THE NAPA TRIAL: N esiritide A dministered P eri- A nesthesia in Patients Undergoing Cardiac Surgery

1. THE NAPA TRIAL:Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery Mark J. Russo, MD, MS Division of Cardiothoracic Surgery & International Center for Health Outcomes and Innovation Research College of Physicians and Surgeons, Columbia University, New York, NY

2. BACKGROUND • Nesiritide is recombinant human B-type natriuretic peptide • When administered to patients with heart failure, it: • decreases preload and afterload • decreases pulmonary vascular resistance • increases cardiac output • In some studies: • increased urine output • reduced diuretic requirements • suppression of aldosterone, endothelin, norepinephrine Introduction Methods Results Summary

3. BACKGROUND • Nesiritide is approved for treatment of patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity • Several small, retrospective studies suggested beneficial effects in patients undergoing cardiac surgery Introduction Methods Results Summary

4. OBJECTIVES To explore the effects of perioperative administration of nesiritide on clinical outcomes and safety in heart failure patients undergoing cardiac surgery. Introduction Methods Results Summary

5. NAPA TRIAL DESIGN • Multi-center (54 centers) • Randomized • Double-blind • Placebo-controlled Introduction Methods Results Summary

6. NAPA TRIAL DESIGN • LV dysfunction (EF≤40%) • NYHA Class II - IV • undergoing CABG ± MVS • using cardiopulmonary bypass Introduction Methods Results Summary

7. EXCLUSION CRITERIA • Planned AVR/r • Off-pump • Ongoing or chronic dialysis • Hemodynamic criteria • Mean PAP < 15 mm Hg • CVP < 6 mm Hg • SBP < 90 mm Hg Introduction Methods Results Summary

8. STUDY PROTOCOL Introduction Methods Results Summary

9. OUTCOME MEASURES • Mean peak change in serum Cr and GFR through hospital discharge or POD #14 • Cardiac, renal, and pulmonary adverse events • Mortality (30-day and 180-day) • Mean ICU LOS & total hospital LOS Introduction Methods Results Summary

10. STUDY POPULATION Introduction Methods Results Summary

11. STUDY POPULATION Introduction Methods Results Summary

12. 30-DAY ADVERSE EVENTS* Introduction Methods Results Summary

13. MEAN PEAK CHANGE IN SCr* Introduction Methods Results Summary *Through hospital discharge or study Day 14, whichever came first

14. RENAL BENEFIT WAS GREATER IN PATIENTS WITH RENAL DYSFUNCTION AT BASELINE Baseline SCr ≤ 1.2mg/dl Baseline SCr > 1.2mg/dl Introduction Methods Results Summary

15. 180-DAY SURVIVAL WAS IMPROVED WITH NESIRITIDE Introduction Methods Results Summary

16. LENGTH OF STAY WAS SHORTER WITH NESIRITIDE Introduction Methods Results Summary

17. LIMITATIONS • Usual-care medications and other treatment interventions were not specified in the protocol. • Patients enrolled in this study represent only a subset of patients undergoing CABG • The 180-day mortality end point was added late in the study as an additional safety end point Introduction Methods Results Summary

18. NAPA FINDINGS • Improved Survival at 180 days • Improved Postop Renal Function • Greater improvement in patients with renal dysfunction at baseline • Decreased LOS Introduction Methods Results Summary

19. Safety and Efficacy of Therapies for Acute Decompensated Heart Failure Clyde W. Yancy, MD Medical Director Baylor Heart and Vascular Institute Baylor University Medical Center Dallas, TX

20. Disclosure InformationClyde W. Yancy, MD • Grants/Research Support: GlaxoSmithKline; Medtronic, Inc.; NitroMed, Inc.; Scios Inc. • Support/Consultant: AstraZeneca Pharmaceuticals LP; GlaxoSmithKline; Medtronic, Inc.; NitroMed, Inc.; Scios Inc. • Speaker’s Bureau: GlaxoSmithKline; Novartis Pharmaceuticals Corporation

