MANAGEMENT OF ACUTE DECOMPENSATED HEART FAILUREJournal Review

MANAGEMENT OF ACUTE DECOMPENSATED HEART FAILUREJournal Review

MANAGEMENT OF ACUTE DECOMPENSATED HEART FAILURE Journal Review Dr. Benny J. Panakkal Senior Resident Dept. of Cardiology Govt. Medical College Kozhikode. 2 1. General considerations a) b) c) d) Role of Oxygen and artificial ventilation Factors affecting symptom relief -blockers their role in AHFblockers their role in AHF Management of AF in special situations AF with fast ventricular rate with acute systolic heart failure

Cardiorenal syndrome e) Targets of decongestion BP control f) Invasive hemodynamic monitoring g) Pre-blockers their role in AHFdischarge planning 2. Individual drug classes and their role a) b) c) d) e) f) g) Diuretics Vasodilators Inotropes and inodilators AVP antagonists Ultrafiltration Hypertonic Saline Novel therapies

3. Devices in AHF The Questions POTENTIAL QUESTIONS TO BE ANSWERED 3 O2 and Artificial Ventilation O2 and Artificial Ventilation Role of Supplemental inhaled Oxygen 4 Lee DS, Stitt A, Austin PC, et al. Prediction of heart failure mortality in emergent care: A cohort study. Ann Intern Med 2012 Multicenter: 86 hospitals in Canada 12,591 patients presenting to ED between 2004 and 2007 Aim was to create a multivariate prediction model for Acute Heart Failure mortality within 7 days

Variables showing mortality were Higher presentation heart rate (as a continuous variable) Higher creatinine levels Lower systolic blood pressure Lower initial Oxygen Saturation O2 and Artificial Ventilation Role of Supplemental inhaled Oxygen 5 Park JH, Balmain S, Berry C, et al. Potentially detrimental cardiovascular effects of oxygen in patients with chronic left ventricular systolic dysfunction. Heart 2010

Pilot study On O On Air P value Randomized, double blind, placebo-blockers their role in AHFcontrolled crossover trial 13 men presenting with heart failure-blockers their role in AHF0.02 Cardiac output (L/ -blockers their role in AHF0.58 0.031 min) FiO2 0.40 vs. <0.40 OnlyHeart hemodynamic effects were measured and not outcomes Rate (bpm) -blockers their role in AHF4.02 0.41

0.021 2 Applanation tonometry Imepedence Cardiography SVR (dyne/s/m5) 875 Venous occlusion plethysmography ANP BNP 235 0.050 O2 and Artificial Ventilation Role of Supplemental inhaled Oxygen

6 3CPO trial investigators: Noninvasive ventilation in acute cardiogenic pulmonary edema NEJM 2008 Multicenter, prospective, open label, RCT Standard O2 therapy CPAP vs. NIPPV vs. No mortality benefit with NIV End point for comparison between noninvasive ventilation and standard O2 therapy But more rapid Death within 7 days resolution of symptoms with End point for comparison between theNIV two modes of noninvasive ventilation Death or intubation within 7 days

O2 and Artificial Ventilation 7 Standard O2 therapy vs. positive pressure ventilation Vital FM, Saconato H, Ladeira MT, et al. Non-blockers their role in AHFinvasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary edema. Cochrane Database Syst Rev 2013 Inclusion of acute or acute on chronic cardiogenic pulmonary edema randomized to NPPV vs. standard medical care alone 32 studies (2916 participants) Variable RR (95% CI) for NPPV arm Hospital mortality 0.66 (0.48-blockers their role in AHF0.89)

Endotracheal intubation 0.52 (0.36-blockers their role in AHF0.75) AMI during NPPV 1.24 (0.79-blockers their role in AHF1.95) AMI after NPPV 0.70 (0.11-blockers their role in AHF4.26) 8 Ashar Salman, Eric B Milbrandt and Michael R Pinsky The role of noninvasive ventilation in acute cardiogenic pulmonary edema Critical Care 2010 Standard O2 therapy (367) prospective RCT CPAP (346) NIPPV (356) Open,

7-blockers their role in AHF26 in UK between 2003 and 2007 day EDs mortality 9.8% 9.5% 1069 patients No difference in 7-blockers their role in AHFday combined death or 11.7% 11.1% mortality intubation Significant and more rapid resolution of Dyspnoea at 1 RRR 0.7 hr symptoms with NIV P value 0.87

0.81 0.008 Acidosis at 1 hr RRR pH 0.03 <0.001 Hypercapnia at 1 hr RRR 5.2 mm Hg <0.001 O2 and Artificial Ventilation Standard O2 therapy vs. positive pressure ventilation 9 Symptom Relief

The URGENT-blockers their role in AHFdyspnoea study investigators: The impact of early standard therapy on dyspnoea in patients with acute heart failure. Eur Heart J 2010 International, multicenter, observational cohort study For assessment of symptom improvement after emergent diuretic therapy 524 patients Faster symptom relief with early institution of diuretics Symptom Relief 10 Early initiation of diuretics effect on dyspnea Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of high-blockers their role in AHFdose isosorbide dinitrate plus low-blockers their role in AHFdose furosemide versus high-blockers their role in AHFdose furosemide plus low-blockers their role in AHFdose isosorbide dinitrate in severe pulmonary oedema. Lancet 1998

