Download Supplemental Table 1 - JACC: Heart Failure

Supplemental Table 1
Inclusion and Exclusion Criteria for the AVOID-HF Trial
Inclusion Criteria
1. Age ≥ 18 years
2. Male or non-pregnant female patients
3. Admitted to the hospital with a primary diagnosis of acutely decompensated HF
4. On regularly scheduled daily oral loop diuretics
5. Fluid overload manifested by at least two of the following:
a. Pitting edema ≥ 2+ of the lower extremities
b. Jugular venous distention > 8 cm
c. Pulmonary edema or pleural effusion on chest x-ray
d. Paroxysmal nocturnal dyspnea or ≥ two- pillow orthopnea
e. Respiration rate ≥ 20 per minute.
6. Have received ≤ 2 IV loop diuretics doses before randomization
7. Must be able to be enrolled into the trial ≤ 24 hours of their admission to the hospital
8. Provide written informed consent form as required by the local IRB
Exclusion Criteria
1. Acute coronary syndromes
2. Renal insufficiency with a sCr ≥ 3.0 mg/dl or planned renal replacement therapies
3. Systolic blood pressure < 90 mmHg at time of enrollment
4. Pulmonary Arterial Hypertension not secondary to left heart disease
5. Contraindications to systemic anticoagulation
6. Hematocrit > 45%
7. Inability to obtain venous access
8. Hemodyanmic instability severe enough to require IV positive inotropic agents, IV vasodilators or both
9. Use of iodinated radiocontrast material within the previous 72 hours or planned study requiring IV
contrast during the current hospitalization
10. Severe concomitant disease expected to prolong hospitalization
11. Severe concomitant disease expected to cause death in ≤ 90 days
12. Sepsis or ongoing systemic infection
13. Severe uncorrected valvular stenosis
14. Active myocarditis
15. Hypertrophic obstructive cardiomyopathy
16. Constrictive pericarditis or restrictive cardiomyopathy
17. Liver cirrhosis
18. Previous solid organ transplant
19. Requirement for mechanical ventilatory support
20. Presence of a mechanical circulatory support device
21. Unwillingness or inability to complete follow up
22. Active drug or alcohol abuse
23. Participation in another clinical trial
1
Supplemental Table 2
Secondary End-Points of the AVOID-HF Trial
I.
Efficacy
a. Total fluid removed during the index hospitalization
b. Net fluid removed during the index hospitalization
c. Weight loss at 72 hours after randomization
d. Total weight loss during the index hospitalization
e. Time to freedom from congestion, freedom from congestion is defined as
i. jugular venous distention of < 8 cm
ii. no orthopnea t
iii. race peripheral edema or no edema
f. Freedom from congestion, defined as
i. jugular venous distention of < 8 cm
ii. no orthopnea
iii. trace peripheral edema or no edema at hospital discharge
g. Changes in B-type natriuretic peptide (BNP) levels over time (72 hours, discharge, 30, 60
and 90 days)
II. Clinical
a. Length of stay (LOS) during the index hospitalization
b. Total number of days re-hospitalized for HF at 30 and 90 days after discharge
c. Total number of Emergency Department (ED) or unscheduled office visits requiring IV
therapy for HF , including diuretics and/or positive inotropic agents and/or vasodilators
at 30 and 90 days after discharge
d. Total number of HF re-hospitalizations at 30 and 90 days after discharge
e. Total number of cardiovascular (CV) re-hospitalizations at 30 and 90 days after discharge
f. Total number of days for CV re-hospitalizations at 30 and 90 days after discharge
g. All cause re-hospitalization rates at 30 and 90 days
h. Mortality rates up to 90 days after randomization
i.
j.
Days alive and out of hospital at 30 and 90 days after discharge
Quality of life assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ) at
30-, 60- and 90-days after discharge
k. Global clinical score at 30 and 90 days after discharge
III. Safety
a. Changes in renal function variables after treatment up to 90 days after randomization
i. serum creatinine (sCr)
ii. blood urea nitrogen (BUN)
iii. BUN/sCr
iv. glomerular filtration rate (eGFR) estimated with the Modification of Diet in
Renal Disease(MDRD) formula
2
Supplemental Table 3
Treatment Guidelines for the Loop Diuretic Arm
The goal of therapy is for the patient to reach dry weight and rapidly transition to oral medications
suitable for outpatient therapy.
