1. Future perspectives in Heart failure Sarajevo, May 2010

2. Have we been successful?

3. Cumulative benefit of poly-pharmacy in mild-moderate HF
Diuretic/
digoxin
ACE inhib.
13.2
8.8
8.7
6.1 5 10 15 20
1 year mortality (%)
15.7
12.4
Beta-blocker
ARB
CHARM-Added
(Beta-blocker subgroup)
2003
CIBIS 2
1999
SOLVD-T
1991

4. Are there failures?

5. ACUTE HEART FAILURE

6. Negative trials TRIAL Drug Duration (Mo) N PEP ESSENTIAL Enoximone
Low dose
NEGATIVE 6
1.854
. AC death/CV hosp.
. PGA
. 6 MWT
SURVIVE
Levosimendan vs Dobutamine
1.327
AC death
REVIVE
Levosimendan vs pbo
Composite better
Increase death
600
Composite
EVEREST
Tolvaptan
3.600
. AC death 6

7. EVEREST: Primary Endpoint
All-Cause Mortality
CV Mortality or HF Hospitalization
HR 0.98; 95% CI (.87–1.11)
Meets criteria for non-inferiority 3 6 9 12 15 18 21 24
2072
1812
1446
1112
859
589
404
239 97
2061
1781
1440
1109
840
580
400
233 95
0.0
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.0
HR 1.04; 95%CI (.95–1.14)
0.9
0.8
0.7
Proportion alive
Proportion without event
0.6
0.5
0.4
Peto-Peto Wilcoxon Test: P = .68
Peto-Peto Wilcoxon Test: P = .55
0.0
TLV
2072
1562
1146
834
607
396
271
149 58
TLV
PLC
2061
1532
1137
819
597
385
255
143 55
PLC 3 6 9 12 15 18 21 24
Months In Study
Months In Study
Tolvaptan
Placebo
Konstam MA. JAMA 7

8. Probability of Surviving Days Since Start of Study Drug Infusion
SURVIVE
1.0
Levosimendan
0.9
Dobutamine
0.8
Probability of Surviving
0.7
Overall 180-d
Mortality: 27%
0.6
0.5
During the 180 days after study drug infusion, there were 173 deaths (26%) in the levosimendan group and 185 deaths (28%) in the dobutamine group. Analysis of all-cause mortality at 31 days and cardiovascular mortality at 180 days also showed no statistically significant difference between the treatment groups.
0.4 30 60 90
120
150
180
Days Since Start of Study Drug Infusion
A Mebazaa et al. JAMA 2007; 297: 8 45

9. Adenosine Antagonists
Afferent arteriolar constriction
Proximal tubular sodium reabsorption
Furosemide
Increasd distal tubular sodium concentration
Adenosine release

10. Randomisation Rolofylline to placebo, 2:1
PROTECT
Placebo
Rolofylline
30 mg
Treatment phase Follow-up
Randomisation Rolofylline to placebo, 2:1
All cause mortality
CV/Renal hosp
All cause
mortality
Kidney Function
Days
Screening
AHF & fluid overload, need of iv loop diuretic
CrCl, ml/min

11. Odds ratio (95% CI) vs Pbo: 0.92 (0.78, 1.09)
Primary Endpoint
Odds ratio (95% CI) vs Pbo: 0.92 (0.78, 1.09)
Percent of Patients
36.0
44.2
19.8
40.6
37.5
21.8 20 40 60 80
100
Placebo
Ro 30 mg
Treatment Success
Patient Unchanged
Treatment Failure
p=0.348 for comparison of distribution using the van Elteren extension of Wilcoxon test

12. Patient heterogeneity
Substrate (ischaemic / non ischaemic, HT).
Trigger ( ACS, arrhythmias, Hypertension crisis).
Pathophysiology ( systolic vs diastolic HF / low vs high BP).
Lack of standard comparator.
Dose, Time points, Endpoints.

