(4 suppl 1):187. FUSION: Improvement in Left Ventricular Systolic Function Standard Care (n=38) Nesiritide 0.005 Dose (n=40) Nesiritide 0.01 Dose (n=37) All Nesiritide (n=77) EF at Baseline Change at 12 Weeks P value* 29.6 +/- 18.6 3.2 +/- 3.8 N/A 28.8 +/- 15.8 4.0 +/- 3.3 0.44 27.7 +/- 13.8 28.25 +/- 14.8 5.3 +/- 5.0 0.03 4.6 +/- 4.2 0.09 *compared to standard care FUSION Results Summary       Nesiritide was safely administered in an outpatient setting for 12 weeks; most patients received highest dose allowed Symptomatic hypotension occurred more frequently in the Standard Care group Subjects on nesiritide were alive and out of hospital longer compared to Standard Care. Consistent with previous trials, higher risk patients may derive more benefit No mortality concern compared to Standard Care. Fewer deaths in nesiritide group Significant improvement in Clinical Status assessed by Physician FUSION pilot supports further development for a Phase III study Chronically Implanted Hemodynamic Monitor: Chronicle Device RVSP; RVDP, estimated PAD; +dP/dt and –dP/dt Implantable Hemodynamic Monitor UCLA Cardiac Arrhythmia Center Ahmanson UCLA Cardiomyopathy Center 68y/o male DM, severe diffuse IHD, EF 45%, severe diastolic dysfunction, chronic renal insufficiency Chronic Meds: torsemide 150 bid metolazone prn spironolactone 50 bid atenolol 25 qDay Chronically Implanted Hemodynamic Monitor Heart Rate RV Systolic Pressure (mmHg) RV Diastolic Pressure (mmHg) --- mean pressures before nesiritide --- mean pressures during/after nesiritide Non-compliant, admit with class IV CHF, 4 lb weight gain ePAD (estimated pulmonary arterial diastolic) Pressure (mmHg) Nesiritide + IV diuretics Cytokines and Pathophysiology of Heart Failure  TNF-alpha levels are elevated in patients with heart failure  Administration of TNF decreases contractility (myocardial depressant factor of sepsis) TNF is an independent risk factor for mortality Animal models that over-express TNF develop cardiomyopathy and HF TNF-blocking therapy is beneficial in inflammatory diseases, such as rheumatoid arthritis    Anti-TNF Therapy for Heart Failure Risk ratios for death or CHF hospitalization Trial name 25 mg once per week 1.01 25 mg 2 times per week 0.87 25 mg 3 times per week – RECOVER RENAISSANCE – 1.21 1.23 RECOVER randomized 900 patients to placebo or etanercept once per week or 2 times per week. RENAISSANCE randomized 900 patients to placebo or etanercept 2 times per week or 3 times a week. Mann et al. Presented at: The European Society of Cardiology's Heart Failure Update 2002. Heart Failure Pathophysiology Myocardial injury Fall in LV performance Activation of RAAS, SNS, ET, and others Myocardial toxicity ANP BNP Peripheral vasoconstriction Hemodynamic alterations Morbidity and mortality Remodeling and progressive worsening of LV function Heart failure symptoms Fonarow GC. Rev Cardiovasc Med. 2001;2:7-12. Endothelin Antagonist Bosentan for Lowering Cardiac Events (ENABLE) Trial Endpoint Placebo (n=808) Bosentan (n=805) P value Death and CHF hospitalization All-cause mortality 321 173 312 160 0.8976 0.5450 Presented at: American College of Cardiology 51st Annual Scientific Session. Anemia and Heart Failure  Anemia is common in patients with heart failure Little was known regarding the relationship of anemia to heart failure symptoms and exercise capacity in HF Little was known regarding the relationship of anemia to mortality in HF   Horwich and Fonarow. J Am Coll Cardiol. 