1. Strategie terapeutiche Strategies of Medical Therapy Mariell Jessup MD Professor of Medicine University of Pennsylvania Philadelphia, Pennsylvania

2. Advanced Heart Failure: after ACEI or ARB and beta-blockade add ARB if on ACEI add Aldactone evaluate for CRT/ICD Disease management consider hydralazine-nitrate Heart transplant Ventricular re-shaping or restraint surgery Correct anemia or sleep disturbance Intravenous inotropes or BNP Ultrafiltration Mechanical circulatory support device Proven to improve survival in clinical trials ??

3. Advanced Heart Failure: after ACEI or ARB and beta-blockade add ARB if on ACEI add Aldactone evaluate for CRT/ICD Disease management consider hydralazine-nitrate Heart transplant Ventricular re-shaping or restraint surgery Correct anemia or sleep disturbance Intravenous inotropes or BNP Ultrafiltration Mechanical circulatory support device

4. Pfeffer, M. A. et. al. N Engl J Med 2003;349:1893-1906 Kaplan-Meier Estimates of the Rate of Death from Any Cause (Panel A) and the Rate of Death from Cardiovascular Causes, Reinfarction, or Hospitalization for Heart Failure (Panel B), According to Treatment Group VALIANT

5. Val-HeFT: Combined Morbidity Endpoint ACEI/Beta-Blocker Subgroups Placebo Valsartan 0 10 20 30 40 50 ACEI (No) BB (No) ACEI (Yes) BB (No) ACEI (No) BB (Yes) ACEI (Yes) BB (Yes) (N = 1606) (N = 3038) (N = 139) (N = 227) 47.0% 27.7% 36.3% 30.9% 34.8% 20.5% 22.0% 25.5%

6. Mortality in the placebo arm of Val-HeFT by treatment group: 23-month mean follow-up Slide courtesy of J. Cohn

7. Advanced Heart Failure: after ACEI or ARB and beta-blockade add ARB if on ACEI add Aldactone evaluate for CRT/ICD Disease management consider hydralazine-nitrate Heart transplant Ventricular re-shaping or restraint surgery Correct anemia or sleep disturbance Intravenous inotropes or BNP Ultrafiltration Mechanical circulatory support device

8. Aldosterone Blockade in Heart Failure RALES: Randomized Aldactone Evaluation Study 1663 pts NYHA III and IV, ave age 65 and LVEF 0.25, on ACEI and loop diuretic Randomized to Aldactone 25 mg PO qd vs Placebo Pitt NEJM 1999;341:709-17

9. Juurlink et al. NEJM 2004;351:543 after RALES: RX

10. Juurlink et al. NEJM 2004;351:543 after RALES::Death

11. Advanced Heart Failure: after ACEI or ARB and beta-blockade add ARB if on ACEI add Aldactone evaluate for CRT/ICD Disease management consider hydralazine-nitrate Heart transplant Ventricular re-shaping or restraint surgery Correct anemia or sleep disturbance Intravenous inotropes or BNP Ultrafiltration Mechanical circulatory support device

12. Role of ICDs MADIT-II (16% women) –NYHA IV excluded from MADIT I and II –No benefit of ICD for women –Other minorities not listed SCD-HeFT (23% women, 24% non-white) –NYHA IV excluded –No benefit of ICD for women or non-whites COMPANION (32% women, 15% class IV) Redberg. JAMA 2007;298:1564

13. COMPANION NYHA IV: 217/1520 patients Lindenfeld et al. Circulation 2007;115:204 Death or hospitalization

14. JACC 2009; 53:765-73

15. CRT in Advanced Heart Failure JACC 2009; 54: 600-607

16. CRT in Advanced Heart Failure Am Heart J 2006; 151: 837-43

17. Advanced Heart Failure: after ACEI or ARB and beta-blockade add ARB if on ACEI add Aldactone evaluate for CRT/ICD Disease management consider hydralazine-nitrate Heart transplant Ventricular re-shaping or restraint surgery Correct anemia or sleep disturbance Intravenous inotropes or BNP Ultrafiltration Mechanical circulatory support device

18. Clark et al. BMJ 2007; 337:942 All cause mortality

19. Clark et al. BMJ 2007; 337:942 All cause hospitalization

20. Advanced Heart Failure: after ACEI or ARB and beta-blockade add ARB if on ACEI add Aldactone evaluate for CRT/ICD Disease management consider hydralazine-nitrate Heart transplant Ventricular re-shaping or restraint surgery Correct anemia or sleep disturbance Intravenous inotropes or BNP Ultrafiltration Mechanical circulatory support device

21. Taylor et al. NEJM 2004; 351:2049 AHEFT 1050 patients death 43%

22. Advanced Heart Failure: after ACEI or ARB and beta-blockade add ARB if on ACEI add Aldactone evaluate for CRT/ICD Disease management consider hydralazine-nitrate Heart transplant Ventricular re-shaping or restraint surgery Correct anemia or sleep disturbance Intravenous inotropes or BNP Ultrafiltration Mechanical circulatory support device

