1. Guideline Recommended Approach to the Evaluation and Management of Heart Failure William T. Abraham, MD, FACP, FACC Professor of Medicine Chief, Division of Cardiovascular Medicine Associate Director, Davis Heart & Lung Research Institute The Ohio State University Columbus, Ohio

2. Heart Failure At Risk for Heart Failure Therapy: Goals All measures under Stage A Therapy: Drugs ACEI or ARB in appropriate patients  -blockers in appropriate patients Therapy: Goals All measures under Stages A, B, and C Discussion re: appropriate level of care Therapy: Options Compassionate end-of-life care/hospice Extraordinary measures Heart transplant Chronic inotropes Permanent mechanical support Experimental surgery or drugs Therapy: Goals All measures under Stages A and B Dietary salt restriction Therapy: Drugs—Routine Diuretics for fluid retention ACEIs  -blockers Therapy: Drugs—Select Pts Aldosterone antagonist ARBs Digitalis Hydralazine/nitrates Therapy: Devices—Select Pts Biventricular pacing Implantable defibrillators ACC/AHA 2005 Guideline: HF Stages Stage A At high risk for HF but without structural heart disease or Sx of HF Stage B Structural heart disease but without Sx of HF Stage C Structural heart disease with prior or current Sx of HF Stage D Refractory HF requiring specialized inter- ventions Therapy: Goals Treat hypertension Encourage smoking cessation Treat lipid disorders Encourage regular exercise Discourage alcohol intake, illicit drug use Control metabolic syndrome Therapy: Drugs ACEI or ARB in appropriate patients for vascular disease or diabetes Therapy: Goals All measures under Stages A, B, and C Discussion re: appropriate level of care Therapy: Options Compassionate end-of-life care/hospice Extraordinary measures Heart transplant Chronic inotropes Permanent mechanical support Experimental surgery or drugs Therapy: Goals All measures under Stage A Therapy: Drugs ACEI or ARB in appropriate patients  -blockers in appropriate patients Therapy: Goals Treat hypertension Encourage smoking cessation Treat lipid disorders Encourage regular exercise Discourage alcohol intake, illicit drug use Control metabolic syndrome Therapy: Drugs ACEI or ARB in appropriate patients for vascular disease or diabetes Therapy: Goals All measures under Stages A and B Dietary salt restriction Therapy: Drugs—Routine Diuretics for fluid retention ACEIs  -blockers Therapy: Drugs—Select Pts Aldosterone antagonist ARBs Digitalis Hydralazine/nitrates Therapy: Devices—Select Pts Biventricular pacing Implantable defibrillators Hunt SA, Abraham WT, Chin MH, et al, J Am Coll Cardiol, 2005

3. Heart Failure Prevention A careful and thorough clinical assessment, with appropriate investigation for known or potential risk factors, is recommended in an effort to prevent development of LV remodeling, cardiac dysfunction, and HF. Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122

4. HF Risk Factor Treatment Goals Risk FactorGoal HypertensionGenerally < 130/80 DiabetesSee ADA guidelines HyperlipidemiaSee NCEP guidelines Inactivity20-30 min. aerobic 3-5 x wk. ObesityWeight reduction < 30 BMI AlcoholMen ≤ 2 drinks/day, women ≤ 1 SmokingCessation Dietary SodiumMaximum 2-3 g/day Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122

5. Treating Hypertension to Prevent HF Aggressive blood pressure control: Aggressive BP control in patients with prior MI: Decreases risk of new HF by ~ 80% Decreases risk of new HF by ~ 50% 56% in DM2 Decreases risk of new HF by ~ 50% 56% in DM2 Lancet 1991;338:1281:1281-5 (STOP-Hypertension JAMA 1997;278:212-6 (SHEP) UKPDS Group. UKPDS 38. BMJ 1998;317:703-713

6. Prevention: ACEI and Beta Blockers ACE inhibitors are recommended for prevention of HF in patients at high risk for this syndrome, including those with: Coronary artery disease Peripheral vascular disease Stroke Diabetes and another major risk factor ACE inhibitors and beta blockers are recommended for all patients with prior MI Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122

7. Management of Patients with Known Atherosclerotic Disease But No HF Treatment with ACE inhibitors decreases the risk of CV death, MI, stroke, or cardiac arrest Placebo Ramipril Placebo Perindopril 20% rel. risk red. p =.0003 22% rel. risk red. p <.001 HOPE EUROPA NEJM 2000;342:145-53 (HOPE) Lancet 2003;362:782-8 (EUROPA)

