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Influence of Atrial Fibrillation on Efficacy and Safety of Omecamtiv Mecarbil in Heart Failure: the GALACTIC-HF Trial

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Influence of Atrial Fibrillation on Efficacy and Safety of Omecamtiv Mecarbil in Heart Failure: the GALACTIC-HF Trial Influence of Atrial Fibrillation on Efficacy and Safety of Omecamtiv Mecarbil in Heart Failure: The GALACTIC-HF Trial Scott D. Solomon, MD on behalf of the GALACTIC-HF Executive Committee and Investigators Disclosures Dr Solomon reports: • Employment: Brigham and Women’s Hospital • Grant funding: NIH/NHLBI, Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos • Consulting: Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta • The GALACTIC-HF study was funded by Amgen, Cytokinetics, and Servier Background • The myosin activator, omecamtiv mecarbil, augments cardiac sarcomere function by facilitating the actin-myosin interaction resulting in an increase in contractile force1. • In the GALACTIC-HF trial, omecamtiv mecarbil reduced the risk of a composite of cardiovascular death or first heart failure event in patients with heart failure and reduced ejection fraction2. • Atrial fibrillation is common in patients with heart failure and contributes to morbidity and mortality. • Atrial fibrillation has not modified the treatment effect of renin- angiotensin-aldosterone inhibitors that have proven beneficial in heart failure1,2, but may modify the treatment effect of beta-blockers5. 1. Malik FL.. Science. 2011 2. Teerlink JR et al. GALACTIC-HF Investigators, N Engl J Med 2020 3. Olsson LG et al. CHARM Investigators J Am Coll Cardiol. 2006 4. Swedberg K, et al. EMPHASIS-HF Investigators. J Am Coll Cardiol. 2012 5. Kotecha et al. Lancet, 2014 Primary Outcome: Subgroup Results 0.7 1.0 1.3 Teerlink JR, et al. N Engl J Med 2021;384:105-116. Objectives • The objective of this analysis was to assess whether baseline Atrial Fibrillation or Flutter (AFF) modified the effectiveness of omecamtiv mecarbil and explore additional potential factors that may have influenced this effect modification. GALACTIC-HF Trial Design Hypothesis: Selectively improving cardiac function with the cardiac myosin activator, omecamtiv mecarbil, will improve clinical outcomes in patients with HFrEF Screening: • Chronic HF, NYHA II-IV Omecamtiv Mecarbil + Standard HF Therapy • LVEF ≤35% Starting dose: 25 mg PO BID; Pharmacokinetic-guided dose selection Randomization (1:1) (25, 37.5 or 50 mg PO BID) • Elevated BNP/ NTproBNP (depending on AFF status) Stratification • – Inpatient or Managed with Standard HF outpatient therapies – Region End End Studyof • Currently hospitalized for HF Placebo + SoC (Inpatients) OR Urgent ED visit or hospitalization for HF within 1 year prior to Study Visits D1 W2 W4 W6 W8 W12 W24 W36 W48 Q16W screening (Outpatients) • SBP ≥85 mmHg; Pharmacokinetic assessment eGFR ≥20 mL/min/1.73m2 for dose adjustment • AFF at baseline capped at 25% Multicenter, international, randomized, double-blind, placebo-controlled, event-driven Phase 3 study Teerlink JR, et al. JACC