MANAGEMENT OF ACUTE DECOMPENSATED HEART FAILURE

Journal ReviewDr. Benny J. PanakkalSenior ResidentDept. of CardiologyGovt. Medical CollegeKozhikode.

2

POTENTIAL QUESTIONS TO BE ANSWERED

1. General considerations a) Role of Oxygen and artificial ventilationb) Factors affecting symptom reliefc) β-blockers → their role in AHFd) Management of AF in special situations

AF with fast ventricular rate with acute systolic heart failure

Cardiorenal syndromee) Targets of decongestion

BP controlf) Invasive hemodynamic monitoring g) Pre-discharge planning

2. Individual drug classes and their rolea) Diuretics b) Vasodilators c) Inotropes and inodilators d) AVP antagonistse) Ultrafiltrationf) Hypertonic Salineg) Novel therapies

3. Devices in AHF

Th

e Q

uestio

ns

3O2 and Artificial Ventilation

4

Role of Supplemental inhaled Oxygen

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

O2 a

nd

Artifi

cia

l V

en

tilatio

n

Variables showing ↑ mortality were Higher presentation heart rate (as a continuous

variable) Higher creatinine levels Lower systolic blood pressure Lower initial Oxygen Saturation

5

Role of Supplemental inhaled Oxygen

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 Randomized, double blind, placebo-controlled crossover trial 13 men presenting with heart failure FiO2 ≥ 0.40 vs. <0.40 Only hemodynamic effects were measured and not outcomes

Applanation tonometry Imepedence Cardiography Venous occlusion plethysmography ANP BNP

O2 a

nd

Artifi

cia

l V

en

tilatio

n

On O2 On Air P value

Cardiac output (L/min) -0.58 -0.02 0.031

Heart Rate (bpm) -4.02 0.41 0.021

SVR (dyne/s/m5) 875 235 0.050

6

Role of Supplemental inhaled Oxygen

3CPO trial investigators:Noninvasive ventilation in acute cardiogenic pulmonary edemaNEJM 2008

Multicenter, prospective, open label, RCT Standard O2 therapy vs. CPAP vs. NIPPV

End point for comparison between noninvasive ventilation and standard O2 therapy Death within 7 days

End point for comparison between the two modes of noninvasive ventilation Death or intubation within 7 days

O2 a

nd

Artifi

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No mortality benefit with NIV

But more rapid resolution of

symptoms with NIV

7

Standard O2 therapy vs. positive pressure ventilation

Vital FM, Saconato H, Ladeira MT, et al.Non-invasive 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 (0.48-0.89)

Endotracheal intubation 0.52 (0.36-0.75)

AMI during NPPV 1.24 (0.79-1.95)

AMI after NPPV 0.70 (0.11-4.26)

O2 a

nd

Artifi

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en

tilatio

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Standard O2 therapy vs. positive pressure ventilation

Ashar Salman, Eric B Milbrandt and Michael R PinskyThe role of noninvasive ventilation in acute cardiogenic pulmonary edemaCritical Care 2010

Open, prospective RCT 26 EDs in UK between 2003 and 2007 1069 patients

8

O2 a

nd

Artifi

cia

l V

en

tilatio

n

Standard O2

therapy (367)CPAP (346) NIPPV (356) P value

7-day mortality 9.8% 9.5% 0.87

7-day combined death or

intubation11.7% 11.1% 0.81

Dyspnoea at 1 hr RRR 0.7 0.008

Acidosis at 1 hr RRR pH 0.03 <0.001

Hypercapnia at 1 hr RRR 5.2 mm Hg <0.001

No difference in mortality

Significant and more rapid resolution of symptoms with NIV

9 Symptom Relief

10

Early initiation of diuretics – effect on dyspnea

The URGENT-dyspnoea 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

Sym

pto

m R

elie

f

Faster symptom relief with early institution of diuretics

11

Role of early initiation of nitrates in dyspnea relief

Cotter G, Metzkor E, Kaluski E, et al.Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema.Lancet 1998

110 patients High dose nitrates + low dose frusemide vs. low dose nitrates

+ high dose frusemide Initial treatment of O2 10L/min, frusemide 40mg and

morphine 3mg → 110 patients were randomized to IDN 3mg q5min vs. frusemide 80mg q15min + IDN 1mg/hr ↑ q10min.

