Transcript Pro-BNP Outpatient Tailored CHF Therapy (PROTECT) Study

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
Disclosures
• 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
Introduction
• 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.
Introduction
• 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.
Methods
American Heart Journal, 2010
Investigator-initiated, prospective, randomized controlled trial
Sponsored in part by Roche Diagnostics, Inc
Clinical Trials.Gov NCT00351390
Inclusion/Exclusion Criteria
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
Study Design
Patient with Class II-IV symptoms, EF  40%, recent HF event
Randomization echocardiogram
Standard of Care
Standard of Care + NT-proBNP
Minnesota Living With HF
Questionnaire quarterly
Minnesota Living With HF
Questionnaire quarterly
Therapy adjusted to achieve
optimal drug targets
Therapy adjusted to achieve optimal drug
targets PLUS NT-proBNP  1000 pg/mL
Visits q3 months
Visits q3 months
Extra visits as needed for treatment goals
Extra visits as needed for treatment goals
Close-out echocardiogram
Total cardiovascular events assessed
Endpoints
• 1 endpoint
– Total cardiovascular
events*
•
•
•
•
•
•
Worsening HF†
HF hospitalization
ACS
Ventricular arrhythmia
Cerebral ischemia
Cardiovascular death
• 2 endpoints
– Quality of life
– 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
PROTECT Study
Results
Study flow
151 consented and randomized
Standard of care
plus NT-proBNP
(N=75)
Standard of care
alone
(N=76)
6 elective
withdrawals
6 elective
withdrawals
75 analyzed
0 excluded
76 analyzed
0 excluded
Baseline characteristics
Characteristic
NT-proBNP (N=75) SOC (N=76) P
Age, years
63.0 ± 14.5
63.5 ± 13.5
.41
LV ejection fraction (%)
28.0 ± 8.7
25.9 ± 8.3
.52
NYHA Class II or III (%)
65 (85.5)
64 (84.2)
.46
Male gender (%)
67 (88.2)
61 (81.3)
.24
Caucasian (%)
65 (85.5)
66 (88.0)
.65
Cause of heart failure
Ischemic (%)
Non-ischemic (%)
Other (%)
40 (53.3)
25 (33.3)
10 (13.3)
45 (60.0)
18 (24.0)
12 (16.0)
Past medical history
Hypertension (%)
Coronary artery disease (%)
Myocardial infarction (%)
Atrial fibrillation (%)
Ventricular tachycardia (%)
Obstructive airways disease (%)
Diabetes mellitus (%)
40 (52.6)
42 (55.3)
28 (36.8)
31 (40.8)
23 (30.3)
15 (19.7)
30 (39.5)
39 (52.0)
50 (66.7)
30 (40.0)
30 (40.0)
21 (28.0)
16 (21.3)
32 (42.7)
.94
.09
.69
.92
.76
.81
.19
52 (69.3%)
30 (40.0%)
50 (65.8%)
30 (39.4%)
.70
.68
Implanted devices
Cardioverter-defibrillator (%)
Biventricular pacemaker (%)
.17
HF therapy: Baseline
Medication
Baseline
NT-proBNP (N=75) SOC (N=76)
P
ACE Inhibitors (%)
53 (70.7)
47 (61.8)
.21
Angiotensin receptor blocker (%)
8 (10.7)
15 (19.7)
.11
β blocker (%)
74 (98.7)
71 (93.4)
.19
Aldosterone antagonist (%)
37 (49.3)
26 (34.2)
.10
Loop Diuretics (%)
67 (89.3)
71 (93.4)
.27
5 (6.7)
3 (4.0)
.48
22 (29.3)
25 (32.9)
.89
Hydralazine (%)
4 (5.3)
4 (5.3)
.89
Nitrates (%)
8 (10.7)
16 (21.1)
.07
Thiazide Diuretic (%)
Digoxin (%)
Office visits*
*908 visits overall; mean follow-up 10 ± 3 months
Median number of visits: NT-proBNP 6.0 vs SOC 5.0; P =.05
40
SOC
NT-proBNP
35
% of visits
30
25
20
P = .001
15
10
5
0
1-4 visits
5 visits
6-7 visits
Visit number
≥8 visits
HF therapy: Follow-up
Medication
Follow-up
NT-proBNP (N=75) SOC (N=76)
P
ACE Inhibitors (%)
56 (74.7)
46 (60.5)
.20
Angiotensin receptor blocker (%)
9 (12.0)
17 (22.4)
.05
β blocker (%)
73 (97.3)
73 (96.1)
.56
Aldosterone antagonist (%)
47 (62.7)
34 (44.7)
.001
Loop Diuretics (%)
64 (85.3)
73 (96.1)
.05
5 (6.7)
3 (3.9)
.42
23 (30.7)
23 (30.3)
.90
Hydralazine (%)
2 (2.7)
4 (5.3)
.12
Nitrates (%)
7 (9.3)
14 (18.4)
.06
Thiazide Diuretic (%)
Digoxin (%)
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%).
