Medical Management of HF

Transcription

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2 Medical Management of HF August 7, 2004 Presented by Fran Stier ACNP Northern Arizona Heart Consultants

3 Heart Failure Is the #1 Cardiovascular Problem in America Like cancer or AIDS Heart failure (HF) has a high morbidity rate (patients have multiple hospitalizations) Heart failure carries a high mortality rate (up to 50% at 5 years)

4 Heart Failure Is Not Recognized as the #1 CV Health Problem in America Heart failure symptoms can be very nonspecific and are often dismissed to aging or other causes A high index of suspicion is necessary to identify heart failure early in its course

5 Identifying the Patient With Heart Failure Nonspecific symptoms Exertional dyspnea, edema, or fatigue Physical findings Elevated jugular venous pressure, third heart sound, laterally displaced apical impulse, rales Establish diagnosis Echocardiography or radionuclide ventriculography to measure ejection fraction

6 Etiology of Heart Failure (SOLVD Registry) Valvular heart disease Congenital heart disease Viral Toxic Thyroid Peripartum Other 11.3% Idiopathic cardiomyopathy 12.9% N=6063 Hypertension 7.2% Bourassa et al. J Am Coll Cardiol. 1993;22:14A-19A. Ischemic heart disease 68.6%

7 CHF Patient Population by NYHA Class Class III 1.20 M (25%) Class IV 240 K (5%) Class II 1.68 M (35%) Class I 1.68 M (35%) Class I No limitations of physical activity Class II Slight limitations of physical activity Class III Marked limitations of physical activity Class IV Inability to carry out physical activities without discomfort and/or symptoms at rest AHA Heart and Stroke Statistical Update 2001

8 Stages of CHF D Refractory symptoms rest + hospitalizations ACC/AHA Guidelines 2001 C Structural heart disease, prior or current symptoms B Structural heart disease, asymptomatic: LVH, MI, low LVEF, dilatation, valvular disease A High risk patients: HTN, DM, CAD, + FH, LBBB, cardiotoxic drugs

9 Heart Failure Costs Are Considerable 60.6% Hospitalizations $23.1 billion 38.6% Outpatient care $14.7 billion (3.4 visits/year/patient) 0.7% Transplants $270 million Total = $38.1 billion (5.4% of total healthcare costs) O Connell and Bristow. J Heart Lung Transplant. 1994;13:S107-S112.

10 From Risk Factors to Heart Failure Myocardial infarction Coronary thrombosis Arrhythmias and ventricular dysfunction Sudden death Myocardial ischemia CHD Neurohumoral Mechanisms Remodeling Ventricular enlargement Stage B Atherosclerosis LVH Risk factors HTN Stage Hyperlipidemia A Diabetes Smoking? Renal disease Death HF Stage C & D CP

11 Principles of Heart Failure Management Establish the diagnosis of CHF Cardiac dysfunction as the cause of the patient s signs/symptoms Assess the severity of CHF Determine functional capacity Evaluate cardiac size and severity of cardiac dysfunction Determine the presence and extent of comorbid conditions, particularly CAD Determine the appropriate therapeutic strategy Monitor the patient s response to therapy over time

12 Important Comorbid Conditions Sleep Apnea Anemia Hypothyroidism Hypertension

13 Goals of Heart Failure Therapy Reduce mortality Prevent, slow, or reverse progressive cardiac dysfunction Reduce risk of hospitalization Relieve symptoms Improve functional capacity and quality of life

14 Why Symptom Relief Is Not Enough Heart failure is more than a symptomatic disease Produces symptoms, limits functional capacity, and impairs quality of life Heart failure is a progressive disease Worsening symptoms and clinical deterioration, repeated hospitalization, and death Death occurs frequently even in the presence of minimal symptoms or the absence of progressive symptoms Symptoms do not always correspond with ejection fraction

15 Jessup, NEJM 2003 Natural Evolution of LV Remodeling

16 Steering Committee and Membership of the Advisory Council To Improve Outcomes Nationwide in Heart Failure Approach to the Patient With Heart Failure Assessment of LV function (echocardiogram, radionuclide ventriculogram) EF 40% Assessment of volume status Signs and symptoms of fluid retention No signs and symptoms of fluid retention Diuretic (titrate to euvolemic state) ACE inhibitor ß-Blocker Digoxin