Heart Fail 2020;8:329‒40. Baseline Characteristics by Atrial Fibrillation No AF/Flutter at baseline AF/Flutter at baseline P-value n=5987 n=2245 Demographics Age - yr 63.3 ± 11.6 67.9 ± 9.9 p<0.001 Sex, Female 1340 (22.4%) 409 (18.2%) p<0.001 Race p<0.001 Asian 556 (9.3 %) 154 (6.9 %) Black 487 (8.1 %) 75 (3.3 %) Other 433 (7.2 %) 130 (5.8 %) White 4511 (75.3%) 1886 (84.0%) Geographic Region P<0.001 Asia 522 (8.7 %) 148 (6.6 %) Eastern Europe/Russia 1790 (29.9%) 891 (39.7%) Latin America 1226 (20.5%) 348 (15.5%) US And Canada 1138 (19.0%) 248 (11.0%) Western Europe/South 1311 (21.9%) 610 (27.2%) Africa/Australasia Randomization Setting: In-patient 1361 (22.7%) 723 (32.2%) p<0.001 Baseline Characteristics by Atrial Fibrillation/Flutter Clinical Characteristics No AF/Flutter at Baseline AF/Flutter at Baseline P-value Hypertension Hx 4136 (69.1%) 1648 (73.4%) P < 0.001 Type 2 diabetes mellitus 2431 (40.6%) 878 (39.1%) P = 0.22 History of stroke 497 (8.3 %) 257 (11.4%) P < 0.001 Ischemic heart failure etiology 3341 (55.8%) 1074 (47.8%) P < 0.001 LVEF - % 26.4 ± 6.3 27.1 ± 6.1 P < 0.001 NYHA Classification P < 0.001 Class II 3353 (56.0%) 1015 (45.2%) Class III 2473 (41.3%) 1143 (50.9%) Class IV 161 (2.7 %) 87 (3.9 %) SBP — mmHg 117.0 ± 15.5 115.1 ± 14.8 P < 0.001 Heart rate — beats/min 71.3 ± 11.5 75.1 ± 13.4 P < 0.001 NT-proBNP — pg/mL 1675 [812 , 3579 ] 2873 [1699 , 5294 ] P < 0.001 Cardiac Troponin I — ng/L 25 [13 , 48 ] 31 [16 , 59 ] P < 0.001 eGFR — mL/min/1.73m2 60.6 [45.7 , 76.1 ] 53.4 [40.4 , 68.1 ] P < 0.001 Heart Failure Therapies ACEi, ARB or ARNi 5246 (87.6%) 1913 (85.2%) P = 0.004 BB 5650 (94.4%) 2113 (94.1%) P = 0.66 MRA 4627 (77.3%) 1770 (78.8%) P = 0.13 Digoxin 693 (11.6%) 692 (30.8%) P < 0.001 Cardiac Resynchronization Therapy 815 (13.6%) 343 (15.3%) P = 0.05 Implantable Cardioverter Defibrillator 1913 (32.0%) 701 (31.2%) P = 0.53 Proportion of Patients with AF/Flutter by LVEF Atrial Fibrillation/Flutter Modifies Treatment Effect of Omecamtiv Mecarbil Favors OmecamtivMecarbil Favors Placebol P-interaction = 0.012 P-interaction = 0.002 P-interaction < 0.001 P-interaction = 0.12 Effect Modification for Atrial Fibrillation most Prominent in Patients using Digoxin Favors OmecamtivMecarbil Favors Placebol Exploratory Analyses • PK values of omecamtiv mecarbil at 6-weeks were similar in those taking and those not taking digoxin (median 286 vs. 280 ng/ml, p = 0.78). • In patients in whom digoxin doses were known, digoxin doses were similar in both treatment arms (.12 mg vs. .12mg, p = 0.85) and similar in patients with and without AFF at baseline (.12 mg vs .12 mg, p = 0.44). • In a drug-drug interaction study in healthy subjects, omecamtiv mecarbil did not affect digoxin levels Serious Adverse Events of Atrial Fibrillation by Treatment Group Serious Adverse Events of Atrial Fibrillation p = 0.046 78 events / 3013 pts 55 events / 2974 pts Limitations and Caveats • While the presence of AF/Flutter at baseline was a prespecified subgroup, the use of digoxin was not; these additional analyses were data-driven and should be considered hypothesis generating. • While we do not see