CRS-I-Treatment. Alan Maisel MD. Director Coronary Care Unit And Heart Failure Program San Diego Veterans Hospital

Transcription

1 CRS-I-Treatment Alan Maisel MD Professor of Medicine, University of California, San Diego Director Coronary Care Unit And Heart Failure Program San Diego Veterans Hospital

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3 Outcomes in Patients Hospitalized With HF 100 Hospital Readmissions 100 Mortality % 50% % 33% 50% 0 30 Days 6 Months 0 30 Days 12 Months 5 Years Median LOS: 6 days N = 38,702 Aghababian RV. Rev Cardiovasc Med. 2002;3(suppl 4):S3 Jong P et al. Arch Intern Med. 2002;162:1689

4 Until recently we didn t really have any effective, nontoxic treatments for CHF

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7 Treatment of Acute HF Diuretics Vasodilators Inotropes Natriuretic Peptides Fluid volume Preload and/or afterload Contrac - tility Fluid volume Preload Afterload Neurohormes Increase lusitropy

8 Profiles and Therapies of Advanced Heart Failure Low Perfusion at Rest No Yes Congestion at Rest No Warm and Dry PCW and CI normal Cold and Dry PCW low/normal CI decreased Yes Warm and Wet PCW elevated CI normal Cold and Wet PCW elevated CI decreased Nl SVR High SVR Vasodilators Nitroprusside Nitroglycerine Nesiritide Inotropic Drugs Dobutamine Milrinone Calcium Sensitizers R. Bourge, UAB Cardiology (adapted from L. Stevenson) Stevenson LW. Eur J Heart Failure 1999;1:

9 Complications of Diuretic Therapy for Heart Failure Diuretic Therapy Renal Reabsorption of Na (and Mg) Plasma Volume Hypomagnesemia Hyponatremia Cardiac Output Renal Blood Flow PRA Neurohumoral Activation Pre-renal Azotemia GFR Uric Acid Clearance Proximal Reabsorption Distal Ca++ Reabsorption Calcium Clearance Aldosterone Kaliuresis Hypokalemia Hyperuricemia Hypocalcemia Glucose Intolerance Na = sodium; Mg = magnesium; GFR = glomerular filtration rate; PRA = plasma renin activity. Kaplan NM., Treatment of Hypertension: Drug Therapy in Clinical Hypertension (p. 203) in Clinical Hypertension, 6 th. Ed. Baltimore: William and Wilkins 1994.

10 The Natriuretic Peptide System is Overwhelmed in Acute Decompensated Heart Failure Endothelin Aldosterone Angiotensin II Epinephrine ANP BNP Adapted from Burnett JC, J Hypertens 1999;17(Suppl 1):S37-S43

11 Human B-type Natriuretic Peptide (hbnp) Nesiritide is identical to endogenous hbnp Mechanism of Action: via receptor binding to GC-A receptor and cgmp production (no impact on camp)

12 Effects of Nesiritide Venous, arterial, coronary VASODILATION RENAL CARDIAC INDEX Preload Afterload PCWP Dyspnea CARDIAC HEMODYNAMIC No increase in HR Not proarrhythmic rhbnp D R I S P K M K R G F C G M V Q G S S S S S S G L S G H C K V L R R NATRIURESIS DIURESIS Fluid volume Preload Diuretic usage Aldosterone Endothelin Norepinephrine SYMPATHETIC AND NEUROHORMONAL SYSTEMS

13 Reference: VMAC Clinical Benefit VMAC demonstrated that NATRECOR with standard therapy is superior in improving dyspnea and reducing filling pressure compared to placebo with standard therapy Standard care medications during study drug included any of the following: IV diuretics (73%) non-iv diuretics (48%) oral ACE inhibitors (58%) aspirin (45%) oral, topical, or sublingual nitrates (34%) beta-blockers (27%) NATRECOR Full Prescribing Information. Data on file, Scios Inc. warfarin (15%) statins (26%) class III antiarrhythmics (16%) A-II receptor antagonists (8%) hydralazine (9%) dobutamine (23%) dopamine (6%)

14 Change From Baseline in PCWP (mm Hg) Hemodynamic Effects of Nesiritide * vs Placebo vs IV NTG Time on Study Drug (hr) * * * * * PCWP Placebo PCWP IV NTG PCWP Nesiritide 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 *P 0.05 vs placebo P 0.05 vs IV NTG End of Placebo-Controlled Period Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531

