Diuretic Strategies in AHF:

Dose DOSE Matter?

Michael Felker, MD, MHS, FACC, FAHA

Professor of Medicine

Chief, Heart Failure Section

Duke University School of Medicine

Does DOSE Matter?

• It matters to some people

– Me

– My mom

– Dr. Shah

– My Department Chair/Dean

It Matters to Patients!

Lucas C, et al. Am Heart J. 2000;140:840-847.

Fonarow GC, et al. Circulation.

1994;90(pt. 2):1-488.

Logeart D, et al. J Am Coll Cardiol.

2004;43:635-641

Signs and symptoms PCWP BNP

Persistent Congestion (Clinical or Subclinical)

Associated with Poor Outcomes in AHF

Contemporary Pharmacotherapy for ADHF

0

10

20

30

40

50

60

70

80

90

%

Diuretics Dopamine Dobutamine Milrinone Nesiritide NTG

Fonarow,GC et al. AHJ 2007

Fra

cti

on

al E

xcre

tio

n o

f S

od

ium

Diuretic Concentration

Normal

Heart Failure

Diminished

maximal

responsiveness

Higher doses

required to

achieve same

diuretic effect

Ellison DH. Cardiology, 2001.

Acute Heart Failure (1 symptom AND 1 sign)

<24 hours after admission

2x2 factorial randomization

Low Dose (1 x oral)

Q12 IV bolus

48 hours

1) Change to oral diuretics

2) continue current strategy

3) 50% increase in dose

Co-primary endpoints

High Dose (2.5 x oral)

Q12 IV bolus

Low Dose (1 x oral)

Continuous infusion High Dose (2.5 x oral)

Continuous infusion

72 hours

DOSE: Study Design

Clinical endpoints

60 days

Felker GM et al, NEJM 2011

Patient Global Assessment :

Results from DOSE

Felker GM et al, NEJM 2011

Change in Creatinine at 72 hours

0.05 0.07

0.04

0.08

0

0.05

0.1

0.15

Ch

an

ge i

n C

reati

nin

e (

mg

/dL

)

Felker GM et al, NEJM 2011

Q12 Continuous Low High

P = 0.21 P = 0.45

Secondary Endpoints: Low vs. High

Low High P value

Dyspnea VAS AUC at 72 hours 4478 4668 0.041

% free from congestion at 72 hrs 11% 18% 0.091

Change in weight at 72 hrs -6.1 lbs -8.7 lbs 0.011

Net volume loss at 72 hrs 3575 mL 4899 mL 0.001

Change in NTproBNP at 72 hrs (pg/mL) -1194 -1882 0.06

% Treatment failure 37% 40% 0.56

% with Cr increase > 0.3 mg/dL

within 72 hrs

14% 23% 0.041

Length of stay, days (median) 6 5 0.55

Felker GM et al, NEJM 2011

Change in Cystatin C over Time

0

0.05

0.1

0.15

0.2

0.25

0 10 20 30 40 50 60

Low High

Days

Ch

an

ge i

n C

ysta

tin

C

What about other alternatives/adjuncts to

furosemide?

• Alternative loop diuretics?

• Sequential nephron blockade with thiazides?

• Natriuretic doses of MRA?

• “renal dose” dopamine?

• “renal dose” nesiritide?

• Vasopressin antagonists revisited?

Are All Oral Diuretics Created Equal?

HR 0.56 (0.36-0.87)

P = 0.038

*Adjustment variables: country of randomization, age, previous

hospitalization for HF, baseline SBP, baseline sodium, baseline BUN, and

having a qualifying episode with JVD Mentz, RM under review

Sequential Nephron Blockade

Jentzer, J. et al JACC,2010

Sequential Nephron Blockade

• Use of loop diuretic in combination with thiazide or

thiazide like diuretic (metolazone)

• Has not been rigorously studied

• Can induce potent diuresis in patients with diuretic

resistance, but

• Associated with multiple electrolyte abnormalities

– Hypokalemia

– Hyponatremia

– Hypomagnesemia

• Use with caution

European J Int Med, 2014

Natriuretic Doses of MRAs?