21. Outcomes in Patients Hospitalized With HF Mortality Hospital Readmissions 100 100 75 75 50% 50% 50 50 33% 20% 12% 25 25 0 0 30 days 6 mo 30 days 12 mo 5 yr Annual mortality rate- NYHA class III HF- 12% [COPERNICUS DATA] NYHA class II HF- 7% [SCD-HeFT DATA] Median hospital LOS: 6 days Jong P et al. Arch Intern Med. 2002;162:1689

22. Explanations for Increased Mortality Risk in ADHF • Absence of understanding • What is the relevant pathophysiology of ADHF? • Acts of commission • Administration of agents that cause harm • Acts of omission • Failure to administer therapies known to be effective • Failure of follow-up

23. OR (95% CI) of characteristics as predictors of short-term and long-term all-cause mortality after hospitalization with acute HF Goldberg RJ et al. Arch Intern Med 2007; 167:490-496.

24. Treatment Options for Acute HF-TODAY- are these agents safe and effective? Diuretics, Aquaretics & Ultrafiltration Vasodilators Inotropes Natriuretic Peptides  Fluid volume Preload Afterload Neuro- hormones  Increaselusitropy  Preload and/or Afterload  Fluid volume  Contrac -tility

25. Potential Deleterious Effects of Diuretics and Cardiorenal Syndrome of HF Increased morbidity and mortality Diuretic therapy Pathologic remodeling Neurohormonal activation Congestion Vasoconstriction Neurohormonal activation Diminished blood flow Diuretic resistance Decreased renal perfusion Impaired renal function

26. Diuretic Resistance Predicts Mortality in Advanced HF Neuberg GW et al. Am Heart J. 2002;144:31.

27. Treatment Options for Acute HF-TODAY- are these agents safe and effective? Diuretics, Aquaretics & Ultrafiltration Vasodilators Inotropes Natriuretic Peptides  Fluid volume Preload Afterload Neuro- hormones  Increaselusitropy  Preload and/or afterload  Fluid volume  Contrac -tility

28. Reduces preload Relieves ischemia Improves symptomatic HF Vasodilators Nitroglycerin • Reduces afterload • Reduces blood pressure • Increases cardiac output Nitroprusside • Reduces preload & afterload • Increases cardiac output • Decreases neurohormonal activation • Relieves dyspnea Nesiritide None of the above have been shown to improve mortality for ADHF in randomized controlled clinical trials

29. Hemodynamic Effects of Nesiritide vs Placebo vs IV NTG Time on Study Drug (hr) 0 0.25 0.5 1 2 3 6 9 12 24 36 48 0 PCWP – Placebo –1 PCWP – IV NTG PCWP – Nesiritide –2 –3 * During 3-hr placebo period Placebo n = 62 IV NTG n = 60 Nesiritide n = 124 After 3-hr period IV NTG n = 92 Nesiritide n = 154 Change From Baseline in PCWP (mm Hg) –4 †* –5 † * * –6 † * † * † –7 † –8 † † –9 End of Placebo-Controlled Period *P0.05 vs placebo †P0.05 vs IV NTG Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531

30. VMAC: Dyspnea Improvement Dyspnea at 3 hr P=0.034 100 Markedly better P=0.191 90 80 Moderately better 70 60 Minimally better 50 40 No change Proportion of Subjects (%) 30 Minimallymarkedly worse 20 10 0 10 20 30 40 Nitroglycerin* (n = 143) Nesiritide*(n = 204) Placebo* (n = 142) *Added to standard care Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531

31. What are the risks of nesiritide therapy?

32. Risk of Worsening Renal Failure:Nesiritide Relative to Control Therapies Sackner-Bernstein JD et al. Circulation 2005;111:1487-1491. ≤0.03 mcg/kg/min ≤ 0.015 mcg/kg/min ≤ 0.06 mcg/kg/min P ≤ 0.003 P ≤0.012 P ≤ 0.002

33. Nesiritide Worse Nesiritide Better 0.01 mcg/kg/min 0.015 mcg/kg/min 0.03 mcg/kg/min P=0.17 P=0.02 P=0.001 0 5 1 3 4 2 Odds Ratio (and 95% confidence intervals) Odds Ratios Of Worsening Serum Creatinine (>0.5 mg/dL) By Nesiritide Dose Group Abraham WT. Serum Creatinine Elevations in Patients Receiving Nesiritide are Related to Starting Dose HFSA 2005