2002;39:1780-1786. Relationship Between Anemia and Heart Failure Precipitating Cause Anemia Heart Failure Precipitating Cause Role in Progression? Impact of Anemia in Advanced Heart Failure: Study Design  Analyzed a cohort of 1061 patients with advanced heart failure (NYHA Class III or IV and LVEF <40%) Mean LVEF 22%, Peak VO2 13.1, SBP 109, DBP 67, HR 90, PCW 25, CI 2.1 and 1 year death + UT of 35% Patients were divided into hemoglobin (Hb) quartiles: Q1 <12.3; Q2 12.3-13.6; Q3 13.7-14.8; Q4 >14.9 g/dL Mean Hgb was 13.6 g/dL (range 7.1-19.0)    Horwich and Fonarow. J Am Coll Cardiol. 2002;39:1780-1786. Impact of Anemia on Heart Failure: Symptoms and Functional Status Hemoglobin quartiles Parameter LVEF NYHA Peak VO2 Q1 23.0 3.74 12.9 Q2 Q3 Q4 ANOVA NS P=0.0001 P=0.0001 22.2 22.2 22.0 3.67 3.54 3.57 12.4 13.8 14.6 Horwich and Fonarow. J Am Coll Cardiol. 2002;39:1780-1786. Relationship Between Hemoglobin and Mortality in Patients with Advanced Heart Failure 1 Survival (%) 0.8 Hb>14.8 Hb 13.7-14.8 Hb 12.3-13.7 0.6 P=0.00001 Hb<12.3 0.4 0 2 4 6 Months Horwich and Fonarow. J Am Coll Cardiol. 2002;39:1780-1786. 8 10 12 Impact of Anemia on Mortality in Heart Failure Hemoglobin quartiles (g/dL) Q1 (<12.3) n Death or urgent transplant Mortality or urgent transplant rate at Year 1 Relative risk (95% CI) P value 271 109 43.5% 2.015 (1.482–2.741) Q2 (12.3–13.7) 253 82 36.2% 1.490 (1.076–2.063) Q3 (13.7–14.9) 256 66 28.3% 1.099 (0.779–1.549) Q4 (14.9) 281 65 25.2% 1.0 0.0001 0.0001 0.592 Horwich and Fonarow. J Am Coll Cardiol. 2002;39:1780-1786. Anemia and Heart Failure     Anemia is common in patients with heart failure, especially those with advanced disease Anemia is independently associated with increased HF symptoms and worse exercise capacity Anemia is independently associated with increased mortality Pilot studies have shown erythropoietin improves functional capacity and reduces symptoms Horwich and Fonarow. J Am Coll Cardiol. 2002;39:1780-1786. Study of Anemia in Heart Failure Trial (STAMINA-HF)       Randomized, double-blind trial of darbepoetin alfa on exercise capacity in heart failure Class II-IV HF, due to systolic dysfunction (LVEF <0.40) Anemia (Hb 9.0 to 12. 5 mg/dL) Darbepoetin vs placebo Exercise testing, QOL, global score, mortality Ongoing clinical trial Statins and Heart Failure  Statins are of proven benefit in coronary heart disease, reducing the risk of atherosclerotic events and new onset heart failure Approximately 2/3 of HF patients in US have CHD Non-lipid effects of statins may be beneficial in HF regardless of etiology Low total cholesterol and lipoprotein levels associated with increased mortality in HF patients No prospective trials of statins in HF     Effect of Pravastatin on Patients With and Without LV Dysfunction Placebo 50 RR 2.1 Pravastatin CHD Event Rate (%) 40 32 RR 1.5 30 24 25 20 10 0 20 LVEF ≤0.40 CARE (706 patients with LVEF between 0.25 and 0.40) Sacks. N Engl J Med. 1996;335:1001-1009. LVEF >0.40 Relationship Between Total Cholesterol and Mortality in Advanced Heart Failure 100 90 80 Death or Urgent Tx (%) 70 60 50 40 30 20 10 0 Total cohort (n=1134) Ischemic CMY (n=542) Non-ischemic CMY (n=592) P=0.00001 P=0.00001 P=0.00001 Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 1134 Advanced HF patients: Q1 <129; Q2 129-160; Q3 161-189; Q4 190-224; Q5 >224 Horwich. J Card Failure. 