8. Treatment of Post-MI Patients with Asymptomatic LV Dysfunction (LVEF ≤ 40%) SAVE Study All-cause mortality ↓19% CV mortality ↓21% HF development ↓37% Recurrent MI ↓25% Placebo Captopril Years Mortality Rate 19% rel. risk reduction p = 0.019 Pfeffer et al. NEJM 1992;327:669-77

9. The Additional Value of Beta Blockers Post-MI: CAPRICORN Studied impact of beta blocker (carvedilol) on post-MI patients with LVEF ≤ 40% already receiving contemporary treatments, including revascularization, anticoagulants, ASA, and ACEI: All-cause mortality reduced (HR = 0.077; p = 0.03) Cardiovascular mortality reduced (HR = 0.75; p =.024) Recurrent non-fatal MIs reduced (HR =.59; p =.014) Dargie HJ. Lancet 2001;357:1385-90

10. Heart Failure Patient Evaluation Recommended evaluation for patients with a diagnosis of HF: Assess clinical severity and functional limitation by history, physical examination, and determination of functional class* Assess cardiac structure and function Determine the etiology of HF Evaluate for coronary disease and myocardial ischemia Evaluate the risk of life threatening arrhythmia Identify any exacerbating factors for HF Identify co-morbidities which influence therapy Identify barriers to adherence and compliance *Metrics to consider include the 6-minute walk test and NYHA functional class Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122

11. Evaluation: Follow Up Assessments Recommended Components of Follow-Up Visits Signs and symptoms evaluated during initial visit Functional capacity and activity level Changes in body weight Patient understanding of and compliance with dietary sodium restriction Patient understanding of and compliance with medical regimen History of arrhythmia, syncope, pre-syncope or palpitation Compliance and response to therapeutic interventions Exacerbating factors for HF, including worsening ischemic heart disease, hypertension, and new or worsening valvular disease Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122

12. Rationale for Evidence-Based Drug Selection in Heart Failure 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 (e.g.,  -blockers) Hunt SA, Abraham WT, Chin MH, et al., Circulation and JACC, Sept. 2005 Available beginning August 15, 2005 at www.acc.org and www.americanheart.org.www.acc.orgwww.americanheart.org

13. Target HFDosage StudyDrugSeverity (mg) Outcome US Carvedilol 1 carvedilol mild/6.25-25  48% disease progression † moderateBID(P=.007) CIBIS-II 2 bisoprolol moderate/ 10 QD  34% mortality severe(P .0001) MERIT-HF 3 metoprolol mild/ 200 QD  34% mortality succinatemoderate(P=.0062) COPERNICUS 4 carvedilol severe 25 BID  35% mortality (P=.0014) CAPRICORN 5 carvedilol Post-MI LVD 25 BID  23% mortality (P=.031) 1 Colucci WS, et al. Circulation. 1996;94:2800-2806. 2 CIBIS II Investigators and Committees. Lancet. 1999;353:9-13. 3 MERIT-HF Study Group. Lancet. 1999;353:2001-2007. 4 Packer M, et al. N Engl J Med. 2001;344:1651-1658. 5 The CAPRICORN Investigators. Lancet. 2001;357:1385-1390. Effect of  -Blockade on Outcome in Patients With HF and Post-MI LVD

14.  -Blockers Differ in Their Long-Term Effects on Mortality in HF Bisoprolol 1 Bucindolol 2 Carvedilol 3-5 Metoprolol tartrate 6 Metoprolol succinate 7 Nebivolol 8 Xamoterol 9 Beneficial No effect Beneficial No effect Beneficial No effect Harmful 1 CIBIS II Investigators and Committees. Lancet. 1999;353:9-13. 2 The BEST Investigators. N Engl J Med 2001; 344:1659-1667. 3 Colucci WS, et al. Circulation 1996;94:2800-2806. 4 Packer M, et al. N Engl J Med 2001;344:1651-1658. 5 The CAPRICORN Investigators. Lancet. 2001;357:1385-1390. 6 Waagstein F, et al. Lancet. 1993;342:1441-1446. 7 MERIT-HF Study Group. Lancet. 1999;353:2001-2007. 8 SENIORS Study Group. Eur Heart J. 2005; 26:215-225. 9 The Xamoterol in Severe heart Failure Study Group. Lancet. 1990;336:1-6.

