Acute Heart Failure: Current Standards and Evolution of Care.2015

clinicaloptions.com/cardiologyAcute Heart Failure: Current Standards and Evolution of Care

Acute Heart Failure: Current Standards and Evolution of Care

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Faculty

Javed Butler, MD, MPH, MBAProfessor of MedicineChief of CardiologyDivision of CardiologyStony Brook UniversityStony Brook, New York

G. Michael Felker, MD, MHS, FACC, FAHAProfessor of MedicineChief, Heart Failure SectionDivision of CardiologyDuke UniversityDurham, North Carolina


Disclosures

Javed Butler, MD, MPH, MBA, has disclosed that that he has received consulting fees from Amgen, Bayer, CardioCell, Celladon, Novartis, Stealth Peptides, Trevena, Zensun, and ZS Pharma and fees for non-CME/CE services from Novartis.

G. Michael Felker, MD, MHS, FACC, FAHA, has disclosed that he has received consulting fees from Amgen, Bristol-Myers Squibb, Celladon, Merck, Novartis, Relypsa, Roche Diagnostics, Singulex, Stealth Peptides, and Trevena and funds for research support from Amgen, Novartis, Otsuka, and Roche Diagnostics.


Patient Case: History 71-yr-old woman with history of hypertension, diabetes,

and obesity

No prior history of HF

Presents to emergency department with chief complaint of breathlessness that has gradually progressed over 4 days; has also noticed some peripheral edema

ROS: no chest pain + orthopnea

Current medicines at home: ASA, insulin, lisinopril


Biomarkers in Diagnosis and Prognosis


Natriuretic Peptides in AHF Diagnosis ACCF/AHA guidelines: measurement of BNP or NT-proBNP is useful in aiding a

diagnosis of ADHF[1]

Breathing Not Properly study: prospective study assessing the use of BNP in diagnosing pts with HF (N = 1586)

1. Yancy CW, et al. J Am Coll Cardiol. 2013;62:e147-e239. 2. Maisel AS, et al. N Engl J Med. 2002;347:161-167.

Levels of BNP Differentiating Dyspnea due to CHF vs Other Causes[2]

BNP (pg/mL) Accuracy50 79

80 83

100 83

125 83

150 84

*Pts had a history of ventricular dysfunction.

140012001000

800600400200

0

Dyspnea due to CHF

(N = 744)

Dyspnea due to Noncardiac

Causes* (n = 72)

No CHF (n = 770)

Median BNP Levels[2]

BN

P (p

g/m

L)


Additional Biomarkers in AHF Diagnosis and Risk Stratification Cardiac troponins[1]

– Markers of myocardial injury; increased circulating levels are associated with poorer clinical outcomes and mortality

– ACCF/AHA: assessment recommended for additive risk stratification

Galectin-3 and sST2[1]

– Markers of myocardial fibrosis; prognostic for hospitalization and mortality

– ACCF/AHA: assessment recommended for additive risk stratification

Additional prognostic biomarkers[2]

– Cystatin C, AST, ALT

1. Yancy CW, et al. J Am Coll Cardiol. 2013;62:e147-e239. 2. Metra M, et al. J Am Coll Cardiol. 2013;61:196-206.


Impact of Troponin Release on Survival in AHF Analysis of the ADHERE registry for pts hospitalized for ADHF who

had troponin measurements at initial evaluation

Peacock WF, et al. N Engl J Med. 2008;358:2117-2126.

0

2

4

6

8

2.02.7

3.4

5.3

> 0.20> 0.10-0.20

> 0.04-0.10

≤ 0.04

Troponin I Quartile9534932310,36711,090Pts, n

In-H

ospi

tal M

orta

lity

(%)


Clinical Considerations


Stratification of Pts With AHF

Yancy CW, et al. J Am Coll Cardiol. 2013;62:e147-e239.

