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Recent updates in acute heart
failure management
Piotr Ponikowski, MD, PhD, FESC
Medical University, Centre for Heart Disease
Clinical Military Hospital
Wroclaw, Poland
Management of Acute Heart Failure Syndromes
1. Challenges in everyday clinical practice
guidelines & reality
2. Results (disappointing) of the recent trials
3. Outlook for the future
different approach needed ?
1
Acute Heart Failure:
landscape at the beginning of the 21st century
Cardiologist’s summary:
EURObservational Research Program:
The Heart Failure Pilot Survey
„broadly speaking, the pharmacological
All-cause death or HF hospitalization
armamentarium for AHFS – loop diuretics,
1892 pts with acute HF& 3226 pts with chronic HF
vasodilators and inotropes – is largely
Acute HF: 35.1%
1-year all cause mortality:
unchanged from 1970s…”
acute HF – 16.8%
Felker GM et al., Circ Heart Fail 2010;3:314-25
chronic HF – 6.8%
Chronic HF: 17.2%
Cardiologist’s question:
Why all successful phase II studies are
followed by failures in phase III trials ?
Do we need shift in a „AHF paradigm” ?
Days from enrolment
A. Maggioni ESC 2011
Acute Heart Failure Syndromes:
Clinical challenges
Incidence
Mortality:
pre-hospital
in-hospital
60-90 days
Targets of therapy
Clinical trials results
Guidelines (level of evidence)
AHFS
ACS
~ 1.000.000/y
~ 1.000.000/y
?
3 – 6%
10%
high
3 – 4%
2%
Unclear
Clearly defined
Minimal / no benefit /
harmful
Beneficial
A/B – minimal
mostly C
A/B – mostly
Modified from Weintraub NL et al., Circulation 2010
2
Hospitalization for HF: why so important ?
Cardiac
Function &
CHF severity
Risk of death increases
substantially with each
subsequent HF hospitalization
Hypothesis: With each
hospitalization, there is
myocardial and/or renal
damage leading to further
progression of the disease
Setoguchi S et al. Am Heart J 2007
Hospitalization
Hospitalization
Hospitalization
Gheorghiade M et al.
Am J Cardiol. 2005; 96 (6A)
Time
HF hospitalization: a. independent predictor of poor outcome; b. major
contributor to impaired QoL; c. responsible for majority of HF-related costs
Hospitalization for HF: why so important ?
Divergent trends in survival and readmission for HF
Analysis in 50 125 patients with HF hospitalization from 2002 to 2006 in the VA Health Care System
1.2
Increase
30-day HF rehospitalization
1.4
1.0
0.8
0.6
Decrease
Adjusted odds ratio for outcomes
1.6
0.4
30-day mortality
0.2
0.0
2002
2003
2004
2005
2006
Heidenreich PA et al. J Am Coll Cardiol. 2010;56(5):362-8.
3
Management of acute heart failure:
why so difficult ?
Clinical Factors:
 Underlying causes: multifactorial, precipitating factor often not
identified
 Clinical presentation: spectrum of various conditions,
heterogeneous pathophysiology, different risk of subsequent
complications
 Cardiovascular and non-cardiovascular comorbidities
Pathophysiological targets: uncertain
End-points selection: not standardized
ADHERE: precipitating factors
for hospitalisations
Fonarow, G. C. et al. Arch Intern Med 2008;168:847-854.
4
Acute Heart Failure: clinical classification
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008
Demographics and concomitant diseases
of hospitalized patients with HF in registries
ADHERE
(n=107,920)
EURO HF
(n=11,327)
OPTIMIZE-HF
(n=34,059)
Mean age (y)
75
71
73
Women (%)
52
47
52
Prior HF (%)
75
65
87
LVEF <40%
51
46
52
Coronary artery disease (%)
57
68
50
Hypertension (%)
72
53
71
Diabetes (%)
44
27
42
Atrial fibrillation (%)
31
43
31
Renal insufficiency (%)
30
18
NA
Fonarow GC. Am Heart J 2008;155:200−207
Other non-CV comorbidities: anaemia (20-40%), iron deficiency (30-50%), COPD (20-50%)
5
Management of Acute Heart Failure Syndromes
1. Challenges in everyday clinical practice
guidelines & reality
2. Results (disappointing) of the recent trials
3. Outlook for the future
different approach needed ?