15 Nitroglycerin Dose (mcg/min) Nitroglycerin Dose and Change in PCWP During Treatment With Nitroglycerin n = 9 ( 3 hr); n = 12 (>3 hr) Time (hr) Added to standard therapy NTG dose * 4 80 Change in PCWP 5 60 * * 40 * * 6 20 * * P<0.05 vs baseline Change in PCWP (mm Hg) Elkayam U et al. Am J Cardiol. 2004;93:237

16 Nesiritide Versus Other Vasodilators Parameters Nitroglycerin NitroprussideNesiritide Tachyphylaxis Yes No No Toxic Metabolites No Yes No Hypotension Yes Yes Yes Special handling Glass Light No Headache Yes Yes Yes Action on RAAS? Renin Aldosterone Difficult titration No Yes No

17 Limitations of Current Therapies for Acute HF: Positive Inotropes Increased mortality 1-3 Milrinone Enoximone Imazodan Vesnarinone Dobutamine Xamoterol Ibopamine Increased risk of hospitalization Aggravation and induction of arrhythmias (need telemetry) 4 Milrinone Dobutamine Dopamine Tachycardia Tachyphylaxis (dobutamine) 1 Packer M et al. N Engl J Med. 1991;325: Cohn JN et al. N Engl J Med. 1998;339: The Xamoterol in Severe Heart Failure Study Group. Lancet. 1990;336:1 4 Ewy GA. J Am Coll Cardiol. 1999;33:572 Neurohormonal activation and/or lack of suppression Physiologic effects antagonized by -blockade (dobutamine, dopamine)

18 J Sackner-Bernstein, M Kowalski, M Fox. JAMA. 293 (15) , April 20, 2005

19 Acute Decompensated Heart Failure: Nesiritide and Mortality No short-term therapy for ADHF has been proven to improve short- or long-term mortality rates. Nesiritide is the only approved ADHF therapy which has been shown in large, randomized trials to provide both significant symptomatic and hemodynamic improvement when added to standard care. Nesiritide has not been studied in a trial powered to evaluate an effect on mortality. 30-day mortality data available for 7 trials 6-month mortality data available for 4 trials

20 J Sackner-Bernstein, M Kowalski, M Fox. JAMA. 293 (15) , April 20, 2005

21 30-Day Mortality Hazard Ratios Mills et al. Efficacy Comparative PRECEDENT VMAC PROACTION FUSION I Note: Arrows depict studies included in JAMA publication

22 NAPA Trial Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery A prospective, multi-center, randomized, double-blind, pilot study Included 279 randomized and treated heart failure patients undergoing cardiac surgery with or without mitral valve repair/replacement NAPA was a Phase II, exploratory study No pre-specified primary endpoints; however there were pre-specified areas of interest Not the labeled dose (no bolus) Limitations with this analysis 180-day mortality endpoint was added late in the study; as a result subjects were lost to follow-up (3%), declined consent (9%) or did not respond to request for information (13%), other* (6%) at 180 days. This study is too small to draw definitive mortality conclusions This study is not designed to demonstrate safety and effectiveness for this use * Documented alive at days 174 to 179. More robust trials are planned

23 NAPA Trial 30-Day and 180-Day Mortality Kaplan-Meier rate within 30 days Kaplan-Meier rate within 180 days Nesiritide (n=141) % (n) 2.8% (4/141) 6.7% (8/141) Placebo (n=138) % (n) 5.9% (8/138) 14.7% (17/138) Hazard Ratio (95% CI) 0.48 (0.14, 1.59) 0.44 (0.19, 1.01) P value day mortality data were available for 132 patients in the nesiritide group and 127 in the placebo group. 180-day mortality data were available for 94 patients treated with nesiritide and 95 patients treated with placebo. Reference: Luber JM, Jr., on behalf of the NAPA Investigators. J Card Fail. 2006; 12(6, suppl 1):S73-S74. Abstract 235. Scios will submit a final report to FDA once its own internal validation of the data is complete.

24 NAPA Trial Kaplan-Meier Survival Curve by Treatment Goup In seven NATRECOR clinical trials, through 30 days, 5.3% in the NATRECOR treatment group died as compared with 4.3% in the group treated with other standard medications. In four clinical trials, through 180 days, 21.7% in the NATRECOR treatment group died as compared with 21.5% in the group treated with other medications. There is not enough information to know about the effect of NATRECOR on mortality. Reference: Luber JM, Jr., on behalf of the NAPA Investigators. J Card Fail. 2006; 12(6, suppl 1):S73-S74. Abstract 235. Scios will submit a final report to FDA once its own internal validation of the data is complete.

