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Heart Failure Liviu Klein MD, MS http://www.cardiologyfellows.northwestern.edu/cculectures Outline • Definition • Pathophysiology • Epidemiology (prevalence, incidence, trends) • Epidemiology (mortality and associated morbidity) • Risk factors • Heart failure stages and treatment • Advanced heart failure and transplant Heart Failure Definition • A complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. • Cardinal manifestations are dyspnea and fatigue (which may limit exercise tolerance), and fluid retention (which may lead to pulmonary congestion and peripheral edema). • Both abnormalities can impair the functional capacity and quality of life of affected individuals, but they do not necessarily dominate the clinical picture at the same time. Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86. Heart Failure Definition • Some patients have exercise intolerance but little evidence of fluid retention, whereas others complain primarily of edema and report few symptoms of dyspnea or fatigue. • Because not all patients have volume overload at the time of initial or subsequent evaluation, the term “heart failure” is preferred over the older term “congestive heart failure.” • One line definition: LV EDP > 12 mmHg Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86. Outline • Definition • Pathophysiology • Epidemiology (prevalence, incidence, trends) • Epidemiology (mortality and associated morbidity) • Risk factors • Heart failure stages and treatment • Advanced heart failure and transplant Heart Failure Pathophysiology Cardiac injury Increased load Reduced systemic perfusion Activation of RAS, SNS, and cytokines Altered gene expression Growth and remodeling Ischemia and energy depletion Apoptosis Necrosis Cell death Direct toxicity Progression of Heart Failure Coronary artery disease Cardiomyopathic factors Atrial Fibrillation Hypertension Valvular disease Left ventricular injury Diabetes Pathologic Remodeling Death Low ejection fraction Heart Failure Clinical Stages NORMAL Asymptomatic LV Dysfunction No symptoms Normal exercise Normal LV fxn No symptoms Normal exercise Abnormal LV fxn Compensated No symptoms Exercise Abnormal LV fxn Decompensated Symptoms Exercise Abnormal LV fxn Refractory Symptoms not controlled with treatment Outline • Definition • Pathophysiology • Epidemiology (prevalence, incidence, trends) • Epidemiology (mortality and associated morbidity) • Risk factors • Heart failure stages and treatment • Advanced heart failure and transplant Prevalence of Heart Failure Source: CDC/NCHS and NHLBI. Prevalence of Heart Failure Western Europe Eastern Europe Former Soviet Union North America Japan South America Asia Absolute Numbers (millions patients) Rate (per thousand) 5.3 1.3 5.6 5.2 2.4 ? ? 14 13 19 18 19 ? ? Murray CJL, Lopez AD. Global health statistics: a compendium of incidence, prevalence and mortality estimates for over 200 conditions. Geneva: World Health Organization; 1996. Sys/Diastolic Dysfunction Prevalence Redfield MM et al. JAMA. 2003; 289: 194-202. Systolic Dysfunction Prevalence Wang TJ et al. Ann Intern Med. 2003; 138: 907-916. 4% Temporal Changes in Incidence Roger VL et al. JAMA. 2004; 292: 344-351. Outline • Definition • Pathophysiology • Epidemiology (prevalence, incidence, trends) • Epidemiology (mortality and associated morbidity) • Risk factors • Heart failure stages and treatment • Advanced heart failure and transplant Cardiovascular Deaths 300,000 death/yr Survival according to NYHA Class Placebo Conventional therapies (diuretics, digoxin) NYHA Class IV (CONSENSUS) Mortality (%) 100 90 80 70 60 50 40 30 20 10 0 NYHA Class II–III (SOLVD Treatment Trial) 0 6 12 18 24 Months 30 CONSENUS Trial Study Group. N Engl J Med. 1987; 316: 1429-1435. The SOLVD Investigators. N Engl J Med. 1991; 325: 293-298. The SOLVD Investigators. N Engl J Med. 1992; 327: 685-690. NYHA Class I–II (SOLVD Prevention Trial) 36 42 48 Trends in Heart Failure Mortality Roger VL et al. JAMA. 2004; 292: 344-351. Mode of Death by NYHA Class NYHA II NYHA III Other 15% NYHA IV Other 11% Other 24% HF 12% SD 64% HF 26% MERIT-HF Study Group. Lancet. 