Heart Failure ESC guidelines: two decades of history
Committee for Practice Guidelines
Document Reviewers
26 authors
6
Goals of treatment in each phase of AHF management
Immediate:
• Treat life-threatening conditions
• Confirm AHF diagnosis
• Restore oxygenation
• Improve organ perfusion &
haemodynamics
• Treat symptoms
• Limit cardiac/renal damage
• Prevent thrombo-embolism
• Minimize ICU length of stay
Intermediate:
• Stabilise patient and optimise
treatment strategy
• Initiate and up-titrate diseasemodifying pharmacological
therapy
• Consider device therapy in
appropriate patients
• Identify aetiology and relevant
co-morbidities
Initial (ED/ICU/CCU)
In-hospital
Pre-discharge and long-term
management:
• Plan follow-up strategy
• Plan to up-titrate/optimize
disease-modifying drugs
• Assess for appropriate device
therapy
• Prevent early readmission
• Enrol in disease management
programme, educate, initiate
lifestyle adjustments
• Improve symptoms, QoL and
survival
Consecutive phases
of AHF management
Discharge
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
Pang PS et al. Eur Heart J 2010;31:784-93
Initial phase in ED/ICU/CCU
Profiling and strategizing care
Clinical profile is fundamental
for decision-making in AHF
Strategy: identify and treat
life-threatening conditions
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
7
Initial phase in ED/ICU/CCU: profiling and strategizing care
CLINICAL PROFILES
Low perfusion
at rest ?
NO
(eg. narrow PP,
cool extremities,
hypotension)
YES
NO
YES
Congestion at rest ?
(eg. orthopnea, elevated JVP, pulmonary rales, S3, oedema)
ESC Guidelines for the Diagnosis and Treatmentof Acute and Chronic Heart Failure 2008
ACCF/AHA Guidleline for the Management of Heart Failure 2013
8
Initial phase in ED/ICU/CCU: profiling and strategizing care
Hemodynamic profiles: therapeutic implications
• diuretics
• ultrafiltration
„dry-out”
Warm & Wet
Warm & Dry
Vasodilators
• nitroglycerin
• nesiritide
B
A
Cold & Dry
Cold & Wet
L
C
• nitroprusside
Adapted from Stevenson LW, Eur J Heart Failure 2005;7:323
Fluid retention or redistribution ?
Interventions to Relieve Congestion
 Sodium & fluid restriction
Diuretics*
 Vasodilators
 Ultrafiltration / dialysis
•
BNP (nesiritide)
•
Vasopressin antagonists
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
9
Low-dose dopamine or low-dose nesiritide for
AHF patients with renal dysfunction: ROSE trial
Conclusion: in AHF patients with renal dysfunction neither low-dose dopamine nor
low-dose nesiritide enhanced decongestion or improved renal function when added
to diuretic therapy.
Chen HH et al. JAMA 2013
Fluid redistribution
Fluid accumulation
Gheorghiade M et al.; Am J Cardiol 2005;96[suppl]:11G–17G
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
10
Initial phase in ED/ICU/CCU: profiling and strategizing care
Hemodynamic profiles: therapeutic implications
Patients with hypotension, hypoperfusion or shock
„warm-up” & „dry-out”
Warm & Dry
Warm & Wet
A
B
Cold & Dry
Cold & Wet
L
C
Inotropes
• dobutamine
• dopamine
• levosimendan
• nitroprusside
Adapted from Stevenson LW, Eur J Heart Failure 2005;7:323
Limitations of Inotropic Agents
 Tachyarrhythmias


↑ ventricular arrhythmias
↑ ventricular rate in atrial fibrillation
 Myocardial ischemia →
progression of LV dysfunction?


Hypotension / coronary hypoperfusion
↑ myocardial VO2 (contractility & HR)
 Mechanisms

↑ cytoplasmic Ca2+
Myocardial efficiency (work/VO2)?

