Professor Dan Atar is a cardiologist who has contributed significantly to clinical trials and guidelines on heart failure and atrial fibrillation. He discloses relationships with several pharmaceutical companies. He summarizes key landmark trials in heart failure treatment. RALES showed spironolactone reduced mortality in severe heart failure. EPHESUS found eplerenone beneficial post-myocardial infarction. EMPHASIS showed benefit in mild heart failure. COMMANDER-HF found no benefit to anticoagulation in sinus rhythm heart failure patients. TOPCAT found spironolactone reduced heart failure hospitalizations but not overall in those with preserved ejection fraction. PARADIGM established mortality benefit for sacubitril/valsart

1. Professor Dan Atar, MD, FESC
Dept. of Cardiology
Oslo University Hospital Ullevål
Norway
Vice-President of the ESC (2014-16)
Secretary/Treasurer of the ESC (2018-2020)
2.2.2019 – Mauritius
Latest Landmark Trials in Heart Failure

2. • Co-author of the 2010, 2012 and 2016 ESC Guidelines on Atrial Fibrillation and
2012 ESC STEMI Guidelines, as well as the 2018 Universal Definition of AMI GL.
• Steering Committee member, National Coordinator for Norway, and Co-author
of ACTIVE, RELY, ARISTOTLE, AVERROES, APPRAISE, GARFIELD, ENGAGE-AF,
XANTUS, RE-ALIGN, RE-VERSE, ARTESIA, NOAH, ENTRUST-AF-PCI, REPORT-AF,
RE-SONANCE, REPORT-HF, PARAGON, VICTORIA.
• Adjudication Committee member for the AVRO and Roxadustat trials, DSMB for
the CHILL-MI, OPTIMUM, LUPUS, BETA-3 and HOMAGE trials. Chair of the FIRE
and MITOCARE trial (EU-FP7 fundet). Chair of the BETAMI-trial.
• Fees, honoraria from Boehringer- Ingelheim, Bayer, BMS/Pfizer, Cardiome,
Astra-Zeneca, MSD, Sanofi-Aventis, Amgen.
Prof. Dan Atar
Disclosures

3. 3

4. Heart Failure
• Hippocrates 460 - 377 BC:
– The flesh is consumed and becomes water, the abdomen
fills with water, the feet and legs swell, the shoulders,
clavicles, chest and thighs melt away.

7. COMMANDER-HF

13. TOPCAT

14. Spironolactone
Placebo
Months
RR = 0.70
P < 0.001
ProbabilityofSurvival
0.40
0.50
0.60
0.70
0.80
0.90
1.00
0 12 24 36
Epleronone
Placebo
RR = 0.85
P < 0.008
0.40
0.50
0.60
0.70
0.80
0.90
1.00
0 12 24 36
Months
RR = 0.78
P = 0.014
MRAs Beneficial
in HFrEF and Post-MI LVD
30% Risk Reduction 15% Risk Reduction
0 12 24 36
0.50
0.70
0.80
0.90
0.40
1.00
0.60
Epleronone
Placebo
22% Risk Reduction
RALES
(Severe HFrEF)
EPHESUS
(Post-MI)
EMPHASIS
(Mild HFrEF)
Reviews of Mechanisms : Pitt Heart Fail Rev 2012; Kamalov,…,Weber JCV Pharm 2013
Pitt NEJM 1999 Pitt NEJM 2003 Zannad NEJM 2011
Months

