Hot messages from ESC London
Heart Failure 2015
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
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Hot messages from ESC London
Heart Failure 2015
DISCLOSURE INFORMATION:
The following relationships exist related to this presentation:
Bayer, Novartis, Pfizer, Servier, Orion, Medtronic, Biotronik,
Thoratec, Heartware
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Heart Failure – the magnitude of the problem
Coronary deaths are down by half
Coronary Deaths
Source: National Hospital Discharge Survey data. Centers for Disease Control and
Prevention/National Center for Health Statistics and National Heart, Lung, and
Blood Institute.
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
But heart failure has almost tripled
Heart Failure
Heart Failure 2015
Eugene Braunwald
The war against heart failure
(LANCET 2015)
Thomas Lüscher
Heart failure – the cardiovascular epidemic of the 21th century
(EUROPEAN HEART JOURNAL 2015)
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
ESC Guideline Heart Failure 2012 –
Mineralocorticoid Receptor Antagonists (MRA)
Diuretics to relieve symptoms / signs of congestion2
+
Recommendations
Classa
ACE inhibitor (or ARB if not tolerated)b
ADD a beta-blockerb
Still NYHA class II-IV?
Yes
ADD a MR antagonistb,d
An MRA is recommended
for all patients with
persisting symptoms (NYHA
class II–IV) and an EF
≤35%, despite treatment
with an ACE inhibitor (or an
I
A
ARB if an ACE inhibitor is
not tolerated) and a betaMRA
underuse
is mainly related to existing
c
No
blocker, to reduce the risk of
or perceivedHFrisk
of hyperkalemia
and/or
hospitalization
and the
risk of premature
death.
worsening renal
function.
But:
Patients at risk do profit from MRAs
regarding clinical endpoints
McMurray et al., European Heart Journal 2012 | ESC 2012
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Levelb
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Finerenone versus eplerenone in patients with
worsening heart failure and diabetes and/or chronic
kidney disease – ARTS-HF: Study Design
Filippatos G, ESC London Sept 2015
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
ARTS-HF: Finerenone reduces all-cause death
and cardiovascular hospitalizations
Phase III study (FINESSE) will compare
Finerenone with Eplerenone in patients
with worsening heart failure and diabetes
and/or kidney disease
Filippatos G, ESC London Sept 2015
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Williams B, ESC London Sept 2015
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
PATHWAY 2 Study demonstrated overwhelming efficacy
of spironolactone in patients with resistant hypertension
There is a high clinical need for novel MRAs
with a better risk/benefit profile for the
treatment of patients with heart failure,
hypertension, diabetes, kidney disease
Williams B, ESC London Sept 2015
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
TOPCAT (Spironolactone in HFpEF / diastolic heart failure)
Heart failure hospitalisations
In total cohort:
 Primary endpoint not
significantly improved, but
 Significant reduction of heart
failure hospitalisations
American patients:
(whose high event rate is
representative of a HFpEF
patient cohort):
 Significant improvement of
primary endpoint
Pitt et al., NEJM 2014
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Is there an effect of Digoxin on mortality?
Kotecha, ESC London Sept 2015; Ziff OJ et al, BMJ 2015
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Perceived increase in mortality with Digitalis treatment is
related to marked bias in non-randomised studies
Kotecha, ESC London Sept 2015;
Ziff OJ et al, BMJ 2015
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
DIGitoxin to Improve ouTcomes
in patients with advanced
chronic systolic Heart Failure
multicenter, randomized,
double blind, placebocontrolled trial
Bavendiek, Bauersachs, DFG / BMBF Study program
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Intervention group:
Standard of care (SOC) +
digitoxin p.o. (0.05-0.1 mg/die)
Dose adjustment at 6 weeks
and, if indicated, at 12 weeks
after start of treatment.
Target serum concentration of
digitoxin preferably 8-18 ng/ml
Personal recommendations for Digitalis treatment
in heart failure
 Patients with HFrEF (EF<35%)
 NYHA III-IV despite standard therapy with BB, ACE-I,
MRA, and Ivabradine (if indicated)
 (Recurrent) heart failure hospitalisations
 Tachyarrhythmia despite betablocker
(but no co-treatment digitalis/amiodarone!)