110 patients High IDN group Low IDN group P value High dose nitrates + low dose frusemide vs. low dose nitrates + high Mechanical dose frusemide 13% 40% 0.0041 ventilation Initial treatment of O2 10L/min, frusemide 40mg and Significant in need for morphine MI 3mg mechanical 110 patients were 37% randomized to IDN 3mg 17% 0.047 ventilation, MI q5min vs. frusemide q15min IDN 1mg/hr q10min.

and80mg composite end+points Target toDeath stop titiration 1 3 Endpoints 0.61 SO2 > 96% Death 30% drop inend MAP Composite mechanical 25% 46% Need for0.041 points SBP 90 mm Hg ventilation Myocardial infarction Symptom Relief 11 Role of early initiation of nitrates in

dyspnea relief 12 blockers Nohria A, Lewis E, Stevenson LW Medical management of advanced heart failure. JAMA 2002 Metanalysis of trials looking into the use of beta-blockers their role in AHFblockers in ADHF RCTs enrolling atleast 150 patients between 1985 to 2001. Beta-blockers their role in AHFblockers need not be stopped in those with ADHF with preserved BP, warm extremities and do not appear to require inotropes. Due to reduced mortality among patients continuing to receive BBs. blockers 13 Beta-blockers their role in AHFblockers in acute decompensated heart failure

Hershberger RE, Nauman DJ, Byrkit J, et al. Prospective evaluation of an outpatient heart failure disease management program designed for primary care: the Oregon model. J Card Fail 2005 165 patients enrolled in HF clinics 1 yr outcomes before and after enrolling to the clinic Statistically significant improvements in outcomes for those on beta blockers. Those requiring hospitalization, worsening renal status, resistance to IV diuretics 50% reduction in BB doses blockers 14 Beta-blockers their role in AHFblockers in acute decompensated heart failure In the setting of ADHF requiring inotropic support Role of beta-blockers their role in AHFblockers and the strategy of withdrawing/continuing the drug has not been studied. Scope for research

blockers 15 Beta-blockers their role in AHFblockers in acute decompensated heart failure Lowes BD, Tsvetkova T, Eichhorn EJ, et al. Milrinone versus dobutamine in heart failure subjects treated chronically with carvedilol. Int J Cardiol 2001 12 patients analysed with right heart catheterization Parameters assessed Cardiac index Heart rate Mean pulmonary artery pressures Pulmonary capillary wedge pressures Statistically sig improvements in cardiac index, mean PAP and PCWP without much change in HR with milrinone compared to dobutamine.

blockers 16 Beta-blockers their role in AHFblockers in acute decompensated heart failure Choice of inotropes Metra M, Nodari S, DAloia A, et al. Beta-blockers their role in AHFblocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure: a randomized comparison of dobutamine and enoximone before and after chronic treatment with metoprolol or carvedilol. J Am Coll Cardiol 2002 Additionally a rise in 1. Cardiac causes index remained 1. PAP unchanged. 2. PCWP 3.2. SVR But magnitude of drop in 4. PVR mean PAP and PCWP

declined blockers 17 Beta-blockers their role in AHFblockers in acute decompensated heart failure Choice of inotropes Bollano E, Tang MS, Hjalmarson A, et al. Different responses to dobutamine in the presence of carvedilol or metoprolol in patients with chronic heart failure. Heart 2003 differential responses noted as Metra et al. blockers 18 Beta-blockers their role in AHFblockers in acute decompensated heart failure Choice of inotropes ?? No data blockers

19 Beta-blockers their role in AHFblockers in acute decompensated heart failure While on inotropes 20 Special Situations Kanji S, Stewart R, Fergusson DA et al. Treatment of new-blockers their role in AHFonset atrial fibrillation in non-blockers their role in AHFcardiac intensive care unit patients: a systematic review of randomized controlled trials Crit Care Med 2008 The only metanalysis that has looked into the situation although in general and not particularly among those the systolic heart failure Only 4 studies since 1995 Only 1 study looked into hemodynamically unstable patients Hence no clear recommendations for ideal treatment in this scenario Only expert consensus available Special Situations

21 Atrial Fibrillation with fast ventricular rate and acute systolic heart failure 22 Testani JM, Chen J, McCauley BD, et al. Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation 2010 Single center trial 336 patients Baseline-blockers their role in AHFto-blockers their role in AHFdischarge changes in hemoconcentration, RAP and PCWP and their effect on worsening renal failure and 180-blockers their role in AHFday mortality Results Only hemoconcentration was associated with WRF marker of aggressive diuresis Significantly lesser 180-blockers their role in AHFday mortality in hemoconcentration group even after multivariate analysis (hazard ratio, 0.16; P=0.001) Special Situations

Cardiorenal syndrome 23 Metra M, Davison B, Bettari L, et al. Is worsening renal function an ominous prognostic sign in patients with acute heart failure? The role of congestion and its interaction with renal function. Circ Heart Fail 2012 Single center study 599 consecutive patients with AHF 1 yr mortality rates and rehospitalization assessed Results Worsening renal failure not an independent predictor of morbidity or mortality Persistent of signs of congestion at discharge the only predictor of the same Special Situations Cardiorenal syndrome CARESS-blockers their role in AHFHF trial investigators. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012