13. Heart failure with Preserved Ejection Fraction

14. RAAS blockade in HF-PEF: two key trials
CHARM-Preserved
Death or HF hospitalization
PEP-CHF
Death or HF hospitalization
Cumulative incidence (%)
HR 0.92; 95% CI ( );
p=0.545
Placebo
Perindopril 10 20 30 40 12 24 36
Cumulative incidence (%)
Month 48 40
Placebo
Candesartan 30 20 10
HR 0.92; 95% CI ( );
p=0.221 12 24 36 48
Month
Yusuf et al. Lancet 2003
Cleland et al. Eur Heart J 2006

15. Cumulative Incidence of Primary Events (%)
I-PRESERVE: Primary Endpoint Death or protocol specified CV hospitalization
Months from Randomization
Cumulative Incidence of Primary Events (%)
40 -
0 -
10 -
20 -
30 - 6 12 18 24 36 42 30 48 60 54
2067
1929
1812
1730
1640
1513
1291
1569
1088
497
816
2061
1921
1808
1715
1618
1466
1246
1539
1051
446
776
No. at Risk
Irbesartan
Placebo
HR (95% CI) = 0.95 ( )
Log-rank p=0.35

16. Treatment Of Preserved Cardiac function heart failure with an Aldosterone anTagonist

17. New drugs

18. New drug trials Safe Inotropes (Istaroxime/Cardiac Myosin activator)?
Renin inhibitors (ATMOSPHERE: aliskiren vs enalapril vs combination)?
Safe Inotropes (Istaroxime/Cardiac Myosin activator)?
New vasodilators /GMPc modulators.
Chimeric Natriuretic peptides.
Sinus node inhibition (SHIFT: ivabradine vs placebo.
NEP inhibitors(+ ARB).

19. ATMOSPHERE: design overview
Primary outcome: CV death or heart failure hospitalization
(event driven: 2162 patients)
Randomization
Enalapril 10 mg twice daily (n=2,200)
Open-label run-in
Enalapril
Enalapril +Aliskiren
Aliskiren 300 mg once daily (n=2,200)
Patients enrolled in the ALLAY study will be randomized to receive 2-weeks’ once-daily treatment with aliskiren 150 mg, losartan 50 mg, or aliskiren/losartan 150/50 mg combination therapy. After 2-weeks, the dosage of each treatment will be doubled for the remaining 34 weeks of the study.
References
1. Clinicaltrials.gov. A Clinical Study Comparing the Efficacy and Safety of Aliskiren in Combination With Losartan Compared to Losartan on the Regression of Left Ventricular Hypertrophy in Overweight Patients With Essential Hypertension. ClinicalTrials.gov Identifier: NCT Accessed at:
2. Data on File, Novartis Study SPP100A2316.
Aliskiren 300mg/enalapril
20 mg Daily (n=2,200)
Double-blind
4-8 weeks
~48 weeks (event driven) 19

20. CK-1827452: Background Preclinical
Selective activator of cardiac myosin
Prolongs duration of systole by
Increasing entry rate of myosin into force-producing state
Therefore overall number of active cross-bridges increases
Increases stroke volume
No change in dP/dtmax
No increase in MVO2

21. A New Calcium Cycling Modulator
Istaroxime
A New Calcium Cycling Modulator

22. HORIZON-HF PCWP
During infusion, there was a rapid and sustained decrease in PCWP that was maintained at 6 hours with all 3 doses of istaroxime when compared to placebo. Note the trend towards increase in PCWP after discontinuation of istaroxime.
PCWP
Infusion period Post-infusion

23. HORIZON-HF Conclusions
Istaroxime given over a short period in patients admitted with HF and LVEF ≤ 35% receiving standard therapy:
decreased PCWP and LVEDV
increased CI
Improved some indices of diastolic function.*
No changes in neurohormones, renal function, or troponin release.
In contrast to other inotropic agents available, these changes were associated with:
Increase in SBP.
Reduction in HR.
In conclusion, Mr. Chairman,
A six-hour infusion of istaroxime in patients admitted with heart failure and reduced ejection fraction improved central hemodynamics, decreased left ventricular end-diastolic volume, improved indices of diastolic function. This hemodynamic improvement observed with istaroxime was not associated with changes in neurohormonal profile, renal function, or troponin release.
In contrast to other available inotropes, these changes were associated with increases in systolic blood pressure and a reduction in heart rate.
NEXT