25 J Sackner-Bernstein, HA Skopick, KD Aronson. Circ , 2005

26 Methods/Results 5 studies, N = 1,269 Dose ranging from 0.01 to 0.06 g/kg/min Even low-dose nesiritide (0.015 g/kg/min) significantly increased risk (p=0.012 and p=0.006 compared with non-inotrope and inotrope based controls, respectively) J Sackner-Bernstein, HA Skopick, KD Aronson. Circ , 2005

27 SCr Increases with Nesiritide: Renal Outcomes Prescribing Information, Precautions: Renal Effects When NATRECOR was initiated at doses higher than 0.01 mcg/kg/min (0.015 and 0.03 mcg/kg/min), there was an increased rate of elevated SCr compared with standard therapies, although the rate of acute renal failure and the need for dialysis was not increased. In the 30-day follow-up period in VMAC, 5 patients in the NTG group (2%) and 9 patients in the NATRECOR group (3%) required first-time dialysis. (p=0.418) Reference: NATRECOR Full Prescribing Information.

28 NAPA Trial Mean Change in Serum Creatinine (SCr) and Calculated Glomerular Filtration Rate (cgfr) by Treatment Group and Baseline Renal Function PARAMETERS OF INTEREST NESIRITIDE PLACEBO P Peak SCr Increase (mg/dl)* All Patients (n=266) <0.001 Patients with baseline SCr >1.2 (n=62) Maximum Decrease in cgfr (ml/min)* All Patients (n=266) Patients with baseline SCr >1.2 (n=62) Postoperative SCr Increase >0.5 mg/dl* All Patients (n=271) 7% 23% <0.001 Postoperative Urine Output (first 24 hrs.) (ml) * All Through Patients discharge (n=271) or hospital day 14, whichever came first <0.001 NATRECOR may affect renal function in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with NATRECOR may be associated with azotemia. In the VMAC trial, through day 30, the incidence of elevations in creatinine to >0.5 mg/dl above baseline was 28% and 21% in the NATRECOR and nitroglycerin groups, respectively. When NATRECOR was initiated at doses higher than 0.01 mcg/kg/min, there was an increased rate of elevated serum creatinine over baseline compared with standard therapies, although the rate of acute renal failure and need for dialysis were not increased. Reference: Hebeler RF Jr. on behalf of the NAPA investigators. Circulation May 30, Abstract 292

29 NAPA Trial Mean Change from Baseline in Post-Op SCr NATRECOR may affect renal function in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with NATRECOR may be associated with azotemia. In the VMAC trial, through day 30, the incidence of elevations in creatinine to >0.5 mg/dl above baseline was 28% and 21% in the NATRECOR and nitroglycerin groups, respectively. When NATRECOR was initiated at doses higher than 0.01 mcg/kg/min, there was an increased rate of elevated serum creatinine over baseline compared with standard therapies, although the rate of acute renal failure and need for dialysis were not increased. Reference: Luber JM, Jr., on behalf of the NAPA Investigators. J Card Fail. 2006; 12(6, suppl 1):S73-S74. Abstract 235. Scios will submit a final report to FDA once its own internal validation of the data is complete.

30 Ideal Agent for Acute HF Vasodilator (venous and arterial) Rapidly decreases ventricular filling pressures Rapidly decreases symptoms of congestion Does not increase heart rate or directly increase contractility (decreases myocardial oxygen demand) Not proarrhythmic No tolerance Provides neurohormonal suppression Promotes diuresis/natriuresis Conveniently dosed (with or without PA catheterization) Minimal titration needed Fonarow GC. Rev Cardiovasc Med. 2001;2(suppl 2):S7

31 Braunwald Panel Recommendations Nesiritide is approved for inpatient management of acute HF Use of nesiritide should be limited to patients presenting to the hospital with acute HF who have dyspnea at rest Physicians considering the use of nesiritide should consider Its efficacy in reducing dyspnea Possible risks of the drug Availability of alternate therapies to relieve HF symptoms Scios Inc. press release. June 13, Available at: Accessed July 13, 2005