15. Kaplan-Meier Curves for Clinical Outcome trials in HFpEF
TOPCAT
CHARM-preserved
I-PRESERVE
PEP-CHF

16. • Objective
 To determine if treatment with spironolactone can produce a clinically
meaningful reduction in the composite endpoint of cardiovascular
mortality, aborted cardiac arrest, or hospitalization for the management of
heart failure, compared with placebo, in adults with HF-Preserved EF.
• Inclusions:
Symptomatic Heart Failure, Age ≥ 50, LVEF ≥ 45%, stratified according to:
 Hospitalization within the past year for management of heart failure, or
 Elevated natriuretic peptides (BNP ≥100 pg/mL or NT-proBNP ≥360
pg/mL)
• Major Exclusions:
eGFR<30 mL/min/1.7m2, serum potassium ≥5 mmol/L, uncontrolled
hypertension, AF with rate > 90/min, recent ACS, restrictive, infiltrative, or
hypertrophic cardiomyopathy
Treatment Of Preserved Cardiac Function
Heart Failure with an Aldosterone anTagonist
(TOPCAT)
Rationale and design: (A. Desai, Am Heart J 2011)

17. Variable*
Spironolactone
N = 1722
Placebo
N = 1723
NYHA Class
II
III
63.3%
33.0%
64.3%
32.2%
LVEF % 56 (51, 61) 56 (51, 62)
Stratum
Hosp. for HF
Natriuretic Peptide**
71.5%
28.5%
71.5%
28.5%
Age 69 (61, 76) 69 (61, 76)
Female 52% 51%
Hypertension 91% 92%
Coronary Artery Disease 57% 60%
Myocardial Infarction 26% 26%
Stroke 7% 8%
Atrial Fibrillation 35% 35%
Diabetes Mellitus 33% 32%
Smoking (current) 10% 11%
**(BNP ≥100 pg/mL or NT-proBNP ≥360 pg/mL)
*Reported as % or median (Q1, Q3)
S. Shah Circ HF 2012
Baseline

18. Spironolactone
Placebo
HR = 0.89 (0.77 – 1.04)
p=0.138
351/1723 (20.4%)
320/1722 (18.6%)
1°Outcome
(CV Death, HF Hosp, or Resuscitated Cardiac Arrest)

19. Total HF Hosp
Spiro : 394
Placebo: 475
P<0.01*
*poisson regression
245/1723 (14.2%)
206/1722 (12.0%)
Heart Failure Hospitalizations
Spironolactone
Placebo
HR = 0.83 (0.69 – 0.99)
p=0.042

20. TOPCAT

21. HR=0.82 (0.69-0.98)
HR=1.10 (0.79-1.51)
Interaction p=0.122
US, Canada,
Argentina, Brazil
Russia, Rep Georgia
Placebo:
280/881 (31.8%)
Placebo:
71/842 (8.4%)
Exploratory (post-hoc):
Placebo vs. Spiro by region

22. Potassium Spiro Placebo P (chi-
sq)
Hyperkalemia
(≥ 5.5 mmol/L)
322
(18.7%)
157
(9.1%)
<0.001
Hypokalemia
(<3.5 mmol/L)
279
(16.2%)
394
(22.9%)
<0.001
No deaths related to hyperkalemia were reported.
Serum Potassium*
*Monitoring at each dose change and visit (algorithm in Desai Am Heart J 2011)

23. HF Treatment

24. 24
Norwegian HF Registry
• 12 quality indicators and 17 risk indicators
• 92% of all patients use both ACEi/ARB and BB
• However MRA are severely underutilized
(spironolactone or eplerenone)

25. PARADIGM

26. Packer et al, ESC2014
LCZ696 - first-in-class
angiotensin receptor neprilysin inhibitor
(ARNI)
Valsartan
AHU377 (sacubitril)
LBQ657 (active)

29. Randomization
n=8442
PARADIGM-HF: Study design
*Enalapril 5 mg BID (10 mg TDD) for 1–2 weeks followed by enalapril 10 mg BID (20 mg TDD) as an optional starting run-in dose for
those patients who are treated with ARBs or with a low dose of ACEI; †200 mg TDD; ‡400 mg TDD; §20 mg TDD.
McMurray et al. Eur J Heart Fail. 2013;15:1062–73; McMurray et al. Eur J Heart Fail. 2014;16:817–25;
McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.
2 Weeks 1–2 Weeks 2–4 Weeks
Single-blind active
run-in period
LCZ696 200 mg BID‡
Double-blind
Treatment period
On top of standard HFrEF therapy (excludingACEIs andARBs)
Median of 27 months’follow-up
LCZ696
200 mg BID‡
LCZ696
100 mg BID†
Enalapril
10 mg BID*
Enalapril 10 mg BID§
Stabil HF
EF <40 (35%)
proBNP>71 pmol/L
eGFR>30