Target to stop titiration SO2 > 96% 30% drop in MAP SBP ≤ 90 mm Hg

Sym

pto

m R

elie

f

Endpoints Death Need for mechanical

ventilation Myocardial infarction

High IDN group Low IDN group P value

Mechanical ventilation 13% 40% 0.0041

MI 17% 37% 0.047

Death 1 3 0.61

Composite end points 25% 46% 0.041

Significant ↓ in need for mechanical ventilation, MI and composite end points

12 β blockers

13

Beta-blockers in acute decompensated heart failure

Nohria A, Lewis E, Stevenson LWMedical management of advanced heart failure. JAMA 2002

Metanalysis of trials looking into the use of beta-blockers in ADHF

RCTs enrolling atleast 150 patients between 1985 to 2001.

β b

lockers

Beta-blockers 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.

14

Beta-blockers 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.

β b

lockers

Those requiring hospitalization, worsening renal status, resistance to IV diuretics 50% reduction in BB doses

15

Beta-blockers in acute decompensated heart failure

In the setting of ADHF requiring inotropic support

Role of beta-blockers and the strategy of withdrawing/continuing the drug has not been studied.

β b

lockers

Scope for research

16

Beta-blockers in acute decompensated heart failure – Choice of inotropes

Lowes BD, Tsvetkova T, Eichhorn EJ, et al.Milrinone versus dobutamine in heart failure subjects treatedchronically 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

β b

lockers

Statistically sig improvements in cardiac index, mean PAP and PCWP without much change in HR with milrinone compared to dobutamine.

17

Beta-blockers in acute decompensated heart failure – Choice of inotropes

Metra M, Nodari S, D’Aloia A, et al.Beta-blocker 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

1. Cardiac index remained unchanged.

2. But magnitude of drop in mean PAP and PCWP declined

β b

lockers

Additionally causes a rise in 1. PAP2. PCWP3. SVR4. PVR

18

Beta-blockers 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 ormetoprolol in patients with chronic heart failure. Heart 2003

≈ differential responses noted as Metra et al.

β b

lockers

19

Beta-blockers in acute decompensated heart failure – While on inotropes

?? No data

β b

lockers

20 Special Situations

21

Atrial Fibrillation with fast ventricular rate and acute systolic heart failure

Kanji S, Stewart R, Fergusson DA et al. Treatment of new-onset atrial fibrillation in non-cardiac intensive care unit patients: a systematic review of randomized controlled trialsCrit 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

Sp

ecia

l Situ

atio

ns

Hence no clear recommendations for ideal treatment in this scenario

Only expert consensus available

22

Cardiorenal syndrome

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-to-discharge changes in hemoconcentration, RAP

and PCWP and their effect on worsening renal failure and 180-day mortality

Sp

ecia

l Situ

atio

ns

Results Only hemoconcentration was associated with WRF –

marker of aggressive diuresis Significantly lesser 180-day mortality in

hemoconcentration group even after multivariate analysis (hazard ratio, 0.16; P=0.001)

23

Cardiorenal syndrome

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

Sp

ecia

l Situ

atio

ns

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

24

Cardiorenal syndrome – the ideal approach to treatment

CARESS-HF 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

therapy

Sp

ecia

l Situ

atio

ns

Results 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

60 days

25 Targets for decongestion

26

Blood pressure control

Mebazaa A, Parissis J, Porcher R, et al.Short-term survival by treatment among patients hospitalized with acute heart failure: The global ALARM-HF registry using propensity scoring methods. Intensive Care Med 2011

Global registry post-hoc analysis for in-hospital outcomes 1007 propensity matched pairs Total of 1805 (diuretics + vasodilators) vs. 2362 (diuretics

alone)

