Benefits of Natriuretic Peptide Guided Heart
Failure Therapy for Patients With Chronic
Left Ventricular Systolic Dysfunction
Results of the Pro-BNP Outpatient Tailored
Chronic Heart Failure Therapy (PROTECT) Study
James L. Januzzi, Jr, MD, Shafiq U. Rehman, MD, Asim A. Mohammed, MD, Anju
Bhardwaj, MD, Linda Barajas, RN, Justine Barajas, Han-Na Kim, MD MPH, Aaron L.
Baggish, MD, Rory B. Weiner, MD, Annabel Chen-Tournoux, MD, Jane E. Marshall, RDCS,
Stephanie A. Moore, MD, William D. Carlson, MD, Gregory D. Lewis, MD, Jordan Shin, MD,
Dorothy Sullivan, ANP, Kimberly Parks, DO, Thomas J. Wang, MD, Shawn A. Gregory, MD,
Shanmugam Uthamalingam, MD, and Marc J. Semigran, MD
Heart Center, Massachusetts General Hospital
Boston, Massachusetts

• Dr. Januzzi:
– Grant support: Roche Diagnostics, Siemens
Diagnostics, Critical Diagnostics
– Consulting: Roche Diagnostics, Critical Diagnostics
– Speaking: Roche Diagnostics, Siemens Diagnostics,
Ortho Clinical Diagnostics
• No other authors have disclosures to report

• Despite great success in development of therapies for chronic heart failure (HF), affected patients nonetheless suffer significant morbidity and mortality.
• Standard of care (SOC) management for chronic HF includes use of therapies based on symptoms, signs, and achievement of a maximal medical program.
• Although such an approach is standard, titration of therapies remains sub-optimal, and even when optimal, higher risk patients may go unrecognized.
• This has led to greater interest in alternative means to monitor patients with HF, in an effort to “guide” therapy.

• Concentrations of amino-terminal pro-B type natriuretic peptide (NT-proBNP), are strongly associated with the presence and severity of HF, and are markedly prognostic in affected patients.
• Values of NT-proBNP often fall in response to therapy change, and such a fall in NT-proBNP is associated with more favorable outcomes.
• It remains unclear whether “guiding” HF therapy with NTproBNP is beneficial.
– Clinical trials of guided therapy (with heterogeneous inclusion criteria and patient demographics) have returned mixed results.

American Heart Journal, 2010
Investigator-initiated, prospective, randomized controlled trial
Sponsored in part by Roche Diagnostics, Inc
Clinical Trials.Gov NCT00351390

Inclusion Criteria
•
•
•
• Age > 21 years of age
Left ventricular ejection fraction ≤ 40%
New York Heart Association class II-IV symptoms
Hospitalization, ED visit, or outpatient therapy for ADHF within 6 months
Exclusion criteria
•
•
•
•
•
•
• Serum creatinine > 2.5 mg/dl
Inoperable aortic valve disease
Life expectancy <1 year due to causes other than HF
Cardiac transplantation or revascularization expected within 6 months
Severe obstructive or restrictive pulmonary disease
PCI or CABG within the previous 3 months
Subject unable or unwilling to provide written informed consent

Patient with Class II-IV symptoms, EF

40%, recent HF event
Randomization echocardiogram
Standard of Care
Minnesota Living With HF
Questionnaire quarterly
Standard of Care + NT-proBNP
Minnesota Living With HF
Questionnaire quarterly
Therapy adjusted to achieve optimal drug targets
Visits q3 months
Extra visits as needed for treatment goals
Therapy adjusted to achieve optimal drug targets PLUS NT-proBNP

1000 pg/mL
Visits q3 months
Extra visits as needed for treatment goals
Close-out echocardiogram
Total cardiovascular events assessed

• 1
 endpoint • 2
 endpoints
– Total cardiovascular events*
– Quality of life
• Worsening HF
†
• HF hospitalization
• ACS
• Ventricular arrhythmia
• Cerebral ischemia
• Cardiovascular death
– Changes in echo parameters
•
•
•
LV ejection fraction
LVESVi
LVEDVi
*Assessed using generalized estimating equations
† Requiring at least 2 from the following: symptoms of congestion or falling cardiac output, signs of new congestion on exam, use of “bail out” decongestive therapy, or rising NT-proBNP in the un-blinded arm