1999; 353: 2001-2007. SD 59% SD 33% HF 56% Heart Failure Hospitalizations Source: CDC/NCHS. Heart Failure Hospitalizations Hospitalizations/100,000 Population 250 1 mil hospitalizations/ year 200 65+ years 150 100 45-64 years 50 0 1970 1975 1980 1985 Year Rosamond W et al. Circulation. 2008; 115: e2-e122. 1990 1995 393.5 254.8 Hypertensive Disease Rosamond W et al. Circulation. 2008; 115: e2-e122. 27.9 Total CVD* 59.7 Congestive Heart Failure 56.8 Stroke 142.1 Coronary Heart Disease 450 400 350 300 250 200 150 100 50 0 Heart Disease Billions of Dollars Estimated Direct and Indirect Costs Heart Failure Direct Costs Drugs/Medical Durables ($3 billion) 10% Physicians/Other Providers ($2 billion) 7% Home Health ($3.0 billion) 10% Total Expenditure (direct costs) = $29 billion Rosamond W et al. Circulation. 2008; 115: e2-e122. Hospital/Nursing Home ($21 billion) 73% Outline • Definition • Pathophysiology • Epidemiology (prevalence, incidence, trends) • Epidemiology (mortality and associated morbidity) • Risk factors • Heart failure stages and treatment • Advanced heart failure and transplant Outline • Definition • Pathophysiology • Epidemiology (prevalence, incidence, trends) • Epidemiology (mortality and associated morbidity) • Risk factors • Heart failure stages and treatment • Advanced heart failure and transplant New Classification of Heart Failure Stage Patient Description A High risk for developing heart • Hypertension • CAD failure (HF) B Asymptomatic HF C Symptomatic HF D Refractory end-stage HF Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86. • • • • • • • • • Diabetes mellitus Family history of cardiomyopathy Previous MI LV systolic dysfunction Asymptomatic valvular disease Known structural heart disease Shortness of breath and fatigue Reduced exercise tolerance Marked symptoms at rest despite maximal medical therapy (eg, those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions) Management of Chronic HF • • • • • • Establish diagnosis (BNP, echo) Determine etiology Define syndrome (e.g. systolic vs. diastolic) Correct precipitating factors (NSAIDS, COX2, etc.) Evaluate and correct ischemia Initiate chronic therapy • • • • Nonpharmacologic (e.g. exercise, tx. of sleep apnea, etc) Pharmacologic (ACE - I, b - Blockers, ARB, diuretics, digoxin, etc.) Electrical Surgical • Assess response to therapy Stage C: Symptomatic HF Class I • Level A evidence – Diuretics in patients with fluid retention – ACE inhibition, unless contraindicated – Beta blockade in stable patients, unless contraindicated – Digitalis, unless contraindicated • Level B evidence – Withdrawal of drugs known to adversely affect the clinical status of patients All Class I recommendations for Stages A and B Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86. Diuretics • • • • • Loop diuretics in pts. with CrCl < 30 Torsemide ↓ hospitalizations compared to furosemide Have to be given bid to avoid rebound Na reabsorbtion May use thiazides if CrCl > 30 Use combination (e.g. furosemide + thiazide), iv bolus or iv drips • Metolazone in refractory HF or in pts. with renal failure. Should not be used daily. • Add spironolactone if Cr < 2.5 and K < 5. Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86. ACE - I and Mortality in HF Mortality Trial Drug (mean dose) ACEI Placebo RR (95% CI) CONSENSUS I Enalapril (18.4 mg) 39% 54% 0.56 (0.34-0.91) SOLVD (T) Enalapril (11.2 mg) 35% 40% 0.82 (0.70-0.97) SOLVD (P) Enalapril (12.7 mg) 15% 16% 0.92 (0.79-1.08) SAVE Captopril (150 mg)* 20% 25% 0.81 (0.68-0.97) AIRE Ramipril (1.25-5 mg)† 17% 23% 0.73 (0.60-0.89) TRACE Trandolapril (1-4 mg)† 35% 42% 0.78 (0.67-0.91) SMILE Zofenopril (7.5-30 mg)† 5% 6.5% 0.75 (0.40-1.11) 21% 25% 0.84 Chronic HF Post-MI Totals * No mean given; target dose † No mean given; dose range ACE Inhibitors • • • • • • • Most pts. tolerate ACE - I. ACE - I improve symptoms immediately (days). Pts. should not be “too dry” (no orthostatic ↓ BP). If ↓ BP, check for orthostatic changes. If none, ACE - I OK. Low BP and CRF are not CI for ACE - I. If BUN/ Cr are raising, adjust the diuretic dose. Low BP, low Na, renal dysfunction: low dose, short acting ACE - I, titrate to target dose or the highest dose tolerated. • Low vs. high dose ACE - I: difference in outcomes. Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86. Beta - Blockers in HF Study All - cause mortality All - cause hospitalizations CIBIS II 1 (bisoprolol) 2647 pts. NYHA III - IV 34% (p < 0.0001) 20% (p = 0.0006) MERIT – HF 2 (metoprolol XL) 3991 pts. NYHA II - IV 34% (p = 0.0062) 8.6% (p = 0.005) COPERNICUS 3 (carvedilol) 2289 pts. NYHA IV 35% (p = 0.0014) 15% (p = 0.0029) 1 CIBIS II Investigators and Committees. Lancet. 1999; 353: 9-17. 2 MERIT - HF Study Group. Lancet. 1999; 353: 2001-2007. 3 Packer M et al. N Engl J Med. 2001; 344: 1651-1658. Beta-Blockers: Not Created Equal Study BEST1 (bucindolol) 2708 pts. NYHA III - IV SENIORS2 (nebivolol) 2135 pts. NYHA II - III 1 BEST All - cause mortality All - cause hospitalizations 10% (p < 0.1) 8% (p = 0.08) 12% (p = 0.21) Investigators. N Engl J Med. 2001; 344: 1659-1667. 2 Flather MD et al.Eur Heart J . 2005; 26: 215-221. 4%* (p = 0.47) * All-cause mortality/ CV hospitalizations Beta-Blockers: Not Created Equal ? COMET: Metoprolol vs. Carvedilol 40 Mortality (%) Metoprolol IR 50 mg bid 30 Carvedilol 25 mg bid 20 HR 0.83 (0.74 - 0.93) p = 0.0017 10 0 0 1 2 3 Time (years) Poole-Wilson PA et al. Lancet. 2003; 362: 7-16. 4 5 Beta - Blockers • Only bisoprolol, carvedilol and metoprolol succinate. • Start at low doses, increase every 2 weeks to target dose or the highest tolerated dose. • Intermediate vs. high dose: no difference in outcomes. • Do not start in pts. dependent of inotropic support. • Can start before hospital discharge in pts. not fluid overloaded. • Do not stop BB in hospitalized pts. who are on chronic BB therapy (may worsen HF). • BB will take 3-6 months to improve symptoms. • Low BP and severe HF are not CI for BB. Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86. Time Course of Changes in LV EF Ejection Fraction 0.40 Standard Therapy Metoprolol p < 0.0001 0.35 p = 0.013 for metoprolol vs. standard therapy 0.30 p < 0.05 0.25 0.20 Baseline Day 1 1 Mo 3 Mo Hall SA et al. J Am Coll Cardiol. 1995; 25: 1154-1160. Baseline Day 1 1 Mo 3 Mo Which First: ACE or BB? Death/Hospitalization Willenheimer R et al. Circulation.. 