Global registry post-hoc analysis for in-hospital outcomes 954 propensity matched pairs To assess the effects of dopamine/dobutamine and

catecholamines on mortality

Targ

ets

for d

econ

gestio

nResults

Lower mortality in diuretics + vasodilator group 7.8 vs. 11.0% (p=0.016)

Higher mortality in those receiving inotropes 25.9 vs. 5.2% (p<0.001) 1.5 fold ↑ in mortality in dopamine/dobutamine

group 2.5 fold ↑ in mortality in IV catecholamine group

27

Invasive hemodynamic monitoring

28

Pulmonary artery catheterization

ESCAPE trial investigators:Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness.JAMA 2005

433 patients randomized 26 sites Between 2000 to 2003

Outcomes Primary end point

Days alive out of hospital at 6 months Secondary end points

Exercise Quality of life Biochemical parameter improvent Echocardiographic changes

Invasiv

e h

em

od

yn

am

ic

mon

itorin

g

Results No change in primary end point of no of

days alive out of hospital, in-hospital or 30-day mortality

Secondary end points → trend towards improvement with PAC group (non-significant)

Symptomatic improvement → ≈ in both groups

29 Pre-discharge planning

30

Predictors of worse outcomesFunctional status

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- and 90-day mortality and combined mortality and hospitalization rates

Pre

-dis

ch

arg

e p

lan

nin

g

Results Worse the clinical status, worse the

outcomes Beta blocker at discharge → reduced

mortality and hospitalization ACEI/ARB at discharge → reduced mortality

and hospitalization

31

Predictors of worse outcomesPersistent congestion

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

Pre

-dis

ch

arg

e p

lan

nin

g

Results Greater rehospitalization rates among those with persistent

congestion at discharge

32

Predictors of worse outcomesBNP levels

Kociol RD, Horton JR, Fonarow GC, et al.Admission, discharge, or change in BNP and long-term outcomes: Data from OPTIMIZE-HF linked to medicare claims. Circ Heart Fail 2011

US registry data of 41,267 patients 7039 patients considered from 220 hospitals Age ≥ 65 yrs

Pre

-dis

ch

arg

e p

lan

nin

g

Results Discharge BNP predicts ↑ 1-yr mortality and

rehospitalization

33 DIURETICS

34

Diuretic efficacy

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

DIU

RETIC

S

35

Diuretic efficacy

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

DIU

RETIC

S

36

Diuretic efficacy

De Bruyne LK. Mechanisms and management of diuretic resistance incongestive 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

DIU

RETIC

S

37

Diuretic – initializing therapy

DOSE trial investigators:Diuretic strategies in patients with acute decompensated heart failure.NEJM 2011

308 patients RCT, double blind, 2x2 factorial, 26 centers (US and Canada)

To evaluate the safety and efficacy of various initial strategies of furosemide therapy in patients with ADHF

Route of administration: Q12 hours bolus Continuous infusion

Dosing Low intensification (1 x oral dose) High intensification (2.5 x oral dose)

Efficacy end points Patient Global Assessment by visual analog scale over 72 hours

Safety end points Change in creatinine from baseline to 72 hours

DIU

RETIC

S

Results There was no statistically significant difference in global

symptom relief or change in renal function at 72 hours for either: Q12 bolus vs. Continuous infusion Low intensification vs. High intensification

There was no evidence of benefit for continuous infusion compared to Q12 hour bolus

Despite transient changes in renal function, there was no evidence for higher risk of clinical events at 60 days associated with the high intensification strategy

Results (contd.) High intensification (2.5 x oral dose) was associated with

trends towards greater improvement in multiple domains: Symptom relief (global assessment and dyspnea) Weight loss and net volume loss Proportion free from signs of congestion Reduction in NT-proBNP