Vasodilation /hypotension

Courtesy M.Metra
11
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
Algorithm for management of acute pulmonary oedema/congestion
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
12
Goals of treatment in each phase of AHF management
Immediate:
• Treat life-threatening conditions
• Confirm AHF diagnosis
• Restore oxygenation
• Improve organ perfusion &
haemodynamics
• Treat symptoms
• Limit cardiac/renal damage
• Prevent thrombo-embolism
• Minimize ICU length of stay
Initial (ED/ICU/CCU)
Intermediate:
• Stabilise patient and optimise
treatment strategy
• Initiate and up-titrate diseasemodifying pharmacological
therapy
• Consider device therapy in
appropriate patients
• Identify aetiology and relevant
co-morbidities
In-hospital
Pre-discharge and long-term
management:
• Plan follow-up strategy
• Plan to up-titrate/optimize
disease-modifying drugs
• Assess for appropriate device
therapy
• Prevent early readmission
• Enrol in disease management
programme, educate, initiate
lifestyle adjustments
• Improve symptoms, QoL and
survival
Consecutive phases
of AHF management
Discharge
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
Pang PS et al. Eur Heart J 2010;31:784-93
AHF: management after stabilization
ACE inhibitor/angiotensin receptor blocker
In patients with reduced EF not already receiving an ACE inhibitor(or ARB), this treatment should
be started as soon as possible, blood pressure and renal function permitting*.
Beta-blocker
In patients with reduced EF not already receiving a beta-blocker, this treatment should be started
as soon as possible after stabilization, blood pressure and heart rate permitting*. Beta-blocker
treatment may be continued in many patients during an episode of decompensation
Mineralocorticoid receptor antagonist
In patients with reduced EF not already receiving an MRA, this treatment should be started as
soon as possible, renal function and potassium permitting*. As the dose of MRA used to treat HF
has a minimal effect on blood pressure, even relatively hypotensive patients may be started on
this therapy during admission.
* - The dose of ACEi/ARB, beta-blockers, MRA should be up-titrated as far as possible before discharge, and a plan made to complete dose uptitration after discharge.
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
13
Regional differences in the management of AHF
ALARM-HF: Data from 4953 pts with AHF treated in 9 countries; Oct 2006 – Mar 2007
Treatment strategies among participating countries
Follath F, et al. Intensive Care Med (2011) 37:619–626
Management of Acute Heart Failure Syndromes
1. Everyday clinical practice
guidelines & reality
2. Results (disappointing) of the recent trials
3. Outlook for the future
different approach needed ?
14
RECENT AHFS TRIALS
Study
Patients
Primary End Point
Natriuretic Peptide (Nesiritide)
VMAC
489
PCWP 3 h and Dyspnoea 3 h
PRECEDENT
255
Arrhythmias
ASCEND HF
7147
Change in dyspnoea at 6 and 24h
HF hospitalization and death at 30 days
Vasopressin Antagonists (Tolvaptan)
ACTIV HF
319
Body wt 24 h and Worse HF 60 d
EVEREST
3433
Short term: Body wt + GCA at 7 days
Long term: Mortality and Re-hospitalization
SERCA agonist & Na/K ATPase inhibitor (Istaroxime)
HORIZON-HF
120
PCWP Changes from baseline
Selective adenosine A1-receptor antagonist (Rolofylline)
PROTECT
2033
Changes in dyspnoea
Death or readmission through day 7
Courtesy of M. Metra
RECENT AHFS TRIALS
Study
Patients
Primary End Point
Endothelin Antagonist (Tezosentan)
RITZ-1
675
Dyspnea 6 h
RITZ-2
292
Change in CI 6 h
VERITAS
1800
Dyspnea 24 h and Worsen HF 7 d
Calcium Sensitizer (Levosimendan)
LIDO
203
Change CI 24 h and PCWP 24 h
CASINO
299
Mortality 30 d and Mortality 180 d
REVIVE II
600
Composite global assess. at 6 h, 24 h 5 d
SURVIVE
800
Mortality 180 d
Phosphodiesterase Inhibitor (Milrinone)
OPTIME-CHF
951
Days Hospitalized within 60 d
Courtesy of M. Metra
15
Ideal properties for AHF therapy
Pang PS et al. Eur Heart J 2010;31:784-93
Novel therapies for AHF
Pang PS et al. Eur Heart J 2010;31:784
It´s hard to make predictions, particularly about the future….