Standard of care plus NT-proBNP
(N=75)
6 elective withdrawals
75 analyzed
0 excluded
Standard of care alone
(N=76)
6 elective withdrawals
76 analyzed
0 excluded

Characteristic
Age, years
LV ejection fraction (%)
NYHA Class II or III (%)
Male gender (%)
Caucasian (%)
Cause of heart failure
Ischemic (%)
Non-ischemic (%)
Other (%)
Past medical history
Hypertension (%)
Coronary artery disease (%)
Myocardial infarction (%)
Atrial fibrillation (%)
Ventricular tachycardia (%)
Obstructive airways disease (%)
Diabetes mellitus (%)
Implanted devices
Cardioverter-defibrillator (%)
Biventricular pacemaker (%)
NT-proBNP (N=75) SOC (N=76) P
63.0 ± 14.5
28.0
± 8.7
63.5 ± 13.5
25.9 ± 8.3
.41
.52
65 (85.5)
67 (88.2)
65 (85.5)
64 (84.2)
61 (81.3)
66 (88.0)
.46
.24
.65
40 (53.3)
25 (33.3)
10 (13.3)
40 (52.6)
42 (55.3)
28 (36.8)
31 (40.8)
23 (30.3)
15 (19.7)
30 (39.5)
52 (69.3%)
30 (40.0%)
45 (60.0)
18 (24.0)
12 (16.0)
39 (52.0)
50 (66.7)
30 (40.0)
30 (40.0)
21 (28.0)
16 (21.3)
32 (42.7)
50 (65.8%)
30 (39.4%)
.17
.70
.68
.94
.09
.69
.92
.76
.81
.19

Medication
ACE Inhibitors (%)
Angiotensin receptor blocker (%)
β blocker (%)
Aldosterone antagonist (%)
Loop Diuretics (%)
Thiazide Diuretic (%)
Digoxin (%)
Hydralazine (%)
Nitrates (%)
Baseline
NT-proBNP (N=75) SOC (N=76) P
53 (70.7) 47 (61.8) .21
8 (10.7)
74 (98.7)
37 (49.3)
15 (19.7) .11
71 (93.4) .19
26 (34.2) .10
67 (89.3)
5 (6.7)
22 (29.3)
4 (5.3)
8 (10.7)
71 (93.4) .27
3 (4.0) .48
25 (32.9) .89
4 (5.3) .89
16 (21.1) .07

*908 visits overall; mean follow-up 10 ± 3 months
Median number of visits: NT-proBNP 6.0 vs SOC 5.0; P =.05
40
35
30
25
20
15
10
5
0
1-4 visits 5 visits 6-7 visits
Visit number
≥8 visits
SOC
NT-proBNP
P = .001

Medication Follow-up
ACE Inhibitors (%)
Angiotensin receptor blocker (%)
β blocker (%)
Aldosterone antagonist (%)
NT-proBNP (N=75) SOC (N=76) P
56 (74.7)
9 (12.0)
73 (97.3)
47 (62.7)
46 (60.5)
17 (22.4)
.20
.05
73 (96.1) .56
34 (44.7) .001
Loop Diuretics (%)
Thiazide Diuretic (%)
Digoxin (%)
Hydralazine (%)
64 (85.3)
5 (6.7)
23 (30.7)
2 (2.7)
73 (96.1)
3 (3.9)
23 (30.3)
4 (5.3)
.05
.42
.90
.12
Nitrates (%) 7 (9.3) 14 (18.4) .06
Rates of achievement of ≥50% of goal dose were higher in NT-proBNP arm for
ACEi/ARBs (56.5% versus 50.8%) and β blockers (53.4% versus 41.9%).