HF therapy: Titration
Medication
Titration
NT-proBNP (N=75) SOC (N=76)
P
ACE Inhibitors (%)
+25.4%
+18.1%
.15
Angiotensin receptor blocker (%)
+5.8%
+22.3%
.01
β blocker (%)
+46.0%
+34.5%
.05
Aldosterone antagonist (%)
+22.7%
+5.8%
<.001
Loop Diuretics (%)
+23.7%
+25.6%
.65
Thiazide Diuretic (%)*
-16.7%
-12.5%
.88
Digoxin (%)*
-10.9%
+2.0%
.78
Hydralazine (%)*
+27.5%
-50.0%
.20
Nitrates (%)*
+59.4%
-3.7%
.08
*Limited number of observations
NT-proBNP Concentrations
Overall
Baseline
Follow-up
P
2118 [1122-3831] 1321 [554-3197] .02
By treatment allocation
Treatment
Baseline
Follow-up
P
SOC
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
NT-proBNP Concentrations
Overall
Baseline
Follow-up
P
2118 [1122-3831] 1321 [554-3197] .02
By treatment allocation
Treatment
Baseline
Follow-up
P
SOC
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
Primary Endpoint
P =.009
120
100 events
Number of events
100
80
60
40
20
58 events
*Logistic OddsNT-proBNP= 0.44
(95% CI= .22-.84; P =.019)
0
Total CV Events
*Adjusted for age, LVEF, NYHA Class, and eGFR
SOC
NT-proBNP
Individual Endpoints
60
NB: 0 cerebral ischemia events in either arm
SOC
NT-proBNP
Number of events
50
40
NB: 3 of 4 CV deaths in NT-proBNP arm
occurred after elective withdrawal from study
30
20
10
P =.001
P =.002
P =.72
P =.41
P =.52
Worsening
HF
HF hosp
ACS
VT/VF
CV death
0
Kaplan-Meier Analysis
Event free survival
1.0
Log rank P =.03
0.8
0.6
0.4
NT-proBNP (N=75)
0.2
Standard-of-care (N=76)
0
0
73
146
219
292
Days from enrollment
365
Age and outcomes
Mean number of events
1.8
1.6
SOC
NT-proBNP
1.4
1.2
1
0.8
0.6
0.4
P =.008
P =.005
Age < 75 years
Age ≥ 75 years
0.2
0
*No interaction between age and NT-proBNP guided care was found (P =.11)
Safety
SOC
NT-proBNP
P =.08
P =.47
Acute
renal failure
Dizziness
Hypo or
hyperkalemia
Hypotension
Syncope
H
/h
y
yp
o
H
yn
co
S
te
n
rk
a
pe
yp
o
ss
in
e
iz
z
D
fa
al
A
cu
t
e
re
n
Adverse events
pe
P =.32
si
on
P =.70
le
m
ia
P =.72
ilu
re
% with events
8
7
6
5
4
3
2
1
0
Minnesota Living with Heart
Failure Questionnaire
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
38.8%
61.2%
.03
≥10 point 
Selected echo results
20
SOC (N= 56)
NT-proBNP (N=60)
15
% change
10
P =.06
P =.01
LV end-systolic LV end-diastolic
volume index
volume index
5
0
-5
-10
-15
-20
LVEF
Absolute 
LVEF
Relative 
P <.001
P =.008
PROTECT: Limitations
• 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
PROTECT: Summary
• 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
PROTECT: Summary
• 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.
PROTECT: Conclusion
• 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
Number of office visits*
*908 visits overall; mean follow-up 10 ± 3 months
Number of visits
12
P = .05
9
6
3
0
SOC
(N=76)
NT-proBNP
(N=75)
Achieved NT-proBNP
Concentrations of NT-proBNP at the end of the study
Treatment arm
Achieved value SOC NT-proBNP
<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
2
Mean number of events
1.8
P <.001
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
1000 pg/mL
1001-2000 pg/mL
2001-3000 pg/mL
Achieved NT-proBNP value
>3000 pg/mL
Mean Number of Events/Patient
P =.03
1.4
1.3 events
Number of events
1.2
1
0.8
0.6
0.4
0.2
0
0.77 events
SOC
NT-proBNP
% of Patients with Events
P =.04
60
% with events
50
48.6%
40
29.3%
30
20
10
0
SOC
NT-proBNP
Safety
Adverse event
NT-proBNP (N=75)
SOC (N=76)
P
Abdominal pain
1.3%
0%
.84
Acute renal failure
5.3%
3.9%
.72
Anemia
1.3%
0%
.90
Atrial fibrillation
2.7%
3.9%
.67
Cough
2.7%
1.3%
.41
Diarrhea
2.7%
1.3%
.65
Dizziness
6.7%
5.3%
.70
Fever
1.3%
1.3%
.89
GI bleeding
1.3%
1.3%
.78
Hyper/hypokalemia
2.7%
1.3%
.32
Hypotension
5.3%
0%
.08
Respiratory infection
2.7%
5.3%
.25
Syncope
2.7%
1.3%
.70
Statistics
•
Differences in characteristics
between subjects in each arm
were assessed using χ2 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 151st
subject for assessment of
primary endpoint.
Statistics
•
Differences in characteristics
between subjects in each arm
were assessed using χ2 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 151st
subject for assessment of
primary endpoint.