188 patients Developed CRS while on treatment for AHF but were STILL RESPONSIVE TO DIURETICS Control arm: stepped up diuretics metolazone vasoactive Results therapy Greater in creatinine in ultrafiltration group Greater adverse events in ultrafiltration group Renal failure Bleeding complications IV catheter related complications Equivalent decongestion in both groups No diff in combined death or HF rehospitalization at Special Situations 24 Cardiorenal syndrome the ideal approach to treatment 25 Targets for decongestion 26

Mebazaa A, Parissis J, Porcher R, et al. Short-blockers their role in AHFterm survival by treatment among patients hospitalized with acute heart failure: The global ALARM-blockers their role in AHFHF registry using propensity scoring methods. Intensive Care Med 2011 Resultsfor in-blockers their role in AHFhospital outcomes Global registry post-blockers their role in AHFhoc analysis 1007 propensity matched pairs Lower mortality in diuretics + vasodilator group 7.8 Total of 1805 (diuretics + vasodilators) vs. 2362 (diuretics vs. 11.0% (p=0.016) alone) Higher mortality in those receiving inotropes 25.9 vs.registry 5.2% (p<0.001) Global post-blockers their role in AHFhoc analysis for in-blockers their role in AHFhospital outcomes 1.5 fold in mortality in dopamine/dobutamine 954 propensity matched pairs To assessgroup the effects of dopamine/dobutamine and 2.5 fold in mortality in IV catecholamine group catecholamines on mortality

Targets for decongestion Blood pressure control 27 Invasive hemodynamic monitoring 28 ESCAPE trial investigators: Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness. JAMA 2005 433 patients randomized Results 26 sites No change in primary end point of no of days alive out of hospital, in-blockers their role in AHFhospital or 30-blockers their role in AHF Between 2000 to 2003 day mortality Outcomes Secondary Primary

end point end points trend towards Days alive improvement with group (non-blockers their role in AHF out of hospital atPAC 6 months Secondary significant) end points Exercise Quality of life Symptomatic improvement in both Biochemical parameter improvent groups Echocardiographic changes Invasive hemodynamic

monitoring Pulmonary artery catheterization 29 Pre-discharge planning Fonarow GC, Abraham WT, Albert NM, et al. Association between performance measures and clinical outcomes for patients hospitalized with heart failure. JAMA 2007 Prospective multicenter randomized trial 5791 patients in 91 US hospitals Endpoints 60-blockers their role in AHF and 90-blockers their role in AHFday mortality and combined mortality and hospitalization rates Results Worse the clinical status, worse the outcomes Beta blocker at discharge reduced mortality and hospitalization ACEI/ARB at discharge reduced mortality and hospitalization

Pre-discharge planning 30 Predictors of worse outcomes Functional status Ambrosy AP, Pang PS, Khan S, et al. Clinical course and predictive value of congestion during hospitalization in patients admitted for worsening signs and symptoms of heart failure with reduced ejection fraction: Findings from the EVEREST trial. Eur Heart J 2013 Subanalysis of those with heart failure and persistent congestion at discharge Results Greater rehospitalization rates among those with persistent congestion at discharge Pre-discharge planning 31 Predictors of worse outcomes Persistent congestion

Kociol RD, Horton JR, Fonarow GC, et al. Admission, discharge, or change in BNP and long-blockers their role in AHFterm outcomes: Data from OPTIMIZE-blockers their role in AHFHF linked to medicare claims. Circ Heart Fail 2011 US registry data of 41,267 patients 7039 patients considered from 220 hospitals Age 65 yrs Results Discharge BNP predicts 1-blockers their role in AHFyr mortality and rehospitalization Pre-discharge planning 32 Predictors of worse outcomes BNP levels 33 DIURETICS 34 Ellison DH. Diuretic therapy and resistance in congestive heart failure.

Cardiology 2001 Felker GM. Diuretic management in heart failure. Congest Heart Fail 2010 Steep dose response curve of diuretics Higher dose required for equivalent response in HF patients More frequent dosage DIURETICS Diuretic efficacy 35 Heywood JT, Fonarow GC, Costanzo MR, et al. High prevalence of renal dysfunction and its impact on outcome in 18,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J Card Fail 2007 Prevalence of renal insufficiency >50% in AHF patients on diuretics DIURETICS

Diuretic efficacy 36 De Bruyne LK. Mechanisms and management of diuretic resistance in congestive heart failure. Postgrad Med J 2003 Mechanisms involved in diuretic resistance in AKI Organic anions compete with diuretic binding sites in tubules Higher dose required for effectiveness DIURETICS Diuretic efficacy 37 DOSE trial investigators: Diuretic strategies in patients with acute decompensated heart failure. NEJM 2011 Results Results

308 patients RCT, double blind, 2x2(contd.) factorial, 26 centers (US and High Thereintensification was no statistically in global (2.5 x significant oral dose) difference was associated with Canada) To evaluate the safetygreater and efficacy various initial strategies of symptom relief or change inofrenal

function at 72 hours trends towards improvement in multiple furosemide therapy in patients with ADHF for either: domains: Q12 bolus relief vs. Continuous infusion and dyspnea) Symptom (global assessment Low intensification vs. High intensification Weight Q12 hours bolus loss and net volume loss Proportion Continuous infusion free from signs of congestion Dosing There

