1. Beatrice Wong, PharmD, BCPS October 22, 2013

2. Objectives  Review current guidelines for the management of heart failure with emphasis on updates.  Discuss case scenarios and evaluate treatment strategies.  Review recent trials that have impacted clinical practice.

3. Heart Failure Syndrome caused by cardiac dysfunction, generally resulting from myocardial muscle dysfunction or loss and characterized by either LV (left ventricular) dilation or hypertrophy or both. Reduced EF HF-REF (ejection fraction ≤ 40%) Preserved EF HF-PEF (ejection fraction ≥50% ) HFSA 2010 guidelines, ACC 2013 guidelines

4. Neurohormonal Imbalance in HF Achieving the Right Balance Norepinephrine Angiotensin II Endothelin Aldosterone Vasopressin Vasoconstriction Fluid Retention Tachycardia Vasodilation Vasodilation Suppress sympathetic NS Suppress sympathetic NS Suppress RAAS Natriuresis/diuresis Rev Cardiovasc Med. 2001;2(suppl 2):S2-S6. Atrial natriuretic peptide (ANP) Brain natriuretic peptide (BNP) Nitric Oxide Bradykinin Prostaglandins

5. Prevalence, age ≥20 yr Incidence (new cases), age ≥ 45 yr MortalityCost NHANES 2007-20105.1 million670,00056,41032 billion Heart Disease & Stroke Statistics 2013 Projected 2030 6.375 million 70 billion Circulation 2012;125:e2-220.

6. Guidelines for Management  American College of Cardiology Foundation/American Heart Association (ACCP/AHA)  Heart Failure Society of America (HFSA)  Canadian Cardiology Society (CCS)  European Society of Cardiology (ESC) ACC/AHA 2009 HFSA 2010 CCS 2012 ESC 2012 ACC/AHA 2013

7. Classification of Recommendations  Classes of Recommendations Class I- Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective. Class II- Conflicting evidence and/or divergence of opinion ○ IIa- Weight of evidence/opinion is in favour ○ IIb- Usefulness is less well established Class III- Evidence or general agreement that given treatment is not useful/effective and in some cases may be harmful.  Level of Evidence Level A- derived from multiple randomized clinical trials or meta-analyses Level B- derived from a single randomized clinical trial or large non- randomized studies Level C- consensus of opinion of the experts and/or small studies, retrospective studies, or registries

8. Case 1 JK is a 65 yo male with ischemic cardiomyopathy with an EF of 35%. He presents with shortness of breath and fatigue even with walking up the 1 flight of stairs in his home. Meds: Furosemide 20mg po daily Aspirin 81mg po daily What class of heart failure does this patient have? What other medications should JK be on?

9. Types of Classification NYHA (New York Heart Association)  I- Cardiac disease but no limitation of physical activity.  II- Slight limitation of activity. Ordinary activity results in fatigue, palpitation, dyspnea, or anginal pain.  III- Marked limitation of physical activity. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.  IV-Inability to carry on any physical activity without discomfort, maybe even present at rest. ACC-AHA Stages of Heart Failure  A- At high risk but no structural disease or symptoms.  B- Asymptomatic, + structural heart disease (impaired LV [left ventricular] function, hypertrophy, or chamber distortion)  C- Prior or current symptoms of HF, + structural heart disease  D- Refractory HF requiring specialized interventions

10. Case 1 JK is a 65 yo male with ischemic cardiomyopathy with an EF of 35%. He presents with shortness of breath and fatigue even with walking up the 1 flight of stairs in his home. Meds: Furosemide 20mg po daily Aspirin 81mg po daily What class of heart failure does this patient have? Stage C, NYHA class III What other medications should JK be on?

11. Systolic Heart Failure  Goals of treatment Reduction in symptoms Decrease the rate of hospitalization Prevention of premature death  Therapeutic approaches Lifestyle modification Implantable devices Surgery – ventricular assist devices Pharmacologic therapy

12. Loop Diuretics Equivalent dose (po) Bioavailability T½ Bumetanide Furosemide Torsemide 1 mg40 mg20 mg 85%60%85% 1-1.5hr1.5-3hrs IV:PO conversion1:11:21:1 “Maximum” dose10 mg400 mg200 mg 3-6 hrs  Additional characteristics Torsemide is absorbed more rapidly/completely than bumetanide or furosemide Furosemide – metabolized/excreted in the kidney Torsemide/bumetanide – metabolized in liver  Ethacrynic acid (Edecrin) Loop diuretic lacking sulfonamide moiety, ~ equipotent to furosemide Dosing ○ Oral: 50-100mg/day in 1-2 divided doses, max 400mg/day ○ IV: 25-100mg/dose, dose qd to q8h as required Side effect profile ○ Similar to other loops, except incidence of GI bleed and hematologic manifestations

