Μedical management of heart failure: Update 2014

Dr John T ParissisDr John T Parissis

Attikon University Hospital

Athens, Greece

Disclosures: Received honoraria as consultant or research grants by Orion-

Pharma, Servier, Pfizer

Evidence-Based Treatment for Heart Failure with Reduced LVEF

Control VolumeReduce Mortality

Sodium Restriction*

Diuretics*

β-Blocker

ivabradine

ACEI

or ARB

Aldosterone

Antagonist

Treat Residual Symptoms

Digoxin*

Treat Residual SymptomsCRT ±

an ICD*Hyd/ISDN*

*For select indicated patients.

ICD*

Treat Comorbidities

Aspirin*

Warfarin*

Statin*

Enhance Adherence

Education

Disease Management

Performance Improvement Systems18

ESC 2012

Hospitalization

free survival

1.0

0.9

0.8 High (100%)

Adherence to HF guidelines predicts HF

hospitalizations

0.7

0.6

0.5

0 20 60 100 120

Log rank test p = 0.002

Low (0-33%)

Moderate (50-67%)

days

40 80 140 160 180

Komajda M et al. Eur Heart J 2005.

Heart Failure Guidelines and Clinical Practice

(Please mind the gap)

Overall, only 25% of patients are discharged from hospital receiving ACE/ARB + BB + diuretic oral combination therapy, suggesting poor compliance with guidelines (ALARM REGISTRY)

20%16%

31%16%

5%

Mexico

Brazil

Australia

Turkey

Oral heart failure medications on discharge

All patients receiving BB + ACE and/or ARB + DIUR

19%60%

25%20%

38%20%

0% 10% 20% 30% 40% 50% 60% 70%

Greece

UK

Spain

Italy

Germany

France

Sample =All discharged/surviving AHF patients, 4491

Follath F, Yilmaz B, Parissis J, et al. Intensive Care Med 2011 Sept;38(1):170-177

Maggioni A P et al. Eur J Heart Fail 2010;12:1076-1084

Impact of Discharge Use of Beta Blocker on Early Clinical Outcomes in Heart Failure

Survival Probability

1.00

0.95

0.90

0.85

P=0.0003

30 day Survival

P<0.01

*Only subset of patients with 60- to 90-day follow-up are included. Patients with beta-blocker contraindications are excluded.

Survival Probability

0.85

0.80

0.75

0.700 10 20 30 40 50 60 70 80 90 100 110 120 130

Patients at Risk

Beta-blocker 1,946 1,855 1,649 333 68

No Beta-blocker 362 337 304 60 7

Days After Hospital Discharge

Beta-Blocker No Beta-Blocker

Fonarow et al. J Am Coll Cardiol. 2008;52:190-199.27

ESC HF LONG TERM REGISTRY

Patient education and support reduces HF hospitalization rates and cost

Krumholz et al. J Am Coll Cardiol 2002;39:83–9

A Maisel JACC 2013

Primary Results of the HABIT Trial(Heart Failure Assessment With BNP in the Home)

Maisel et al. J Am Coll Cardiol 2013;61:1726–35

ESC guidelines 2012

Conventional Treatments of Acute Heart Failure

Diuretics

Reduce

fluid

Vasodilators

Decrease

preload

Inotropes

Augment

contrac-

Fonarow GC. Rev Cardiovasc Med. 2001;2(suppl 2):S7–S12.

fluid

volume

preload

and/or

afterload

contrac-

tility

Patients with EF<40%Whole cohort of ALARM

Impact of high vs low dose of diuretics on short term

mortality of AHF patients using propensity matched scores

A. Mebazaa and J. Parissis on behalf of ALARM investigators EJHF 2012

Role of Congestion and Its Interaction With Renal Function in Advanced HF

Metra M et al. Circ Heart Fail 2012

Short-term Survival by Treatment Among Patients Hospitalized with Acute Heart Failure: The Global ALARM-HF Registry Using Propensity Scoring Methods

0.2

0.3

0.4In-hospital mortality

Inotropes

0 5 10 15 20 25 30

0.0

0.1

0.2

Days

In-hospital mortality

Whole cohort

Diuretics

Vasodilators

Mebazaa A, Parissis J, Porcher R, et al. Intensive Care Med 2011 Feb;37(2):290-301

Dobutamine: cl IIa, Level evidence C

PDEIs: cl III, Level evidence B

Available inotropic agents

Dopamine: cl IIb, Level evidence C

Levosimendan: cl IIb,Level evidence C

for patients on beta-blocker

ESC Guidelines 2012.