Limitations Not powered for long term outcomes

38

Diuretic – combination therapyloop + thiazide

Robson et al. (18) 1964Dettli and Spring (17) 1966Olesen et al. (19) 1970Olesen et al. (20) 1971aOlesen et al. (21) 1971bBeck and Asscher (22) 1971Gunstone et al. (23) 1971Asscher (24) 1974Sigurd et al. (25) 1975Epstein et al. (26) 1977Ram and Reichgott (27) 1977Sigurd and Olesen (28) 1978Furrer et al. (29) 1980Ghose and Gupta (30) 1981Allen et al. (31) 1981Bamford (32) 1981Grosskopf et al. (33) 1986Gage et al. (34) 1986Aravot et al. (35) 1989Friendland and Ledingham (36) 1989Kiyingi et al. (37) 1990Channer et al. (38) 1990Kröger et al. (39) 1991Dormans and Gerlag (40) 1993Channer et al. (41) 1994Mouallem et al. (42) 1995Dormans and Gerlag (43) 1996Vanky et al. (44) 1997Rosenberg et al. (45) 2005

DIU

RETIC

S

Jentzer JC, Tracy A, DeWald RD, et al.Combination of Loop Diuretics With Thiazide-Type Diuretics in Heart FailureJACC 2010

Metanalysis comparing loop and thiazide diuretics

Showed ↑ diuretic response in those having diuretic resistance

39 VASODILATORS

40

Nitrates

Benefit shown as mentioned earlier in the ALARM-HF registry subanalysis

VA

SO

DIL

ATO

RS

41

Nesiritide vs. NTG

VMAC Investigators: Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: A randomized controlled trial. JAMA 2002

Randomized, double blind, placebo controlled IV Nesiritide vs. IV NTG vs. Placebo 489 patients between 1999 – 2000

Endpoints measured at 3 hrs and 24 hrs PCWP Patient self-reported dyspnea

VA

SO

DIL

ATO

RS

Results Nesiritide better than placebo for dyspnea at 3

hrs

No diff between Nesiritide and NTG in primary end points at 3 hrs

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

42

Nesiritide and renal function

Sackner-Bernstein 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

VA

SO

DIL

ATO

RS

43

Nesiritide and mortality

Aaronson KD, Sackner-Bernstein J: Risk of death associated with nesiritide in patients with acutely decompensated heart failure. JAMA 2006

VA

SO

DIL

ATO

RS

Results

↑ mortality with nesiritide

44

Nesiritide the final statement

ASCEND-HF investigators:Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart FailureNEJM 2011

Randomized, double blind, placebo controlled 2007-2010, 398 centers worldwide, 30 countries, 7141 patients

VA

SO

DIL

ATO

RS

Co-primary objectives Reduction in rate of HF

rehospitalization or all-cause mortality through Day 30

Significant improvement in self-assessed dyspnea at 6 or 24 hrs using 7-point Likert scale

Secondary endpoints: Overall well-being at 6

and 24 hours Persistent or worsening

HF and all-cause mortality from randomization through discharge

Number of days alive and outside of the hospital

Cardiovascular rehospitalization and cardiovascular mortality

Safety endpoints: All cause mortality Renal: 25% decrease in

eGFR at any time from study drug initiation through Day 30

Hypotension: As reported by investigator as symptomatic or asymptomatic

No reduction in rate of rec HF hospitalization or death at 30 days

Non-sig modest reduction in dyspnea at 24 hrs

No worsening of 30-day all cause mortality or renal failure

45

Sodium Nitroprusside

Mullens W, Abrahams Z, Francis GS, et al.Sodium nitroprusside for advanced low-output heart failure. J Am Coll Cardiol 2008

Non-randomized, retrospective, observational study Between 2000-2005 → 175 patients Consecutive patients with HF undergoing right heart

catheterization

Inclusion criteria CI ≤ 2.0 L/min/m2

PCWP ≥ 18 mm Hg and/or RAP ≥ 8 mm Hg

Exclusion criteria Use of inotropes Use of Nesiritide MAP ≤ 60 mm Hg

VA

SO

DIL

ATO

RS

Results No ↑ requirement of

inotropes No worsening renal

status No ↑ in

rehospitalization rates

Greater improvement in PCWP

Lower all-cause mortality (29 vs. 44%, p=0.005)