evidence of a pharmacokinetic interaction between digoxin and omecamtiv mecarbil, we cannot rule out the possibility of a pharmacodynamic interaction in patients in AFF taking omecamtiv mecarbil and digoxin. • The findings of a reduction in serious adverse events attributed to AF/Flutter in patients randomized to omecamtiv mecarbil should be considered hypothesis generating. Conclusions • Atrial fibrillation or flutter at baseline modified the treatment effect of omecamtiv mecarbil, even after multivariable adjustment, with greater benefit observed in patients not in AFF. • The treatment effect modification by AFF was concentrated in patients using digoxin in AFF with minimal evidence of effect modification in non- users in AFF. • Digoxin did not modify the treatment effect of omecamtiv mecarbil in patients not in AFF. • These findings suggest caution should be exercised when treating patients in AFF with both digoxin and omecamtiv mecarbil Acknowledgements EXECUTIVE COMMITTEE: John R. Teerlink, MD (Chair); Rafael Díaz, MD; G. Michael Felker, MD, MHS; John J. V. McMurray, MD; Marco Metra, MD; Scott D. Solomon, MD DATA MONITORING COMMITTEE: Marvin A. Konstam, MD (Chair); Javed Butler, MD, MPH; Henry Dargie, MD; Joseph Massaro, PhD; Barry H. Greenberg, MD; James L. Januzzi, MD; Lawrence J. Lesko, PhD (Non-Voting Member); Jenica N. Upshaw, MD, MS (Non-Voting Member) CLINICAL EVENT ADJUDICATION COMMITTEE: G. Michael Felker, MD, MHS (Co-Chair); Renato Lopes, MD, PhD (Co-Chair); W. Schuyler Jones, MD Karen P. Alexander, MD; Sana M. Al-Khatib, MD, MHS; Robert W. Harrison, MD; J. Dedrick Jordan, MD, PhD; David F. Kong, MD; Robin Mathews, MD; Robert W. McGarrah, MD; Rajendra H. Metha, MD, MS; Chiara Melloni, MD, MHS; Thomas J. Povsic, MD, PhD; Shreyansh Shah, MBBS SPONSOR LEADERSHIP: Fady I. Malik, MD, PhD; Christopher E. Kurtz, MD; Siddique Abbasi, MD, MSc; Beat Knusel, PhD; Thomas Hucko, MD; John Groarke, MBBCh, MPH, MSc; Narimon Honarpour, MD, PhD; Jason C. Legg, PhD; Lucie Sharpsten, PhD; Claire Varin, MD INDEPENDENT STATISTICIAN: Brian Claggett, PhD NATIONAL LEAD INVESTIGATORS: Kirkwood Adams, MD; Inder Anand, MD, PhD; Alexandra Arias Mendoza, MD; Tor Biering-Sørensen, MD; Michael Böhm, MD; Diana Bonderman, MD; John Cleland, MD; Ramon Corbalan Herreros, MD; Marisa Crespo Leiro, MD, PhD; Ulf Dahlstrom, MD, PhD; Rafael Diaz, MD; Luis Eduardo Echeverria, MD; James Fang, MD; Gerasimos Filippatos, MD; Candida Fonseca, MD, PhD; Eva Goncalvesova, MD, PhD; Assen Goudev, MD, PhD; Jonathan Howlett, MD; Lixin Jiang, MD, PhD; David Lanfear, MD, MS; Jing Li, MD; Mayanna Lund, MD; Peter MacDonald, MD, PhD; Viacheslav Mareev, MD, PhD; Marco Metra, MD; Shin-ichi Momomura, MD; Eileen O'Meara, MD; Alexander Parkhomenko, MD, PhD; Piotr Ponikowski, MD, PhD; Felix Ramires, MD, PhD; Pranas Serpytis, MD, PhD; Karen Sliwa, MD, PhD; Jindrich Spinar, MD, PhD; Thomas Suter, MD; Janos Tomcsanyi, MD, PhD; Hans Vandekerckhove, MD; Dragos Vinereanu, MD, PhD; Adriaan Voors, MD, PhD; Mehmet Birhan Yilmaz, MD; Faiez Zannad, MD, PhD 945 Site Investigators in 35 Countries .
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