30. PARADIGM study
KM plots for Outcomes, According to Study Group
(primary outcome: CV death or first hosp for HF).
McMurray JJ et al. N Engl J Med 2014. DOI:
10.1056/NEJMoa1409077

31. The cumulative probability of a first hospitalization
for heart failure during the first 30 days after
randomization
HR 0.60 (95% CI: 0.38–0.94)
p=0.027
10 20
Days after randomization
Kaplan-Meierestimateof
cumulativerate
1.5
Enalapril (N=4,212)
LCZ696 (N=4,187)
1.0
0.5
0
0 30
Packer et al. Circulation. 2015 Jan 6;131(1):54-61

32. Clinical outcomes of cardiovascular death or heart failure
hospitalization, cardiovascular death, heart failure
hospitalization, and all-cause mortality by age category and
treatment group.
H Burnett Cir Heart Fail 2017;10:e003529

33. Sacubitril/valsartan vs Enalapril
• Less symptoms and better quality of life in HF
• Total mortality  16% (life increase 1-2 yrs)
• CV mortality  20%
• SCD 
• 30 days rehospitalizatsion rate  40%

34. HF Treatment

35. Which patients should be considered for
ARNi treatment?
– NYHA II-IV
– LVEF<35%
– Maximal tolerated dose of BB, ACE-I/ARB,
preferably also MRA
– Price is limitation. Generic to be expected.

36. CASTLE-AF

37. Catheter Ablation vs.
Standard Conventional
Treatment in Patients With
LV Dysfunction and AF
(CASTLE-AF)

38. AF and CHF: rhythm control ?

39. Catheter Ablation vs. Standard Conventional
Treatment in Patients With LV Dysfunction and
AF (CASTLE-AF)
• Inklusjon
– HF, NYHA>II, EF <35%, implanert ICD/CRT
– Paroksysmal eller permanent atrieflimmer
– Ikke effekt, eller bivirkn til antiarytmika
• Randomisert til kateter ablasjon n=179,
eller medinsk behandling n=184
• Primary end point:All-cause mortality or
worsening heart failure requiring
unplanned hospitalization

42. CASTLE-HF: Outcome
End point Hazard ratio 95% CI
All cause mortality and
worening heart failure
0.62 0.43-0.87; p=0.007
All cause mortality 0.53 0.32-0.86; p=0.0117
Worsening HF
admissions
0.56 0.37-0.83; p=0.0004
Cardiovasular mortaality 0.49 0.29-0.84; p=0.008
Cardiovascular
hospitalization
0.72 0.52-0.99 ; p=0.041
Change EF 8% vs 0%

43. CASTLE-HF: Serious adverse events
Pulmonary vein
ablation
Control
Acute bleding 3 0
Pericardial effusion 3 0
Stroke/TIA 7 12
Pulmonary vein steonsis 1 0
Pneumonia 3 1
Groin infetion 1 0

44. Conclusions
 COMMANDER-HF does not establish an indication for
OAC in HF patients in SR.
 TOPCAT does not provide a significant primary endpoint in
patients with HFpEF, but it reminds us of the importance of
using MRA in HF, shown to be the most under-utilized
medication.
 PARADIGM establishes a mortality benefit of
Sacubitril/Valsartan over Enalapril and is recommended in
current guidelines.
 CASTLE-AF may point to an advantage of rhythm-control
in HF patients with concomitant Afib.

45. 45
Thank you for your attention