No

Warm and Dry

Yes

Warm and Wet

Cold and Dry Cold and WetYes

No

Congestion at Rest?(eg, orthopnea, elevated jugular venous pressure,

pulmonary rales, S3 gallop, edema)

Low

Per

fusi

on a

t Res

t?(e

g, n

arro

w p

ulse

pre

ssur

e,

cool

ext

rem

ities

, hyp

oten

sion

)


Systolic Blood Pressure at Admission in Pts Hospitalized for AHF Data from the OPTIMIZE-

HF registry (48,612 pts)

~ 75% pts with SBP ≥ 120 mm Hg

Gheorghiade M, et al. JAMA. 2006;296:2217-2226.

24.9% 25.2%

24.9% 24.9%

SBP < 120 mm HgSBP 140-161 mm HgSBP 120-139 mm HgSBP > 161 mm Hg


Precipitating Causes of AHF Are Poorly Understood Increased sodium diet

Myocardial ischemia

Mild respiratory or urinary tract infection

Arrhythmia (eg, atrial fibrillation )

Poorly controlled hypertension

Pneumonia

Noncompliance with chronic medications



ACCF/AHA Definitions of HFrEF and HFpEF


Classification EF, % DescriptionI. HFrEF ≤ 40 Also referred to as systolic HF. Randomized controlled trials have

mainly enrolled pts with HFrEF, and it is only in these pts that efficacious therapies have been demonstrated to date

II. HFpEF ≥ 50 Also referred to as diastolic HF. Several different criteria have been used to further define HFpEF. The diagnosis of HFpEF is

challenging because it is largely one of excluding other potential noncardiac causes of symptoms suggestive of HF. To date,

efficacious therapies have not been identified

a. HFpEF, borderline

41-49 These pts fall into a borderline or intermediate group. Their characteristics, treatment patterns, and outcomes appear

similar to those of pts with HFpEF

b. HFpEF, improved

> 40 It has been recognized that a subset of pts with HFpEF previously had HFrEF. These pts with improvement or recovery in EF may be clinically distinct from those with persistently preserved or reduced

EF. Further research is needed to better characterize these pts


Distribution of LVEF in AHF Pts

LVEF (%)

0-5

6-10

11-15

16-20

21-25

26-30

31-35

36-40

41-45

46-50

51-55

56-60

61-65

66-70

71-75

76-80

81-85

86-90

91-95

96-100

Pts

(n)

Documented LVEF Measured Prior to or During HospitalizationHFrEF HFpEF

Fonarow GC, et al. J Am Coll Cardiol. 2007;50:768-777.

5000

4000

3000

2000

1000

0


ADHERE CART Analysis: In-Hospital Mortality Assessed 33,046 pts

hospitalized with AHF

Pts could be classified as having a low, intermediate, or high risk of in-hospital mortality based on admission levels of:

– BUN

– SBP

– Serum creatinine

Pats with lowest mortality risk (2.14% crude mortality [445/20,834]):

– BUN < 43 mg/dL

– SBP ≥ 115 mm Hg

Pts with highest mortality risk (21.94% crude mortality [136/620]):

– BUN ≥ 43 mg/dL

– SBP < 115 mm Hg

– Serum creatinine ≥ 2.75 mg/dL

Fonarow G, et al. JAMA. 2005;293:572-580.


Worsening Renal Function as a Prognostic Indicator for Pts With AHF Study assessed 1681 pts 65 yrs of age or older

Krumholz H, et al. Am J Cardiol. 2000;85:1110-1113.

Outcome RF Not Worse(n = 1212)

RF Worse(n = 469) OR (95% CI)

In-hospital mortality, % 3 7 2.7 (1.6-4.6)

30-day mortality, % 6 10 1.9 (1.3-2.8)

6-mo mortality, % 19 25 1.6 (1.2-2.1)