2005; 112: 2426-2430. All-cause mortality SCD/All-cause Mortality with First Bisoprolol Compared with Enalapril End point HR (95% CI) p Monotherapy phase 12 months End of study 0.50 (0.21-1.16) 0.54 (0.29-1.00) 0.84 (0.51-1.38) 0.107 0.049 0.487 0.72 (0.42-1.24) 0.69 (0.46-1.02) 0.88 (0.63-1.22) 0.24 0.06 0.44 Sudden death All-cause mortality Monotherapy phase 12 months End of study Willenheimer R. World Congress of Cardiology 2006; September 6, 2006; Barcelona, Spain. Beta - Blockers Angiotensin Receptor Blockers • Combination ARB + ACE - I + Beta - Blockers is safe. • No mortality benefit when ARB is added to ACE - I. • ARB are useful in pts. who are ACE intolerant. • ARB could be added to ACE - I for symptomatic improvement. • Triple RAAS blockade (ACE - I, ARB, aldosterone blockers) should not be used (Hyper K). CHARM Program 3 component trials comparing candesartan to placebo in patients with symptomatic HF CHARMAlternative CHARMAdded CHARMPreserved n=2028 n=2548 n=3025 LVEF < 40% ACE inhibitor intolerant LVEF < 40% ACE inhibitor treated LVEF > 40% ACE inhibitor treated/not treated Primary outcome for each trial: CV death or HF hospitalization Primary outcome for overall program: All-cause death Pfeffer MA et al. Lancet. 2003; 362: 759-767. Effect of Candesartan on Mortality and HF Hospitalizations Cardiovascular death/ HF hospitalizations All-cause mortality Alternative Added Preserved Overall 0.7 0.8 0.9 Pfeffer MA et al. Lancet. 2003; 362: 759-767. 1.0 1.1 1.2 0.6 0.7 0.8 0.9 1.0 1.1 1.2 Aldosterone Antagonists: Spironolactone 1.00 0.95 30% Relative risk reduction 0.90 Mortality 0.85 0.80 0.75 Spironolactone 0.70 0.65 0.60 p < 0.001 0.55 Placebo 0.50 0.45 0.00 0 3 6 9 12 15 18 Months Pitt B et al. N Engl J Med. 1999; 341; 709-715. 21 24 27 30 33 36 Eplerenone post MI: Mortality 22 20 18 16 14 Placebo Eplerenone Cumulative 12 Incidence (%) 10 8 RR = 0.85 (95% CI, 0.75–0.96) P = 0.008 6 4 2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Since Randomization Pitt B et al. N Engl J Med. 2003; 348: 1309-1315. Eplerenone and SCD post MI All Patients 10 9 Cumulative Incidence (%) Patients with Baseline Ejection Fraction 30% 16 14 8 12 7 Placebo Placebo 10 6 5 8 Eplerenone Eplerenone 4 6 3 1 2 0 0 0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 RR = 0.67 (95% CI, 0.50–0.91) P = 0.009 4 RR = 0.79 (95% CI, 0.64–0.97) P = 0.03 2 3 3 3 6 0 3 6 9 12 Months Since Randomization Pitt B et al. N Engl J Med. 2003; 348: 1309-1315. 15 18 21 24 27 30 33 36 Sudden Death Post MI in VALIANT Solomon SD et al. N Engl J Med. 2005; 352: 2581-2588. Eplerenone and SCD Post MI Pitt B et al. J Am Coll Cardiol. 2005; 46: 425-430. Risk of Death and Serum Digoxin Hazard Ratio (Dig versus Placebo) 1.5 1.4 Women All Men 1.3 1.2 1.1 1.04 1.0 0.9 0.8 0.7 0.6 0.5 Undetectabl < 0.5 e 0.5 0.8 1.0 1.2 1.4 1.6 1.8 Serum Digoxin Concentration (ng/ml) Adams KF et al. J Am Coll Cardiol. 2005; 46: 505-510. 2.0 Digoxin: Mortality/ Hospitalizations Total mortality/ hospitalization HF mortality/ hospitalizations All pts. EF< 45% 0.94 (0.88 - 1.00) 0.69 (0.63 - 0.76) EF < 25% 0.84 (0.76 - 0.93) 0.84 (0.76 - 0.93) EF 25 - 45% 0.99 (0.91 - 1.07) 0.74 (0.66 - 0.84) EF > 45% 1.04 (0.88 - 1.23) 0.72 (0.53 - 0.99) NYHA I/ II 0.96 (0.89 - 1.04) 0.70 (0.62 - 0.80) NYHA III/ IV 0.88 (0.80 - 0.97) 0.65 (0.57 - 0.75) CTR ≤ 55% CTR > 55% 0.98 (0.91 - 1.06) 0.85 (0.77 - 0.94) 0.71 (0.63 - 0.81) 0.65 (0.57 - 0.75) DIG Investigators. N Engl J Med. 1997; 336: 525-532. * At 24 months ISDN – Hy in African Americans Taylor AL et al. N Engl J Med. 2004; 351: 2049-2057. Hy – ISDN and NO Genotype NOS3 exon 7 genotype GRACE whites GRACE blacks A-HeFT Asp-Asp (%) 14 2 1 Asp-Glu (%) 45 31 20 Glu-Glu (%) 41 67 79 McNamara DM et al. Heart Failure Society of America 2005 Annual Scientific Meeting; September 18-21, 2005; Boca Raton, FL. Primary End-point in A-HeFT Parameter Placebo ISDNhydralazine p Glu-Glu -0.22 0.18 0.051 Heterozygous or Asp-Asp 0.29 0.38 0.82 Glu-Glu -0.08 0.43 0.046 Heterozygous or Asp-Asp 0.58 0.61 0.93 Genotype subset (treatment impact on composite score) Genotype subset (treatment impact on composite's QOL component) McNamara DM et al. Heart Failure Society of America 2005 Annual Scientific Meeting; September 18-21, 2005; Boca Raton, FL. ICD for Primary Prevention • Patients with heart failure due to severe LV systolic dysfunction (EF < 30%) with class II and III symptoms, with survival > 12 months. • At least 40 days post MI, > 3 months for NICM. SCD-HeFT Trial: Survival .4 Mortality .3 HR 97.5% Cl P Amiodarone vs Placebo 1.06 0.86-1.30 0.53 ICD vs Placebo 0.77 0.62-0.96 .007 †22% .2 †17% Amiodarone .1 0 ICD Therapy Placebo 0 6 12 18 24 30 36 Months of Follow-Up Bardy GH et al. N Engl J Med. 2005; 352: 225-231. 