15. COMET: Primary Endpoint of Mortality Poole-Wilson PA, et al. Lancet. 2003;362:7-13. Metoprolol mean dose: 85 mg QD; Coreg mean dose: 42 mg QD. Time (years) Mortality (%) Carvedilol Metoprolol Tartrate 0 10 20 30 40 0 12345 Risk Reduction  17% (7%, 26%) P=.0017 Metoprolol Tartrate1,359 1,234 1,1059333521,518 1,366 1,259 1,1551,002383 Carvedilol 1,511 Number at Risk: Mortality rates: metoprolol 40%; carvedilol 34%.

16.  -Blockers: Stage C Heart Failure Class I Indication:  -blockers (using 1 of 3 proven to reduce mortality, ie, bisoprolol, carvedilol, and sustained-release metoprolol succinate) are recommended for all stable patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated Level of Evidence: A Hunt SA, Abraham WT, Chin MH, et al., Circulation and JACC, Sept. 2005 Available beginning August 15, 2005 at www.acc.org and www.americanheart.org.www.acc.orgwww.americanheart.org

17. 1 Pfeffer MA, et al. Lancet. 2003;362:759-766. 2 Cohn JN, et al. N Engl J Med. 2001;345:1667-1675. CHARM and Val-HeFT Trials Addition of candesartan 1 or valsartan 2 to ACEI and  -blocker in NYHA functional Class II-III 0%-10% lower risk of death (P .05) 13%-15% lower risk of death or hospitalization for HF in both trials (both P .01) Higher risk for hypotension, renal insufficiency, and hyperkalemia with ARB treatment

18. VALIANT: ACE Inhibitor, Angiotensin Receptor Blocker, or Both in Post-MI LVD Months Probability of Event Valsartan Valsartan  captopril Captopril 061218243036 0.1.2.3.4 Valsartan4,4644,2724,0072,6481,4374,909 4,4144,2653,9942,6481,435 Valsartan  captopril 4,885 Number at Risk: 4,4284,2414,0182,6351,432Captopril4,909 357 382 364 3,9213,6673,3912,1881,2044,909 3,8873,6463,3912,2211,1854,885 3,8963,6103,3552,1551,1484,909 290 313 295 1 Pfeffer MA et al. N Engl J Med. 2003;349:1893-1906. Death From Any Cause Combined Cardiovascular End Point 061218243036 0.1.2.3.4

19. ARBs: Stage C Heart Failure Class I Indication: ARBs approved for HF are recommended in patients with current or prior symptoms of HF and reduced LVEF who are ACEI intolerant Level of Evidence: A Class IIa Indication: ARBs are reasonable to use as alternatives to ACEIs as first-line therapy for patients with mild to moderate HF and reduced LVEF, especially for patients already taking ARBs for other indications Level of Evidence: A Hunt SA, Abraham WT, Chin MH, et al., Circulation and JACC, Sept. 2005 Available beginning August 15, 2005 at www.acc.org and www.americanheart.org.www.acc.orgwww.americanheart.org

20. ARBs: Stage C Heart Failure (cont’d) Class IIb Indication: The addition of an ARB may be considered in persistently symptomatic patients with reduced LVEF who are already being treated with conventional therapy (ie, ACEI and  -blocker) Level of Evidence: B Hunt SA, Abraham WT, Chin MH, et al., Circulation and JACC, Sept. 2005 Available beginning August 15, 2005 at www.acc.org and www.americanheart.org.www.acc.orgwww.americanheart.org

21. 554/3,319 478/3,313.85.008 (.75,.96) HazardLog-rank Placebo Aldosterone Antagonist RatioP Value Primary Endpoint: All-Cause Mortality EPHESUS 284/822 386/841.70 <.001 (.60,.82) RALES Trial Pitt B. N Engl J Med. 2003;348:1309-1321. Pitt B. N Engl J Med. 1999;341:709-717. Trials With Aldosterone Antagonist

22. Aldosterone Antagonists: Stage C Heart Failure Class I Indication: Addition of an aldosterone antagonist is reasonable in selected patients with moderately severe to severe symptoms of HF and reduced LVEF who can be carefully monitored for preserved renal function and normal potassium concentration Level of Evidence: B Hunt SA, Abraham WT, Chin MH, et al., Circulation and JACC, Sept. 2005 Available beginning August 15, 2005 at www.acc.org and www.americanheart.org.www.acc.orgwww.americanheart.org