Reduction was no evidence of benefit for continuous infusion in NT-blockers their role in AHFproBNP Low intensification (1 x oral dose) compared to Q12 hour bolus High intensification (2.5 x oral dose) Limitations Despite Not transientfor changes in renal function, there was powered long term outcomes Efficacy end points Patient Global Assessment by visual analog scale over 72 hours no evidence

for higher risk of clinical events at 60 days Safety end pointswith the high intensification strategy associated Route of administration: Change in creatinine from baseline to 72 hours DIURETICS Diuretic initializing therapy Jentzer JC, Tracy A, DeWald RD, et al. Combination of Loop Diuretics With Thiazide-blockers their role in AHFType Diuretics in Heart Failure JACC 2010 Metanalysis comparing loop and thiazide diuretics Showed diuretic response in those having diuretic resistance

Robson et al. (18) 1964 Dettli and Spring (17) 1966 Olesen et al. (19) 1970 Olesen et al. (20) 1971a Olesen et al. (21) 1971b Beck and Asscher (22) 1971 Gunstone et al. (23) 1971 Asscher (24) 1974 Sigurd et al. (25) 1975 Epstein et al. (26) 1977 Ram and Reichgott (27) 1977 Sigurd and Olesen (28) 1978 Furrer et al. (29) 1980 Ghose and Gupta (30) 1981 Allen et al. (31) 1981 Bamford (32) 1981 Grosskopf et al. (33) 1986 Gage et al. (34) 1986 Aravot et al. (35) 1989 Friendland and Ledingham (36) 1989 Kiyingi et al. (37) 1990 Channer et al. (38) 1990 Krger et al. (39) 1991 Dormans and Gerlag (40) 1993 Channer et al. (41) 1994

Mouallem et al. (42) 1995 Dormans and Gerlag (43) 1996 Vanky et al. (44) 1997 Rosenberg et al. (45) 2005 DIURETICS 38 Diuretic combination therapy loop + thiazide 39 VASODILATORS 40 Benefit shown as mentioned earlier in the ALARM-blockers their role in AHFHF registry subanalysis VASODILATORS Nitrates 41

VMAC Investigators: Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: A randomized controlled trial. JAMA 2002 Results Randomized, Nesiritide double blind, better thanplacebo placebocontrolled for dyspnea at 3 IV Nesiritide vs. IV NTG vs. Placebo hrs 489 patients between 1999 2000 No diff between Nesiritide and NTG in primary Endpoints 3 hrs and 24 hrs end measured points at 3at hrs

PCWP Patient self-blockers their role in AHFreported dyspnea Greater reduction in PCWP with Nesiritide at 24 hrs but no sig diff in dyspnea or functional status reported by patients although trend to improvement seen VASODILATORS Nesiritide vs. NTG 42 Sackner-blockers their role in AHFBernstein JD, Skopicki HA, Aaronson KD: Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005 Metanalysis of 5 randomized trials 1269 patients Nesiritide vs. placebo Results

Sig risk of worsening renal function No diff in need for dialysis Impact on outcome unknown VASODILATORS Nesiritide and renal function 43 Aaronson KD, Sackner-blockers their role in AHFBernstein J: Risk of death associated with nesiritide in patients with acutely decompensated heart failure. JAMA 2006 Results mortality with nesiritide VASODILATORS Nesiritide and mortality VASODILATORS 44

Co-blockers their role in AHFprimary objectives Nesiritide Reduction in rate of HF the final statement rehospitalization or all-blockers their role in AHF cause mortality through Day 30 ASCEND-blockers their role in AHFHF investigators: Significant Acute Study of Clinical Effectiveness of Nesiritide in improvement in self-blockers their role in AHF Decompensated Heart Failure assessed dyspnea at 6 NEJM 2011 or 24 hrs using 7-blockers their role in AHFpoint scale Likert No reduction in rate Randomized, double blind, placebo controlled endpoints: of recpatients HF Secondary 2007-blockers their role in AHF2010, 398 centers worldwide, 30 countries, 7141 Overall well-blockers their role in AHFbeing at 6

Safety endpoints: or hospitalization and 24 hours All cause mortality death at 30 days Persistent or worsening Renal: 25% decrease in HF and all-blockers their role in AHFcause eGFR atNon-blockers their role in AHF anystime from ig modest mortality from study drug initiation reduction in randomization through throughdyspnea Day 30 at 24 hrs discharge Hypotension: As Number of days alive

reported investigator Noby worsening of 30-blockers their role in AHF and outside of the as symptomatic or day all cause hospital asymptomatic mortality or renal Cardiovascular failure 45 Mullens W, Abrahams Z, Francis GS, et al. Sodium nitroprusside for advanced low-blockers their role in AHFoutput heart failure. J Am Coll Cardiol 2008 Non-blockers their role in AHFrandomized, retrospective, observational study Results Between 2000-blockers their role in AHF2005 175 patients No requirement of Consecutive patients with HF undergoing right heart inotropes

catheterization No worsening renal Improvements seen Inclusion status criteria in despite worse CI 2.0No L/min/m2 PCWP rehospitalization 18 mm Hg and/orrates RAP 8 mm Hg baseline PCWP & CVP in Greater improvement nitroprusside group Exclusion criteria in PCWP Use of inotropes Nesiritide Lower all-blockers their role in AHFcause Use of MAP 60 mortality mm Hg (29 vs. 44%,

p=0.005) VASODILATORS Sodium Nitroprusside 46 INOTROPES AND INODILATORS 47 ALARM-blockers their role in AHFHF registry (2011) in-blockers their role in AHFhospital mortality OPTIME-blockers their role in AHFCHF study (2003) long term mortality (esp in ischemic cardiomyopathy)