32 ADHERE CART: Predictors of Mortality Less than BUN 43 N = 33,046 Greater than 2.68% n = 25, % n = 7202 SYS BP 115 n = 24,933 SYS BP 115 n = % n = % n = 20, % n = % n = 5102 Highest to Lowest Risk Cohort OR 12.9 (95% CI ) Cr % n = % n = 620 Fonarow GC et al. JAMA :572

33 InHospital Mortality InHospital Mortality In-Hospital Mortality Risk by Initial BNP Levels Reduced vs. Preserved Systolic Function HF LVEF < 0.40 LVEF > P< Q1 (<622) Q2 ( ) Q3 ( ) 6.4 Q4 (>2310) P< Q1 (<336) Q2 ( ) Q3 ( ) Q4 (>1230) 5 48,629 (63%) out of 77,467 pt episodes had BNP assessment at initial evaluation 19,544 patients with LVEF < 0.40 and 18,164 patients with LVEF > 0.40 Q to Q4 2004

34 Patient Outcomes by Quartiles of BNP Levels in the ADHERE Registry Q1 (<430) Q2 ( ) Q3 ( ) 48,629 (63%) out of 77,467 pt episodes had BNP assessment at initial evaluation. Q to Q Q4 (>1730) P Value Ventilation P= CPR P< Ultrafiltrat P< LOS (days) P< ICU admit % P< ASx at DC P<0.0001

35 ALGORITHM FOR USE IN BNP TESTING IN PATIENTS WITH CHF Draw BNP, BUN Initial BNP > 600 & Initial BUN > 40 Yes No IV diuretic for 6 to 12 hours Low Risk Patient: BNP level decreased Adequate diuresis ( cc) No deterioration in renal function High risk patient: No change or increase in BNP level Inadequate diuresis (<500cc) Worsening renal function Continue diuretics/vasodilators until euvolemic BNP < 400 Discharge BNP 400 Re-evaluate Volume status Yes Euvolemic No SBP 90 Nesiritide 1-2 days IV Diuretics BNP level 6h after Nesiritide cessation then re-check BNP SBP < 90 Inotropes Pressors +/- Swan Ganz Catheter Improvement in symptoms/ BNP Yes No Discharge with early follow-up Nesiritide plus diuretics Oral vasodilators and diuretics until euvolemic. D/C BNP level Nesiritide 1-2 days, then po Vasodilators,d iuretics Consider Angiography IABP Transplant LVAD

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39 Continuous Aortic Flow Augmentation Orqis Cancion Ax Fem graft f Cath : Fem:Fem single Fem c e a a inflow (fem artery) b b pump d c pump motor d controller e flow sensor

40 Mechanism of Action Continuous Aortic Flow Augmentation Nitric Oxide Other mediators Ventricular Unloading Vasodilation Renal Effects Hemodynamic improvement Diuresis Clinical Benefit

41 mg% Effects of CAFA on Renal Function 1.5 Serum Creat n= p= BASELINE DAY 1 DAY 2 DAY 3

42 Mechanical Therapy Smaller devices Less infection? Opportunity for explant

43 % Event Free Survival REMATCH Trial: All Cause Mortality P= LV Assist Device (n=68) Control (n=61) N Engl J Med 2001; 345: 1435 Months RR 0.52 (0.34,0.78)

44 Limitations of Current LVAD Therapy Very expensive. Major commitment on the part of physicians, nurses and hospitals for continuing care. Small increase in survival rates after 2 years. Substantial risk of bleeding, infection and device malfunction requiring in-hospital care.

45 Limitations of Current LVAD Therapy Very expensive. Major commitment on the part of physicians, nurses and hospitals for continuing care. Small increase in survival rates after 2 years. Substantial risk of bleeding, infection and device malfunction requiring in-hospital care.

46 Mechanical Unloading Reverses The Heart Failure Phenotype Donor Myocytes Dilated CMP Post LVAD

47 Cell Transplantation For Treating HF End stage heart failure Undefined mechanisms Functional recovery of diseased hearts animals, human New Myocytes Possible Graft neonatal/adult CM embryonic stem cell bone marrow stem cell skeletal myoblast others GM fibroblast cardiac stem cells

48 BOOST Results Wollert KC et al. Lancet, July 20

49 Titrating therapy by Natriuretic NP levels above baseline usually mean volume overload NP levels can help one achieve euvolemia and monitor treatment NP levels can help determine appropriate discharge from the hospital peptide levels