26. Advanced Heart Failure: after ACEI or ARB and beta-blockade add ARB if on ACEI add Aldactone evaluate for CRT/ICD Disease management consider hydralazine-nitrate Heart transplant Ventricular re-shaping or restraint surgery Correct anemia or sleep disturbance Intravenous inotropes or BNP Ultrafiltration Mechanical circulatory support device

27. Co-morbid Conditions and HF Myocardial IschemiaContribution to LV dysfunction. Atrial arrhythmiasWorsens symptoms, decreases cardiac performance. AnemiaCommon. Associated with worse outcome and increased symptoms. Sleep apneaCommon. Associated with arrhythmias, pulmonary hypertension, biventricular dysfunction. Thyroid disordersEither hypo- or hyperthyroidism can exacerbate HF. DepressionCommon. Worsens symptoms and complicates interpretation. ArthritisTreatment with NSAIDs can exacerbate HF and renal dysfunction. Vioxx off market for ↑ CV events. DiabetesAssociated with CAD and hyperlipidemia. Treatment (metformin and glitizones) can complicate HF. HyperlipidemiaAssociated with CAD. Statin effect important? Erectile dysfunctionCommon. Associated with depression, non-compliance. Worsens QOL. Impact on outcomes or life quality.Co-morbidity

28. Circulation 2008;117:526 Correcting anemia?

29. Advanced Heart Failure: after ACEI or ARB and beta-blockade add ARB if on ACEI add Aldactone evaluate for CRT/ICD Disease management consider hydralazine-nitrate Heart transplant Ventricular re-shaping or restraint surgery Correct anemia or sleep disturbance Intravenous inotropes or BNP Ultrafiltration Mechanical circulatory support device

30. Circ HF 2009; 2:90-97

31. IV Inotropic Agents During Hospitalization for Decompensated Heart Failure Cuffe MS et al. JAMA. 2002;287:1541–1547. Event Rate (%) Treatment Failure From Adverse Event (48 h) Sustained Hypotension Acute MIMortality Milrinone Placebo Afib P < 0.001 P = 0.18 P = 0.004 P = 0.19 12.6 2.1 10.7 3.2 1.5 0.4 4.6 1.5 3.8 2.3 0 5 10 15 20 OPTIME-CHF: In-hospital Adverse Events

32. Impact of Inotropes on Survival Circulation 2003; 108:492-97

33. Continuous Outpatient Support with Inotropes 36 inotrope-dependent patients EF <0.20 Class IV symptoms Hypoperfusion and end-organ dysfunction 46 rehospitalizations Median survival=3.4 months (0.2-26.3) Most patients died at home 51% 26% 6% J Cardiac Failure 2003;9:180-7

34. REVIVE II Day5143190 Placebo151235 Levosimendan5142045 * Time to death by Cox proportional hazard model Time to Death During 90 Days of Follow-up Period

35. FUSION II Study Design Nesiritide* 1x/wk + Intensive Disease Management (n = 300) Nesiritide* 2x/wk + Intensive Disease Management (n = 300) Phase IIb Double-blind Randomized Multi-center n = 900 Placebo 2x/wk + Intensive Disease Management (n = 150) Placebo 1x/wk + Intensive Disease Management (n = 150) 12 week treatment period 1° and 2 ° Endpoints 12 week blinded follow-up period * Dosing: 2  g/kg bolus, then 0.01  g/kg /min infusion x 4-6 hours Additional Endpoints Yancy CW et al. Am Heart J 2007

36. FUSION II: Primary Composite Endpoint Through Week 12 Placebo Combined N=306 Nesiritide Combined N=605 *P-value All cause mortality and CV/renal hospitalization † 36.8%36.7%0.79 All Cause Mortality9.6%9.5%0.98 CV/renal hospitalization33.9%32.9%0.95 *P value: NES vs. placebo stratified by dose group † Modified ITT: all treated ITT patients Slide courtesy of C.Yancy

37. Advanced Heart Failure: after ACEI or ARB and beta-blockade add ARB if on ACEI add Aldactone evaluate for CRT/ICD Disease management consider hydralazine-nitrate Heart transplant Ventricular re-shaping or restraint surgery Correct anemia or sleep disturbance Intravenous inotropes or BNP Ultrafiltration Mechanical circulatory support device

38. Mechanical Circulatory Support Devices

39. When the Failing, End-Stage Heart Is Not End-Stage Dale G. Renlund, M.D., and Abdallah G. Kfoury, M.D. NEJM, 2006

40. Survival In NYHA IIIb % SLIDE COURTESY OF J. LINDENFELD

41. % Survival for LVAD SLIDE COURTESY OF J. LINDENFELD

42. Big Gap in Mortality SLIDE COURTESY OF J. LINDENFELD

43. Big Gap in Stroke Risk Heart failure 1.8% first year after dx 5.0% at five years 0.8% per year in chronic HF ( Witt RJ et al J Cardiac Failure 2007;13:489) LVAD 19% to 5.2% year Post REMATCH ( Lietz K et al Circulation 2007;116; 497) 6 fold increase in risk of stroke

44. Difficult decisions of end stage heart failure: Mechanical Circulatory Support A balance: The risks of multi-system organ failure from progressive heart failure (> 50% death in 1 year) The risks of surgical intervention for MCSD and ongoing MCSD support versus