A. At Randomization
UO > 5 L/day → Reduce current diuretic regimen if desired
UO 3-5 L/day → Continue current diuretic regimen
UO < 3 L/day → See table
Current Dose
Suggested Dose
Loop (/day)
thiazide
Loop (/day)
thiazide
A
≤ 80
+ or 40 mg IV bolus+5 mg/hr
0
B
81-160
+ or 80 mg IV bolus+10 mg/hr)
5 mg metolazone QD
C
161-240
+ or 80 mg IV bolus + 20 mg/hr
5 mg metolazone BID
D
> 240
+ or 80 mg bolus + 30 mg/hr
5 mg metolazone BID
“Loop” refers to IV furosemide. 1 mg bumetanide or 10 mg torsemide = 40 mg furosemide
B. At 24 Hours
Persistent Volume Overload Present
UO > 5 L/day → Reduce current diuretic regimen if desired
UO 3-5 L/day → Continue current diuretic regimen
UO < 3 L/day → Advance to next step on table
C. At 48 Hours
Persistent Volume Overload Present
UO > 5 L/day → Reduce current diuretic regimen if desired
UO 3-5 L/day → Continue current diuretic regimen
UO < 3 L/day → Advance to next step on table and consider:
a) IV inotropes if SBP < 110 mmHg and EF<40% or RV systolic dysfunction.
b) Nitroglycerin or Nesiritide if SBP > 120 mmHg (any EF) and Severe Symptoms
D. At 72 Hours
Persistent Volume Overload Present
UO > 5 L/day → Reduce current diuretic regimen if desired
UO 3-5 L/day → Continue current diuretic regimen
UO < 3 L/day → Advance to next step on table and consider:
a) IV inotropes if SBP < 110 mmHg and EF<40% or RV systolic dysfunction.
b) Nitroglycerin or Nesiritide if SBP > 120 mmHg (any EF) and Severe Symptoms
c) Right Heart Catheterization
E. Repeat 72 hour step until treatment complete
F. Patient evaluation guideline
a. Every 6 hours evaluate recent BP, HR, UO, Net intake/output
b. Every 12 hours evaluate serum chemistries
G. Consider Decreasing or Holding Diuretic Dose if:
a. sCr rises by >30% or 0.4 mg/dl (whichever is less) compared to prior measurement
b. Resting SBP decreases > 20mmHg compared to prior 6 hours or drops <80mmHg
c. Resting HR >30bpm compared to prior 6 hours or > 120 bpm
H. Consider Completion of Therapy if ONE of the following:
1. Resolution of congestion (all of following):
3
a. Jugular venous pressure <8cm H20
b. No orthopnea
c. Trace or no peripheral edema
2. Best Achievable “Dry Weight” has been reached
a. Hemodynamic evidence of poor tolerance of fluid removal by persistent
hemodynamic changes
AND
b. Net negative <1 liter/24hr
3. Persistent elevation in sCr >1.0 mg/dl above baseline at start of IV Diuretic Treatment
4. Persistent hemodynamic instability
I. After Completion of IV Loop Diuretic Therapy:
1. If satisfactory “dry weight” has been reached AND sCr is stable:
b. Initiate oral loop diuretics with goal to keep net even (new dose of loop diuretics may
be less than baseline dose in some patients)
c. GDMT
2. If sCr, hemodynamics, or UO are NOT stable:
a. Hold diuretics until creatinine is stable for minimum of 12 hours, and then initiate oral
diuretics as above
b. If elevated sCr or hemodynamic instability persist, then consider bolus of IV fluid
Abbreviations:
BID: twice daily; BP= Blood Pressure; BPM=Beats per Minute; EF=Ejection Fraction; GDMT: Guidelines
Determined Medical Therapy; HR= Heart Rate; IV=Intravenous; QD=once daily; RV=Right ventricle; SBP=
Systolic Blood Pressure; sCr= serum creatinine level; UO= Urine Output.
4
Supplemental Table 4
Treatment Guidelines for the Aquapheresis Arm
General Comments:
1. Once an initial UF rate is chosen, avoid increasing the UF rate unless there are clear
indications to do so.
2. Because patients’ plasma refill rate usually declines as fluid is removed, it should be
expected that UF rate will need to be decreased during the course of therapy.