Improvements seen despite worse baseline PCWP & CVP in nitroprusside group

46

INOTROPES AND INODILATORS

47

General considerations

ALARM-HF registry (2011) ↑ in-hospital mortality

OPTIME-CHF study (2003) ↑ long term mortality (esp

in ischemic cardiomyopathy)

Neutral in non-ischemic cardiomyopathy

INO

TR

OP

ES

AN

D IN

OD

ILATO

RS

Recommendations have been usually based on large registries and various retrospective and observational studies

48

Dobutamine vs. placebo trials 1982-1999

INO

TR

OP

ES

AN

D IN

OD

ILATO

RS

Small sample size and short follow up periods limited their value.

49

Dobutamine vs. placebo – largest trial

CASINO investigators:Calcium Sensitizer or Inotrope or None in Low-Output Heart Failure StudyJACC 2004

INO

TR

OP

ES

AN

D IN

OD

ILATO

RS

Clear ↑ in mortality with dobutamine vs. placebo

50

Dobutamine

Catherine L. Tacon, John McCaffrey, Anthony Delaney.Dobutamine for patients with severe heart failure: a systematic review and meta-analysis of randomized controlled trialsESCIM 2012

14 studies, 673 participants

INO

TR

OP

ES

AN

D IN

OD

ILATO

RS

Results Non-sig ↑ in

mortality

51

Dopamine

Friedrich JO, Adhikari N, Herridge MS, Beyene J.Low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med 2005

Metanlysis of 61 trials, 3369 patients

INO

TR

OP

ES

AN

D IN

OD

ILATO

RS

But no benefit seen in patients with or at risk of developing AKI

Results

No demonstrated benefit on Mortality Need for RRT Adverse events

Non-sig improvement in Creatinine clearance Urine output

52

Dopamine – effect on renal function and mortality

DAD-HF 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)

INO

TR

OP

ES

AN

D IN

OD

ILATO

RS

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-day mortality or rehospitalization rates

53

Dopamine – effect on renal function and decongestion in patients with AKI

ROSE trial investigators:Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction. JAMA 2013

Low-dose dopamine vs. placebo and low-dose Nesiritide vs. placebo

Inclusion → eGFR 15-60 ml/min/m2

Co-primary end points Decongestion end point: 72-hr cumulative urine volume Renal function end point: 72-hr ∆ Sr. cystatin C

INO

TR

OP

ES

AN

D IN

OD

ILATO

RS

Results Neither dopamine nor Nesiritide improved

renal function or decongestion when added to diuretic therapy

54

Epinephrine

Theoretical advantage in patients with systolic heart failure and cardiac transplant patients in whom endogenous catecholamine stores are already depleted.

No trials available

INO

TR

OP

ES

AN

D IN

OD

ILATO

RS

55

Milrinone vs. placebo

OPTIME-CHF trial investigators:Short-term intravenous milrinone for acute exacerbation of chronic heart failure.JAMA 2002

Prospective, randomized, double-blind, placebo controlled 1997-1999, 951 patients, NOT REQUIRING INOTROPIC

SUPPORT

INO

TR

OP

ES

AN

D IN

OD

ILATO

RS

60-day outcomes No sig diff in days hospitalized ↑ risk of hypotension and

arrhythmias ↑ mortality among those with

ischemic causes of heart failure

56

Levosimendan vs. placebo

REVIVE II trial investigators:Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC 2013

600 patients, randomized, double-blind Outcomes at 6hrs, 24hrs and 5 days

INO

TR

OP

ES

AN

D IN

OD

ILATO

RSResults

Improvement in patient reported dyspnea, BNP levels and hospital length of stay

↑ cardiac adverse effects with Levosimendan Hypotension Arrhythmias

Numerically more (non-sig) ↑ in mortality with levosimendan

57

Levosimendan vs. dobutamine

SURVIVE trial investigators:Levosimendan vs dobutamine for patients with acute decompensated heart failureJAMA 2007

RCT, 9 countries, 75 centers, 1327 patients who required inotropic support

Main outcome: 180 day all-cause mortality

INO

TR

OP

ES

AN

D IN

OD

ILATO

RS

58

Levosimendan vs. dobutamine

SURVIVE trial investigators:Levosimendan vs dobutamine for patients with acute decompensated heart failureJAMA 2007

INO

TR

OP

ES

AN

D IN

OD

ILATO

RS

Only mean change in BNP was greater in Levosimendan group

All other parameters like 180-day composite mortality, cardiovascular mortality, symptom relief and mean days alive out of hospital were no different in the two groups.