17 Adrenergic Pathway in Heart Failure Progression CNS sympathetic outflow Cardiac sympathetic activity Sympathetic activity to kidneys + blood vessels β 1 receptors β 2 receptors α 1 receptors Myocyte hypertrophy + death, dilatation, ischemia + arrhythmias Vasoconstriction, sodium retention

18 Neurohormonal Activation in CHF Norepinephrine Plasma renin activity Vasopressin Natriuretic peptides Endothelin Aldosterone

19 Medical Management of Systolic HF ACEI: low vs. high dose..depends on the BP, ARB: if ADRs develop on ACEI, or may be added. Must watch creatinine levels, development of hyperkalemia. BB: only 3 are approved for HF: Coreg, Toprol XL, Zebeta/Ziac. May be used in pts. With COPD. Follow closely. Diuretics: loop, and occasionally Zaroxolyn given 30 minutes before loop Aldosterone Blockade: Spironolactone or Eplerenone/Inspra.

20 The RALES Trial: Effect of Spironolactone on Survival in CHF Probability of survival Spironolactone Placebo RR= % CI= P<0.001 RALES = Randomized Aldactone Evaluation Study. Pitt et al. N Engl J Med. 1999;341: Months

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23 Medical Management of Systolic HF Digoxin: if needed due to tachycardia, rate control Afib. Dig Study did show symptom relief but no affect on mortality. Antiarrhythmic: Amiodarone is the choice Must check TSH. Anticoagulation: ongoing study Watch evaluating warfarin, aspirin, or placebo. Statin agents should a risk reduction in HF patients regardless of LDL.

24 Medical Management of Systolic HF Acute or Chronic Decomensation B-type Natriuretic Peptide: Nesiritide/Natrecor CHF Clinic

25 First a Word on Beta-Blockers Research tells us it is not a class effect All BB are not created equally Attention: Atenolol, Lopressor, Metoprolol tartarte (short-acting) will not have the same treatment outcomes as the BB approved for HF. Coreg: most data, and appears to be superior to the others. Toprol XL: may have less reactive airway problems. Bisoprolol (Zebeta, Ziac): also a B 1 selective agent

26 What Differences Exist Between β-blocking Agents in Heart Failure? Pharmacology Effects on ejection fraction Doses demonstrated effective in controlled clinical trials

27 Adrenergic Pathway in Heart Failure Progression CNS sympathetic outflow Cardiac sympathetic activity Sympathetic activity to kidneys + blood vessels β 1 receptors β 2 receptors α 1 receptors Myocyte hypertrophy + death, dilatation, ischemia + arrhythmias Vasoconstriction, sodium retention

28 Selectivity of β-blocking Agents Sympathetic Activation Metoprolol Propranolol β 1 receptors β 2 receptors Cardiotoxicity α 1 receptors Carvedilol

29 Differences in β-blocking Agents β 1 -Selectivity α 1 -blockade Intrinsic Sympathomimetic effect Inverse agonism Receptor up-regulation Ancillary properties Antioxidant Endothelin regulation

30 Major Trials of β-blockade in Heart Failure Target Mean Dosage Patients Follow-up Dosage Achieved Effects on (n) (yrs) (mg) (mg/day) Outcomes CIBIS qd 3.8 All-cause mortality: NS CIBIS-II qd 7.5 All-cause mortality: 34% (P<.0001) MDC to 75 bid 108 Death or need for transplant (primary end point): NS MERIT-HF qd 159 All-cause mortality: 34% (P=.0062) US Carvedilol to 50 bid 45 All-cause mortality*: Trials months 65% (P=.0001) COPERNICUS bid 37 All-cause mortality: months 34% (P=.00013) *Not a planned end point. Carvedilol and metoprolol CR/XL are the only agents with β-blockade approved by the FDA for the treatment of mild to moderate heart failure.