Length of hospital stay, days 6.93 9.14


Patient Case: Initial Assessment Exam

– BP 174/93, HR 90, BMI 39

– JVP difficult to assess due to body habitus

– RRR: no murmurs or gallops

– Basilar rales

– 2+ lower extremity edema to knees

Labs and Imaging

– Serum creatinine 1.8 mg/dL

– Troponin levels not elevated

– ECG shows NSR and narrow QRS, with nonspecific ST-T wave changes

– CXR shows cardiomegaly with increased interstitial markings


Current Treatment Options


Diuretics in Hospitalized Pts ACCF/AHA guidelines (Class I, LOE B recommendation)

– Pts with HF admitted with evidence of significant fluid overload should be promptly treated with IV loop diuretics to reduce morbidity

– If pts are already receiving loop diuretic therapy, the initial IV dose should equal or exceed their chronic oral daily dose and should be given as either intermittent boluses or continuous infusion. Urine output and signs and symptoms of congestion should be serially assessed, and the diuretic dose should be adjusted accordingly to relieve symptoms, reduce volume excess, and avoid hypotension



DOSE: Loop Diuretics in AHF Double-blind, randomized trial of low- vs high-dose IV furosemide via bolus or

continuous infusion in AHF pts (N = 308)

Coprimary endpoints: pts’ global assessment of symptoms and change in serum creatinine level from baseline to 72 hrs

0.08

0.10

Cha

nge

in C

reat

inin

e (m

g/dL

)

Low Dose

P = .21

Felker GM, et al. N Engl J Med. 2011;364:797-805.

0.05

00.04

100

80

60

40

20

0

Glo

bal A

sses

smen

t of

Sym

ptom

s (G

loba

l VA

S Sc

ore)

0 10 20 30 40 50 60 70Hrs

AUC with low-dose strategy: 4171 ± 1436AUC with high-dose strategy: 4430 ± 1401P = .06

High dose Low dose

High Dose


Vasodilators in AHF ACCF/AHA guidelines (Class IIb, LOE A recommendation)

– If symptomatic hypotension is absent, IV nitroglycerin, nitroprusside or nesiritide may be considered an adjuvant to diuretic therapy for relief of dyspnea in pts admitted with acutely decompensated HF



8.69.5

10

ASCEND-HF: 6- and 24-Hr Dyspnea and Mortality/Rehospitalization Randomized, placebo-controlled phase III study of nesiritide for 24-168 hrs in

hospitalized pts with AHF (N = 7141)

O’Connor CM, et al. N Engl J Med. 2011;365:32-43.

12

10

8

6

4

2

0

10.1

4.0

9.4

6.1

3.6

6.0

Death or Rehospitalization

for HF

Death Rehospitalization for HF

Death From Any Cause or Rehospitalization for HF at 30 Days

-0.4 (-1.3 to 0.5)

-0.7 (-2.1 to 0.7)

-0.1 (-1.2 to 1.0)

Percentage point difference (95% CI)

P = .31HR: 0.93 (95% CI: 0.8-1.08)

Placebo Nesiritide

42.113.4

28.7

34.1

21.7

44.515.0

29.5

32.8

20.3

706050403020

0102030405060

Placebo(n = 3444)

Nesiritide (n = 3416)

66.1

27.5

38.6

22.1

68.2

30.4

37.8

21.2

Placebo(n = 3398)

Nesiritide

(n = 3371)

6 HrsP = .03

24 HrsP = .007

Self-Assessed Change in Dyspnea

Markedly better

Moderately better

Minimally better

No change

Minimally worse

Moderately worse

Markedly worse

Pts

(%)

Pts

(%)


1-yr mortality rates did not change over the last decade[2]

Nearly 1 in 4 AHF ptsreadmitted within 30 days[1]

1. Dharmarajan K, et al. JAMA. 2013;309:355-363. 2. Chen J, et al. JAMA. 2011;306:1669-1678.

Postdischarge Outcomes in AHF

30

0

5

25

10

20

15

Pts

Rea

dmitt

ed (%

)

Days FollowingHospital Discharge

20100 30 40

100

0

20R

isk-

Adj

uste

dM

orta

lity

Rat

e* (%

)

Yr

2003

2002

1999

2001

2005

2000

2008

2007

40

2006

2004

80

60

*Risk-adjusted rates relative to 1999.