Neutral in non-blockers their role in AHFischemic cardiomyopathy Recommendations have been usually based on large registries and various retrospective and observational studies INOTROPES AND INODILATORS General considerations Small sample size and short follow up periods limited their value. INOTROPES AND INODILATORS 48 Dobutamine vs. placebo trials 1982-blockers their role in AHF1999 CASINO investigators: Calcium Sensitizer or Inotrope or None in Low-blockers their role in AHFOutput Heart

Failure Study JACC 2004 Clear in mortality with dobutamine vs. placebo INOTROPES AND INODILATORS 49 Dobutamine vs. placebo largest trial 50 Catherine L. Tacon, John McCaffrey, Anthony Delaney. Dobutamine for patients with severe heart failure: a systematic review and meta-blockers their role in AHFanalysis of randomized controlled trials ESCIM 2012 14 studies, 673 participants Results Non-blockers their role in AHFsig in mortality INOTROPES AND INODILATORS

Dobutamine 51 Friedrich JO, Adhikari N, Herridge MS, Beyene J. Low-blockers their role in AHFdose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med 2005 Metanlysis of 61 trials, 3369 patients Results No demonstrated benefit on Mortality Need for RRT Adverse events Non-blockers their role in AHFsig improvement in Creatinine clearance Urine output But no benefit seen in patients with or at risk of developing AKI INOTROPES AND INODILATORS Dopamine

DAD-blockers their role in AHFHF trial investigators: Impact of dopamine infusion on renal function in hospitalized heart failure patients: Results of the Dopamine in Acute Decompensated Heart Failure. J Card Fail 2010 60 consecutive patients with ADHF High dose furosemide (HDF) vs. low dose furosemide + low dose dopamine (LDFD) Results No change in mean urine output or dyspnea improvement Worse renal function and potassium levels with HDF No stat sig diff in length of hospital stay, 60-blockers their role in AHF INOTROPES AND INODILATORS 52 Dopamine effect on renal function and mortality ROSE trial investigators: Low-blockers their role in AHFdose dopamine or low-blockers their role in AHFdose nesiritide in acute heart failure with renal dysfunction. JAMA 2013

Low-blockers their role in AHFdose dopamine vs. placebo and low-blockers their role in AHFdose Nesiritide vs. placebo Inclusion eGFR 15-blockers their role in AHF60 ml/min/m2 Co-blockers their role in AHFprimary end points Decongestion end point: 72-blockers their role in AHFhr cumulative urine volume Renal function end point: 72-blockers their role in AHFhr Sr. cystatin C Results Neither dopamine nor Nesiritide improved renal function or decongestion when added to diuretic therapy INOTROPES AND INODILATORS 53 Dopamine effect on renal function and decongestion in patients with AKI 54 Theoretical advantage in patients with systolic heart failure

and cardiac transplant patients in whom endogenous catecholamine stores are already depleted. No trials available INOTROPES AND INODILATORS Epinephrine 55 OPTIME-blockers their role in AHFCHF trial investigators: Short-blockers their role in AHFterm intravenous milrinone for acute exacerbation of chronic heart failure. JAMA 2002 Prospective, randomized, double-blockers their role in AHFblind, placebo controlled 1997-blockers their role in AHF1999, 951 patients, NOT REQUIRING INOTROPIC SUPPORT 60-blockers their role in AHFday outcomes No sig diff in days hospitalized risk of hypotension and arrhythmias mortality among those with ischemic causes of heart failure INOTROPES AND INODILATORS

Milrinone vs. placebo 56 REVIVE II trial investigators: Effect of levosimendan on the short-blockers their role in AHFterm clinical course of patients with acutely decompensated heart failure. JACC 2013 600 patients, randomized, double-blockers their role in AHFblind Outcomes at 6hrs, 24hrs and 5 days Results Improvement in patient reported dyspnea, BNP levels and hospital length of stay cardiac adverse effects with Levosimendan Hypotension Arrhythmias Numerically more (non-blockers their role in AHFsig) in mortality with levosimendan INOTROPES AND INODILATORS Levosimendan vs. placebo 57 SURVIVE trial investigators:

Levosimendan vs dobutamine for patients with acute decompensated heart failure JAMA 2007 RCT, 9 countries, 75 centers, 1327 patients who required inotropic support Main outcome: 180 day all-blockers their role in AHFcause mortality INOTROPES AND INODILATORS Levosimendan vs. dobutamine 58 SURVIVE trial investigators: Levosimendan vs dobutamine for patients with acute decompensated heart failure JAMA 2007 Only mean change in BNP was greater in Levosimendan group All other parameters like 180-blockers their role in AHFday composite mortality, cardiovascular mortality, symptom relief and mean days alive out of hospital were no different in the two groups.