ATHENA–HF Primary Objective and Endpoint

Objective

To determine if high-dose

spironolactone administered

to patients with AHF will lead

to greater reductions in N-

terminal pro-B-type natriuretic

peptide (NT-proBNP) levels

from randomization to 96 hr.

Primary Endpoint

Change in NT-proBNP from

randomization to 96hr.

Patients admitted with AHFNot on or on low dose MRA on admission

K ≤5.0 mmol/leGFR ≥30 ml/min/1.73m2

BNP >250 pg/ml or NT pro BNP >1000 pg/ml≤24 hours from first dose of IV diuretics

Baseline Assessment, NT-proBNP

Not on MRA On low dose MRA

PlaceboHigh Dose

spironolactone (100mg)

Low Dose spironolactone (25mg)

High Dose spironolactone

(100mg)

In-hospital: K and Cr Assessment q24 hours until 96 hours & pre-discharge

Adjust dose accordingly if needed

96 HoursPrimary Endpoint – Change in NT proBNP

Multiple Secondary Endpoints

30 Day Phone CallMultiple Tertiary Endpoints

From 96 hours to discharge and post-dischargeMRA use per treating physician discretion

6 Month Phone CallVital Status

ROSE Study Design

Standardized Diuretic Dosing For 1st 24 hours

2.5 x Outpt Furosemide Equivalent in Divided (BID) IV Doses

Low Dose Dopamine:

Co-primary End-points

72 Hour Urine

Volume

Change in

Cystatin-C

Chen, HH et al. JAMA 2013

Low Dose Nesiritide

Co-primary End-points

8.3 8.6

0

5

10

15

72-h

ou

r u

rin

e v

olu

me (

L)

Placebo Nesiritide

P=0.25

0.11

0.07

0.00

0.05

0.10

0.15

0.20

Ch

an

ge in

Cysta

tin

C (

mg

/L)

Placebo Nesiritide

P=0.35

72 Hour Urine

Volume

Change in

Cystatin-C

Chen, HH et al. JAMA 2013

Safety Endpoints

Study Drug Tolerance Nesiritide

(n=119)

Placebo

(N = 119)

P

Value

Study drug d/c - Hypotension 18.8% 10.4% 0.07

Study drug d/c - Tachycardia 0% 0.9% 0.50

Study drug d/c – Any Cause 25% 25% 0.94

Study Drug Tolerance Dopamine

(n=122)

Placebo

(N = 119)

P

Value

Study drug d/c - Hypotension 0.9% 10.4% <0.001

Study drug d/c - Tachycardia 7.2% 0.9% <0.001

Study drug d/c – Any Cause 23% 25% 0.72

EVEREST: Decongestion at 24 hours

– 1.7

± 1.8 – 1.0

± 1.8 – 1.8

± 2.0 – 0.9

± 1.9

Both trials

P<0.001

Difference 0.7 kg 0.9 kg

Δ in

Dyspnea

Δ in BW (kg)

Tolvaptan Placebo Tolvaptan Placebo

Both trials

P<0.001

37 35 33 31

24 24 25 23

16 11 14

11

–2 –3 –2 –3

–20

0

20

40

60

80

Tolvaptan Placebo Tolvaptan Placebo (n=894) (n=915) (n=941) (n=914)

Improved

worsened

Markedly better

Moderately better

Minimally better

Worse

Gheorghiade, JAMA 2007

Dyspnea Improvement with Tolvaptan

Pang PS, et al. Eur Heart J 2009

Conclusions and Take Home Message

Decongestion is important by whatever means in improving

outcomes

Current approaches generally lacking in robust evidence

Remains major unmet need in HF that requires ongoing study

Freedom From Congestion at 72-96 Hrs

Felker GM, et al N Engl J Med. 2011 Bart, B et al, N Eng J Med 2012 Chen et al, JAMA 2013

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

DOSE ROSE CARRESS

Fre

ed

om

Fro

m C

on

gesti

on

You will be diuresed. Resistance is futile.