behandeling van hartfalen: over 5 jaar€¦ · 15 university medical center groningen •hfref:...
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University Medical Center Groningen
Behandeling van Hartfalen:
over 5 jaar
Adriaan Voors, cardioloog
UMCG
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University Medical Center Groningen
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University Medical Center Groningen
Over 5 jaar…
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University Medical Center Groningen
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University Medical Center Groningen
• HFrEF: best evidence, biggest pipeline
• Entresto
• Omcamtiv
• LVAD: destination therapy
• HFrEF: no evidence, smallest pipeline
• Entresto
• Septostomy
• Acute Heart Failure: minimal evidence, biggest problem
• Ularitide, Serelaxin
• Preventing early hospital readmission
Heart Failure Treatment in 5 Years
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University Medical Center Groningen
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University Medical Center Groningen
Treatment of HFrEF: getting better!
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University Medical Center Groningen
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University Medical Center Groningen
HFrEF: Unmet Needs?
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University Medical Center Groningen
Beta blocker
Mineralocorticoid receptor
antagonistACE
inhibitor
Angiotensin receptor blocker
Drugs that inhibit the renin-angiotensin system have modest effects on
survival
40%Based on results of SOLVD-Treatment, CHARM-Alternative,
COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF
0%
10%
20%
30%
%D
ec
rea
se
inM
ort
ality
2011: Drugs Reducing Mortality in HFrEF
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X
ARNI have the potential to restore the appropriate
balance of the RAAS and natriuretic peptides in HF
Beneficial physiological response Pathophysiological response
Vasodilation
↓ blood pressure
↓ sympathetic tone
↓ aldosterone level
↓ fibrosis
↓ hypertrophy
Natriuresis/Diuresis
HF
symptoms/
progression
NPs Ang II
NEP
Damage
Inactive
fragmentsAT1 receptor
X
RAASNP system
Vasodilation
↓ blood pressure
↓ sympathetic tone
↓ aldosterone
↓ fibrosis
↓ hypertrophy
NEP/RAAS
inhibition
(LCZ696)
Neurohormonal balance
X
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University Medical Center Groningen
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University Medical Center Groningen
Prospective comparison of ARNI with ACEI to
Determine Impact on Global Mortality and
morbidity in Heart Failure trial (PARADIGM-HF)
LCZ696400 mg daily
Enalapril 20 mg daily
Aim of the PARADIGM-HF Trial
Specifically Designed To Replace Current Use Of Ace
Inhibitors And Angiotensin Receptor Blockers As The
Cornerstone Of The Treatment Of Heart Failure
WC
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University Medical Center Groningen
LCZ696
(n=4187)
Enalapril
(n=4212)
Hazard
Ratio
(95% CI)
P
Value
Primary
endpoint
914
(21.8%)
1117
(26.5%)
0.80
(0.73-0.87)
0.0000002
Cardiovascular
death
558
(13.3%)
693
(16.5%)
0.80
(0.71-0.89)
0.00004
Hospitalization
for heart failure
537
(12.8%)
658
(15.6%)
0.79
(0.71- 0.89)
0.00004
Effect of LCZ696 vs Enalapril on Primary
Endpoint Components
NEJM 2014
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University Medical Center Groningen
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Entresto approved by EMA and FDA
"Entresto is indicated in
adult patients for treatment
of symptomatic chronic
heart failure with reduced
ejection fraction.”
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University Medical Center Groningen
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University Medical Center GroningenHasenfuss and Teerlink; Eur Heart J 2011;32:1838-45
University Medical Center Groningen
COSMIC-HF
Chronic Oral Study of Myosin Activation
to Increase Contractility in Heart Failure
• Primary objectives
• To select an oral modified release formulation and dose for chronic
twice daily dosing in patients with symptomatic HFrEF (NYHA II/III,
LVEF ≤ 40%, NT-proBNP ≥ 200 pg/mL/≥ 1200 pg/mL if AF)
• Secondary objectives
• Safety and tolerability
• Changes in SET, SV, LVESD, LVEDD, heart rate and NT-pro BNP
levels
JR Teerlink, Late-Breaking Clinical Trial Session at the American Heart Association (AHA) Scientific Sessions 2015
University Medical Center Groningen
Efficacy of Omecamtiv Mecarbil
JR Teerlink, Late-Breaking Clinical Trial Session at the American Heart Association (AHA) Scientific Sessions 2015
University Medical Center Groningen
Efficacy of Omecamtiv Mecarbil, Cardiac
troponin I levels
JR Teerlink, Late-Breaking Clinical Trial Session at the American Heart Association (AHA) Scientific Sessions 2015
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University Medical Center Groningen
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Left Ventricular Assist Device
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HFrEF versus HFpEF
HFrEF: LVEF <40%
HFpEF: LVEF >50%
Between 40-50%: grey-area
ESC Heart Failure Guidelines 2012
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University Medical Center Groningen
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Treatment of Diastolic Heart Failure
No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HFPEF. Diuretics are used to control sodium and water retention and relieve breathlessness and oedema. Adequate treatment of hypertension and myocardial ischaemia is also considered to be important, as is control of the ventricular rate in patients with AF.