A. Choose Initial UF Rate:
SBP <100mmHg: 150cc/hr
SBP 100-120mmHg: 200cc/hr
SBP >120mmHg: 250cc/hr
B. Decrease starting UF rate by 50cc/hr if any of the following are present:
a. RV > LV systolic dysfunction
b. sCr increase 0.3mg/dl above recent baseline
c. Baseline sCr > 2.0mg/dl
d. History of instability with diuresis or UF in the past
C. Re-evaluate UF. rate every 6 hours:
1. Evaluate recent BP, HR, UO, Net intake/output, sCr
2. Consider decreasing Aq. by 50cc/hr and checking STAT sCr (unless sent in past 2
hours) if:
a. sCr rise >15% or >0.2mg/dl (whichever is less) compared to prior measurement
b. resting SBP decreases > 10mmHg compared to prior 6 hours, but remains >80mmHg
c. UO drops > 50% compared to prior 6 hours, but remains >125cc/6hr
d. resting HR increases by >20bpm compared to prior 6 hours, but remains <120bpm
3. Strongly consider holding UF and checking STAT sCr if:
a. sCr rise by >30% or >0.4mg/dl (whichever is less) compared to prior measurement
b. resting SBP decreases > 20mmHg compared to prior 6 hours or is < 80mmHg
c. UO < 125cc/6hr
d. resting HR increases by 30bpm compared to prior 6 hours or is >120bpm
4. If UF held, re-evaluate after laboratory values are available:
a. If hemodynamics are stable and sCr has plateaued, then consider re-starting UF at
rate 50-100cc/hr less than previous rate
b. If persistent volume overload is present, then consider:
i. IV inotropes in patients with LVEF < 40% or RV systolic dysfunction
ii. Weaning venodilators, especially in patients with HFpEF
iii. Right heart catheterization
D. Consider completion of UF therapy If ONE of the following occurs:
1. Resolution of congestion (all of following):
a. Jugular venous pressure <8cm H20
b. No orthopnea
c. Trace or no peripheral edema
2. Best Achievable “Dry Weight” has been reached
a. Evidence of poor tolerance of fluid removal
AND
b. UF rate <100cc/hr or net negative <1 liter/24hr
3. Persistent elevation in sCr >1.0 mg/dl above baseline at start of UF treatment
5
4. Persistent hemodynamic instability
E. After completion of UF Therapy:
1. If satisfactory “dry weight” has been reached AND sCr is stable:
a. Initiate oral loop diuretics with goal to keep net even (new dose of loop diuretics may
be less than baseline dose in some patients)
b. GDMT
2. If sCr, hemodynamics, or UO are NOT stable:
a. Hold diuretics until sCr is stable for minimum of 12 hours, then:
i. If “Dry Weight” /adequate decongestion has been reached then initiate oral
diuretics as above
ii. If “Dry Weight”/adequate decongestion has NOT been reached then initiate
IV diuretics
a. If elevated sCr or hemodynamic instability persist, then consider bolus of IV fluids
Abbreviations:
BP= Blood Pressure; BPM=Beats per Minute; GDMT= Guidelines Directed Medical Therapy; HR= Heart
Rate; IV=Intravenous; LV= Left Ventricle; RV=Right ventricle; SBP= Systolic Blood Pressure; sCr= serum
creatinine level; UF= Ultrafiltration; UO=Urine Output.
6
Supplemental Table 5
Change of Quality of Life According to the Kansas City Cardiomyopathy Questionnaire
From Baseline to 30, 60 and 90 days of Follow Up after Discharge
Interval
Baseline
30 Days
P Value*
60 Days
P Value*
90 Days
P Value*
AUF
N=107
25.4±19.4
(0-92)
N=85
31.0±24.3
(0-92)
< 0.001
N=76
34.0±21.5
(0-83)
< 0.001
N=72
36.0±23.0
(0-100)
< 0.001
ALD
N=110
28.6±22.6
(0-100)
N=90
26.1± 23.0
(0-100)
< 0.001
N=72
31.4±22.4
(0-92)
< 0.001
N=76
33.6±23.0
(0-92)
< 0.001
P Value
0.433 (a)
0.182 (a)
0.450 (a)
0.558 (a)
a: P-value is from Wilcoxon's rank-sum test.
*b: P-value is testing difference from baseline and from Wilcoxon's rank-sum test.
7
Supplemental Table 6
Change in Global Clinical Score from Baseline to 30, 60 and 90 Days Follow-up after Discharge
Interval
AUF
ALD
P Value
Baseline
N=107
N=110
0.122 (a)
28.3±18.6
31.8±18.6
(2-80)
(0-76)
N=85
N=91
28.2±20.1
25.4± 18.1
(0-70)
(0-77)
P Value*
< 0.001
< 0.001
60 Days
N=76
N=72
31.6±20.3
28.0±20.3
(1-78)
(1-85)
P Value*
< 0.001
< 0.001
90 Days
N=72
N=76
31.6±20.4
30.6±21.1
(1-79)
(0-86)
< 0.001
< 0.001
30 Days
P Value*
0.449 (a)
0.197 (a)
0.697 (a)
a: P-value is from Wilcoxon's rank-sum test.