31 COMET* More than 3000 patients with class II IV heart failure due to ischemic or nonischemic cardiomyopathy Randomized to carvedilol or metoprolol (in addition to usual therapy) for over 3 years Prespecified end points: all-cause mortality and combined risk of death and hospitalization Results expected 2002 *Carvedilol or Metoprolol European Trial

32 Effect of β-blockade on All-Cause Mortality by Etiology and NYHA Class NYHA II NYHA III NYHA IV Ischemic Nonischemic Relative Risk and 95% Confidence Intervals CIBIS-II MERIT-HF US CARV TRIALS

33 Effect of β-blockade on All-Cause Mortality by Sex and Diabetic Status Diabetic Nondiabetic Men Women Relative Risk and 95% Confidence Intervals *Not a planned end point. MERIT-HF US Carv Trials*

34 β-blockade in Heart Failure Consensus Recommendations All patients with stable class II or III heart failure due to left ventricular systolic dysfunction should receive a β-blocker (in addition to an ACE inhibitor) unless they have a contraindication to its use or cannot tolerate treatment with the drug Treatment with a β-blocker should not be delayed until the patient is found to be resistant to treatment with other drugs Steering Committee and Membership of the Advisory Council to Improve Outcomes Nationwide in Heart Failure. Am J Cardiol. 1999;83(suppl 2A):1A 39A.

35 Dosing for Beta-Blockers in Heart Failure The Medical Letter, June 26, 2000 Drug Starting Dose Target Dose Bisoprolol* 1.25 mg QD 10 mg QD Carvedilol Metoprolol* mg BID 12.5 to 25 mg QD 6.25 to 25 mg BID 200 mg QD * Not FDA approved for use in heart failure

36 Me toprolol Carvedilol 200 mg QD 25 mg QD 100 mg QD 50 mg QD 25 mg BID 12.5 mg BID 6.25 mg BID 12.5 mg QD mg BID Wee ks Wee ks

37 Me toprolol Carvedilol 200 mg QD 25 mg QD 100 mg QD 50 mg QD 25 mg BID 12.5 mg BID 6.25 mg BID 12.5 mg QD mg BID Wee ks Wee ks

38 ACE Inhibitors and Angiotensin Receptor Blockers

39 Limitations of ACE Inhibitors: AII Formation by Non ACE-Dependent Pathways Angiotensin I ACE ACE inhibitor Angiotensin II Chymase CAGE Cathepsin G Angiotensin II antagonist AT 1 receptor CAGE = chymostatin-sensitive angiotensin II generating enzyme.

40 Large Clinical Trials of AT 1 -Receptor Antagonists in HF ELITE II Val-HeFT Population Background therapy Agent N=3152; age 60 y NYHA class II-IV mostly ACEI-naïve EF 40% Digoxin, diuretics, β-blockers (25%) Losartan 50 mg qd N=5010 NYHA class II-IV EF <40% LVDd >2.9 cm/m 2 Digoxin, diuretics, ACEI (93%), β-blockers (35%) Valsartan 160 mg bid Comparator Captopril 50 mg tid Placebo Primary endpoint(s) All-cause mortality All-cause mortality Combined morbidity/mortality ELITE II = Evaluation of Losartan In The Elderly II; Val-HeFT = Valsartan Heart Failure Trial; NYHA = New York Heart Association; EF = ejection fraction ; LVDd = left ventricular end-diastolic diameter; qd = daily; bid = twice a day; tid = three times a day. Pitt et al. Lancet. 2000;355:1582; Presented at 73rd Scientific Session, AHA, November 2000.

41 Val-HeFT: End Points Analysis Events Valsartan Placebo (n=2511) (n=2499) RR (CI) P Value All-cause mortality 495 (19.7%) 484 (19.4%) 1.02 (0.90, 1.15) Combined all-cause mortality and morbidity 723 (28.8%) 801 (32.1%) 0.87 (0.79, 0.96) Cohn. AHA 73rd Scientific Sessions, Nov 2000.

42 Val-HeFT: All-Cause Mortality and Morbidity Event-free probability 10 Valsartan 0 Placebo RR=13.3% 70 P= Months Cohn. AHA 73rd Scientific Sessions, Nov

43 Charm Study: Candesartan/Atacand Three Trials: Alternative, Added, and Preserved AS good as the ACEI NO significant added effects when given with ACEI. Did not reduced mortality. Unlike the Val-HeFT: showed improvement when ARB was given with ACEI and BB. No improvement in the Preserved HF patients Preserved HF: EF > 40% but patient has s/s of HF. This represents about 1/3 of the patients, and more common in elderly and women.