13. Diuretic Resistance  Decreased perfusion due to low cardiac output/vol. overload (require active transport to site of action) Intestine – decreased/delayed absorption of diuretics Kidney – decreased delivery of diuretics to the site of action  Decreased GFR results in decreased filtered load of sodium  Intravascular volume depletion activates plasma renin activity and stimulates SNS  Increased proximal tubule reabsorption of sodium, particularly in setting of elevated AII and elevated catecholamine levels  Increased distal reabsorbtion of sodium, stimulated by aldosterone Na+ rebound - Elevation of AVP  upregulation of Na + -K + -2Cl  Associated with tubular hypertrophy: resetting basal rates of sodium reabsorbtion  Poor dosing strategies and patient compliance

14. Combination Therapy  Loop or Thiazide + Potassium Sparing Rationale: prevent hypokalemia  Loop + Thiazide Rationale: synergy when diuresis is inadequate with monotherapy or utilizing high doses of loops  Loop + Albumin Rationale: questionable, may promote  in UOP during oliguric renal failure

16. Pathogenesis and Therapeutic Approaches  LV Function  Cardiac Output Neurohormone Activation Progressive Heart Failure Diuretics  Impedance Sodium and Water Regulation RAA System ANP Catecholamines ACE-I, ARB, AA Digoxin { B-blockers Vasodilators ACE-I, ARB, AA ACE-I = Angiotensin converting enzyme inhibitors, ARB= Angiotensin receptor blockers, AA= Aldosterone antagonists, B-blockers= Beta blockers, LV= Left ventricular, RAA= Renin angiotensin aldosterone, ANP= Atrial natriuretic peptide

17. Ann Pharmacother 2007; 41:456-64

18. Starting dose Number of doses/day Target Total Daily Dose Mean Daily Dose in Outcome Trials Trial ACE Inhibitors Captopril 6.25 mg3150 mg121 mgSAVE Enalapril 2.5 mg220 – 40 mg16.6 mg CONSENSUS SOLVD Lisinopril 2.5 – 5 mg120 – 35 mgVariedATLAS Ramipril 2.5 mg1 or 210 mg8.7 mgAIRE Trandolapril 1 mg14 mg3 mgTRACE

19. Angiotensin II Receptor Blockers (ARBs)  Alternatives in patients who can not tolerate ACE inhibitors due to cough.  Consider in patients who have experienced angioedema with ACE inhibitors, with recognition that angioedema has been reported infrequently with ARBs.  Addition of an ARB may be considered in persistently symptomatic patients with reduced LVEF who are already on conventional therapy. Starting dose Number of doses/day Target Total Daily Dose Mean Daily Dose in Outcome Trials Trial ARBs Candesartan 4 mg132 mg24 mgCHARM- Added Valsartan 40 mg2320 mg254 mgValHeFT Losartan 50 mg1150 mg129 mgHEAAL

20. Practical Considerations in Use of ACEi/ARBs  All agents ↑K +, ↑ SCr, symptomatic/asymptomatic hypotension (↓ Na+, ↓ volume) ○ Change in SCr is to be expected - what is an acceptable % change?? Monitoring recommendations – SCr, K + within 5 to 7 days of initiation and with dose titrations  ACE Inhibitors Angioedema (≤ 1%), non-productive cough (5-15%), skin rash  ARBs Angioedema cross-reactivity  Renin Inhibitors ○ Angioedema cross-reactivity ??

