OUTSMART HF: A Randomized Controlled Trial of ... - acc.org · • ACC/AHA and ESC guidelines provide a class I-IIarecommendation for C in patients with HF however level of evidence

OUTSMART HF: A Randomized Controlled

Trial of Routine Versus Selective Cardiac

Magnetic Resonance in Non-Ischemic

Heart Failure (IMAGE-HF project 1B)

Paterson I, Erthal F, Garrard L, Mielniczuk L, O'Meara E, White

J, Connelly K, Knuuti J, Radja M, Laine M, Chow B, Chen L,

Wells G, Ezekowitz J, Beanlands R, Chan K

Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada; Ottawa Heart Institute, Ottawa, ON, Canada;

Université de Montréal, Montreal, QC, Canada; University of Calgary, Calgary, AB, Canada; University of Toronto, Toronto, ON,

Canada;. Turku University, Turku, Finland; Dalhousie University, Halifax, NS, Canada; Helsinki University, Helsinki, Finland.

Disclosures

Peer Review Funding

– Canadian Institutes for Health Research

– TEKES, the Finnish funding agency for Technology and Innovation

Industry Funding

– Speaker honoraria/consultant fees: none

– Unrestricted grant: General Electric (<$10K)

ACC.18, LBCT, March 12, 2018

Background

• Non-ischemic heart failure (HF) is highly prevalent and world-

wide has overtaken ischemic HF

• Management of non-ischemic HF is complex given multiple

potential etiologies, with many having specific therapies

• Bedside and echocardiographic assessments do not reliably

distinguish non-ischemic subtypes


Background

• Cardiac Magnetic Resonance (CMR) is increasingly used to

characterize non-ischemic cardiomyopathies but at increased cost

and lower availability compared to echocardiography

• ACC/AHA and ESC guidelines provide a class I-IIa recommendation

for CMR in patients with HF however level of evidence is C


Primary Aim

• In patients with non-ischemic HF, determine if a strategy using

routine CMR yields more specific diagnoses of the underlying

HF etiology compared to a strategy using CMR selectively

Design

• Randomized, controlled multi-centre trial

• Two arm, 1:1 allocation routine versus selective CMR in

patients with non-ischemic HF

• Analyzed as intention to treat

OUTSMART-HF: Routine versus

selective cardiac magnetic resonance

in non-ischemic heart failure

ACC.18, LBCT, March 12, 2018Paterson et al. Trials 2013.

Halifax

Quebec City

Montreal

Ottawa

Toronto (SBHC, SMHC)

London

Edmonton

Calgary

Vancouver

OUTSMART-HF Sites

March 12, 2018

CanadaFinland

Turku

Helsinki

Kuopio


Eligibility

Inclusion

• newly diagnosed HF or patients with established HF and

deterioration/decompensation within the past 12 months

• working diagnosis of either non-ischemic cardiomyopathy (any LVEF) or

heart failure with preserved ejection fraction (HFPEF)

• NYHA class II-IV HF symptoms within the last 12 months

Exclusion

• prior CMR and no change in clinical condition

• previous well-documented specific HF etiology

• significant CAD; previous STEMI or non-STEMI in LAD territory

• advanced HF with ongoing need for supportive therapy

• life expectancy < 3 months

• contraindication to CMRACC.18, LBCT, March 12, 2018

OUTSMART-HF Design Overview


R

Eligible

patient

with non-

ischemic HF

Echo +

Routine CMR

*suspicion of ARVC, infiltrative, congenital, or pericardial disease

3mo 12mo

Echo +

Selective CMR*

Phase 2:

IMAGING ASSESSMENT

Phase 1:

CLINICAL ASSESSMENT

Phase 3:

CLINICAL ASSESSMENT

Baseline HF Etiology Imaging-based HF etiology Clinical HF etiology

Potential HF Etiologies

• Inflammatory

• Infiltrative

• Hypertrophic

• Ischemic

• Valvular

• Mixed

• Other

• Dilated

• HFPEF

• Unknown

Paterson et al. Trials 2013.ACC.18, LBCT, March 12, 2018

Clinical and Imaging Assessments

Specific HF etiology

Non-specific HF etiology

Primary Outcome

• Clinical Assessment of HF etiology at 3 months follow-up

Secondary Outcomes

• Imaging Assessment of HF etiology

– Routine CMR arm: CMR interpretation used

– Selective CMR arm: Echo interpretation used unless CMR performed

– Post-hoc analysis of HF etiology for CMR vs Echo in Routine arm

• Clinical events (death or cardiovascular hospitalization)

– Routine vs. Selective CMR

– Post-hoc Specific vs. Non-specific HF etiology

Paterson et al. Trials 2013.ACC.18, LBCT, March 12, 2018

Outcomes

Sample Size Estimation

Based on a study of patients with non-ischemic HF

which found that endomyocardial biopsy improved

specific diagnosis from 35% to 50%

Assumed

• specific HF etiology rate of 50% in routine and 35% in

selective CMR strategies

• two proportions will be compared based on the Chi-

square test (Z test) with a pooled variance estimate

• 90% power, two-sided alpha = 0.05

• 10% loss to follow-up or study withdrawal

• Total of 504 patients (252 patients per arm)ACC.18, LBCT, March 12, 2018

Felker et al. N Engl J Med 2000.

IMAGE-HF Project 1BPatients Randomized

13 sites, n = 518


Echo + Routine CMR n=249 Echo + Selective CMR n=251

4 - Withdrew consent

1 - Admin withdrawal

4- site withdrawal*

3 - Withdrew consent

2 - Admin withdrawal

4 - site withdrawal*

3 month follow-up n=248 3 month follow-up n=250

2 -Lost to follow-up

8 - Death

1 - patient withdrawal

12 month follow-up n=236

4 - Lost to follow-up

7 - Death

1 - Incomplete follow up

12 month follow-up n=239

1 - Lost to follow-up1 - patient withdrawal

n=258 n=260

Recruitment from January 2011 – October 2016

*1 site withdrawn – unable to meet protocol requirements n = 8

CONSORT DIAGRAM

Baseline Patient Characteristics

Routine CMR Selective CMR

Age (years), mean±SD 59±13 58±14

Male 174 (70%) 170 (68%)

Hypertension 133 (53%) 132 (53%)

Diabetes mellitus 62 (25%) 70 (28%)

Myocardial Infarction 14 (6%) 10 (4%)

Atrial fibrillation 59 (24%) 66 (26%)

NYHA class: I

II

III

IV

9 (4%)

108 (44%)

100 (40%)

31 (13%)

10 (4%)

112 (45%)

110 (44%)

18 (7%)

SBP, mean±SD 122±20 123±22

HR, mean±SD 84±20 85±22

LVEF (%) , mean±SD 29±12 29±15

Creatinine (umol/L) , mean±SD 94±28 94±26



Beta blockers 217 (87%) 217 (87%)

ACE Inhibitors/ARB 212 (85%) 209 (83%)

MRAs (Spironolactone) 85 (34%) 96 (38%)

Diuretics 169 (68%) 175 (70%)

Nitrates 28 (11%) 21 (8%)

Digoxin 35 (14%) 39 (16%)

Anticoagulants 90 (36%) 111 (44%)

ASA/Other anti-platelet 118 (47%) 108 (43%)

Ca blockers 22 (9%) 34 (14%)

Antiarrhythmics 18 (7%) 18 (7%)


Baseline Medications

Baseline Clinical Assessment

of HF Etiology

Routine CMR Selective CMR P value

HFPEF 18 (7%) 17 (7%)

Dilated 137 (55%) 136 (54%)

Inflammatory 12 (5%) 13 (5%)

Infiltrative 2 (1%) 3 (1 %)