INOTROPES AND INODILATORS Levosimendan vs. dobutamine No trials VASOPRESSORS 59 Phenylephrine Norepinephrine 60 AVP ANTAGONISTS 61 Udelson JE, Orlandi C, Ouyang J, et al. Acute hemodynamic effects of tolvaptan, a vasopressin V2 receptor blocker, in patients with symptomatic heart failure and systolic dysfunction. J Am Coll Cardiol 2008 RCT, double-blockers their role in AHFblind, placebo controlled 181 patients

Parameters assessed PCWP RAP PAP Urine output Results Sig but modest improvement in filling pressures Sig in 3 hr urine output No change in renal function AVP ANTAGONISTS Tolvaptan effect on hemodynamics 62 EVEREST clinical status trial investigators: Short-blockers their role in AHFterm clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure

JAMA 2007 Prospective, randomized,Results double-blockers their role in AHFblind placebo controlled Americas and Europe (multicenter) 4133 patients, 2003-blockers their role in AHFend 2006 Primary point better with tolvaptan Primary outcomes (composite) Secondary end points Global clinical status based on VASinand body weight at day 7 Sig improvements or discharge Body weight Secondary outcomes Peripheral edema Dyspnea (day 1) Dyspnea

Global clinical status (day 7 or discharge) Body weight (day 1 and day 7 or discharge) No sig improvement in Peripheral edema (day 7 or discharge) Global clinical status AVP ANTAGONISTS Tolvaptan effect on clinical status EVEREST outcome trial investigators: Effects of oral Tolvaptan in patients hospitalized for worsening heart failure JAMA 2007 RCT, double-blockers their role in AHFblind, placebo controlled 4133 patients Treatment duration min 60 days of Tolvaptan or placebo Mean follow up 9.9 months No diff in Tolvaptan

produced better symptom Primary endpoints primary or improvement compared to placebo, but All-blockers their role in AHFcause mortality secondary with no mortality benefit. Cardiovascular death or hospitalization for heart failure endpoints Secondary endpoints

Dyspnea Body weight Edema AVP ANTAGONISTS 63 Tolvaptan effect on mortality and CV outcomes Goldsmith SR, Elkayam U, Haught WH, et al. Efficacy and safety of the vasopressin V1A/V2-blockers their role in AHFreceptor antagonist conivaptan in acute decompensated heart failure. J Card Fail 2008 RCT, double-blockers their role in AHFblind, multicenter, placebo controlled 170 patients Results No sig diff in clinical improvement No worsening heart failure Sig in urine output but no stat sig in body weight Adverse effects No sig diff in vital signs, electrolyte disturbances or arrhythmias

AVP ANTAGONISTS 64 Conivaptan efficacy and safety Pilot study 65 ULTRAFILTRATION 66 UNLOAD trial investigators. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007 Multicenter, RCT: 28 US centers : 200 patients (100+100) Results Enrollment June 2004safe to July 2005 from

Ultrafiltration in ADHF Greater weight and fluid loss than IV Endpoints assessed diuretics Reduced 90-blockers their role in AHFday rehospitalization Safety end points Primary RFT Weight loss and dyspnea at 48hrs Hence, effective alternative to diuretics Electrolytes BP Secondary Net fluid loss at 48 hrs

Functional capacity, HF rehospitalization and unscheduled visits at 90 days ULTRAFILTRATION Ultrafiltration vs. diuretics in AHF and normal RFT CARESS-blockers their role in AHFHF trial investigators. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012 Results Greater in creatinine in ultrafiltration group 188 patients Greater adverse events in ultrafiltration group Renal failure Developed CRS while on treatment for AHF but were STILL complications RESPONSIVEBleeding TO DIURETICS IV catheter related complications

Equivalent in metolazone both groups vasoactive Control arm: steppeddecongestion up diuretics therapy No diff in combined death or HF rehospitalization at 60 days ULTRAFILTRATION 67 Ultrafiltration vs. diuretics in AHF and deranged RFT 68 HYPERTONIC SALINE 69 Liszkowski M, Nohria A: Rubbing salt into wounds: Hypertonic saline to assist with volume removal in heart failure.

Curr Heart Fail Rep. 2010 Novel counter-blockers their role in AHFintuitive proposition for use of hypertonic saline in patients with AHF and diuretic resistance to improve diuresis, renal function and offset neurohumoral stimulation. HYPERTONIC SALINE The hypothesis generation 70 SMAC-blockers their role in AHFHF study investigators. Short-blockers their role in AHFterm effects of hypertonic saline solution in acute heart failure and long-blockers their role in AHFterm effects of a moderate sodium restriction in patients with compensated heart failure with New York Heart Association class III. Am J Med Sci. 2011 Group 1 showed in diuresis and Na levels Randomized blind trialtime : 1771 patients

Reduction in single hospitalization Ischemic and non-blockers their role in AHFischemic cardiomyopathy patients Lower readmissions during the 60 month follow up EF < 40%, Creatinine < 2.5 mg/dl, Urea nitrogen < 60 mg/dl Lower mortality Group 1 Group 2 30-blockers their role in AHFmin infusion of 30-blockers their role in AHFmin infusion of Group 2 showed