ESC Heart Failure Guidelines EJHF 2008 +2012
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HFpEF: Unmet Needs?
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PARAMOUNT: main results
Solomon et al. Lancet 2012
301 HFpEF patients; LVEF≥45%; NT-proBNP>400 pg/mL
LCZ696 2 dd 200 mg or Valsartan 2 dd 160 mg
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• Target patient population: 4,300 patients with symptomatic HF
(NYHA Class II–IV) and LVEF 45%
PARAGON-HFPEF: study design
*Valsartan 40 mg BID (up to 2 weeks) followed by
valsartan 80 mg BID as an optional starting run-in dose for
those patients being treated with less than the minimum
dose of ACEI or ARB at Visit 1
up to 2 weeks ~240 weeks
Valsartan 160 mg BID
LCZ696 200 mg BIDLCZ696
100 mg BID
On top of optimal background medications for
co-morbidities (excluding ACEIs and ARBs)
Primary outcome: CV death and total (first and recurrent)
HF hospitalizations (anticipated ~1,721 primary events)
Valsartan
80 mg BID*Screening
3–8 weeks
Active run-in period
Double-blind treatment period
Randomization 1:1
Solomon SD, et al. Poster presentation at ESC-HF Congress, 25 May 2013;
Clinicaltrials.gov NCT01920711;accessed March 2014
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Interatrial Shunt Device:
Novel therapy for HFpEF?
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• Prospective, nonrandomized, open-label trial
• A minimum of 60 patients: LVEF>40% and NYHA III-IV
• PCWP >15 mm Hg at rest or >25 mm Hg during exercise
• All patients receive IASD System II
• Primary outcome measures for safety are periprocedural
and 6-month major adverse cardiac and cerebrovascular
events (MACCE) and systemic embolic events (excluding
pulmonary thromboembolism).
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Group Medication
Class recommendation,
Level of evidence
Diuretics Indication I, B
Vasodilators Nitrates IIa, B
Sodium Nitroprusside IIb, B
Morphine Indication IIa, C
Inotropics Dopamine IIb, C
Dobutamine IIa, C
Acute Heart Failure: Recommendations and levels of evidence
McMurray et al. Eur J Heart Fail 2012; 33:1787–847
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PDE inhibitors: milrinone: OPTIME-CHF
Endothelin antagonists: tezosentan: VERITAS
Calcium sensitizers: levosimendan; SURVIVE/REVIVE
AVP antagonists: tolvaptan; EVEREST
Adenosine A1-receptor antagonist: rolofylline; PROTECT
Natriuretic peptides: nesiritide: ASCEND-HF
Wrongconcept?
Wrong study
design?
Wrong drugs?
Several Drugs in AHF Not Successful
AVP = arginine vasopressin;PDE = phosphodiesterase
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University Medical Center Groningen Mitrovic V, et al. Eur Heart J. 2006;27(23):2823-2832.
Ularitide: Sirius II
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Ularitide: TRUE-AHF
• A phase 3, double-blind, randomized, placebo-controlled,
multicenter study
• 48-hour IV infusion with ularitide, 15 ng/kg body
weight/min
• 2152 patients hospitalized for acute heart failure
• Study treatment within 12 hours after ED admission
• Co-Primary endpoint:
• hierarchical clinical composite including dyspnea relief,
worsening of heart failure, and all-cause mortality
• CV-mortality
ClinicalTrials.gov NCT01661634
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Relaxin
Hsu et al. Science 2002;295:671–674; Jeyabalan et al. Adv Exp Med Biol 2007;612:65–87;
Dschietzig et al. Circ Res 2003;92:32–40
• Naturally occurring hormone, discovered in 1929
• Elevated in circulation in first trimester of
pregnancy and throughout 9 months
• Relaxin receptors, identified in 2002, localized in
blood vessels
• Mechanism of action involves activation of the
endothelial endothelin type B receptor
• Contributes to maternal hemodynamic
adjustments to pregnancy
Relaxin
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University Medical Center GroningenTeichman SL, et al. Curr Heart Fail Rep. 2010;7(2):75-82.