44 Trials of Angiotensin Receptor Blockers in CHF: Lessons Learned, Unanswered Questions Lessons Learned Questions Currently, there is no compelling evidence supporting replacement of ACEIs with ARBs for treatment of patients with CHF: ACEIs continue to be the therapy of choice for this indication For CHF patients who do not tolerate ACEIs, ARBs are an excellent alternative Unanswered What is the optimal role of ARBs in the treatment of patients with CHF? What are the optimal doses of ARBs, alone and in combination with an ACEI? Is there an interaction between β- blocking therapy and a combination of an ARB with an ACE inhibitor? If a patient is contraindicated for β-blocker therapy, consideration should be given to adding an ARB to an ACEI

45 The Art of Medical Management or Tricks of the Trade Start low and go slow Especially in the elderly and light weight women Establish euvolemia ACEI vs BB first Depends on confounding problems Low dose ACEI or high dose ACEI vs ACEI and BB

46 Should Physicians Increase the Dose of ACE Inhibitor or Add β-blockade? Low dose ACEI Average dose ACEI High dose ACEI* + β-blockade Symptoms Unchanged Improved Morbidity/ 12% 35%-40% mortality Mortality 8% 30%-35% *Adapted from Packer et al. Eur Heart J. 1998;19(suppl):142. Adapted from Lechat et al. Circulation. 1998;98:

47 Should We Maximize the Dose of an ACE Inhibitor Before Initiating β-blockade? ATLAS Trial 3164 patients with congestive heart failure were randomized to low-dose ( mg daily) or high-dose ( mg daily) lisinopril for > 5 years No difference in survival or symptoms Slightly lower risk (12%) of death and hospitalization in high-dose group (P=.002) Packer M. et al. Circulation. 1999;100:

48 May cause Incidence Carvedilol Placebo Withdrawal Carvedilol Placebo Initiation of Carvedilol α-blockade Early transient hypotension/ dizziness 18.0% 10.0% 0.1% 0 β-blockade Slowing of heart rate/av conduction 4.0% 0.5% 0.4% 0 Sympathetic Blockade Fluid retention/ worsening symptoms 5.0% 4.0% 0.9% 0 Management Adjust ACEI timing Adjust carvedilol dose Adjust diuretic dose Events during blinded uptitration period (from 6.25 to 50 mg bid); Or delay uptitration; May occasionally require temporary reduction in diuretics (rarely dose of ACE inhibitor). Adapted from Fowler et al. J Am Coll Cardiol. 1997;29(suppl A):285A.

49 What To Expect From Traditional and Newer Therapeutic Approaches to CHF Diuretics Digoxin ACEIs Beta-blockers Symptom relief Yes Yes Yes Late Exercise capacity Yes Yes + No Hospitalizations Probably Yes Yes Yes Mortality No No Yes Yes

50 What To Expect From Traditional and Newer Therapeutic Approaches to CHF (cont d) ACEI + ARB Hydralazine-ISDN Spironolactone Symptom relief Yes Yes Yes Exercise capacity Yes Yes? Hospitalizations Yes? Yes Mortality Under investigation Yes Yes

51 Case Studies

52 JR, a 55 yo male presents to ED with increasing SOB, weakness, and new onset AFib at 73 hr. Echo reveals a dilated heart with EF 15-20%. Cardiac cath: normal coronaries. Nonsmoker, no hx HTN, or valvular disease, no anemia, and his BMI 24. After diuresis, started on Coreg, Lisinopril, Spironolactone, coumadin and lovenox as bridge. Developed VT, nonsustained. Started on Amiodarone Cause of cardiomyopathy? Does he need an ICD?

53 Case Study: JR Pt seen frequently in office for uptitration of meds. Cardioversion performed after 6 weeks of therapeutic INR. Amiodarone contiuned. 6 months later. Repeat Echo - EF 57%! Normal size heart. Now what to do with meds?

54 AP, a 64 yo man, developed severe lower extremity edema for over one year prior to his admission for severe PND, orthopnea, weakness and 30 lb. weight gain. On physical exam: inc. JVD, lower ext edema from thighs down, loud systolic murmur, AFib with RVR. Echo shows mod. MR & TR, EF 20%, large dilated heart. What to do? What is the cause for his HF?