35. DID WE LEARN ANYTHING FROM FUSION-II?

36. FUSION II: Primary Composite Endpoint Through Week 12 *P value: NES vs. placebo stratified by dose group †Modified ITT: all treated ITT patients

37. SAFETY Protocol Specified Changes in Serum Creatinine* P=0.046 Percent of patients with SCr increases P=0.931 P=0.458 *Outpatient Clinic Visit Values Only

38. Treatment Options for Acute HF-TODAY- are these agents safe and effective? Diuretics, Aquaretics & Ultrafiltration Vasodilators Inotropes Natriuretic Peptides  Fluid volume Preload Afterload Neuro- hormones  Increaselusitropy  Preload and/or afterload  Fluid volume  Contra- ctility

39. Calcium Sensitizing Agents: Overview • Increase cardiac contractility by increasing sensitivity of myofilaments to Ca2+ • Do not increase intracellular Ca2+ levels • Generate increased contractile force for a given level of intracellular Ca2+ • May provide a “more economical” increase in inotropic effect (i.e. without a significant increase in myocardial O2 consumption) Mathew and Katz, Drugs Aging, 1998 Haikala and Linden, J Cardiovasc Pharmacol, 1995

40. Relationship between i[Ca2+] and Cell Shortening Ca2+ sensitizers 15 Desensitizing agents 10 % cell shortening 5 0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Intracellular calcium concentration

41. Hemodynamic Effects and Mortality Rates of Levosimedan vs. Dobutamine--LIDO Follath et al. Lancet 2002;360:196

42. REVIVE-2 • 600 pts c ADHF • Randomized to placebo vs. levosimendan • Composite endpoint- • Improvement in 6 hrs • Requirement for vasoactive Rx • Death 75% of patients treated with Levosimendan were either unchanged or worsened

43. Approximate Time-dependent Rates of “Moderate or Marked" Improvement in Patient Global Assessment Packer M et al.American Heart Association Scientific Sessions 2005; November 13–16, 2005; Dallas, TX.

44. Adverse Events in REVIVE-2 Packer M et al.American Heart Association Scientific Sessions 2005; November 13–16, 2005; Dallas, TX.

45. All-cause Mortality by Time since the First Infusion in the SURVIVE-W Trial Mebazaa A. American Heart Association Scientific Sessions 2005; November 13–16, 2005; Dallas, TX.

46. Evaluation and Management of Patients With ADHF: Recommendations • Patients admitted with ADHF and evidence of fluid overload be treated initially with loop diuretics • When congestion fails to improve in response to diuretic therapy, the following options should be considered • Sodium and fluid restriction • Increased doses of loop diuretics • Continuous infusion of a loop diuretic • Addition of a second type of diuretic • Ultrafiltration • In the absence of symptomatic hypotension, IV NTG, NTP, or nesiritide may be considered as an addition to diuretic therapy for rapid improvement of congestive symptoms in patients with ADHF Adams KF et al. J Card Fail. 2006;12:10

47. Section 12: Evaluation and Management of Patients with ADHF • 12.15- “In the absence of hypotension, IV NTG, sodium nitroprusside or nesiritide may be considered as an addition to diuretic therapy for rapid improvement of congestive symptoms in patients admitted with ADHF”. [Strength of evidence B] • 12.17- “Intravenous vasodilators, (nitroprusside, nitroglycerin or nesiritide) may be considered in patients with ADHF and advanced HF who have persistent severe HF despite aggressive treatment with diuretics and standard oral therapies” [Strength of evidence C] J Cardiac Failure. 2006;12:10–38

48. Evaluation and Management of Patients With ADHF: Recommendations • 12.16 IV vasodilators (IV NTG or NTP) and diuretics are recommended for rapid relief in patients with acute pulmonary edema or severe hypertension • IV inotropes (milrinone or dobutamine) may be considered to relieve symptoms and improve end-organ function in patients with advanced HF J Cardiac Failure. 2006;12:10–38

49. Question & Answer

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