21. Practical Considerations  Drug Interactions K + supplements, K + sparing diuretics Aldosterone antagonists “Low-salt” substitutes with high K + content NSAIDs Lithium  Contraindications/Precautions/Warnings History of angioedema Bilateral renal artery stenosis SCr > 2.5 mg/dL at baseline Serum K+ level > 5 mEq/L SBP < 90 mmHg Pregnancy category C (1 st trimester)/ D (2 nd /3 rd trimester)

22. Beta-blockers  Beta-blockers mediate their effect by complex interactions with  -adrenoreceptors (2 subtypes)  1 -receptors ○ Heart and kidney (juxtaglomerular cells) ○ Stimulation -  HR, contractility and renin release  2 -receptors ○ Lungs, liver, pancreas, and arteriolar smooth muscle ○ Stimulation - bronchodilation and vasodilation  The ability to reduce plasma renin levels and thus angiotensin II concentrations – major cardiovascular benefit

23. Beta-blockers AgentStarting DoseMax DoseMean Dose Achieved in Trials Bisoprolol1.25mg QD10mg QD8.6mg/day Carvedilol3.125mg BID50mg BID37mg/day Metoprolol XL12.5-25mg QD*200mg QD159mg/day *Metoprolol XL commonly dosed BID in clinical practice. Circulation. 2013;128:e240-327.

26. Significant Trials of Beta-Blockers *NOT AN APPROVED INDICATION; # METOPROLOL SUCCINATE NOT APPROVED FOR SEVERE HF OR FOR MORTALITY REDUCTION ALONE † Not a planned end point. TargetMean Dosage HFPatientsFollow-upDosageAchievedEffects on StudyDrugSeverity(n) (yrs) (mg) (mg/day)Outcomes CIBISbisoprolol*moderate/6411.95 qd3.8All-cause mortality Circ. 1994 severeNS CIBIS-II bisoprolol* moderate/ 26471.310 qd7.5All-cause mortality Lancet 1999 severe  32% (P<.0001) MDCmetoprololmild/3831100-150/day108Death or need for Lancet 1993 tartrate*moderate(bid -tid)transplant (primary endpoint)NS MERIT-HF metoprolol mild/ 39911200 qd159All-cause mortality Lancet 1999 succinate # moderate  34% (P=.0062) BEST bucindolol* moderate/2708250-100 152All-cause mortality NEJM 2001 severebid NS US Carvedilol carvedilol mild/ 10946.56.25 to 5045All-cause mortality † NEJM 1996 moderatemonthsbid  65% (P=.0001) COPERNICUS carvedilol severe 2289 10.4 25 bid37All-cause mortality NEJM 2001 months  35% (P =.0014) COMET carvedilol mild/ 3029 4.8 25 bid 41.8 All-cause mortality Lancet 2003 metoprolol tart* moderate 50 bid 85 ↓15% (P=0.0017)

27. Pharmacologic Management HFrEF Stage C Treatment: (Class I, LOE A) ACEI or ARB + Beta blocker Circulation. 2013;128:e240-327

28. Case 1 (continued) JK is seeing you at clinic for f/u after recent hospitalization. He reports having to stop due to fatigue when he walks about a block. Current meds: Lisinopril 10mg po BID Carvedilol 25mg po BID Furosemide 20mg po QD Aspirin 81mg po QD EF 30% (echo in hospital) BP: 90/67, HR 72 Labs: Scr 1.5 (stable), K 4.2 What other meds could you consider adding at this point?

29. Other therapies: Which one do we add?  Aldosterone antagonists/Mineralocorticoid receptor antagonists (MRAs)  ARBs  Hydralazine/nitrates  Digoxin

30. Aldosterone Potassium, Magnesium loss Ventricular arrhythmias Sodium/ Fluid retention Cardiac, Vascular Remodeling Sympathetic activation /parasympathetic inhibition Myocardial Fibrosis Vascular inflammation J Cardiovasc Pharmacol Ther 2011;16(2):150-9

31. Aldosterone Antagonists  AKA – “Mineralocorticoid Receptor Antagonists”  Mechanism Competitively inhibits the mineralocorticoid receptor in the collecting tubules  Spironolactone ○ Non-specific affinity for receptor ○ Possess antiadrogenic and progestational activity ○ Antiandrogenic and progestational activity Men: gynecomastia and impotence Women: menstrual irregularities ○ Other adverse effects: hyperkalemia  Eplerenone Competitive and highly specific Lacks hormone activity

32. Aldosterone Antagonists Starting dose Number of doses/day Target Total Daily Dose Mean Daily Dose in Outcome Trials Trial Aldosterone Blockers Eplerenone25 mg150 mg43 mgEPHESUS EMPHASIS- HF Spironolactone25 mg125 – 50 mg26 mgRALES

33. EMPHASIS-HF NYHA Class II, age ≥ 55 yrs, EF ≤30% (randomized within 6 mo after hospitalization) N=2737 EplerenonePlacebo NEJM 2011;364:11-21.