55 Case Study: AP Discharged on: Lasix, KCL, Coreg, Dig, Altace, coumadin. Seen frequently in office: Spironolatone added, and prn use of Zaroxolyn. Progress was slow and he remained in Afib but rate controlled After 4 months he had a cardiac cath: severe 3 vessel CAD with EF 15%! A 3 vessel PCI was performed

56 Case study: AP Continued to follow frequently: many ADRs to medications. Developed significant gynecomastia from spironolactone. Swithched to eplerenone Inspra cough with ACEI, switched to ARB Tried EECP, did not tolerate. Eventfully he improved. 1 yr after his 3 vessel stenting: stress test is normal and the Echo reveals EF 30-35%!!!!!!

57 KR, a 44 yo woman, presents to ED with CP, SOB, weakness, and wt. gain. On physical exam, JVD to jawline, abdominal distention, lower ext. edema from thighs down, positive S 3 & S 4. Indeterminant Troponin levels. Echo reveals 15% EF, mild to mod MR&TR. Pt diuresed. Cath normal coronaries. What are the possible etiologies for her HF?

58 Case Study: KR TSH 115!!!!!

59 Medical Management of Systolic HF Acute or Chronic Decomensation Role of Nesirtide/Natrecor And BNP Measurement

60 How Can Chronic Decompensated Heart Failure, [Stage C/D], Be Treated?

61 Clinical Characteristics in Trials of Severe Heart Failure REMATCH FIRST PROMISE COPERNICUS RALES CONSENSUS LVEF (%) NYHA IV IV III-IV IIIB-IV III-IV IV SBP Na Creatinine year mortality 73%* (OMM arm) 49% 40% 18.5% 24% 45% Source: Lynne Warner Stevenson, MD (3/4/02). * 1 year mortality (4/02).

62 Inotrope Infusion: ACC/AHA 2001 Guidelines Because of lack of evidence to support their efficacy and concerns about their toxicity, physicians should not utilize intermittent infusions of positive inotropic agents (at home, in an outpatient clinic, or in a short-stay unit) in the long-term treatment of HF, even in its advanced stages. Hunt SA et al. ACC/AHA Guidelines for Evaluation and Management of Chronic Heart Failure in the Adult. 2001:27.

63 Introducing a New Paradigm: Do the Natriuretic Peptides Have a Profile That Would Be Beneficial in the Management of Chronic Decompensated Heart Failure [CDHF]?

64 Opposition of Neurohormonal Forces in Heart Failure Renin-Angiotensin-Aldosterone Endothelin Catecholamines Vasodilation Natriuresis/Diuresis Cardiac Stress Remodeling Natriuretic Peptides Vasoconstriction Sodium/Fluid Retention Chronic Cardiac Stress Tissue Remodeling/Fibrosis

65 The Natriuretic Peptides

66 Natriuretic Peptides: Origin and Stimulus of Release Peptide Primary Origin Stimulus of Release ANP Cardiac atria Atrial distension BNP Ventricular myocardium Ventricular overload CNP Endothelium Endothelial stress ANP = Atrial Natriuretic Peptide BNP = B-type Natriuretic Peptide CNP = C-type Natriuretic Peptide Adapted from Burnett JC, J Hypertens 2000;17(Suppl 1):S37-S43

67 Physiologic Effects of the RAAS and NPS RAAS (Renin-Angiotensin Aldosterone System) Activation of AT 1 receptors by angiotensin II NPS (Natriuretic Peptide System) ANP, BNP CNP Vasoconstriction Sodium retention Increased aldosterone release Increased cellular growth Increased sympathetic nervous activity Vasodilation Sodium excretion Decreased aldosterone levels Inhibition of RAAS Inhibition of sympathetic nervous activity Vasodilation Decreased vascular smooth muscle growth Decreased aldosterone levels Adapted from Burnett JC, J Hypertens 1999;17(Suppl 1):S37-S43

68 Physiology of Natriuretic Peptides + Cardiac Overload - Neutral ANP+BNP Endopeptidase Cytokines Clearance NPR-C CNP + NPR-A/NPR-B NPR-A Urodilatin Decreased Vascular Growth Decreased Increased Blood Pressure Na/H 2 0 Excretion Adapted from Wilkins MR. Redondo J. Brown LA. Lancet 1997;349:

69 Release of BNP from Cardiac Myocytes preprobnp (134 aa) probnp (108 aa) signal peptide (26 aa) myocyte secretion NT-proBNP (1-76) BNP (77-108)

70 B-Type Natriuretic Peptide (BNP) Found in the cardiac ventricles Released in response to stretch and increased volume in the ventricle BNP levels are related to: Left ventricular end-diastolic pressure NYHA classification