Inotropic Support ACCF/AHA guidelines (Class IIb, LOE B recommendation)

– Short-term, continuous IV inotropic support may be reasonable in those hospitalized pts presenting with documented severe systolic dysfunction who present with low blood pressure and significantly depressed cardiac output to maintain systemic perfusion and preserve end-organ performance



AE

Rat

e (%

)

Treatment Failure From AE (48 hrs)

Sustained Hypotension

Acute MI Mortality

Milrinone

Placebo

Afib

P < .001P < .001

P = .18

P = .004 P = .19

12.6

2.1

10.7

3.21.5

0.4

4.6

1.5

3.82.3

0

5

10

15

20

OPTIME-CHF: In-Hospital AEs Randomized, double-blind, placebo-controlled trial of short-term IV milrinone

in pts hospitalized due to chronic heart failure exacerbation (N = 951)

Cuffe MS, et al. JAMA. 2002;287:1541-1547.


Ultrafiltration ACCF/AHA guidelines

– Ultrafiltration may be considered for pts with obvious volume overload to alleviate congestive symptoms and fluid weight (Class IIb, LOE B recommendation)

– Ultrafiltration may be considered for pts with refractory congestion not responding to medical therapy (Class IIb, LOE C recommendation)



WeightGain(lb)

CARRESS: Change in Creatinine and Weight at 96 Hrs Randomized trial of ultrafiltration vs stepped pharmacologic therapy

in pts with AHF, worsened renal function, and persistent congestion (N = 188)

Bart BA, et al. N Engl J Med. 2012;367:2296-2304.

P = .003

WeightLoss(lb)

Creatinine Increase (mg/dL)

Creatinine Decrease (mg/dL)

1.00.8

0.60.4

0.20

-0.2-0.4

-0.6-0.8

0-2-4-6-8-10-12-14-16-18-20

Ultrafiltration(n = 92)

Pharmacologic therapy(n = 94)


CARRESS: Change in Creatinine Over 60 Days

Bart BA, et al. N Engl J Med. 2012;367:2296-2304.

0.30

0.20

0.10

0

-0.10

-0.20

-0.30

-0.40

-0.50

P = .35

72 Hrs

48 Hrs

24 Hrs

96 Hrs

7 Days

30 Days

60 Days

Serum Creatinine

P = .048 P = .007P = .002

P = .50

P = .17

P = .03Mea

n C

reat

inin

e C

hang

e Fr

om

Bas

elin

e (m

g/dL

)

Pharmacologic therapyUltrafiltration


Patient Case: Treatment Echocardiogram shows EF 30% with global hypokinesis,

mild MR/TR

Treated with IV furosemide and continuation of oral medications

Responds with brisk diuresis and improvement in symptoms

Pt is discharged with improved symptoms on hospital Day 6

Added carvedilol and spirolactone to outpatient regimen


Investigational Agents


Ularitide Natriuretic peptide with

vasodilating and diuretic properties

Previously assessed in the randomized, double-blind, placebo-controlled phase II SIRIUS trial (N = 221)[1]

– Standard of care + IV ularitide improved dyspnea and decreased PWCP vs placebo in hospitalized pts with AHF

TRUE-AHF[2] – Multicenter, randomized,

double-blind, placebo-controlled phase III study

– Pts will receive IV ularitide or placebo for 48 hrs within 12 hrs of ED admission

– Pts will have persisting dyspnea at rest despite standard therapy for AHF

Primary endpoints– Clinical composite including

dyspnea relief, worsening of heart failure, and all-cause mortality

– CV mortality1. Mitrovic V, et al. Eur Heart J. 2006;27:2823-2832.2. Clinicaltrials.gov. NCT01661634.


1. Stewart DR, et al. J Clin Endocrinol Metab. 1990;70:1771-1773. 2. Szlachter BN, et al. Obstet Gynecol. 1982;59:167-170. 3. Teerlink JR, et al. Lancet. 2013;381:29-39.