59

Phenylephrine Norepinephrine

No trials

VA

SO

PR

ESS

OR

S

60 AVP ANTAGONISTS

61

Tolvaptan – effect on hemodynamics

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-blind, placebo controlled 181 patients

Parameters assessed PCWP RAP PAP Urine output

AV

P A

NTA

GO

NIS

TS

Results Sig but modest improvement in

filling pressures Sig ↑ in 3 hr urine output No change in renal function

62

Tolvaptan – effect on clinical status

EVEREST clinical status trial investigators:Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failureJAMA 2007

Prospective, randomized, double-blind placebo controlled Americas and Europe (multicenter) 4133 patients, 2003-2006

Primary outcomes (composite) Global clinical status based on VAS and body weight at day 7

or discharge Secondary outcomes

Dyspnea (day 1) Global clinical status (day 7 or discharge) Body weight (day 1 and day 7 or discharge) Peripheral edema (day 7 or discharge)

AV

P A

NTA

GO

NIS

TS

Results

Primary end point → better with tolvaptan

Secondary end points Sig improvements in

Body weight Peripheral edema Dyspnea

No sig improvement in Global clinical status

63

Tolvaptan – effect on mortality and CV outcomes

EVEREST outcome trial investigators:Effects of oral Tolvaptan in patients hospitalized for worsening heart failureJAMA 2007

RCT, double-blind, placebo controlled 4133 patients Treatment duration → min 60 days of Tolvaptan or placebo Mean follow up → 9.9 months

Primary endpoints All-cause mortality Cardiovascular death or hospitalization for heart failure

Secondary endpoints Dyspnea Body weight Edema

AV

P A

NTA

GO

NIS

TS

No diff in primary or secondary endpoints

∴ Tolvaptan produced better symptom improvement compared to placebo, but with no mortality benefit.

64

Conivaptan – efficacy and safetyPilot study

Goldsmith SR, Elkayam U, Haught WH, et al.Efficacy and safety of the vasopressin V1A/V2-receptor antagonist conivaptan in acute decompensated heart failure.J Card Fail 2008

RCT, double-blind, multicenter, placebo controlled 170 patients

AV

P A

NTA

GO

NIS

TS

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

65 ULTRAFILTRATION

66

Ultrafiltration vs. diuretics in AHF and normal RFT

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) Enrollment from June 2004 to July 2005

Endpoints assessed

Primary Weight loss and dyspnea at 48hrs

Secondary Net fluid loss at 48 hrs Functional capacity, HF rehospitalization and unscheduled visits

at 90 days

ULT

RA

FILT

RATIO

N

Safety end points RFT Electrolytes BP

Results Ultrafiltration safe in ADHF Greater weight and fluid loss than IV

diuretics Reduced 90-day rehospitalization

Hence, effective alternative to diuretics

67

Ultrafiltration vs. diuretics in AHF and deranged RFT

CARESS-HF 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 therapy

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Results 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 60 days

68 HYPERTONIC SALINE

69

The hypothesis generation

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-intuitive proposition for use of hypertonic saline in patients with AHF and diuretic resistance to improve diuresis, renal function and offset neurohumoral stimulation.