23. A-HeFT: All-Cause Mortality Taylor AL, et al. N Engl J Med. 2004;351:2049-2057. Days Since Baseline Visit Date Fixed-dose I/H 51846340735931325113 Placebo53246640134028523224 0100200300400500600 85 90 95 100 Survival (%) P=.01 Fixed-dose I/H Placebo Hazard ratio=.57 43% Decrease in Mortality

24. Nitrates/Hydralazine: Stage C Heart Failure Class IIa Indication: The addition of isosorbide dinitrate and hydralazine to a standard medical regimen for HF, including ACEIs and  -blockers, is reasonable and can be effective in blacks with NYHA functional Class III or IV HF Level of Evidence: A Class IIb Indication: A combination of hydralazine and a nitrate might be reasonable in patients with current or prior symptoms of HF and a reduced LVEF who cannot be given an ACEI or ARB because of drug intolerance, hypotension, or renal insufficiency Level of Evidence: C Hunt SA, Abraham WT, Chin MH, et al., Circulation and JACC, Sept. 2005 Available beginning August 15, 2005 at www.acc.org and www.americanheart.org.www.acc.orgwww.americanheart.org

25. Cardiac Resynchronization Therapy: Weight of Evidence  4,000 patients evaluated in randomized controlled trials Consistent improvement in quality of life, functional status, and exercise capacity Strong evidence of reverse remodeling ↓ LV volumes and dimensions  LVEF ↓ Mitral regurgitation Reduction in HF and all-cause morbidity and mortality Abraham WT. Circulation. 2003;108:2596-2603.

26. CRT Improves Quality of Life and NYHA Functional Class *P<.05 Abraham et al. 2003. (%)

27. CARE-HF: Effect of CRT Without an ICD on All-Cause Mortality Cleland JG, et al. N Engl J Med. 2005:352;1539-1549. 571192321365404 Medical Therapy 889213351376409 CRT Number at risk 05001,0001,500.25.50.75 1.00 Event-Free Survival Medical Therapy HR:.64 (95% CI:.48-.85) P=.0019 CRT Days 0

28. CRT: Stage C Heart Failure Class I Indication: Patients with LVEF  35%, sinus rhythm, and NYHA functional Class III or ambulatory Class IV symptoms despite recommended optimal medical therapy and who have cardiac dysynchrony, which is currently defined as a QRS  120 msec, should receive CRT, unless contraindicated Level of Evidence: A Hunt SA, Abraham WT, Chin MH, et al., Circulation and JACC, Sept. 2005 Available beginning August 15, 2005 at www.acc.org and www.americanheart.org.www.acc.orgwww.americanheart.org

29. MADIT II: Effect of Prophylactic ICD in Ischemic LVD (LVEF  30%) Moss AJ, et al. N Engl J Med. 2002;346;877-883. 365 (.69)170 (.78)329 (.90)490 Conventional 9110 (.78)274 (.84)503 (.91)742 Defibrillator Number at Risk 0123.7.8.9 1.0 Probability of Survival Conventional Defibrillator Year.6 0 4

30. Bardy GH, et al. N Engl J Med. 2005;352:225-237. SCD-HeFT: Enrollment Scheme DCM  CAD and CHF EF  35% NYHA Class II or III 6-minute walk, Holter ® Placebo Amiodarone ICD

31. SCD-HeFT Trial: Mortality by Intention-to-Treat HR97.5% ClP Value Amiodarone vs Placebo1.06.86-1.30.53 ICD vs Placebo.77.62-.96.007 Months of Follow-Up Mortality 06121824303642485460 0.1.2.3.4 Amiodarone ICD Therapy Placebo 17% 22% Bardy GH, et al. N Engl J Med. 2005;352:225-237.

32. ICDs: Stage C Heart Failure Class I Indication: An ICD is recommended as secondary prevention to prolong survival in patients with current or prior symptoms of HF and reduced LVEF who have a history of cardiac arrest, ventricular fibrillation, or hemodynamic destabilizing ventricular tachycardia Level of Evidence: A Class I Indication: ICD therapy is recommended for primary prevention to reduce total mortality by reducing sudden cardiac death in patients with ischemic heart disease who are at least 40 days post-MI, have an LVEF  30% with NYHA functional Class II or III symptoms while undergoing chronic optimal medical therapy, and have a reasonable expectation of survival Level of Evidence: A Hunt SA, Abraham WT, Chin MH, et al., Circulation and JACC, Sept. 2005 Available beginning August 15, 2005 at www.acc.org and www.americanheart.org.www.acc.orgwww.americanheart.org