Hypertrophic 2 (1%) 0

Ischemic 2 (1%) 3 (2%)

Valvular heart disease 1 (0.4%) 2 (1%)

Mixed 15 (6%) 9 (4%)

Other 58 (23%) 64 (26%)

Unknown 2 (1%) 3 (1 %)

Specific HF Etiology* 92 (36.9%) 95 (38.0%) 0.88


*Specific = Inflammatory, Infiltrative, Hypertrophic,

Ischemic, Valvular, Mixed or Other


R

Eligible

patient

with non-

ischemic HF

Echo +

Routine CMR

*suspicion of ARVC, infiltrative, congenital, or pericardial disease

Baseline HF etiology Echo +

Selective CMR*

Phase 2:

IMAGING ASSESSMENT

Phase 1:

CLINICAL ASSESSMENT

Imaging Tests Performed

Echo (N=249)

CMR (N=224)

Echo (N=249)

CMR (N=54)

However only 3/54 performed

per protocol (2 infiltrative and

1 ACHD)

Imaging Assessment

of HF Etiology


Routine

CMR

Selective

CMRP value*

Selective CMR

Per ProtocolP value*

HFPEF 16 (6%) 17 (7%) 19 (8%)

Dilated 134 (54%) 135 (54%) 151 (60%)

Inflammatory 20 (8%) 12 (5%) 2 (1%)

Infiltrative 6 (2%) 3 (1%) 2 (1%)

Hypertrophic 4 (2%) 1 (0.4%) 1 (0.4%)

Ischemic 8 (3%) 20 (8%) 22 (9%)

Valvular heart disease 2 (1%) 8 (3%) 7 (3%)

Mixed 17 (7%) 14 (6%) 10 (4%)

Other 18 (7%) 12 (5%) 16 (6%)

Unknown 14 (6%) 24 (10%) 16 (6%)

No heart failure 10 (4%) 4 (2%) 4 (2%)

Specific HF Etiology 85 (34.1%) 73 (29.7%) 0.27 65 (25.7%) 0.04

* compared to Routine CMR

HF Etiology by Imaging Test

(Paired Analysis in Routine CMR)

CMR Echo P value

HFPEF 11 (5%) 21 (9%)

Dilated 122 (55%) 149 (67%)


Infiltrative 6 (3%) 3 (1%)

Hypertrophic 4 (2%) 1 (0.5%)

Ischemic 5 (2%) 17 (8%)

Valvular heart disease 1 (0.5%) 1 (0.5%)

Mixed 17 (8%) 8 (4%)

Other 17 (8%) 11 (5%)

Unknown 11 (5%) 9 (4%)

No heart failure 10 (5%) 2 (1%)

Specific HF Etiology 80 (35.7%) 45 (20.1%) < 0.001


0

10

20

30

40

50

60

70

80

Baseline 3 month 12 month


PRIMARY OUTCOME

Clinical Assessment of

Specific HF Etiologies

(%)


P=0.14P=0.24

P=0.81

P<0.001

PRIMARY OUTCOME

Clinical Outcomes

(Death or CV hospitalization)

Routine vs. Selective CMR


P =0.27

Clinical Outcomes

(Death or CV hospitalization)

CLINICALLY assigned (3 month)