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The evidence

SMAC-HF study investigators.Short-term effects of hypertonic saline solution in acute heart failure and long-term effects of a moderate sodium restriction in patients with compensated heart failure with New York Heart Association class III.Am J Med Sci. 2011

Randomized single blind trial : 1771 patients Ischemic and non-ischemic cardiomyopathy patients EF < 40%, Creatinine < 2.5 mg/dl, Urea nitrogen < 60 mg/dl

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Group 1 30-min infusion of

Furosemide 250mg + HSS 150 ml twice daily

Sodium restriction to 120 mmol/day

Group 2 30-min infusion of

Furosemide 250mg twice daily

Sodium restriction to 80 mmol/day

Group 1 showed ↑ in diuresis and Na levels Reduction in hospitalization time Lower readmissions during the 60 month follow up Lower mortality

Group 2 showed ↑ blood urea nitrogen and creatinine levels

71 Novel therapies

72

Seralaxin vs. placebo[recombinant relaxin]

Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): A randomised, placebo-controlled trial. Lancet 2013

International RCT, double-blind, placebo controlled 1161 patients, 58 centres 48-hr infusion of Seralaxin vs. placebo

Inclusion criteria All had dyspnea, congestion on CXR, ↑ BNP/NT pro-BNP, mild

to mod renal insufficiency, SBP > 125 mm Hg

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Results Sig improvement in dyspnea by VAS but

not Likert scale, shorter hospital stay, signs of congestion on CXR, ↓ in-hospital worsening of heart failure

Improved cardiac, renal and hepatic biomarkers of end-organ damage / dysfunction

No improvement in cardiovascular death / rehospitalization / days alive out of hospital

Sig mortality benefit at day 180

∴ Serelaxin produced improved symptom control. But mortality data needs more RCTs to confirm

73

Urodilatinsynthetic pro-ANP

SIRIUS trial investigators.Effects of the renal natriuretic peptide urodilatin (ularitide) in patients with decompensated chronic heart failure: A double-blind, placebo-controlled, ascending-dose trial. Am Heart J 2005

Mitrovic V, Seferovic PM, Simeunovic D, et al.: Haemodynamic and clinical effects of ularitide in decompensated heart failure. Eur Heart J 2006

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Initial phase II studies for dosing, efficacy and safety

Showed improved hemodynamic profile (PCWP)

TRUE-AHF trial Currently enrolling: 190 centres in North

America, Europe and Latin America Phase III trial Target sample size : 2116 Efficacy and outcome study Primary end points

Global symptom relief and BNP/NT pro-BNP improvements

Secondary end points 90-day mortality and cardiovascular

rehospitalization 90-day adverse events

74

Aliskiren

ASTRONAUT TrialCurrently enrolling

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Tezosentan

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

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Results No sig improvement in dyspnea or

death/worsening heart failure

76

Cinaciguat[soluble cGMP activators]

Lapp H, Mitrovic V, Franz N, et al.Cinaciguat (BAY 58-2667) improves cardiopulmonary hemodynamics in patients with acute decompensated heart failure. Circulation. 119:2781 2009

Gheorghiade M, Greene SJ, Filippatos G, et al.Cinaciguat, a soluble guanylate cyclase activator: Results from the randomized, controlled, phase IIb COMPOSE programme in acute heart failure syndromes. 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

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Decreases PCWP But ↑ non-fatal hypotension led to

premature termination of trials

Unlikely to be tested further for ADHF management

77

Omecamtiv Mecarbil[cardiac myosin 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-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 2011

Double blind, placebo controlled, dose ranging trial Infusions: 2 vs. 24 vs. 72 hr Plasma drug concentration measured at the end of each

infusion Safety and tolerability assessed 45 patients

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Plasma concentration dependent effects

↑ ventricular ejection time with no change in dp/dt

Small ↓ in heart rate Reduction in end-systolic and end-diastolic

volumes ↑ cardiac ischemia

ATOMIC-AHF trial underway

78

Istaroxime

HORIZON-HF trial investigators.Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: A randomized controlled trial in patients hospitalized with heart failure. J Am Coll Cardiol 2008

RCT, double blind, placebo controlled, dose escalating trial 0.5 vs. 1.0 vs. 1.5 μg/kg/min

Parameters assessed

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PCWP Cardiac index RAP SBP and DBP HR Stroke work index