Medication
ACE Inhibitors (%)
Angiotensin receptor blocker (%)
β blocker (%)
Aldosterone antagonist (%)
Loop Diuretics (%)
Thiazide Diuretic (%)*
Digoxin (%)*
Hydralazine (%)*
Nitrates (%)*
Titration
NT-proBNP (N=75) SOC (N=76) P
+25.4% +18.1% .15
+5.8%
+46.0%
+22.7%
+22.3%
+34.5%
.01
.05
+5.8% <.001
+23.7%
-16.7%
-10.9%
+27.5%
+59.4%
+25.6%
-12.5%
+2.0%
-50.0%
-3.7%
.65
.88
.78
.20
.08
*Limited number of observations

Overall
Baseline Follow-up P
2118 [1122-3831] 1321 [554-3197] .02
Treatment
SOC
By treatment allocation
Baseline Follow-up P
1946 [951-3488] 1844 [583-3603] .61
NT-proBNP 2344 [1193-4381] 1125 [369-2537] .01
P = .40 for SOC baseline versus NT-proBNP baseline

Overall
Baseline Follow-up P
2118 [1122-3831] 1321 [554-3197] .02
Treatment
SOC
By treatment allocation
Baseline Follow-up P
1946 [951-3488] 1844 [583-3603] .61
NT-proBNP 2344 [1193-4381] 1125 [369-2537] .01
P = .03 for SOC follow-up versus NT-proBNP follow-up
44.3% of NT-proBNP subjects

1000 pg/mL

P =.009
120
100 events
100
80
58 events
60
40
*Logistic Odds
NT-proBNP
= 0.44
(95% CI= .22-.84; P =.019)
20
0
Total CV Events
*Adjusted for age, LVEF, NYHA Class, and eGFR
SOC
NT-proBNP

60
50
40
30
20
10
0
P =.001
Worsening
HF
NB: 0 cerebral ischemia events in either arm
SOC
NT-proBNP
NB: 3 of 4 CV deaths in NT-proBNP arm occurred after elective withdrawal from study
P =.002
HF hosp
P =.72
ACS
P =.41
VT/VF
P =.52
CV death

1.0
0.8
0.6
0.4
0.2
0
0
NT-proBNP (N=75)
Standard-of-care (N=76)
Log rank P =.03
73 146 219 292
Days from enrollment
365

1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
SOC
NT-proBNP
P =.008
P =.005
Age < 75 years Age ≥ 75 years
*No interaction between age and NT-proBNP guided care was found (P =.11)

8
7
6
5
4
3
2
1
P =.72
A
0 cu te
re na
Acute renal failure l f ai lu re
P =.70
P =.32
P =.08
SOC
NT-proBNP
P =.47
D izzi
Dizziness ne ss
Hypo or al em
Hypotension si on ot en
H yp o/ hy pe rk
H yp
Adverse events
Sy nc op
Adverse event

NT-proBNP patients had larger QOL improvements than SOC, and were more likely to have large
( ≥10 point) improvements in their MLWHF scores
Variable SOC NT-proBNP P
Global Scale -5.0 [-18-0] -10.0 [IQR -17-7] .05
≥10 point 
38.8% 61.2% .03

20
15
10
5
0
-5
-10
-15
-20
SOC (N= 56)
NT-proBNP (N=60)
P =.06
P =.01
LVEF
Absolute

LVEF
Relative

LV end-systolic volume index
LV end-diastolic volume index
P <.001
P =.008

• Small size
• Primary endpoint uses cumulative events
• Effect of NT-proBNP guidance mainly on worsening
HF and HF hospitalization
• Caregivers and patients un-blinded to NT-proBNP results
• Suspension of the study at interim increases the risk for Type I error

• Against a background of excellent overall medical care, addition of NT-proBNP measurement with a goal to reduce and maintain values

1000 pg/mL:
– Was achieved in a large % of subjects
– Resulted in favorable patterns in medication application
– Was well-tolerated

• NT-proBNP guided care was superior to SOC management for the reduction of total cardiovascular events.
– Particular effects on worsening HF and HF hospitalization
– Comparable benefits seen in elderly patients
• Compared to SOC, NT-proBNP guided care was associated with more significant improvements in both QOL and echo parameters.

• If duplicated in larger cohorts, therapy guided by NT-proBNP concentrations may represent a new paradigm for HF care.