33. ICDs: Stage C Heart Failure (cont’d) Class I Indication: ICD therapy is recommended for primary prevention to reduce total mortality by a reduction in sudden cardiac death in patients with nonischemic cardiomyopathy who have an LVEF  30%, with NYHA functional Class II or III symptoms while undergoing chronic optimal medical therapy, and have a reasonable expectation of survival Level of Evidence: B Class IIa Indication: Placement of an ICD is reasonable in patients with an LVEF of 30% to 35% of any origin with NYHA functional Class II or III symptoms who are taking chronic optimal medical therapy and who have a reasonable expectation of survival Level of Evidence: B Hunt SA, Abraham WT, Chin MH, et al., Circulation and JACC, Sept. 2005 Available beginning August 15, 2005 at www.acc.org and www.americanheart.org.www.acc.orgwww.americanheart.org

34. Evidence-Based Treatment Across the Continuum of LVD and HF Control Volume Reduce Mortality Diuretics Digoxin  -Blocker ACEI or ARB Aldosterone Antagonist or ARB Treat Residual Symptoms CRT  an ICD* Hyd/ISDN* *For all indicated patients. Abraham WT, 2005.

35. Acute Decompensated Heart Failure: Treatment Goals for Hospitalized Patients Improve symptoms, especially congestion and low- output symptoms Optimize volume status Identify etiology Identify precipitating factors Optimize chronic oral therapy; minimize side effects Identify who might benefit from revascularization Education patients concerning medication and HF self-assessment Consider enrollment in a disease management program Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122

36. Overview of Treatment Options for Patients with Acute Decompensated HF Fluid and sodium restriction Diuretics, especially loop diuretics Ultrafiltration/renal replacement therapy (in selected patients only) Parenteral vasodilators * (nitroglycerin, nitroprusside, nesiritide) Inotropes * (milrinone or dobutamine) *See recommendations for stipulations and restrictions. Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122

37. Discharge Criteria for Hospitalized ADHF Patients Recommended prior to discharge for all patients with HF: Exacerbating factors addressed Near optimum fluid status achieved Transition from IV to oral diuretic completed Near optimum pharmacologic therapy achieved Follow-up clinic visit scheduled, usually 7-10 days Should be considered prior to discharge for patients with advanced HF or a history of recurrent admissions: Oral regimen stable for 24 hours No IV inotrope or vasodilator for 24 hours Ambulation before discharge to assess functional capacity Plans for post-discharge management Referral to a disease management program Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122

38. Predictors of Mortality Based on Analysis of ADHERE Database Classification and Regression Tree (CART) analysis of ADHERE data shows: Three variables are the strongest predictors of mortality in hospitalized ADHF patients: BUN > 43 mg/dL Systolic blood pressure < 115 mmHg Serum creatinine > 2.75 mg/dL BUN > 43 mg/dL Systolic blood pressure < 115 mmHg Serum creatinine > 2.75 mg/dL Fonarow GC et al. JAMA 2005;293:572-80

39. Heart Failure Patient Education It is recommended that patients with HF and their family members or caregivers receive individualized education and counseling that emphasizes self-care. This education and counseling should be delivered by providers using a team approach. Teaching should include skill building and target behaviors Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122

40. The Potential Impact of Effective Education on Patient Compliance Noncompliance rate when patients... Recall MD adviceDon’t recall advice Medications8.7%66.7% Diet23.6%55.8% Activity76.4%84.5% Smoking60.0%90.4% Alcohol60.0%81.8% Kravitz et al. Arch Int Med 1993;153:1869-78

41. Sample Target Behavior: Be Able to Read and Understand Food Labels Labels from cups of soup

42. Heart Failure Disease Management Patients recently hospitalized for HF and other patients at high risk should be considered for referral to a comprehensive HF disease management program that delivers individualized care

43. HF Disease Management and the Risk of Readmission Risk Ratio Summary RR = 0.76 (95% CI.68-.87) Summary RR for randomized only = 0.75 (CI =.60-.95)

44. End-of-Life Care in Heart Failure End-of-life care should be considered in patients who have advanced, persistent HF with symptoms at rest despite repeated attempts to optimize pharmacologic and non-pharmacologic therapy, as evidenced by one or more of the following: Frequent hospitalizations (3 or more per year) Chronic poor quality of life with inability to accomplish activities of daily living Need for intermittent or continuous intravenous support Consideration of assist devices as destination therapy Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122

45. Heart Failure: A Practical Approach to Treatment