1. THE NAPA TRIAL: Nesiritide A dministered 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 Introduction Methods Results Summary Baseline SCr ≤ 1.2mg/dl Baseline SCr > 1.2mg/dl

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 Introduction Methods Results Summary 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

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

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

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. Goldberg RJ et al. Arch Intern Med 2007; 167:490- 496. OR (95% CI) of characteristics as predictors of short-term and long-term all-cause mortality after hospitalization with acute HF Characteristic3 mo5 y Age 55-640.30 (0.13–0.70)1.27 (0.80–2.01) >851.55 (0.88–2.74)6.27 (3.94–10.00) BMI >300.55 (0.40–0.77)0.62 (0.47–0.82) Edema1.20 (0.92–1.56)1.38 (1.07–1.77) Serum urea nitrogen (per mg/dL rise) 1.02 (1.01–1.03) COPD1.19 (0.94–1.52)1.97 (1.53–2.54) Hypertension0.77 (0.61–0.99)1.00 (0.79–1.28) Stroke1.40 (1.04–1.90)1.49 (1.04–2.13) Heart failure1.04 (0.77–1.40)2.20 (1.72–2.83) Peripheral vascular disease 0.76 (0.55–1.06)1.42 (1.02–1.97)

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

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

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  Fluid volume Vasodilators  Preload and/or afterload Inotropes  Contrac -tility Natriuretic Peptides  Fluid volume Preload Afterload Neuro- hormones  Increase lusitropy

28. Reduces preload Relieves ischemia Improves symptomatic HF Nitroglycerin Nitroprusside Vasodilators Reduces afterload Reduces blood pressure Increases cardiac output Nesiritide Reduces preload & afterload Increases cardiac output Decreases neurohormonal activation Relieves dyspnea 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 * †*†* †*†* † † † † †*†* Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531 During 3-hr placebo period Placebon = 62 IV NTGn = 60 Nesiritiden = 124 After 3-hr period IV NTGn = 92 Nesiritiden = 154 *P  0.05 vs placebo † P  0.05 vs IV NTG PCWP – Placebo PCWP – IV NTG PCWP – Nesiritide End of Placebo-Controlled Period Time on Study Drug (hr) 00.250.51236912243648 –9–9 –8–8 –7–7 –6–6 –5–5 –4–4 –3–3 –2–2 –1–1 0 †*†* * Change From Baseline in PCWP (mm Hg)

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

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. P ≤ 0.003 P ≤ 0.012 P ≤ 0.002 ≤ 0.03 mcg/kg/min ≤ 0.015 mcg/kg/min ≤ 0.06 mcg/kg/min

33. Nesiritide Better 0.01 mcg/kg/min 0.015 mcg/kg/min 0.03 mcg/kg/min Odds Ratio (and 95% confidence intervals) P=0.17 P=0.02 P=0.001 0 1 2 Nesiritide Worse 34 5 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 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 hospitalization 33.9%32.9%0.95 *P value: NES vs. placebo stratified by dose group † Modified ITT: all treated ITT patients

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

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

39. Mathew and Katz, Drugs Aging, 1998 Haikala and Linden, J Cardiovasc Pharmacol, 1995 Calcium Sensitizing Agents: Overview Increase cardiac contractility by increasing sensitivity of myofilaments to Ca 2+ Do not increase intracellular Ca 2+ levels Generate increased contractile force for a given level of intracellular Ca 2+ May provide a “more economical” increase in inotropic effect (i.e. without a significant increase in myocardial O 2 consumption)

40. Intracellular calcium concentration 0 5 10 15 0.00.10.20.30.40.50.60.7 % cell shortening Ca2+ sensitizers Desensitizing agents Relationship between i[Ca 2+ ] and Cell Shortening

41. Hemodynamic Effects and Mortality Rates of Levosimedan vs. Dobutamine-- LIDO End pointLevosimedanDobutamineHR (95% CI) p value Hemodynamic improvement 28%15%1.9 (1.1-3.3)0.022 Mortality at 180 days 26%38%0.57 (0.34- 0.95) 0.029 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 Interval Levosimendan, n=299 (%) Placebo, n=301 (%)p 24 h*60460.026 48 h63580.053 5 d76650.001 *infusions halted at 24 hours Packer M et al. American Heart Association Scientific Sessions 2005; November 13–16, 2005; Dallas, TX.

44. Adverse Events in REVIVE-2 Selected adverse events Levosimendan (%) Placebo (%) Hypotension49.235.5 Headache29.414.6 Ventricular tachycardia24.116.9 Cardiac failure22.426.6 Atrial fibrillation8.40.2 Ventricular extrasystoles7.40.2 Packer M et al. American Heart Association Scientific Sessions 2005; November 13–16, 2005; Dallas, TX.

45. Mebazaa A. American Heart Association Scientific Sessions 2005; November 13–16, 2005; Dallas, TX. All-cause Mortality by Time since the First Infusion in the SURVIVE-W Trial IntervalAnalysisLevosimendan, n=664 (%) Dobutamine, n=663 (%) HR (95% CI) 180 dPrimary end point 26280.91 (0.74-1.13) 31 dSecondary end point 12140.85 (0.63-1.15) 5 dPost hoc46.00.72 (0.44-1.16)

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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