 Aim for lower dosage (target level Digoxin 0.5-1.0 ng/ml)
 Control serum levels (especially during Digoxin treatment)
 Digitoxin instead of Digoxin in CKD and/or the elderly
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
A Phase 2b Trial Investigating the Efficacy and Safety of
the Intracoronary Administration of AAV1/SERCA2a in
Patients with Advanced Heart Failure
CUPID 2 – Background
Greenberg B, ESC London Sept 2015
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
CUPID 2: No significant event reduction of AAV1/SERCA2a
administration in patients with heart failure
Greenberg B, ESC London Sept 2015
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Adaptive Servo-Ventilation (ASV)
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
SERVE-HF: Unexpected increase in cardiovascular
mortality by adaptive servo ventilation in heart failure
Primary Endpoint
Time to first event of all-cause death, life-saving
cardiovascular intervention*, or unplanned
hospitalization for worsening chronic HF
CONCLUSION:
Patients with HFrEF and central sleep apnoea
should not be treated with adaptive servo
ventilation
But:
Patients with obstructive sleep apnoea were
not included in SERVE-HV
Cowie MR, ESC London Sept 2015, Cowie MR et al, New Engl J Med 2015
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Implanted device-based impedance monitoring with telemedicine alerts on mortality and morbidity in heart failure
OptiLink HF – Study design
Michael Böhm, ESC London Sept 2015
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
OptiLink-HF: device-based impedance monitoring
with tele-medicine alerts does not improve mortality
or morbidity in heart failure
Michael Böhm, ESC London Sept 2015
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Guideline based therapy for heart failure with
reduced systolic left ventricular function (HFrEF)
NYHA I
NYHA II
NYHA III
NYHA IV
HTX, LVAD
CRT
Ivabradine / digitalis glykosides
Mineralocorticoid receptor antagonists (MRA)
Diuretics
Beta-Blockers
ARNI
ACE inhibitors (ARB)
non-pharmacological therapies
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Angiotensin receptor / neprilysin inhibition (ARNI)
with LCZ696: Mechanisms of action
Renin‐Angiotensin‐System
LCZ696
Natriuretic Peptides
Angiotensinogen
Valsartan
Angiotensin I
Angiotensin II
AT1‐Receptor
Sacubitril
(AHU377)
LBQ657
ANP BNP
CNP
Adrenomedullin
Substance P
Bradykinin
…
Neprilysin
Inactive
Fragments
Vasoconstriction
Blood pressure increase
Increased sympathicotonus
Aldosterone increase
Fibrosis
Ventricular hypertrophy
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Berliner D, Bauersachs J, 2015
Vasodilatation
Blood pressure lowering
Reduced sympathicotonus
Reduced aldosterone levels
Natriuresis/Diuresis
25
PARADIGM-HF: ARNI vs. ACE inhibitor
- summary of the results p<0.001
20
p<0.001
p<0.001
Events [%]
p<0,001
p<0.001
15
10
p=0.007
5
0
Death from
cardiovascular
causes
Berliner D, Bauersachs J, 2015
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
First hospitalization
for worsening heart
failure
Death from any
cause
LCZ696
Symptomatic
hypotension
Enalapril
Serum creatinine ≥2.5 mg/dl
Cough
PARADIGM-HF: Study design
Patients with symptomatic CHF
• Able to tolerate Enalapril 10 mg and LCZ696 200 mg
• LVEF < 35%
• BNP > 150 (100) pg/ml or NT-proBNP ≥600 (400) pg/ml
Randomization
n=8442
Double-blind
Treatment period
Single-blind active
run-in period
LCZ696 200 mg BID‡
Enalapril
10 mg BID*
LCZ696
100 mg BID†
LCZ696
200 mg BID‡
Enalapril 10 mg BID§
Median of 27 months’ follow-up
2 Weeks
1–2 Weeks
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
2–4 Weeks
On top of standard HFrEF therapy (excluding ACEIs and ARBs)
McMurray et al. Eur J Heart Fail. 2013;, 2014;16:817–25;
McMurray, et al. N Engl J Med 2014
BNP increases during treatment with LCZ696 (mechanism of
action); for determination of prognosis during LCZ therapy
only NT-proBNP is useful!
BNP
500
p<0.0001*
400
NT-proBNP
2,500
p<0.0001*
p<0.0001*
2,000
p<0.0001*
1,500
pg/mL
pg/mL
300
200
1,000
100
500
ENL
0
Entry
LCZ 4 weeks 8 months
Run-in†
Packer et al., Circ 2015
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Entry
Double-blind
= median
ENL
0
Bars represent 25%/75%
interquartile ranges for:
LCZ696
Enalapril
LCZ 4 weeks 8 months
Run-in†
Double-blind
Hot messages from ESC London
Heart Failure 2015
 Spironolactone shows overwhelming efficacy for resistant
hypertension in younger patients already treated with ACE-I/ARB,
calcium antagonist and diuretic; may also be useful for HFpEF
 Optimisation of current medical treatment approaches for HFrEF
(non-steroidal MRA Finerenone, Digitoxin) is promising
 Angiotensin receptor/neprilysin inhibitor (ARNI, LCZ 696) with
proven efficacy over ACE inhibition is approved for HFrEF
 SERCA myocardial gene therapy was not effective in HFrEF
 Intrathoracic impedance and telemedicine-based heart failure
disease management strategy was not effective in HFrEF
 Adaptive servoventilation in patients with HFrEF and central sleep
apnoea did not reduce events and may be harmful
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie
Medizinische Hochschule Hannover
Heart Failure 2016
21 – 24 May, FLORENCE, Italy
4 700+ healthcare professionals
90+ countries represented
4 days of science
1 700+ abstracts and cases submitted
300+ expert faculty members
100+ scientific sessions
40+ industry sessions and workshops
ESC/ HFA Guidelines on
HEART FAILURE
FOCUS ON: ACUTE HEART FAILURE
« Heart failure: State of the Art »
www.mahramzadeh.de
Thank you for
your attention !
Prof. Dr. Johann Bauersachs
Klinik für Kardiologie und Angiologie