Furosemide 250mg Furosemide 250mg blood urea nitrogen and creatinine levels twice daily + HSS 150 ml twice Sodium restriction to daily Sodium restriction to 80 mmol/day 120 mmol/day HYPERTONIC SALINE The evidence 71 Novel therapies Serelaxin, recombinant human relaxin-blockers their role in AHF2, for treatment of

acute heart failure (RELAX-blockers their role in AHFAHF): A randomised, placebo-blockers their role in AHF controlled trial. Lancet 2013 Results Sig improvement dyspnea bycontrolled VAS but International RCT, double-blockers their role in AHFbin lind, placebo not Likert scale, shorter hospital stay, signs 1161 patients, 58 centres of congestion on CXR, in-blockers their role in AHFhospital 48-blockers their role in AHFhr infusion of Seralaxin vs. placebo worsening of heart failure Inclusion criteria Improved cardiac, renal

andhepatic All had dyspnea, congestion on CXR, BNP/NT pro-blockers their role in AHFBNP, mild of end-blockers their role in AHFSBP organ damage / to mod biomarkers renal insufficiency, > 125 mm Hg dysfunction Serelaxin produced improved symptom control. No improvement in cardiovascular death / rehospitalization days alive of to But mortality data /needs moreout RCTs hospital confirm

Novel therapies 72 Seralaxin vs. placebo [recombinant relaxin] SIRIUS trial investigators. Effects of the renal natriuretic peptide urodilatin (ularitide) in TRUE-blockers their role in AHFchronic AHF trial patients with decompensated heart failure: A double-blockers their role in AHF Currently enrolling: 190 centres in North blind, placebo-blockers their role in AHF controlled, ascending-blockers their role in AHFdose trial. Am HeartAmerica, J 2005 Europe and Latin America Phase III trial Target sample size : 2116 Mitrovic V, Seferovic PM, Simeunovic D, et al.: Efficacy and outcome study Haemodynamic and clinical effects of ularitide in

Primary end points decompensated heart failure. Global symptom relief and BNP/NT pro-blockers their role in AHFBNP Eur Heart J 2006 improvements Secondary end points 90-blockers their role in AHFd Initial ay mortality and phase II studies forcardiovascular dosing, efficacy and rehospitalization safety 90-blockers their role in AHFday Showed adverse hemodynamic events improved profile (PCWP) Novel therapies

73 Urodilatin synthetic pro-blockers their role in AHFANP 74 ASTRONAUT Trial Currently enrolling Novel therapies Aliskiren 75 VERITAS study investigators. Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: The VERITAS randomized controlled trials. JAMA 2007 RCT, double blind, placebo controlled Enrollment from April 2003 to Jan 2005 : 1435 patients North America, Europe, Israel and Australia Endpoints

Dyspnea relief by VAS and AUC at 24 hrs Death or worsening heart failure at day 7 Results No sig improvement in dyspnea or death/worsening heart failure Novel therapies Tezosentan Lapp H, Mitrovic V, Franz N, et al. Cinaciguat (BAY 58-blockers their role in AHF2667) improves cardiopulmonary hemodynamics in patients with acute decompensated heart failure. Circulation. 119:2781 2009 Decreases PCWP But non-blockers their role in AHFfatal hypotension led to Gheorghiade premature M, Greene SJ, Filippatosof

G,trials et al. termination Cinaciguat, a soluble guanylate cyclase activator: Results from the randomized, controlled, phase further IIb COMPOSE programme in Unlikely to be tested for ADHF acute heart failure syndromes. management Eur J Heart Fail. 14:1056 2012 Erdmann E, Semigran MJ, Nieminen MS, et al. Cinaciguat, a soluble guanylate cyclase activator, unloads the heart but also causes hypotension in acute decompensated heart failure. Eur Heart J. 34:57 2013 Novel therapies 76

Cinaciguat [soluble cGMP activators] Cleland JG, Teerlink JR, Senior R, et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: A double-blockers their role in AHF blind, placebo-blockers their role in AHFcontrolled, crossover, dose-blockers their role in AHFranging phase 2 trial. Lancet 2011 Plasma concentration dependent effects Double blind, placebo controlled, dose ranging trial Infusions: vs. 24 vs. 72 hr 2ventricular ejection time with no change Plasma drug concentration measured at the end of each in dp/dt infusion Small in heart rate Safety and tolerability assessed Reduction

in end-blockers their role in AHF systolic and end-blockers their role in AHFdiastolic 45 patients volumes cardiac ischemia ATOMIC-blockers their role in AHFAHF trial underway Novel therapies 77 Omecamtiv Mecarbil [cardiac myosin activators] 78 HORIZON-blockers their role in AHFHF trial investigators. Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic Results agent: A randomized controlled trial in patients hospitalized Sig improvement in PCWP, MAP, with heart failure.

SBP and diastolic echo J Am Coll Cardiol 2008 parameters No change in Neurohormones, RCT, double blind, placebo controlled, dose escalating trial function or Troponin I 0.5 vs. 1.0 vs.renal 1.5 g/kg/ming/kg/min Parameters assessed PCWP Cardiac index RAP SBP and DBP HR Stroke work index LVEF LV end-blockers their role in AHFdiastolic and systolic

vol Diastolic function index Neurohormones Renal function Troponin I Novel therapies Istaroxime PROTECT trial investigators. Rolofylline, an adenosine A1-blockers their role in AHFreceptor antagonist, in acute heart failure. N Engl J Med 2010 Results RCT, double blind, placebo controlled 173 No success centres in NorthinAmerica, Israel and Argentina change dyspnea,Europe, death or heart