2002;8:216-224 Potential Non-Ischemic Mediated Benefits of Statins in Heart Failure    Effects on myocardial cellular function Effects on endothelial function Down-regulation of angiotensin AT-1 receptor    Restoration of autonomic function Neoangiogenesis Inhibition of pro-inflammatory cytokines Amelioration of Angiotensin II–Induced Cardiac Injury by a Statin Rats transgenic for human renin and angiotensinogen, Rx with cerivastatin vs control vs SD rats. Dechend. Circulation. 2001;104:576. Statins Down-Regulate Angiotensin II (AT-1) Receptors in Humans AT-1 receptor density 10 8 6 P<0.01 Bmax fmol/mg protein 4 2 1.8 0 Baseline Statin (6 weeks) AT-1 receptor expression pre- and post-simvastatin or atorvastatin 20-40 mg. Nickenig. Circulation. 1999;100:2131. Statins Attenuates LV Remodeling and Heart Failure after Experimental MI Coronary ligation: fluvastatin attenuated remodeling, LVEDP, cell hypertrophy, decreased myocardial MMP, increased eNOS expression Hayashidani. Circulation. 2002;105:868. Statins: Potential LDL-Dependent and LDL-Independent Effects Association Between Statin Use and Mortality in Patients with Advanced Heart Failure Ischemic HF 100 80 Surviva (%) Survival (%) Non-ischemic HF 100 80 60 40 20 0 Statin Rx Statin Rx 60 40 20 0 No Statin Rx No Statin Rx P<0.001 3 6 9 12 15 18 21 P<0.001 3 6 9 12 15 18 21 0 0 Months Months 551 Advanced HF patients (51% on statins: 79% of CAD, and 29% non-CAD) Horwich, Fonarow. J Amer Col Cardiol. 2004;43:642-648. Association Between Statin Use and Mortality in Patients with Advanced Heart Failure Harzard ratios and 95% CI for endpoints Death or Urgent Transplant HR 0.44 (95% CI 0.30-0.67) P=0.0001 Death From Any Cause HR 0.52 (95% CI 0.30-0.90) P=0.017 Progressive Heart Failure Death HR 0.46 (95% CI 0.20-1.05) P=0.055 Sudden Death HR 0.47 (95% CI 0.16-1.37) P=0.152 0.1 0.5 Statin Better 1.0 1.5 No Statin Better 2.0 Horwich, Fonarow. J Amer Col Cardiol. 2004;43:642-648. Association Between Statin Use and Mortality in Patients with Advanced Heart Failure 100 90 Death or Urgent Transplant (%) 80 70 No Statin Rx Statin Rx 60 50 40 30 20 10 0 HR=0.49 P=0.002 HR=0.22 P=0.01 HR=0.44 P=0.002 HR=0.44 P<0.0001 HR=0.38 P=0.05 Men Women TC ≤163 mg/dL TC > 163 mg/dL No Transplant Horwich, Fonarow. J Amer Col Cardiol. 2004;43:642-648. Association Between Statin Use and Mortality in 5195 Patients with Heart Failure 10 Ischemic HF 0 -10 Mortality Risk -20 Non-Ischemic HF -30 -40 -50 -60 -70 -42.0 -46.0 (P=0.038) (P=0.002) 5195 HF patients in ELITE II and 5 HF Centers; Statin use in only 20% of patients Anker. HFSA. 2002. Use of Lipid-Lowering Medications in Recent Heart Failure Trials 100 80 60 41 40 20 0 MERIT HF BEST ELITE II CHARM ENABLE 26 23 11 45 Krum. J Am Coll Cardiol. 2002;39:1567-1573. Statins and Heart Failure  Ongoing placebo-controlled clinical trials are testing statins as therapy for HF  Observational studies show that statin use is associated with lower mortality in ischemic HF and non-ischemic HF Until statins are proven not to benefit HF patients, all HF pts with atherosclerosis, diabetes, or CHD risk equivalents should be treated with statins  Horwich, Fonarow. J Amer Col Cardiol. 2004;43:642-648. Sleep Disordered Breathing and Heart Failure       High incidence of sleep-disordered breathing in patients with heart failure (~50%) [risk factors: male, age, atrial fib] Associated with increased arrhythmias, worsened ventricular function, and higher mortality Randomized trials have demonstrated nightly application of continuous positive airway pressure (CPAP) increases LVEF, reduces MR, and improves QOL Ongoing randomized trials of CPAP (CANPAP) Recently CRT shown to reduce CSA episodes Recommend screening patients with HF (in-laboratory polysomnography) Bradley. Circulation. 