50 PAW (mm Hg) Changes in BNP and PAW* Levels During 24 Hours of Treatment N = 15 (responders) baseline *Pulmonary artery wedge. Hours PAW BNP BNP (pg/ml) Msaisel, A. et al. J Cardiac Failure, Vol. 7, No. 1, 2001

51 BNP level (pg/ml) In volume overloaded patients: BNP level = baseline BNP(dry) plus change due to increased volume(wet) Wet (Change due to volume overload) Dry ( NYHA Euvolemic state) I II III IV NYHA Class - Euvolemic (Dry) BNP

52 Liang, Maisel et al., JACC 2007 Major form of BNP in patients with CHF is probnp 5 CHF patients: kda Rec. A B C D E blank Rec probnp BNP Clinical BNP Results pg/ ml: A B C D E Maisel in-house Triage

53 Serial BNP for Guiding Treatment During Hospitalization? Courtesy of Damien Logeart.

54 BNP: It s About Improving Patient Care

55 Death or readmission (%) Logeart et al. Predischarge BNP Assay for Identifying Patients at High Risk of Re-Admission After Decompensated Heart Failure. JACC 43(4): Predischarge BNP >700ng/l n =41, events =38 p < Predischarge BNP ng/l n =50, events =30 p < Predischarge BNP <350ng/l n =111, events = Follow-up (days) Hazard ratios of 2 nd and 3 rd versus 1 st BNP range Logeart D. et al. J Am Coll Cardiol Feb 18;43(4):635-41

56 Bringing BNP Into the Clinic or Bringing the Clinic to BNP Needs to be interpreted in context Does not take the place of history, physical exam To interpret value must have understanding of BNP and heart failure syndrome Must have previous BNP values to which to refer

57 BNP (pg/ml) A. Decompensated CHF (IV) B. After treatment (II) C. Clinic - 2 months later (II) D. Stopped Meds - 3 months later (IV) E. After treatment (II) A B C D E

58 Algorithms for BNP Outpatient Management TELEMEDICINE

59 Algorithms for BNP Outpatient Management OUTPATIENT CLINC

60 Can BNP levels be used to titrate outpatient therapy? The Holy Grail

61 Targets in Treatment In many conditions treatment can be titrated against a target : Hypertension Blood Pressure Diabetes Lipids glucose, HbA1c Cholesterol

62 Heart Failure Treatment Targets There is currently no target for treatment of heart failure that is: Objective Reliable Practical Inexpensive

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64 Neurohormones in Heart Failure Neurohumoral activation Marker of severity and prognosis in CHF BNP levels Reflect LV wall stress/ filling pressure Correlate with LV ejection fraction Indicate prognosis in CHF and after MI Fall with effective ACEI / diuretic therapy

65 Benefit of BNP plasma levels for optimising therapy in patients with systolic heart failure : The Systolic heart failure treatment Supported by BNP trial (STARS-BNP) multicenter randomised study. STARS BNP For STARS-BNP Investigators on behalf of the working group on Heart failure of the French Society of Cardiology

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67 End Points BNP group Clinical group p all causes hospitalizations N: NS Hospitalizations related to HF N P<0,001 Death all causes N: 7 11 NS Death related to HF N: 3 9 P<0,05 HF related death and hospitalizations N: P<0,001 STARS BNP

68 Patient Our patients really love the BNP test! Doctor

69 People feel better when their BNP levels are lower And they live longer!

70 Patient compliance often improves when patients also have an objective way to monitor their condition

71 BNP on Every Street Corner?

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73 Some would like Nothing better than To burst the bubble

74 BNP and Guidelines As with every new diagnostic or treatment modality, guidelines often lag behind state-of-the-art practice It is very encouraging to see that after only several years of introduction into clinical practice, the use of BNP is already recommended by all major guidelines Suspected Acute Heart Failure Assess Symptoms and Signs Nor Heart Disease? ECG / BNP/ X- Abnorm ray? al Evaluate function by Echocardiography / other Abnorm imaging al Heart Failure, assess by Echocardiography Characterize type and severity mal Consider other diagnosis Nor mal Selected tests (angio, hemodynamic monitoring, PAC) NEED MORE European Heart J. 2005;26:385-6.

75 Diagnostic Tests Alone Will Not Accomplish Our Goals

76 Being an MD at a distance Airport get phone calls foot ball game Or just relaxing What s his BNP?

77 We Need to Be Good Clinicians at the Bedside First!

78 Modern technology is not always available to us

79 It takes longer to use history, physical exam skills AND technology

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81 Thank You!