Serelaxin Relaxin: naturally occurring peptide; normal hormone of pregnancy[1,2]

Benign safety profile

RELAX-AHF[3]

– Randomized, placebo-controlled trial of standard of care + 48 hrs IV serelaxin or placebo in hospitalized pts w/AHF (N = 1161)

– Serelaxin treatment improved dyspnea, as measured by VAS AUC (19.4% increase in AUC with serelaxin from baseline through Day 5 vs placebo)


RELAX-AHF: CV Death Through Day 180

0

14

12

10

8

6

4

2

CV

Dea

th (I

TT) (

%)

0 14 30 60 90 120 150 180

HR: 0.63 (95% CI: 0.41-0.96; P = .028)

55 (9.6)

35 (6.1)

Placebo (n = 580)

Serelaxin (n = 581)

Events, n (%)

NNT = 29

DaysTeerlink JR, et al. Lancet. 2013;381:29-39.


120

16040 80 140

18020 60 1000

Prognostic Indicators of 180-Day Mortality

Metra M, et al. J Am Coll Cardiol. 2013;61:196-206.

< 30% decrease≥ 30% decrease

NT-proBNP

< 22 nmo/L Increase (0.3 mg/L)≥ 22 nmo/L Increase (0.3 mg/L)

Cystatin C

Cum

ulat

ive

Ris

k

Study Day

< 20% increase≥ 20% increase

ALT

Cum

ulat

ive

Ris

k


Troponin T

0

No WHF to Day 5WHF to Day 5

Worsening Heart Failure

0


AST

0.47 (0.31-0.69)P = .0001

2.10 (1.38-3.20)P = .0004

1.96 (1.13-3.40)P = .0152

1.80 (1.16-2.78)P = .0076

1.66 (0.92-3.00)P = .0987

1.90 (1.11-3.22)P = .0164

120

16040 80 140

18020 60 1000

120

16040 80 140

18020 60 1000

120

16040 80 140

18020 60 1000

0

0.20

0.15

0.10

0.05

0

120

16040 80 140

18020 60 1000

0.20

0.15

0.10

0.05

0

120

16040 80 140

18020 60 1000

Study Day

0

Study Day


Omecamtiv Mecarbil Selective activator of cardiac myosin

In a placebo-controlled study in healthy volunteers (N = 34), 6-hr infusions of omecamtiv mecarbil

– Prolonged systole ejection time

– Increased stroke volume

– Increased fractional shortening

– Increased ejection fraction

Teerlink JR, et al. Lancet. 2011;378:667-675.


ATOMIC-AHF Randomized, placebo-controlled phase II study of omecamtiv mecarbil for treating AHF

(N = 606)

3 sequential dose-escalation cohorts received 48-hr IV OM infusion (cohorts 1-3 targeted median OM plasma concentrations of 115, 230, and 310 ng/mL, respectively)

Primary endpoint: dyspnea symptom response (7-point Likert scale) through 48 hrs

Teerlink JR, et al. ESC 2013. Abstract 709.

Response Rate Ratio* (95% CI)

Cohort 1 1.03 (0.79-1.35)

Cohort 2 1.15 (0.90-1.47)

Cohort 3 1.23 (0.97-1.55)

Pooled Placebo(n = 303)

OMCohort 1(n = 103)

OMCohort 2(n = 99)

OMCohort 3(n = 101)

*Relative to pooled placebo.

100

0

41 42 47 51

Overall P = .33

Dys

pnea

Res

pons

e R

ate

(% R

espo

nder

s)

20

40

60

80


Postdischarge Outcomes in AHF Nearly 1 in 4 AHF pts readmitted within 30 days

Dharmarajan K, et al. JAMA. 2013;309:355-363.

30

0

5

25

10

20

15

Pts

Rea

dmitt

ed (%

)

Days FollowingHospital Discharge

20100 30 40


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Acute Heart Failure: Current Standards and Evolution of Care.2015

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