®“edical management of heart failure: Update ... Hospitalized with Acute Heart Failure:...

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Transcript of ®“edical management of heart failure: Update ... Hospitalized with Acute Heart Failure:...

  • 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 Volume Reduce Mortality

    Sodium Restriction*

    Diuretics*

    β-Blocker

    ivabradine

    ACEI

    or ARB

    Aldosterone

    Antagonist

    Treat Residual Symptoms

    Digoxin*

    Treat Residual Symptoms CRT ±

    an ICD* Hyd/ISDN*

    *For select indicated patients.

    ICD*

    Treat Comorbidities

    Aspirin*

    Warfarin*

    Statin*

    Enhance Adherence

    Education

    Disease Management

    Performance Improvement Systems 18

  • 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

    S u rv iv a l P ro b a b ili ty

    1.00

    0.95

    0.90

    0.85

    P=0.0003

    30 day Survival

    P

  • 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

  • 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

    0.4 In -h o s p it a l m o rt a li ty

    Inotropes

    0 5 10 15 20 25 30

    0.0

    0.1

    0.2

    Days

    In -h o s p it a l m o rt a li ty

    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/min Parameter 0.5,

    n=29 1.0, 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 point b. p

  • 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 20 17.8

    13.2

    9.1

    20

    P e rc e n t (% )

    P

  • P ro p o rt io n S u rv iv in g

    0,6

    0,8

    1

    Tolvaptan

    Placebo

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

    Months in Study

    P ro p o rt io n S u rv iv in g

    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) P e rc e n t o f P a ti e n ts

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

    36.0 40.6

    60

    80

    100

    P e rc e n t o f P a ti e n ts

    44.2

    19.8

    37.5

    21.8 0

    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

    C u m u la ti v e R is k

    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.