*b: P-value is testing difference from baseline and from Wilcoxon's rank-sum test
8
Supplemental Table 7
Number of Subjects with at Least One Serious Adverse Event Related to Study Therapy
by MedDRA System Organ Class and Preferred Term
MedDRA System Organ Class
MedDRA Preferred Term
AUF (N=110)
ALD (N=111)
P-value
16 (14.55%)
6 ( 5.41%)
0.026
CARDIAC FAILURE
0 (0.0%)
3 (2.7%)
0.246
CARDIO-RESPIRATORY ARREST
1 (0.9%)
0 (0.0%)
0.498
GASTROINTESTINAL DISORDERS
GASTROINTESTINAL HAEMORRHAGE
2(1.8%)
0(0. 0%)
0.247
INFECTIONS AND INFESTATIONS
INFECTION
1(0.9%)
0(0.0%)
0.498
INVESTIGATIONS
BLOOD CREATININE INCREASED
1(0.9%)
0(0.0%)
0.498
CARDIAC OUTPUT DECREASED
1(0.9%)
0 (0.0%)
0.498
DEHYDRATION
1(0.9%)
0(0.0%)
0.498
HYPERKALAEMIA
1(0.9%)
0(0.0%)
0.498
NERVOUS SYSTEM DISORDERS
NEUROLOGICAL SYMPTOM
1(0.9%)
0(0.0%)
0.498
RENAL AND URINARY DISORDERS
HAEMATURIA
1(0.9%)
0 (0.0%)
0.498
RENAL FAILURE ACUTE
2(1.8%)
2(1.8%)
>0.999
RENAL FAILURE CHRONIC
2(1.8%)
0(0.0%)
0.247
DEEP VEIN THROMBOSIS
1(0.9%)
0(0.0%)
0.498
HYPOTENSION
2 (1.8%)
1(0.9%)
0.622
SERIOUS ADVERSE EVENTS RELATED TO STUDY
PRODUCT
CARDIAC DISORDERS
METABOLISM AND NUTRITION DISORDERS
VASCULAR DISORDERS
N includes all randomized and treated subjects.
P-value is based on two randomized arms.
P-value is from Fisher's Exact test.
9
Supplemental Figure 1
Supplemental Figure 1: Flow of subjects through the study protocol.
10
Proportion of Patients alive and free of HF
Supplementary Figure 2
Time to HF Event or Death after Discharge
1.00
0.98
0.96
0.94
0.92
0.90
0.88
0.86
0.84
0.82
0.80
0.78
0.76
0.74
0.72
0.70
0.68
0.66
0.64
0.62
0.60
0.58
0.56
0.54
0.52
0.50
AQ
LD
0
10
20
30
40
50
60
70
80
90
Time to HF event or death (days)
AUF 105
ALD 108
81
75
52
50
20
16
Supplementary Figure 2 Legend: Supplemental Figure 2: Log rank analysis of the time to first heart
failure event or death from any cause after discharge from index hospitalization up to 90 days in the
AUF (squares) and ALD (triangles) groups. The difference between groups was not statistically
significant (p=0.297) due to the smaller than originally planned sample size.
11
Study Sites and Principal Investigators
Site Name
Advocate Heart Institute
St. Luke’s Hospital
Northern Indiana Research Alliance
St. Thomas Research
Huntsville Hospital
Site State
IL
MO
IN
TN
AL
Principal Investigator (M.D.)
Stan Skaluba
Andrew Kao
Mark Jones
Donald Chomsky
James Smelser
Mission Hospital/ Ashville Cardiology Associates
NC
Benjamin Trichon
Drexel University Hospital
PA
Howard Eisen
Sharp Memorial/ San Diego Cardiac Center
CA
Brian Jaski
Washington Hospital
Piedmont Heart Institute
DC
GA
Samer Najjar
Nirav Raval
Hillcrest Hospital/ Oklahoma Heart Institute
OK
Alan Kaneshige
St. John’s Mercy Hospital
University of California at Los Angeles
Abbington Memorial Hospital
Hennepin County Medical Center
Ohio State University Hospital
University of Minnesota
University of Cincinnati
Tacoma General Hospital
Mayo Clinic Scottsdale
Morton Plant Medical Center
Cleveland Clinic
Northwestern University
University of California at San Diego
MO
CA
PA
MN
OH
MN
OH
WA
AZ
FL
OH
IL
CA
Seth Barbanell
Gregg Fonarow
Robert Watson
Brad Bart
Garrie Haas
S. Carolina Masri
Andrew Burger
Viral Shah
David Eric Steidley
Mahesh Amin
Mazen Hanna
Robert Gordon
Eric Adler
Virginia Commonwealth University Med Center
VA
Richard Cooke
Scottsdale Healthcare Research Institute
AZ
Kris Vijay
Minneapolis VA Medical Center
Emory University
Good Samaritan Hospital - Dayton
Brooke Army Medical Center
MN
GA
OH
TX
Inderjit Anand
Divya Gupta
George T. Broderick
James Watts
12
Clinical Events Committee
Name
Peter E Carson, MD
Address
Washington DC VA Medical Center
50 Irving St. NW
Washington, DC 20422
JoAnn Lindenfeld, MD
Vanderbilt University
1211 Medical Center Dr, Nashville, TN 37232
Nashville, TN
Barry Greenberg, MD
University of California, San Diego
Cardiology Department
9444 Medical Center Drive
La Jolla, CA 92037-7411
13