management of acute decompensated heart failure journal review dr. benny j. panakkal senior resident...
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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
cia
l V
en
tilatio
n
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
cia
l V
en
tilatio
n
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
ULT
RA
FILT
RATIO
N
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.
HY
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70
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
HY
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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
Novel th
era
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s
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
Novel th
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s
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
Novel th
era
pie
s
75
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
Novel th
era
pie
s
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
Novel th
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pie
s
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
Novel th
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s
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
Novel th
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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
Novel th
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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%
Devic
es in
AH
F
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
Devic
es in
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F
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)
Devic
es in
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F
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
Devic
es in
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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)
Devic
es in
AH
F
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)
Devic
es in
AH
F
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
Devic
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
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