34. 1˚ outcome: Death from CV causes or HF hospitalization No. of patients (%) All-cause mortality HF hospitalization Hyperkalemia Eplerenone Placebo P <0.001 P =0.01 P<0.001

35. Hydralazine/nitrates  Initial use of nitrates in combination with hydralazine was based on a hemodynamic concept designed to achieve a “nitroprusside- like” effect  Nitrates + Hydralazine Complementary hemodynamic action ○ Nitrates (preload) – via activation of guanylate cyclase   cGMP in vascular smooth muscle ○ Hydralazine (afterload) – direct-acting vasodilator Effect on HF outcomes? ○ Survival benefit demonstrated in V-HeFT I and V-HeFT II ○ Demonstrated improvement in other markers for cardiac function including exercise tolerance and LVEF

36. V-HeFT I (1980-1985) V-HeFT II (1986-1990)A-HeFT(2001-2004) Sponsor Veterans Affairs NitroMed Number of patients 6428041050 SexMaleMale Male and female Race All races Blacks Drugs studied PlaceboISDN/HYDPrazosinEnalaprilISDN/HYDPlaceboISDN/HYD Target doses of ISDN/HYD ISDN 40 mg QID HYD 75 mg QID ISDN 40 mg QID HYD 75 mg QID ISDN 40 mg TID HYD 75 mg TID ISDN/HYD As individual Products products As fixed-dose combination tablet (BiDil ® ) Severity of HF Mild-to-severeMild-to-severe Moderate-to- severe Background therapy for HF DigoxinDiureticsDigoxinDiureticsDigoxinDiureticsACE-I/ARBsBeta-blockers Aldo’ blockers Characteristics of Major Trials With Isosorbide Dinitrate and Hydralazine in Heart Failure

37. BiDil 518463407359313251 Placebo532466401340285232 BiDil ® Placebo HR = 0.57 P = 0.01 Patients at risk, n 85 90 95 100 0 200300400500 Survival, % Time since baseline visit, days A-HeFT NEJM 2004;351:2049-57.

38. Practical Considerations  Effect of hydralazine on nitrate tolerance HYD potentiates vasorelaxing effect of NTG and reduces the formation of nitrate-mediated vascular superoxide  Nitrates Avoid use with PDE inhibitors such as sildenafil  Hydralazine Reflex tachycardia/palpitations, flushing, exacerbation of angina, Na+/water retention Immunological-type reactions ○ Lupus-like syndrome (dose/duration related, > 6 months) ○ Vasculitis, Dermatitis ○ Glomerulonephritis ○ Peripheral neuropathy, drug-induced hepatitis

39. Digoxin - Plasma Noradrenaline - Peripheral nervous system activity - RAAS activity - Vagal tone - Normalizes arterial baroreceptors NEJM 1988;318:358  Blocks Na + / K + ATPase => Ca + +  “Inotropic” effect  No mortality benefit  Neurohormonal control

40. Digoxin in HF  Optimal serum concentrations “Normal” serum level range: HF patients ○ No added benefit with  from 0.7-0.8 to 1.2-1.5 ng/mL EF, HF symptoms, exercise tolerance and neurohormone levels Escalating levels beyond 0.8 ng/mL more likely harmful ○ PROVED/RADIANCE (retrospective analysis) 0.5 to 0.9 ng/mL; no added benefit with  levels ○ DIG (retrospective analysis) 0.5 to 0.8 ng/mL; may be associated with  mortality, whereas higher concentrations may  mortality Post-hoc analysis –  risk of death in females with levels > 1.2 ; likely similar effect in men with elevated digoxin levels but within normal range JAMA 2003;289:871-8.

41. Case 1 (continued) JK is seeing you at clinic for f/u after recent hospitalization. He reports having to stop due to fatigue when he walks about a block. Current meds: Lisinopril 10mg po BID Carvedilol 25mg po BID Furosemide 20mg po QD Aspirin 81mg po QD EF 30% BP: 90/67, HR 72 Labs: Scr 1.5 (stable), K 4.2 What other meds could you consider adding at this point? Aldosterone antagonist

42. Aldosterone Antagonists  AHA 2013 Aldosterone antagonists are recommended in patients with NYHA class II-IV and who have LVEF of 35% or less, unless contraindicated, to reduce morbidity and mortality. Patients with NYHA class II should have a history of prior cardiovascular hospitalization or elevated plasma natriuretic peptide levels to be considered for AA. Scr ≤ 2.5 in men or ≤ 3 in women and K < 5 mEq/L. (Class I, Level A).  ESC 2012 Recommended for all patients with persisting symptoms (NYHA II-IV) and an EF ≤ 35%, despite treatment with ACE inhibitor and a beta-blocker (Class I, Level A) Circulation 2013;128:e240-327. Eur H J 2012;33:1787-1847.