Classical therapies are insufficient to protect peripheral organs

ESC HF pilot, ALARM-HF, ADHERE, SURVIVE demonstrated:

� Worsening of renal function (30-45%)

� Hepatic dysfunction (20-30%)

� Ongoing myocardial injury (Tn release) (30%)

� Hyponatremia, CNS abnormalities ( 12-20%)

Investigational pharmacotherapies for the management of ADHF

INOTROPES

- Myocin activators

- SERCA enhancers

and Na/K-ATPase

inhibitors

- Ryanodine receptor stabilizers

METABOLIC

MODULATORS

DeComa et al. JACC 2006;48:2397

MODULATORS

- CPT-1 inhibitors

DIURETICS

- Adenosine antagonists

- Vasopressin antagonists

- Natriuretic peptides (ularitide)

VASODILATORS

- Relaxin

The challenge of cardiac myocin activation

- Target the force

generating enzyme cardiac

myosin ATPase, accelerating

its activity.

- Increase fractional

shortening of cardiac shortening of cardiac

myocytes without

altering intracellular

calcium levels in

experimental models.

-An IV formulation of

CK1827452 is currently in

phase I clinical development.

Malic et al. AHA Scientific Sessions 2005 Dallas TX

HFSA 2006

Circ Heart Fail 2010;3:522-527

Istaroxime: a Na/K-ATPase inhibitor with positive lusitropic properties

Sabbah et al. Am J Cardiol 2007;99:41A

Adamson et al. J Cardiovasc Pharmacol 2003;42:169

Changes in hemodynamic and other measures in the HORIZON-HF trial, three dosages of IV istaroxime vs placebo

µg/kg/minParameter 0.5,

n=291.0, n=30

1.5, n=30

Placebo, n=31

PCWPa (mm Hg) -3.2b -3.3c -4.7d 0.0

Systolic BP (mm Hg) +4.9 +8.3b +15.6d +1.3

MAP (mm Hg) +2.2 +3.3 +7.5c +0.9

Gheorghiade M et al. J Am Coll Cardiol 2008; 51:2276-2285.

MAP (mm Hg) +2.2 +3.3 +7.5c +0.9

LVEDV (mL) +2.9 -6.4 -14.1b +3.9

QTc (ms) -25.7e -38.0e -49.2e -2.4

a. Primary end pointb. p<0.05c. p<0.01 d. p<0.001e. p=0.0001PCWP=pulmonary capillary wedge pressureMAP=mean arterial pressureLVEDV=left ventricular end-diastolic volume; QTc=corrected QT interval

Treatment of SR Ca2+ leak in HF with ryanodine receptor stabilizers

Masafumi Yano et al. Circulation. 2003;107:477-484

CURRENT VASOPRESSIN ANTAGONISTS

G. Filippatos and J. Parissis, J Card Fail 2008;14:648-650

60-Day All-cause Mortality

8.7

18.7 2017.8

13.2

9.1

20

Percent (%)

P<0.05P <0.05

Placebo

Tolvaptan

Vasopressin Antagonist for Heart Failure:ACTIV in CHF Trial

* Edema, Dyspnea, and JVD at baseline

Overall Hyponatremia (Na+ <136 mEq/L)

BUN

(> 29 mg/dL)Congestion*

8.7

5.4

9.1

5.5

0

10

Percent (%)

N = 80 239 16 53 30 110 41 163

(20%) (22%) (37%) (46%) (51%) (68%)

Gheorghiade M. JAMA. 2004;291:1963-1971.

Proportion Surviving

0,6

0,8

1

Tolvaptan

Placebo

Kaplan-Meier analysis of all-cause mortality in the EVEREST trial

Months in Study

Proportion Surviving

Log-Rank Test: P=.76

0

0,2

0,4

0 3 6 9 12 15 18 21 24

Konstam et al. JAMA 2007;297:1319-31.