Benefits of Natriuretic Peptide Guided Heart
Failure Therapy for Patients With Chronic
Left Ventricular Systolic Dysfunction
Results of the Pro-BNP Outpatient Tailored
Chronic Heart Failure Therapy (PROTECT) Study
James L. Januzzi, Jr, MD, Shafiq U. Rehman, MD, Asim A. Mohammed, MD, Anju Bhardwaj, MD,
Linda Barajas, RN, Justine Barajas, Han-Na Kim, MD MPH, Aaron L. Baggish, MD, Rory B. Weiner,
MD, Annabel Chen-Tournoux, MD, Jane E. Marshall, RDCS, Stephanie A. Moore, MD, William D.
Carlson, MD, Gregory D. Lewis, MD, Jordan Shin, MD, Dorothy Sullivan, ANP, Kimberly Parks, DO,
Thomas J. Wang, MD, Shawn A. Gregory, MD, Shanmugam Uthamalingam, MD, and Marc J. Semigran, MD
Slides available at www.cardiosource.com

6
3
0
*908 visits overall; mean follow-up 10 ± 3 months
12
P = .05
9
SOC
(N=76)
NT-proBNP
(N=75)

Concentrations of NT-proBNP at the end of the study
<1000 pg/mL 35.6% 44.3%
<2000 pg/mL 57.5% 68.6%
<3000 pg/mL 69.9% 80.0%

Events as a function of NT-proBNP
1
0.8
0.6
0.4
0.2
0
2
1.8
1.6
1.4
1.2
P <.001

1000 pg/mL 1001-2000 pg/mL 2001-3000 pg/mL
Achieved NT-proBNP value
>3000 pg/mL

1.4
1.2
1
0.8
0.6
0.4
0.2
0
P =.03
1.3 events
SOC
NT-proBNP
0.77 events

40
30
20
60
50
10
0
48.6%
P =.04
SOC
NT-proBNP
29.3%

Adverse event
Abdominal pain
Acute renal failure
Anemia
Atrial fibrillation
Cough
Diarrhea
Dizziness
Fever
GI bleeding
Hyper/hypokalemia
Hypotension
Respiratory infection
Syncope
NT-proBNP (N=75)
1.3%
5.3%
1.3%
2.7%
2.7%
2.7%
6.7%
1.3%
1.3%
2.7%
5.3%
2.7%
2.7%
SOC (N=76)
0%
3.9%
0%
3.9%
1.3%
1.3%
5.3%
1.3%
1.3%
1.3%
0%
5.3%
1.3%
.89
.78
.32
.08
.25
.70
P
.84
.72
.90
.67
.41
.65
.70

• Differences in characteristics between subjects in each arm were assessed using χ 2 test,
Student's t test or Wilcoxon rank sum test.
• Comparison of event rates between study arms was performed with use of generalized estimating equations (GEE).
– A logistic β-coefficient, adjusted for age, LVEF, NYHA Class, and eGFR was calculated for the effect of NT-proBNP guidance.
•
Kaplan-Meier analysis performed to analyze time to first event as a function of treatment allocation.
• Associations between treatment strategy and treatment-related serious adverse events were examined, after adjustment for relevant baseline covariates.
• Parametric and non-parametric tests were used to examine secondary objectives, including effects of NT-proBNP guided HF care on QOL, as well as echo parameters.
• Interim analysis performed upon enrollment of 151 st subject for assessment of primary endpoint.

• Differences in characteristics between subjects in each arm were assessed using χ 2 test,
Student's t test or Wilcoxon rank sum test.
• Comparison of event rates between study arms was performed with use of generalized estimation equations (GEE).
– A logistic β-coefficient, adjusted for age, LVEF, NYHA Class, and eGFR was calculated for the effect of NT-proBNP guidance.
•
Kaplan-Meier analysis performed to analyze time to first event as a function of treatment allocation.
• Associations between treatment strategy and treatment-related serious adverse events were examined, after adjustment for relevant baseline covariates.
• Parametric and non-parametric tests were used to examine secondary objectives, including effects of NT-proBNP guided HF care on QOL, as well as echo parameters.
• Interim analysis performed upon enrollment of 151 st subject for assessment of primary endpoint.