43. Circulation. 2013;128:e240-327

44. ACCF/AHA Guidelines 2013 Circulation 2013;128:e240-327

46. Patient Selection and Treatment Congestion at Rest Low Perfusion at Rest YesNo Warm & Dry PCWP normal CI normal (compensated) UNCOMMON Cold & Wet PCWP elevated CI decreased MOST PATIENTS Cold & Dry PCWP low/normal CI decreased UNCOMMON Inotropic Drugs Dobutamine Milrinone No Yes Warm & Wet PCWP elevated CI normal FAIRLY COMMON Vasodilators Nitroprusside Nitroglycerin or Natriuretic Peptides Nesiritide Fonarow GC. Rev Cardiovasc Med. 2001;2(suppl 2):S7–S12.

47. Comparison of Inotropes AgentDose (mcg/kg/min) Effects COHRSVRPVR Dopamine5-10 ↑↑↔↔ 10-15 ↑↑↑↔ Dobutamine2.5-5 ↑↑↓↔ 5-20 ↑↑↔↔ Milrinone0.125-0.75 ↑↑↓↓ Circulation 2013;128:e240-327.

48. Dobutamine  Cardiogenic shock, heart failure  Mechanism Selective beta-2 agonist, ↑CO and HR  Dosing 1-20 mcg/kg/min Dose > 10 mcg/kg/min rarely used  Considerations Dose-related tachyarrhythmias ↑ mVO2 – caution in ischemia, CAD pts

49. Milrinone  “Inodilator”  MOA Phosphodiesterase inhibitor - ↑cAMP levels leading to smooth muscle relaxation and increased cardiac contractility  Dosing 0.25 – 0.75 mcg/kg/min  Considerations Accumulates in renal dysfunction Clinically significant hypotension – avoid loading Good alternative to dobutamine in HF patients with ↑ PA pressures Commonly used with vasopressin for milrinone- induced hypotension

50. Nitroprusside Direct active arterial vasodilator Dosing 0.25-5 mcg/kg/min (max 10 mcg/kg/min) Half life 3-5 minutes, fast onset 1-10mins Main uses Hypertension Aortic dissection (use with beta-blocker) CHF w/ “elevated” BP Considerations Renal insufficiency – accumulation of thiocyanate Liver insufficiency – accumulation of cyanide May increase ICP

51. Nitroglycerin Primary role in pts with ACS, may be used in heart failure MOA Relaxation of smooth muscle Dosing 0.05-4 mcg/kg/min, can be titrated quickly for chest pain Considerations Tolerance occurs within 24 hrs Headache Rebound tachycardia

52. Nesiritide  Targeted for ADHF patients  MOA – numerous (see next slide)  Dosing 0.005-0.02 mcg/kg/min Generally avoid bolus dosing  Considerations Synergy with other vasodilators Used in combination with inotropes

53. Nesiritide  Hemodynamic: Vasodilation of arteries, veins, and coronaries  Preload and  Cardiac Output  Lusitropy  Neuroendocrine: Counter-regulatory effect on RAAS,  Aldosterone  SNS activity,  Endothelin  Renal:  GFR,  Diuresis and Natriuresis Levin ER et al, NEJM 1998; Venugopal J, Journal Clinical Pharmacy and Therapeutics 2001

55. Case 2 DP is a 40 yo male with non ischemic cardiomyopathy (EF of 18%), no atrial arrhythmias. The attending asked if you would like to start DP on Warfarin to prevent embolic events such as a stroke. What is your opinion on starting Warfarin? A. Yes, warfarin should be started. B. No, start Aspirin instead. C. No, start Clopidogrel instead. D. No, do not start any anticoagulant or antiplatelet agent.

56. Rationale  Heart failure is associated with hypercoagulability, formation of left ventricular thrombus, and stroke.  Associated with sudden death and progressive heart failure that may be due to atherothrombotic events. NEJM 2012;366:1859-69.