Niels Bohr or Yogi Berra or Albert Einstein or Mark Twain
16
Cinaciguat in patients with AHF
Phase IIb, placebo-controlled study, 139 AHF patients, PCWP ≥18 mmHg, EF <40%
Erdmann E et al. Eur Heart J 2013;34:57–67
Hemodynamic effcts of stresscopin in HF patients
Double-blind, placebo-controlled study with 62 HF pts with EF ≤ 35% & CI ≤ 2.5 L/min/m2
Conclusion. Stresscopin has demonstrated an ability to safely increase CI and reduce SVR without
significantly affecting HR and SBP, making it potentially unique and advantageous compared with currently
available inotropes. Further studies (also in AHF setting) are needed
Gheorghiade M et al. Eur J Heart Fail 2013;15:679–689
17
A Phase 2 Study of
Intravenous Omecamtiv Mecarbil,
A Novel Cardiac Myosin Activator,
In Patients With Acute Heart Failure
John R. Teerlink, G. Michael Felker, John J. V. McMurray,
Piotr Ponikowski, Marco Metra, Gerasimos S. Filippatos,
Kenneth Dickstein, Justin A. Ezekowitz, John G. Cleland,
Jae B. Kim, Lei Lei, Beat Knusel, Andrew A. Wolff,
Fady I. Malik and Scott M. Wasserman
on behalf of the ATOMIC-AHF Investigators and Patients
Omecamtiv Mecarbil (OM) is a Novel
Selective Cardiac Myosin Activator
Mechanochemical Cycle of Myosin
Omecamtiv mecarbil increases the
entry rate of myosin into the
tightly-bound, force-producing
state with actin
“More hands pulling on the rope”
Increases duration of systole
Increases stroke volume
No increase in myocyte calcium
Force
production
No change in dP/dtmax
No increase in MVO2
Malik FI, et al. Science 2011; 331:1439-43.
18
Summary
 Efficacy
 OM did not meet the 1° endpoint of dyspnoea relief
 Appeared to improve dyspnoea in Cohort 3
 Trends towards reduction of worsening HF
 Safety
 Overall SAE profile and tolerability similar to placebo
 Increase in troponin; no clear relationship to OM concentration
 Numerical imbalance in MIs in Cohort 3
 No evidence of pro-arrhythmia
 Pharmacology
 PK similar to healthy volunteers and stable HF patients
 Systolic ejection time significantly increased consistent with MOA
 No measured adverse effect on heart rate or blood pressure
Management of Acute Heart Failure Syndromes
1. Everyday clinical practice
guidelines & reality
2. Results (disappointing) of the recent trials
3. Outlook for the future
different approach needed ?
19
Initial, short-term therapies (hours-days)
Target
„Traditional” therapeutic
approach
Effects on long-term
outcome
Alleviate congestion
i.v. diuretics
?
May be detrimental
Reduce ↑ LV
filling pressure
i.v. nitrates
?
Potentially favourable
Hypoperfusion
i.v. inotropes
Detrimental
Poor cardiac performance
Dissociation between symptomatic improvement, clinical stabilisation
& favourable long-term outcome
Modified from Pang PS et al. Eur Heart J 2010;31:784-93
Lessons from ACS trials:
short-term intervention can result in long-term benefit
ISIS-2 follow-up
% pts
STK
Control/placebo
15
10
GISSl
ISIS-2
5
21-day mortality
5-week vascular
mortality
Baignet C et al. BMJ 1998;316:1337-43
% pts
PCI
15
Thrombolysis
10
5
Death
Death & re-MI
In-hospital
Death
Death & re-MI
6-month
Grines CL et al. NEJM 1993;328:673-9
20
Need for paradigm shifting in acute heart failure:
short-term intervention and long-term goals (?)
What is needed ?
 Targeted-approach
= characterizing patient’ clinical profile
different pathophysiologies & therapies for different clinical profiles (?)
 An
ideal drug / intervention
symptomatic improvement, „end-organ” protection,
improvement in neurohumoral and proinflammtory profile
 Appropriate
timing = early administration of therapy
„the earlier the better” (?)
