NT-proBNP stratified follow up in outpatients heart failure clinics: A Randomized Danish Multicenter Study Morten Schou, MD, PhD Principal Investigator.

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

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ign

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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