Relaxin
↓ Inflammation ↓ Fibrosis ↑ Vasodilation Renal effects Angiogenesis
↓ TNF-
↓ TGF-
↑ MMP
↓ Collagendeposition
↑ EndothelialETB receptor
ET-1
ET1-32 NOS ↑ VEGF
NO
Relaxin receptor
ETB receptor = endothelin receptor type B; ET-1= endothelin-1; MMP = matrix metalloproteinase; NO = nitric oxide; NOS = nitric oxide synthase; TGF = transforming growth factor; TNF = tumor necrosis factor; VEGF = vascular endothelial growth factor
Serelaxin Is NOT Just Another Vasodilator
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First primary endpoint: change in dyspnea with VAS
Teerlink JR, et al. Lancet. 2013;381(9860):29-39.
35
30
25
20
15
10
5
0
Ch
ange
Fro
m B
ase
line
(mm
)
0 6h Day 1 Day 2 Day 3 Day 4 Day 5Follow-up
12h
Serelaxin (n=581)
Placebo (n=580)
Placebo: mean AUC (SD) = 2308 (3082) mm/h
Serelaxin: mean AUC (SD) = 2756 (2588) mm/h
P = .007
Randomized, Double-Blind, Placebo-Controlled Trial in 1161 ADHF Patients
…but no significant effects on second primary endpoint and secondary endpoints
RELAX-AHF
AUC = area under the curve; SD = standard deviation; VAS = visual analogue scale
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OrthopneaP = .002
EdemaP = .01
RalesP = .008
JVPP = .06
Pat
ien
ts (
%)
100
80
60
40
20
0
None
Mild
Moderate
Severe
NoneNone
None
<6 cm
6–10 cm
>10 cm
<1/3
1/3–2/3
>2/3
1+
2+
3+
1 Pillow
2 Pillows
>30°
DOEP = .02
DOE = dyspnea on exertion; JVP = jugular venous pressure
Signs and Symptoms at Day 2
Teerlink JR, et al. Lancet. 2013;381(9860):29-39.
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12
10
8
6
4
2
0
CV
De
ath
(%
)
0 14 30 60 90 120 150 180
Time Since Randomization (days)
Placebo: 55 CV deaths (9.6%)
Serelaxin: 35 CV deaths (6.1%)
HR, 0.63 (95% CI, 0.41-0.96)
P = .028
n=580
n=581
RELAX-AHF: CV Mortality
Teerlink JR, et al. Lancet. 2013;381(9860):29-39.
CI = confidence interval; HR = hazard ratio
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RELAX-AHF-2: study designPlease note that the study design information for RELAX-AHF-2 is subject to change
Discharge#
Placebo i.v.
Serelaxin 30 µg/kg/d i.v.*
0 6 12 24 48 72 96 120 h 14 60 120 180 d
48 h study drug infusion (i.v.) period
*Same weight range-adjusted dosing as in RELAX-AHF; ‡Standard HF therapy permitted at physician’s discretion; #If discharge visit coincides with a scheduled visit, only the discharge visit will be performed.AHF=acute heart failure; CV=cardiovascular; d=day; h=hour; i.v.=intravenous; SBP=systolic blood pressure
Clinicaltrials.gov: NCT01870778; Novartis, data on file 2013
In addition to standard HF therapy‡
Screening
Double-blind randomized treatment period
Screening occurred after ≥40 mg i.v. furosemide
Presentation <16 h
Randomization 1:1
Target patient population: 6,375 patients hospitalized with AHF, presenting with dyspnea, normal to
elevated SBP (125 mmHg) and mild-to-moderate renal impairment
Primary outcome: time to CV death
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• Better understanding of the disease
• Prevention
• Personalized medicine
General unmet needs
Acute
Heart
Failu
re
University Medical Center Groningen
periods of highest risk for readmission
unavoidable readmissions
AHF early post-discharge vulnerable phase
Desai AS and Stevenson LW .Circulation. 2012;126:501-506.
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• Appropriate discharge therapy
• Training and education before discharge
• Length of hospital stay
• Adequate decongestion during hospital admission
• Discharge planning and disease management programs
How to prevent early re-admission?
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University Medical Center GroningenValente, et al. EHJ 2014
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Diuretic response in AHF related to
re-hospital admission up to day 60
PROTECT: 2033 AHF patients;
Diuretic response = kg weight loss/40 mg furosemide
Valente, et al. EHJ 2014
% r
e-a
dm
issio
n
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Diuretic response: death or HF/RF
readmission through day 60
P<0.0001
Voors et al. Eur J Heart Fail 2014
RELAX-AHF: 1161 AHF patients;
Diuretic response = kg weight loss/40 mg furosemide
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• Better understanding of the disease
• Prevention
• Personalized medicine
General unmet needs
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Differential response to therapy
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Over 5 jaar…
• HFrEF: best evidence, biggest pipeline
• Better drugs in severe HFrEF?
• HFrEF: no evidence, smallest pipeline
• Better understanding, better therapies
• Acute Heart Failure: minimal evidence, biggest problem
• First proven thersapies upcoming?
• Preventing early hospital readmission
• General aims: prevention and personalized medicine