nt-probnp stratified follow up in outpatients heart failure clinics: a randomized danish multicenter...
TRANSCRIPT
NorthStar:
NT-proBNP stratified follow up in outpatients heart failure clinics:
A Randomized Danish Multicenter Study
Morten Schou, MD, PhDPrincipal Investigator
Hillerod University Hospital, CopenhagenThe Danish Heart Failure Clinics Network
On behalf on the NorthStar Steering Group:Finn Gustafsson, Lars Videbaek, Per R Hildebrandt and Morten Schou
Disclosures:• Roche Diagnostics International, Basel, Schwitzerland
Research grant
• Roche Diagnostics, Copenhagen, Denmark Research grant
• Merck, Sharp and Dohme, Copenhagen, Denmark
Research grant
Introduction
NorthStar:• Objectives: To determine the effectiveness of a continued heart failure clinic intervention.
To determine whether NT-proBNP could identify patients with particular benefit of continued follow up.
• Population: Predefined clinical stable systolic heart failure patients on optimal medical therapy.
• Primary outcome: Time to death or a CV hospitalization
The Danish Heart Failure Clinic Program:
GP Echo Lab Dept of Cardiology/ Internal Medicine
Heart failure clinic (HFC):
•Education•Exercise•Etiologi•ACE-I/ARB´s•BB•Aldosterone antagonists•Adjusting doses of diuretics •CRT and/or ICD
Remainsymptomatic
ConsideredStable
HTX ?LVAD ?(2 centers)
Scientific Question:
Where should thesepatients be followed ?
•HFC ?•GP (routine in DK) ?•Only high risk patients in the HFC ? e.g identified by NT- proBNP ?
NT-proBNP monitoring ?
• In the NorthStar Study the patients were on optimal therapy before randomization and only little room was left for a lowering strategy. (EMPHASIS , REVERSE and MADIT-CRT were initiated before NorthStar)
• We, therefore, created a clinical checklist, which should be used if NT-proBNP increased > 30 % compared to the randomization visit even the patient did not become more symptomatic.
Hypotheses:• Clinically stable systolic heart failure patients on optimal medical therapy benefit from long term follow up in a HFC.
• The benefit is driven by an effect only in high risk patients identified by NT-proBNP > 1000 pg/ml. (prespecified interaction analysis)
• High risk patients identified by NT-proBNP > 1000 pg/ml benefit further from NT-proBNP monitoring.
Methods
Study design:
• PROBE design (Prospective Randomized Open-labeled Blinded Endpoint)
• Multicenter (18 sites)
• Investigator Initiated
The NorthStar Intervention(Organizational):
Heart
Failure
Clinic
Handling of comorbidity
Monitoring:
Diuretics
Telephone- service
Continued educationnon-pharmalogical
Adherence to guidelines
The patients visit the HFC with 1-3 months intervals based on the investigators discretion
Checlist if NT-proBNP increased > 30 %:
M. S
cho
u e
t al
. (N
ort
hS
tar
Des
ign
Pap
er):
AH
J 20
08
Randomization:
M. Schou et al. (NorthStar DesignPaper): AHJ 2008
• Simple randomization with strata* (*due to the prespecified interaction analysis (NT-proBNP*HFC))
Results
N = 6180 patients had at least one visit in one of the HFC in the randomization period (registry)
N= 1628 patients considered eligible
N = 1120 patients randomized
N = 460 patients allocated to GP
N= 660 patients allocated to HFC (N=461) or HFC+NT-proBNP (N=199)
N = 508 excluded
Lost to follow up (N=0)Informed consent withdrawn due to traffiic accident (N=1)
N=659 patients included in final analyses
N= 460 patients included in final analyses
Reg
istr
yEn
rollm
en
t
A
llocati
on
Follow
up
An
aly
sis
Lost to follow up (N=0)
Trial Structure:
Patients Characteristics:
Heart failure Clinic
v
General Practice
Demografic variables, % GP (=460)
N= 257 (NT-proBNP < 1000 ) and
N=203 (NT-proBNP > 1000)
HFC (=461)
N= 253 (NT-proBNP < 1000) and
N=208 (NT-proBNP > 1000)
P-value
Age, years 69 68 0.626
Female Sex, % 27 23 0.215
LVEF, % 30 32 0.123
NYHA II-III, % 71 75 0.174
Ischemic Cardiomyopathy, % 57 59 0.573
eGFR, ml/min/1.73 m2 66 69 0.224
NT-proBNP, pg/ml 802 793 0.640
Hosp with 12 months, % 45 41 0.196
ACE/ARB, randomization, % 89 86 0.100
ACE/ARB, target dose (of all patients), % 68 66 0.590
BB, randomization, % 85 84 0.726
BB, target dose (of all all patients), % 49 53 0.277
Aldo-anta, randomization, % 33 31 0.466
Loop diuretics, mg (median) 40 40 0.773
ICD, % (only IHD in DK) 9 10 0.437
CRT, % 4 3 0.728
Patients Characteristics:
Heart failure Clinic (Usual care)
v
Heart Failure Clinic (NT-proBNP monitoring)
* Only patients with NT-proBNP > 1000 pg/ml
Demografic variables, % HFC
Usual Care
N=208
HFC
NT-proBNP-moni
N=199
P value
Age, years 74 72 0.197
Female Sex, % 24 24 0.564
LVEF, % 30 30 0.501
NYHA II-III, % 80 81 0.663
Ischemic Cardiomyopathy, % 55 59 0.661
eGFR, ml/min/1.73 m2 61 64 0.151
NT-proBNP, pg/ml 2042 1884 0.497
Hosp with 12 months 44 37 0.091
ACE/ARB, randomization, % 83 83 0.222
ACE/ARB, target dose (of all patients), % 65 64 0.937
BB, randomization, % 87 84 0.665
BB, target dose (of all all patients), % 52 52 0.861
Aldo, randomization, % 32 25 0.255
Loop diuretics, mg (median) 60 40 0.430
ICD, % 11 9 0.772
CRT, % 4 6 0.668
Primary Composite Endpoint:
Heart failure Clinic
v
General Practice
Primary Composite Endpoint(Time to mortality or a CV hospitalization):
HR: 1.17, 95 % CI : 0.45-1.45, P = 0.145
Blue: GP (N=460)
HFC: Black (N=461)
Events: 159
Events: 177
NT-proBNP stratified hypothesis:
HR: 0.94; 95 CI:0.69-1.27; P = 0.680
HFC*NT-proBNP > 1000 pg/ml; P = 0.721 (test for heterogeneity)
Blue: GP (N= 257 and N= 203)
HFC: Black (N=253 and N=208)
Primary composite Endpoint:
Heart failure Clinic (Usual care)
v
Heart Failure Clinic (NT-proBNP monitoring)
* Only patients with NT-proBNP > 1000 pg/ml
Primary Composite Endpoint:
HR: 0.94; 95 CI:0.69-1.27; P = 0.680
HR: 0.95, 95 % CI: 0.71-1.1.29, P = 0.776
HFC (N=208) Usual care: Black
HFC (N=199)
NT-proBNP:Red
Secondary Endpoints:•Time to death
•Time to a cardiovascular hospitalization
•Time to a heart failure hospitalization
•Time to an over all-hospitalization
•Minnesota Living with Heart Failure Score
•NYHA class
•NT-proBNP
•Patients admitted, admissions and admission days
P > 0.05 for all:
- HFC vs. GP
- NT-proBNP stratified hypothesis
- HFC vs HFC+NT-proBNP
Conclusions
Conclusions:
• Clinically stable systolic heart failure patients on optimal medical therapy do not benefit from long term follow up in a HFC.
• A subgroup of high-risk patients identified by NT-proBNP do not benefit from long term follow up in a HFC.
• The present NT-proBNP monitoring concept does not improve long term clinical outcome.
Interpretation
Interpretation:• Clinically stable HF patients can be referred back to their GP.
• Adherence in GP was suprisingly good – wrong hypothesis ?
• NT-proBNP identified the high-risk patients and did it´s job, but our intervention(s) could not improve outcome for these patients – wrong concept(s) ?
• We did not power the study to look at HF hospitalizations – wrong endpoint ?
• Our patients were primarily NYHA class I-II – will NT-proBNP monitoring only work in NYHA class III-IV – wrong patients ?
• Type II error - Bad luck ?
Thank you for your attention