LVEF LV end-diastolic and systolic

vol Diastolic function index Neurohormones Renal function Troponin I

Results Sig improvement in PCWP, MAP,

SBP and diastolic echo parameters

No change in Neurohormones, renal function or Troponin I

79

Rolofylline (renoprotective agent)[adenosine A1 receptor antagonist]

PROTECT trial investigators.Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010

RCT, double blind, placebo controlled 173 centres in North America, Europe, Israel and Argentina

Eligibility Acute heart failure with dyspnea at rest eGFR 20-60 Elevated BNP/NT pro-BNP Ongoing IV loop diuretic therapy Enrollment within 24 hrs of admission

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Treatment success Patient reported improvement in dyspnea at 24 and

48 hrs

Treatment failure Death or heart failure readmission through day 7 Worsening heart failure during hospital stay Worsening renal function

Unchanged status If patients met neither the criteria for success of

failure

Results

No change in dyspnea, death or heart failure readmissions, worsening heart failure and renal function between 2 groups

Sig ↑ in seizures and unexplained ↑ in stroke in rolofylline group

Not recommended for treamtment of heart failure in this subset of patients.

80 Devices in AHF

81

ECLS (previously ECMO)extracorporeal life support

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 Largest single centre series published till date 2000 consecutive patients requiring ECLS from 1973-2010

Overall weaned = 74% Overall survived to hospital discharge = 64%

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SURVIVAL TO HOSPITAL DISCHARGE RATES

NEONATES CHILDREN ADULTS

RESP FAILURE 84% 76% 50%

CARDIAC FAIL (480)

45% of total 361 patients

38% of total 119 patients

Most common complication Bleeding other than intracranial → 39%

Intracranial bleeding/thrombosis rate = 8% → survival 43%

82

ECLS case series

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

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Overall 51% mortality 21 due to multi organ failure 6 due to cerebral

complications 1 due to heart failure

83

IABP vs. Tandem Heart in AMI with cardiogenic shock awaiting PCI

Thiele H, Sick P, Boudriot E, et al.Randomized comparison of intra-aortic 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)

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Results Sig greater improvement in Cardiac power index with

VAD Sig greater bleeding complications and limb ischemia

Numerically ≈ mortality rates (underpowered)

84

IABP vs. Impella in AMI with cardiogenic shock AFTER PCI

ISAR-SHOCK trial investigators.A randomized clinical trial to evaluate the safety and efficacy of a percutaneous left ventricular assist device versus intra-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)

Endpoint was 30-min improvement in CI after device implantation

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Results Sig greater improvement in CI with Impella Slightly more hemolysis with Impella →

transient

Numerically ≈ 30-day mortality (underpowered)

85

IABP in STEMI with cardiogenic shock

Sjauw KD1, Engström AE, Vis MM, et al.A systematic review and meta-analysis of intra-aortic balloon pump therapy in ST-elevation 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)

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Results of IABP (MET 1) No improvement in 30-day

mortality or LV function Sig higher stroke and

bleeding rates

Results of IABP (MET 2) Sig (18%) ↓ in 30-day

mortality among thrombolysis arm

Sig (9%) ↑ in 30-day mortality among PCI arm

Inconclusive → needs confirmation with RCTs

86

IABP vs. non-IABP assist device in STEMI with cardiogenic shock

Unverzagt S, Machemer MT, Solms A, et al.Intra-aortic balloon pump counterpulsation (IABP) for myocardial infarction complicated by cardiogenic shock.Cochrane Database Syst Rev. 2011

8 RCTs (n=190)

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Results No survival benefit with IABP ≈ mortality compared to non-IABP assist devices Data heterogeneous for adverse events

87

IABP vs. placebo in AMI with cardiogenic shock

IABP-SHOCK II trial investigators.Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial.Lancet. 2013

RCT, open-label, multicenter in Germany March 2009 – June 2012; 600 patients 30-day mortality, 6-month and 12-month follow up data

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es in

AH

FResults No sig difference

Mortality Reinfarction Recurrent

revascularization Stroke

Quality of life measures Mobility Self-care Usual activities Anxiety /

depression etc.

88

THANK YOU