24. Relaxin Mechanisms of Action
Relaxin Receptor LGR7
Vasodilation
NO, cGMP effectors
Induction of NOS II/III
Upregulation of endothelial endothelin type B receptor, which mediates vasodilation
Preferential dilation of constricted vessels
Relaxin-upregulated ETB receptors act as vasodilating ET-1 sink
Anti-inflammatory
Down-modulation of inflammatory cytokines linked to outcome in HF (TNF-, TGF-)
Other: Anti-ischemic, Anti-apoptotic, Anti-fibrotic 24

25. CD-NP: A Rationally Designed Natriuretic Peptide
CNP S G L K C F D R I M
NPR-B agonist
Vasodilation
CD-NP P N A T - +
DNP E V Y H
NPR-A agonist
Renal function = 25

26. HR predicts outcome (placebo group)
Fox K, et al. Lancet. 2008;372:

27. SHIFT design paper

28. Study design 6500 pts randomised Results ESC 2010
NYHA II-IV . EF<35% .HF hosp in prior 12 months .HR >70 bpm
6500 pts randomised Results ESC 2010
Composite primary endpoint
Cardiovascular death
Hospitalisation for worsening heart failure 28

29. Angiotensin Receptor Neprilysin inhibitor
A new approach?
ARNi
Angiotensin Receptor Neprilysin inhibitor

30. LCZ 696 Molecular complex of: An ARB - valsartan
A NEP inhibitor – AHU 377

31. PARADIGM-HF A multicenter, randomized, double-blind, parallel group, active-controlled study to evaluate the efficacy and safety of LCZ696 compared to enalapril on morbidity and mortality in patients with chronic heart failure and reduced ejection fraction
LCZ mg BID (n~4000)
Enalapril 10 mg BID (n~4000)
Outcomes driven (estimated mean f/u = months)
1-2 weeks
Enalapril 5-10 mg bid
LCZ 100 mg bid
LCZ 200 mg bid
2 weeks
Prior ACEi/ARB use discontinued
Single-blind period
Double-blind period
N = 7980 (1:1 randomization)
Primary objectives
Evaluate if LCZ696 is superior in delaying time to first occurrence of either CV mortality or HF hospitalization in CHF pts (NYHA Class II – IV) with reduced ejection fraction
Secondary objectives
All cause mortality
Renal progression (eGFR change)
Clinical summary score (assessed by KCCQ)
Patient population
7980 patients with CHF NYHA class II – IV and reduced ejection fraction (LVEF < 40%)
BNP>150 pg/ml (NTproBNP > 600 pg/ml) or BNP > 100 pg/ml (NTproBNP > 400 pg/ml) and
hospitalization within the last 12 months. 31

32. New trials in acute HF

33. ASCEND-HF design
completed in 2010
# 7000 pts enrolled

34. Design overview Acute HF Aliskiren Aliskiren 300 mg 150 mg Placebo
Primary outcome: CV death or HF hospitalization at 6 months (381 events)
Randomization
Acute HF
LVEF<40%
BNP >400pg/mL
SBP≥110mmHg
~1,800 patients
Aliskiren
150 mg
Aliskiren 300 mg
Placebo
Abbreviations
ACEI = angiotensin-converting enzyme inhibitor
ARB = angiotensin receptor blocker
HF = heart failure
Reference
Data on File, Novartis Pharma AG, 2008: Study SPP100A2368 Protocol.
Conventional therapy‡
In-hospital entry and initiation
2 weeks
~15 months (event-driven)*
‡ Except concomitant use of an ACEI and ARB
* Follow-up at Week 2, Month 1, 2 and 3, with on-going assessments every 3 months thereafter
Aliskiren HF programme slide kit
Item code: TBC Release date: January 2009 34 34

35. THANK YOU !