Treatment failure readmissions, worsening heartat failure Patient reported improvement in dyspnea 24 and Eligibility and renal function between 2 groups 48 hrs Acute heart failure with dyspnea at rest eGFR 0 20-blockers their role in AHF Sig6failure in seizures and unexplained in Treatment Elevated BNP/NT pro-blockers their role in AHFBNP group stroke in rolofylline

Death or heart failure readmission through day 7 Ongoing IV loop diuretic therapy Worsening heart failure hospital stay Enrollment within 24 hrs of during admission Not recommended for treamtment of heart Worsening renal function failure in this subset of patients. Unchanged status If patients met neither the criteria for success of Novel therapies 79

Rolofylline (renoprotective agent) [adenosine A1 receptor antagonist] 80 Devices in AHF Gray BW1, Haft JW, Hirsch JC, et al. Extracorporeal Life Support: Experience with 2000 Patients. ASAIO J 2014 Sep 23. [Epub ahead of print] University of Michigan experience Most common complication Largest single centre series published till date Bleeding other than intracranial 39% from 1973-blockers their role in AHF2010 2000 consecutive patients requiringECLS Intracranial bleeding/thrombosis

rate = 8% survival 43% Overall weaned = 74% Overall survived to hospital discharge = 64% SURVIVAL TO HOSPITAL DISCHARGE RATES RESP FAILURE CARDIAC FAIL (480) NEONATES CHILDREN ADULTS 84% 76% 50% 45% of total 361 patients

38% of total 119 patients Devices in AHF 81 ECLS (previously ECMO) extracorporeal life support 82 Guenther S, Theiss HD, Fischer M, et al. Percutaneous extracorporeal life support for patients in therapy refractory cardiogenic shock: initial results of an interdisciplinary team. Interact Cardiovasc Thorac Surg 2014 Retrospective analysis of data from University hospital, Munich, Germany 41 patients between Feb 2012 and Aug 2013 Overall 51% mortality 21 due to multi organ failure 6 due to cerebral complications 1 due to heart failure

Devices in AHF ECLS case series Thiele H, Sick P, Boudriot E, et al. Randomized comparison of intra-blockers their role in AHFaortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock. Eur Heart J 2005 Single centre RCT 41 patients (20 in IABP & 21 in VAD) Results Sig greater improvement in Cardiac power index with VAD Sig greater bleeding complications and limb ischemia Numerically mortality rates (underpowered) Devices in AHF 83 IABP vs. Tandem Heart in AMI with cardiogenic shock awaiting PCI ISAR-blockers their role in AHFSHOCK trial investigators.

A randomized clinical trial to evaluate the safety and efficacy of a percutaneous left ventricular assist device versus intra-blockers their role in AHF aortic balloon pumping for treatment of cardiogenic shock caused by myocardial infarction. J Am Coll Cardiol 2008 2 centre prospective RCT 25 patients (13 IABP & 12 Impella) Results Endpoint was greater improvement in CIimplantation with Impella 30-blockers their role in AHFm in Sig improvement in CI after device Slightly more hemolysis with Impella transient Numerically 30-blockers their role in AHFday mortality (underpowered) Devices in AHF 84 IABP vs. Impella in AMI with cardiogenic shock AFTER PCI

Sjauw KD1, Engstrm AE, Vis MM, et al. A systematic review and meta-blockers their role in AHFanalysis of intra-blockers their role in AHFaortic balloon pump therapy in ST-blockers their role in AHFelevation myocardial infarction: should we change the guidelines? Eur Heart J 2009 2 part metanalysis First metanalysis (MET 1) included 9 RCTs (n=1009) Second (MET 2) included 9 cohorts (n=10,529) Results of IABP (MET 1) No improvement in 30-blockers their role in AHFday mortality or LV function Sig higher stroke and bleeding rates Results of IABP (MET 2) Sig (18%) in 30-blockers their role in AHFday mortality among thrombolysis arm Sig (9%) in 30-blockers their role in AHFday mortality among PCI arm Inconclusive needs

Devices in AHF 85 IABP in STEMI with cardiogenic shock Unverzagt S, Machemer MT, Solms A, et al. Intra-blockers their role in AHFaortic balloon pump counterpulsation (IABP) for myocardial infarction complicated by cardiogenic shock. Cochrane Database Syst Rev. 2011 8 RCTs (n=190) Results No survival benefit with IABP mortality compared to non-blockers their role in AHFIABP assist devices Data heterogeneous for adverse events Devices in AHF 86 IABP vs. non-blockers their role in AHFIABP assist device in STEMI with cardiogenic shock

IABP-blockers their role in AHFSHOCK II trial investigators. Results in acute myocardial Intra-blockers their role in AHFaortic balloon counterpulsation No by sig cardiogenic difference shock (IABP-blockers their role in AHFSHOCK II): infarction complicated aMortality final 12 month results of randomised, open-blockers their role in AHFlabel trial. Reinfarction Lancet. 2013 Recurrent revascularization RCT, open-blockers their role in AHFlabel, multicenter in Germany Stroke March 2009 June 2012; 600 patients 30-blockers their role in AHFday mortality, 6-blockers their role in AHFmonth and 12-blockers their role in AHFmonth follow up data Quality of life measures Mobility Self-blockers their role in AHFcare Usual activities Anxiety /

depression etc. Devices in AHF 87 IABP vs. placebo in AMI with cardiogenic shock THANK YOU 88

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