42 48 54 60 CRT: Who Should Get It? • Patients with heart failure due to severe LV systolic dysfunction (EF < 35%) with class III and IV symptoms, in spite of adequate and maximum medical therapy. • QRS duration of 120 ms. • Responders? CARE-HF: All-cause Mortality or Unplanned CVD Hospitalizations Event-free Survival 1.00 HR 0.63 (95% CI 0.51 to 0.77) 0.75 CRT 0.50 P < .0001 Medical Therapy 0.25 0.00 0 500 Cleland JGF et al. N Engl J Med. 2005; 352: 1539-1549. 1000 1500 Days CARE-HF: All-Cause Mortality Event-free Survival 1.00 HR 0.64 (95% CI 0.48 to 0.85) 0.75 CRT P = .0019 0.50 Medical Therapy 0.25 0.00 0 500 Cleland JGF et al. N Engl J Med. 2005; 352: 1539-1549. 1000 1500 Days Recommendation for Diastolic HF • Control of systolic and diastolic BP. • Control ventricular rate in pts. with A Fib. • Diuretics to control pulmonary and peripheral edema. • Anticoagulation in pts. with A Fib. • Coronary revascularization in pts. with CAD and ischemia. • Restoration of sinus rhythm in pts. with A Fib. • Addition of Beta - Blockers, ACE - I, ARB, or CCB to control HTN. • ACE –Inhibitors, ARBs, digoxin to minimize HF symptoms. Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86. Perindopril for Diastolic HF Cleland JGF et al. Eur Heart J. 2006; 27: 2338-2346. Digoxin for Diastolic HF? Ahmed A et al. Circulation. 2006; 114: 397-404. Candesartan For Diastolic HF Cardiovascular death/ HF hospitalizations All-cause mortality Alternative Added Preserved Overall 0.7 0.8 0.9 1.0 Pfeffer MA et al. Lancet. 2003; 362: 759-767. 1.1 1.2 0.6 0.7 0.8 0.9 1.0 1.1 1.2 Stage D: End-stage HF Class I • Level A evidence – Refer patient to specialist in HF management • Level B evidence – Closely watch for and control fluid retention – Refer eligible patients for cardiac transplantation, LVAD All Class I recommendations for Stages A- C Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86. LVADs as Destination Therapy Lietz K et al. Circulation. 2007; 116: 497-505. Heart Transplants Reported by Year Taylor DO et al. J Heart Lung Transplant 2006; 25: 869-879. Adult Heart Transplant Survival 100 Survival (%) 80 60 1982-1988 (N=9,071) 1989-1993 (N=17,685) 1994-1998 (N=18,758) 1999-6/2004 (N=16,227) 40 20 Average: 1982-1988: 8.2 years; 1989-1993: 9.7 years; 1994-1998: 10.2 years 0 0 1 2 3 4 5 6 Years Taylor DO et al. J Heart Lung Transplant 2006; 25: 869-879. 7 8 9 10 11 12 CONCLUSIONS: Chronic HF • STAGE A (HTN, CAD or DM): – Routine: ACE-I/ARB; selected pts. BB, statin, antiplatelets • STAGE B (Asymptomatic structural heart disease): – Routine: ACE-I/ARB, BB; selected pts. statin, antiplatelets • STAGE C (Symptomatic HF and low EF): – Routine: ACE-I/ARB, BB, Aldo blockers, diuretics, digoxin – Selected pts. CRT, ICD, Hy-ISDN • STAGE C (Symptomatic HF and preserved EF): – Consider ACE-I/ARB, digoxin ?, BB, CCB, Aldo blockers. • STAGE D (End-stage HF): – Referral to HF program for LVAD, OHT. Paradigm for Management of HF Treat Congestion: Diuretics Slow Disease Progression: ACE – I /ARB Sudden Death: BB BB Aldo bloc. Aldo bloc. ICD Treat Residual Symptoms: Digoxin ARB Cardiac Resynchronization Therapy (CRT) Advanced Disease: LVAD OHT Heart Failure The future is here….