Effects of adenosine antagonists on GFR and diuresis in ADHF

Gottlieb et al. Circulation 2002;105:1348

Primary Endpoint (PROTECT)Percent of Patients

Odds ratio (95% CI) vs Pbo: 0.92 (0.78, 1.09)

36.0 40.6

60

80

100

Percent of Patients

44.2

19.8

37.5

21.80

20

40

60

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

Time to Death or CV or Renal Rehospitalization - Day 60

0.4

0.3

0.2

0.1

Cumulative Risk

Hazard Ratio (95% CI) = 0.98 (0.83, 1.17)

P-value = 0.861

Placebo

Rolofylline 30 mg

0.0

0 5 10 15 20 25 30 35 40 45 50 55 60 65

Study Day

Death: Placebo 9.5% vs rolofylline 8.9%

Re-hospitalization: Placebo 25.6% vs rolofylline 25.7%

New natriuretic peptides: ularitide

� In 1988, Urodilatin, a renally synthesized isoform of ANP was isolated from human urine.

� Both experimental and early clinical trials demonstrated therapeutic effects of urodilatin (diuresis, natriuresis, vasodilation , reduction of PCWP) to a greater extent than ANP.ANP.

� In SIRIUS I (n=24 pts) and II (n=221pts) ularitide caused a greater improvement of CI and reduction of SVR and NT-proBNP than placebo persisting at 24 hours (neutral effect on 30-day mortality and renal function).

� Ularitide at 30 ng/Kg/min caused SBP reduction/ hypotension in 16% of pts.

(SBP< 80 mm Hg in 10.9% of pts)

Mitrovic et al. Am Heart J 2005;150:1239

Mitrovic et al. Eur Heart J 2006; 27:2823

Beneficial effects of ularitide on clinical status of decompensated HF patients: SIRIUS II

Mitrovic, V. et al. Eur Heart J 2006 27:2823-2832; doi:10.1093/eurheartj/ehl337

The Ularitide Global Evaluation in Acute Decompensated Heart Failure (URGENT), a

phase 3, randomized, double-blind, placebo-controlled study of ularitide in the treatment

of patients with AHFS is expected to begin soon.

Relaxin Mechanisms of Action

� Vasodilation

– NO, cGMP effectors

– Induction of NOS II/III

– Upregulation of endothelial endothelin type B receptor, which mediates vasodilation

� Preferential dilation of

Relaxin

� 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-α, TGF-β)

� Other: Anti-ischemic, Anti-apoptotic, Anti-fibrotic

Teichman, SL, et al. Heart Fail Rev 2009; Dschietzig, T, et al. Pharmacol Therap 2006

RELAX-AHFEffect of serelaxin on AHF symptoms

Serelaxin, recombinant

human relaxin-2, is a

vasoactive peptide hormone

with many biological and

haemodynamic effects

Inclusion criteria (1161pts)

Teerlink et al. Lancet 2013;381:29-39

Inclusion criteria (1161pts)

•dyspnoea

•congestion on Rx

•Increased BNP/NT-proBNP

•GFR: 30-75ml/min

•Systolic BP>125 mm Hg.

48-h i.v. serelaxin or placebo (30

μg/kg per day) within 16 h from

presentation

RELAX-AHFEffect of serelaxin on 180d mortality

Teerlink et al. Lancet 2013;381:29-39

Effect of Serelaxin on Cardiac, Renal, and Hepatic Biomarkers in RELAX-AHF

J Am Coll Cardiol 2013;61:196–206)

Serelaxin in AHF patients with preserved LVEF: RELAX-AHF sub-analysis

Filippatos et al Eur Heart J 2013 November 12

Etiology of Anemia inPatients With Advanced Heart Failure

37 advanced CHF pts; NYHA IV; mean LVEF: 37 advanced CHF pts; NYHA IV; mean LVEF: 22%.

Nanas J Nanas J ,,…, Anastasiou…, Anastasiou--Nana MNana M . . J Am Coll Cardiol 2006;48:2485–9

Ferric Carboxymaltose in Patients with HeartFailure and Iron Deficiency(Anker S, Colet C, Filippatos G, et al. NEJM 2009)

CONCLUSION

� Patient education and further implementation of treatment guidelines are essential approaches to improve outcomes in HF.

� There are still no Class I effective therapies in AHF in comparison to � There are still no Class I effective therapies in AHF in comparison to CHF.

� Investigational drugs targeting to novel pathophysiologic concepts are promising treatment approaches and ongoing trials will define their clinical efficacy and safety.