→ prevention of tissue damage;
→ phase of severe symptoms;
→ early clinical stabilization & chance to introduce disease-modifying therapies
Pre-RELAX-AHF and RELAX-AHF:
clinical trials testing the efficacy of serelaxin in AHF
Timeline:
Day 1
Day 5
Day 3
Day 14
Day 60
Treatment
(within 16h
of symptoms)
48h i.v.
Primary EP1
Primary EP2
∆ Dyspnea
Safety
∆ Worsening HF (%)
Safety
Creatinine changes
HE
LoS (days)
Secondary EP1
Days alive out of hospital
Secondary EP2
CV mortality or re-hospitalization for HF or renal failure
Outcome
CV Mortality (%)
Hospital admission
Day 180
„the earlier the better”
Early Relief (Likert)
6, 12, 24 h
Sustained Effect (VAS AUC) 0-100 mm; 0, 6, 12, 24h, D2-D5
Hospital discharge
Day 60 analysis
Follow-up
Teerlink et al. Lancet 2009;373:1429–39; Clinicaltrials.gov 2009 (NCT00520806)
21
1° Endpoint: Dyspnea Relief (VAS AUC)
Change from baseline (mm)
19.4% increase in AUC with serelaxin
from baseline through day 5
(Mean difference of 448 mm-hr)
Placebo
Serelaxin
AUC with placebo, 2308 ± 3082
AUC with serelaxin, 2756 ± 2588
*P=0.0075
6 12 hrs
Days
RELAX-AHF
Teerlink J. LBCT Presentation, AHA 2012
RELAX-AHF: Worsening of Heart Failure
Cumulative proportion of worsening heart failure
to Day 5 (%)
*p<0.001 through Day 5
n=
11
3
16
4
31 10
44 17
57 25
64 36
69 37
Kaplan-Meier estimate
for time to WHF (%)
**HR 0.7 (0.51, 0.96); p=0.024
573
570
573
570
Worsening Heart Failure (WHF) - worsening signs and/or symptoms of HF that required an intensification of IV therapy
for heart failure or mechanical ventilatory or circulatory support.
*p value by Wilcoxon test **p value by log rank test for Serelaxin vs. Placebo; HR estimate by Cox model, HR<1.0 favors Serelaxin
Teerlink J. LBCT Presentation, AHA 2012
RELAX-AHF
22
Changes from baseline in biomarkers related
to organ damage in the RELAX-AHF study
hs-cTnT
≥20% increase
at day 2
%pts
placebo
serelaxin
Cystatin C
≥0.3 mg/l increase
at day 2
Creatinine
≥0.3 mg/dl increase
at day 2
20
AST
≥20%l increase
at day 2
10
Cardiac damage
Renal damage
Liver damage
RELAX-AHF
Metra M et al. JACC 2013;61:196-206
CV Death through Day 180
K-M estimate CV death (ITT) (%)
14
Number of
Events, n (%)
12
HR 0.63 (0.41, 0.96); p=0.028
Placebo (N=580)
10
55 (9.5%)
NNT = 29
8
6
35 (6.0%)
Serelaxin (N=581)
4
2
0
0
14
30
60
90
120
150
180 Days
580
567
559
547
535
523
514
444 Placebo
581
573
563
555
546
542
536
463 Serelaxin
Teerlink J. LBCT Presentation, AHA 2012
RELAX-AHF
23
All-cause Death through Day 180
K-M estimate for All-cause Death ITT (%)
14
Number of
Events, n (KM%)
12
65 (11.3%)
Placebo (N=580)
HR 0.63 (CI 0.43, 0.93); p=0.020
10
NNT = 25
8
42 (7.3%)
6
Serelaxin (N=581)
4
2
0
0
14
30
60
90
120
180 Days
150
580
567
559
547
535
523
514
444 Placebo
581
573
563
555
546
542
536
463 Serelaxin
RELAX-AHF
Teerlink J. LBCT Presentation, AHA 2012
Short-term relief, long-term goals –
the cardiologist’s perspective on a novel
therapeutic approach to acute heart failure
„broadly speaking, the pharmacological
armamentarium for AHFS – loop diuretics,
vasodilators and inotropes – is largely
unchanged from 1970s…”
Will it be changed after RELAX ?
Sunrise or sunset ?
24
25