71 BNP vs. NYHA Classification Median 200 Triage BNP Test Package Insert 0 Normal Class I Class II Class III Class IV (pg/ml)

72 Cumulative Survival Rates in CHF Patients With Left Ventricular Dysfunction Stratified on Median Plasma BNP Concentration Cumulative Survival (%) 100 BNP < 73 pg/ml 80 p < BNP > 73 pg/ml Months Tsutamoto T. et al. Circulation 1997;96:

73 Direct Anti-Remodeling Properties of the Natriuretic Peptides in the Heart Pro-Remodeling Factors: AII, Aldo and ET Anti-Remodeling Factors: ANP, BNP and CNP CP

74 How Could the Natriuretic Peptides Be Anti-Remodeling Factors? Cardiac unloading mechanisms via cardiorenal actions Anti-aldosterone mechanisms Cardioprotective mechanisms via direct actions on endothelial cells and cardiac fibroblasts

75 BELIEVE TRIAL B -TypE Natriuretic Peptide and Post Myocardia L B-TypE MyocardiaL IInfarction nfarction L Eft V entricular R Emodeling Study LEft Ventricular REmodeling BNP The goal is to prevent cardiac remodeling with acute hormonal cardioprotection with BNP at the onset of AMI CP

76 Utility of B-Type Natriuretic Peptide (BNP) in the Diagnosis of Congestive Heart Failure in an Urgent-Care Setting Dao, Q., Maisel, A. et al. Journal of the American College of Cardiology, Vol 37, No. 2, 2001

77 BNP Levels in Patients With Dyspnea Secondary to CHF or COPD /- 138 BNP pg/ml /- 39 COPD CHF N=56 N=94 Cause of Dyspnea Dao, Q., Maisel, A. et al. J. American College of Cardiology, Vol 37, No. 2, 2001

78 BNP Concentration and the Degree of CHF Severity BNP Concentration (pg/ml) ± 22 Mild N = ± 165 Moderate N = ± 266 Severe N = 36 CHF Severity 78

79 Hospital Admission vs. BNP BNP pg/ml /- 60 Not Admitted 700 +/- 116 Admitted Admission Status N=142 N=108 Dao, Q., Maisel, A. et al. J. American College of Cardiology, Vol 37, No. 2, 2001

80 BNP Levels in Patients With Edema Diagnosed With CHF or Without CHF /- 163 BNP pg/ml / No CHF CHF Cause of Edema N=44 N=44 Dao, Q., Maisel, A. et al. J. American College of Cardiology, Vol 37, No. 2, 2001

81 CHF Infusion Clinic Navapache Regional Medical Center

82 FUSION Study Design Screening Weekly Outpatient Visits Follow-up n = 69 Standard Care Inotropes permitted n = 210 n = 72 Nesiritide µg/kg/min, following bolus Inotropes not permitted n = 69 Nesiritide 0.01 µg/kg/min, following bolus Inotropes not permitted -30 to -5 days posthospital discharge 12 Weeks 4 Weeks

83 FUSION: Unanswered Questions What is the correct dose? What is the ideal dosing frequency? What is the optimal duration of treatment? 12 weeks? 16 weeks? Which patient responds best? Is BNP a predictor of response to nesiritide infusion therapy? How does nesiritide impact chronic BNP levels? Does a change in BNP reflect prognosis? Can concomitant oral meds be adjusted [i.e., titrated] on periodic nesiritide therapy?

84 FUSION II

85 Rationale for FUSION II Population LVEF <40% (within 6 months) NYHA Class III with creatinine >1.5 mg/dl (within 30 days of randomization) or NYHA Class IV Standard Care (n = 35) Natrecor Dose (n = 38) Natrecor 0.01 Dose (n = 36) All Natrecor (n = 74) Death by week % 13.3% 5.6% 9.5% Death/All-cause hospitalization 71% 53% 44% 49% Death/Cardiorenal hospitalization 57% 53% 42% 47%

86 FUSION II (Phase IIb) Objectives Evaluate efficacy and safety of serial infusions of Natrecor in patients with advanced heart failure. Evaluate efficacy and safety of two dosing frequencies (1/wk and 2/wk) and select optimal dosing frequency Assess event rates for mortality and rehospitalization to optimize Phase III design

87 Medical Management of HF Questions???? Thank you