57. Warfarin vs Aspirin vs Clopidogrel  WATCH trial Randomized to open-label warfarin (inr 2.5- 3) or double blind Aspirin 162mg or Clopidogrel 75mg N= 1587 patients with EF ≤ 35% and normal sinus rhythm No difference in time to first occurrence of death, nonfatal MI, or nonfatal stroke. Warfarin pts had fewer strokes ○ More major and minor bleeds than pts on Clopidogrel. Circulation 2009;119:1616-24.

58. WARCEF  EF ≤ 35% and normal sinus rhythm  Randomized to warfarin INR goal 2.75 (2-3.5) or Aspirin 325mg a day  Outcome Time to ischemic stroke, intracerebral hemorrhage, or death from any cause NEJM 2012;366:1859-69.

59. WARCEF

61. Anticoagulation in Heart Failure  ACC/AHA guidelines 2013 Pts with chronic HF with permanent/persistent/paroxysmal AF and an additional risk factor for cardioembolic stroke (HTN, DM, prior TIA/stroke, or ≥ 75 yo) should receive chronic anticoagulant therapy (Class I, level A). Reasonable for chronic HF with AF and no additional factor (Class IIa, level B).  ESC guidelines 2012 Other than in patients with AF, there is no evidence that an oral anticoagulant reduces morbidity- mortality compared with placebo or aspirin.

62. Case 2 DP is a 40 yo male with non ischemic cardiomyopathy (EF of 18%), no atrial arrhythmias. The attending asked if you would like to start DP on Warfarin to prevent embolic events such as a stroke. What is your opinion on starting Warfarin? A. Yes, warfarin should be started. B. No, start Aspirin instead. C. No, start Clopidogrel instead. D. No, do not start any anticoagulant or antiplatelet agent.

63. Case 3  MJ is a 55 yo patient dobutamine- dependent who has chronic atrial fibrillation managed with Amiodarone. The resident suggests switching to Dronedarone since it does not have the same long-term adverse effects as Amiodarone. Is this a good idea?

64. ANDROMEDA ↑ mortality with Dronedarone group. Total mortality of 25 pts (D) vs 12 pts (P) with 10 of those patients attributed to worsening heat failure (D) compared to 2 pts (P), respectively. NEJM 2008;358:2678-87.

65. Vasopressin Antagonists  Should we use them in hyponatremia and when?  Tolvaptan (Samsca) Bind to V 2 receptors of distal nephron selectively Common adverse effects- thirst and dry mouth

66. EVEREST Hospitalized patients with LVEF 40%, signs of volume expansion, NYHA III/IV, within 48 hrs of hospitalization Tolvaptan 30mg daily Placebo Primary endpoints: All-cause mortality, Cardiovascular death or hospitalization for heart failure

67. EVEREST Results  No significant differences in primary outcomes.  Tolvaptan pts had greater change in edema at 7 days (or discharge).  Among pts with baseline Na< 134meq/L, mean Na increased by 5.49meq/L by day 7 (or discharge) with Tolvaptan vs 1.85 meq/L (placebo).  Safety: Hypernatremia 1.7% (tolvaptan) vs 0.5% (placebo) JAMA 2007;297:1319-31.

68. Diuretic Strategies in Patients with Acute Decompensated Heart Failure- DOSE trial  How much and what mode?  Presented within 24 hrs with ADHF  On oral diuretic of at least 1 month at dose of Furosemide 80-240mg/day or equivalent.  Excluded pts with SCr > 3mg/dL, IV vasodilators, inotropes (except Digoxin)  Randomized to Low-Dose, High-Dose, IV Bolus, or Continuous IV Infusion NEJM 2011;364:797-805.

69. DOSE Trial: Results P= 0.45 P= 0.21 Change in SCr (mg/dL )

70. SECONDARY ENDPOINTS High Dose group had a greater change in wt and net fluid loss at 72 hrs compared to Low Dose. More pts with increase in Scr of >0.3mg/dL with High Dose. No difference between bolus and continuous infusion groups.

71. On the Horizon-  Ivabradine (approved in Europe) Slows heart rate by selective I f current inhibition in sinus node Reduced hospitalization in SHIFT trial Most beneficial in patients with baseline HR ≥ 75 bpm in post-hoc analysis.  Serelaxin  Angiotensin receptor neprilysin inhibitor  Omecamtiv mecarbil Lancet 2010;376:886-94.