Specific vs. Non-specific HF etiology

IMAGING assigned

Specific vs. Non-specific HF etiology


P =0.65P =0.02

Limitations

• No standardized definitions for HF etiologies

• Abundance of non-protocol CMR in selective strategy

• Limited use of quantitative T1 and T2 mapping on CMR


Conclusions

In patients with non-ischemic HF,

• No difference in the clinical diagnosis of specific HF etiology

between routine and selective CMR strategies

• However more specific HF etiologies were identified by routine

CMR at the time of image assessment

– CMR identified more specific HF etiologies compared to echo alone

• No difference in event-free survival between routine and

selective CMR arms


Conclusions

• Patients with specific HF etiologies defined on imaging had

worse outcomes than those with non-specific diagnoses

• However there was no difference in event-free survival between

specific and non-specific diagnoses determined clinically


Interpretation

In patients with non-ischemic HF,

• CMR increases specific imaging diagnoses but does not change

specific clinical diagnoses

• Imaging based diagnoses enables stratification of risk whereas

clinically defined diagnoses do not

• Greater attention to use of CMR and HF diagnoses from

imaging in general should be considered


OUTSMART HF Team• Edmonton, Canada

• I. Paterson, J. Ezekowitz

• Coordinators: M. Irwin

• Ottawa, Canada

• B.J.W. Chow, R.S. Beanlands, L. Mielniczuk, C. Dennie, A. Dick, L.

Duchesne

• Coordinators: E. Moga, M. Mohammed, V. MacKellar

• Montreal, Canada (Montreal Heart Institute)

• E O’Meara, J-C Tardif

• Coordinators: H. Brown, M. Dardes

• Toronto, Canada (Sunnybrook)

• G. Wright, K. Connelly

• Coordinator: M. Li

• Quebec City, Canada (Laval)

• E. Larose, P. Pibarot

• Coordinator: K. Bibeau

• Toronto, Canada (St. Michael’s)

• K. Connelly, M. Freeman, H. Leong-Poi

• Coordinator: J. Sloninko

• Halifax, Canada

• M. Rajda, H. Brown

• Coordinators: J. Kelly, S. Yarn

• Calgary, Canada

• J. White, A. Howarth

• Coordinators: S. Rivest

• Vancouver, Canada

• J. Leipsic, M. Kiess

• Coordinators: E. Grieve, L. Miklosova

• Turku, Finland

• J. Knuuti, H. Ukkonen, H. Leskinen

• Coordinators: T. Vasankari, K. Lahtonen

•

• Kuopio, Finland

• J. Hartikainen, M. Hedman

• Coordinator: L. Kujanen

• Helsinki, Finland

• M. Laine, H. Hanninen

• Coordinator: C. Salmen

• IMAGE-HF Data & Coordinating Centre

• L. Garrard, RN, BScN

• A Guo, MSc

• G. A. Wells, PhD (Research and Methods)

• L. Chen, PhD

• ML. Tran, MSc

•

• Quality Assurance

• Rob deKemp, PhD

• O. Clarkin, PhD

• I. Paterson, MD, F. Erthal (CMR)

• K. Chan, MD (IEcho)

March 12, 2018


3 month HF Etiology


HFPEF 16 (7%) 12 (5%)

Dilated 118 (49%) 111 (45%)


Infiltrative 2 (1%) 4 (2%)

Hypertrophic 2 (1%) 2 (1%)

Ischemic 7 (3%) 8 (3%)

Valvular heart disease 4 (2%) 4 (2%)

Mixed 17 (7%) 8 (3%)

Other 61 (25%) 79 (32%)

Unknown 1 (0.4%) 1 (0.4%)

No heart failure 1 (0.4%) 3 (1.2%)

Specific HF etiology* 108 (44.4%) 123 (49.8%)


P=0.24




HFPEF 13 (6%) 9 (4%)

Dilated 112 (48%) 98 (42%)


Infiltrative 1 (0.4%) 2 (1%)

Hypertrophic 1 (0.4%) 2 (1%)

Ischemic 8 (3%) 9 (4%)

Valvular heart disease 4 (2%) 4 (2%)

Mixed 19 (8%) 7 (3%)

Other 62 (26%) 81 (34%)

Unknown 1 (0.4%) 3 (1%)

No heart failure 1 (0.4%) 6 (3%)

Specific HF etiology* 110 (46.6%) 126 (53.4%)


12 month HF Etiology

P=0.14



Documents

OUTSMART HF: A Randomized Controlled Trial of ... - acc.org · • ACC/AHA and ESC guidelines provide a class I-IIarecommendation for C in patients with HF however level of evidence