2003;107:1822. Cardiovascular Effects of Continuous Positive Airway Pressure (CPAP) in Patients with HF and Obstructive Sleep Apnea LVEF 25.0 to 33.8% (P<0.001) 24 HF patients with OSA randomized to CPAP vs control. Kaneko. N Engl J Med. 2003;348:1233-1241. LVEDD 54.5 to 51.7 mm (P=0.009) Cell Transplantation x100 Skeletal Myoblasts, Bone Marrow Derived Stem Cells, Peripheral Stem Cells Autologous Bone Marrow Cells to Improve Ventricular Function in Post Myocardial Infarction Patients After PCI: BOOST Randomized, controlled trials to investigate the percutaneous delivery of autologous bone-marrow cells (BMCs) to infarct-related coronary arteries LVEF Baseline (%) 51.3 Six-month follow-up (%) 52 Percent change from baseline 0.7 Control BMC patients 50.0 56.7 6.7 P=0.0026 BMC vs control Percutaneous Transvenous Cellular Cardiomyoplasty: A Novel Nonsurgical Approach for Myocardial Cell Tx Device Therapy for Heart Failure    Cardiac resynchronization therapy (CRT) Implantable cardioverter-defibrillators (ICD) Ventricular assist devices – – Bridge to transplant Destination therapy   Totally implanted artificial hearts Cardiac reshaping devices Mechanical Ventricular Constraint as a Therapy for Heart Failure Acorn CorCap Cardiac Support Device Vasopressin Antagonist for Heart Failure: ACTIV in CHF Trial Mean Body Weight Changes During Hospitalization 24 Hours 0 -1 Kg Discharge -2 * -3 -4 * * -5 Placebo Tolvaptan 30 mg Gheorghiade M. JAMA. 2004;291:1963-1971. * Tolvaptan 60 mg * Tolvaptan 90 mg * P<0.05 vs Placebo Vasopressin Antagonist for Heart Failure: ACTIV in CHF Trial 60-Day All-cause Mortality P<0.05 20 Placebo Tolvaptan 18.7 13.2 20 P <0.05 17.8 Percent (%) 10 8.7 5.4 9.1 5.5 0 N= 80 239 16 53 (20%) (22%) 30 110 (37%) (46%) 41 163 (51%) (68%) Overall Hyponatremia (Na+ <136 mEq/L) BUN (> 29 mg/dL) Congestion* Gheorghiade M. JAMA. 2004;291:1963-1971. * Edema, Dyspnea, and JVD at baseline Ultrafiltration for Acute Heart Failure     Removal of excess volume mechanically A simplified peripheral ultrafiltration system including a miniaturized disposable circuit developed for patients with volume-overload states Evaluated in observational studies; further trials underway Series of 25 AHF pts with 5 lb net weight loss, improved NYHA status, reduction in BNP levels, and stable renal function Jaske B. J Card Fail. 2003;9:227-231. Ultrafiltration for Decompensated Heart Failure Pre- Versus Post- Ultrafiltration Weight -2.6 kg 140 130 Weight (kg) 120 110 100 90 80 P<0.0001 Effect of Ultrafiltration on Signs and Symptoms of HF Baseline Post 24hr Orthopnea 21 PND 13 JVD 23 Rales 15 S3 8 Peripheral Edema 24 12 5 12 10 2 18 -36% -32% -44% -20% -24% -24% 91.9 89.3 70 60 Pre-treatment Post-treatment Jaske B. J Card Fail. 2003;9:227-231. Promising Therapies for Heart Failure  There are a significant number of promising therapies for heart failure  In the past few years, prophylactic ICD and CRT have moved from promising therapies to standards of HF care As there is no perfect surrogate marker in heart failure, to move from promising therapy to standard of care requires large-scale mortality trials As such, we can be reasonably assured that there will be significant opportunities for clinical investigators in heart failure for the foreseeable future   Heart Failure Rages Through American Cities