OUTSMART HF: A Randomized Controlled Trial of Routine Versus Selective Cardiac Magnetic Resonance in Non-Ischemic Heart Failure (IMAGE-HF project 1B)

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1 OUTSMART HF: A Randomized Controlled Trial of Routine Versus Selective Cardiac Magnetic Resonance in Non-Ischemic Heart Failure (IMAGE-HF project 1B) Paterson I, ErthalF, GarrardL, MielniczukL, O'Meara E, White J, Connelly K, KnuutiJ, RadjaM, Laine M, Chow B, Chen L, Wells G, EzekowitzJ, BeanlandsR, Chan K MazankowskiAlberta Heart Institute, University of Alberta, Edmonton, AB, Canada; Ottawa Heart Institute, Ottawa, ON, Canada; Universitéde 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.

2 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)

3 Background Non-ischemic heart failure (HF) is highly prevalent and worldwide 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

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

5 Primary Aim OUTSMART-HF: Routine versus selective cardiac magnetic resonance in non-ischemic heart failure 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 Paterson et al. Trials 2013.

6 OUTSMART-HF Sites Canada Halifax Quebec City Montreal Ottawa Toronto (SBHC, SMHC) London Edmonton Calgary Vancouver Turku Helsinki Kuopio Finland March 12, 2018

7 Inclusion Eligibility 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 CMR

8 OUTSMART-HF Design Overview Phase 1: CLINICAL ASSESSMENT Phase 2: IMAGING ASSESSMENT Phase 3: CLINICAL ASSESSMENT Echo + Routine CMR Eligible patient with nonischemic HF R 3mo 12mo Echo + Selective CMR* Baseline HF Etiology Imaging-based HF etiology Clinical HF etiology *suspicion of ARVC, infiltrative, congenital, or pericardial disease

9 Clinical and Imaging Assessments Potential HF Etiologies Inflammatory Infiltrative Hypertrophic Ischemic Valvular Mixed Other Specific HF etiology Dilated HFPEF Unknown Non-specific HF etiology Paterson et al. Trials 2013.

10 Outcomes 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.

11 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 Chisquare test (Z test) with a pooled variance estimate 90% power, two-sided alpha = % loss to follow-up or study withdrawal Felker et al. N EnglJ Med Total of 504 patients (252 patients per arm)

12 CONSORT DIAGRAM IMAGE-HF Project 1B Patients Randomized 13 sites, n = 518 n=258 n= Withdrew consent 1 - Admin withdrawal 4- site withdrawal* 3 - Withdrew consent 2 - Admin withdrawal 4 - site withdrawal* Echo + Routine CMR n=249 Echo + Selective CMR n= patient withdrawal 1 -Lost to follow-up 3 month follow-up n=248 3 month follow-up n= Lost to follow-up 7 -Death 1 -Incomplete follow up 12 month follow-up n=236 *1 site withdrawn unable to meet protocol requirements n = 8 Recruitment from January 2011 October Lost to follow-up 8 -Death 1 - patient withdrawal 12 month follow-up n=239

13 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

14 Baseline Medications Routine CMR Selective CMR 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%)

15 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

16 Imaging Tests Performed Phase 2: IMAGING ASSESSMENT Phase 1: CLINICAL ASSESSMENT Echo + Routine CMR Echo (N=249) CMR (N=224) Eligible patient with nonischemic HF R Baseline HF etiology Echo + Selective CMR* Echo (N=249) CMR (N=54) However only 3/54 performed per protocol (2 infiltrative and 1 ACHD) *suspicion of ARVC, infiltrative, congenital, or pericardial disease

17 Imaging Assessment of HF Etiology Routine CMR Selective CMR P value* Selective CMR Per Protocol 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%) P value* 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%) (25.7%) 0.04 * compared to Routine CMR

18 HF Etiology by Imaging Test (Paired Analysis in Routine CMR) CMR Echo P value HFPEF 11 (5%) 21 (9%) Dilated 122 (55%) 149 (67%) Inflammatory 20 (9%) 2 (1%) 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

19 PRIMARY OUTCOME Clinical Assessment of Specific HF Etiologies (%) P=0.81 P<0.001 PRIMARY OUTCOME P=0.24 P= Baseline 3 month 12 month Routine CMR Selective CMR

20 Clinical Outcomes (Death or CV hospitalization) Routine vs. Selective CMR P =0.27

21 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 =0.65 P =0.02

22 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

23 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 etiologieswere 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

24 Conclusions Patients with specific HF etiologiesdefined 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

25 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

26 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

27 3 month HF Etiology Routine CMR Selective CMR HFPEF 16 (7%) 12 (5%) Dilated 118 (49%) 111 (45%) Inflammatory 14 (6%) 15 (6%) 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%) *Specific = Inflammatory, Infiltrative, Hypertrophic, Ischemic, Valvular, Mixed or Other P=0.24

28 12 month HF Etiology Routine CMR Selective CMR HFPEF 13 (6%) 9 (4%) Dilated 112 (48%) 98 (42%) Inflammatory 14 (6%) 15 (6%) 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%) *Specific = Inflammatory, Infiltrative, Hypertrophic, Ischemic, Valvular, Mixed or Other P=0.14