Ventricular Functional Response to Spinal Cord Stimulation for - PowerPoint PPT Presentation

Ventricular Functional Response to Spinal Cord Stimulation for Advanced Heart Failure: Primary Results of the Randomized DEFEAT-HF Trial Presenter: Douglas P. Zipes, M.D., Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana Authors: Douglas P. Zipes, M.D., Petr Neuzil, M.D., Heinz Theres, M.D., David Caraway, M.D., Ph.D., Douglas Mann, M.D., Clas Mannheimer, M.D., Peter Van Buren, M.D., Cecilia Linde, M.D., Bengt Linderoth, M.D., Fred Kueffer, M.S., Scott A. Sarazin, B.S., Michael JL De Jongste, M.D., on behalf of the DEFEAT-HF Trial Investigators Sponsor: Medtronic, Inc. Clinical Registration: www.clinicaltrials.gov ID NCT01112579 DEFEAT-HF AHA 2014

Hypothesis and Outcomes • Pre-Clinical: Animal data Lopshire, Zipes Circulation 2009; Clinical: a small nonrandomized clinical study • Hypothesis – Treatment with spinal cord stimulation reverse remodels patients with NYHA Class III heart failure and narrow QRS • Primary outcome – Change in Left-Ventricular End Systolic Volume Index (LVESVi) over six months • Secondary outcomes – Change in peak oxygen uptake over six months – Change in NT-proBNP over six months DEFEAT-HF AHA 2014

Committees and Core Laboratories • Data Monitoring Committee (DMC): Jay Cohn, MD, Committee Chair – Trial results were blinded to all committees, sponsor, and investigators except for DMC who met every six months to monitor the safety of study participants and execution of the trial • Adverse Event Advisory Committee (AEAC): Michael Reiter, MD, Committee Chair • Echo Core Laboratory: United Heart and Vascular Center, St. Paul, MN: Alan Bank, MD, Director • Cardiopulmonary Exercise Test (CPX) Core Laboratory: Henry Ford Hospital, Detroit, MI: Steven J. Keteyian, PhD, Director DEFEAT-HF AHA 2014

24 Study Centers and Enrollments/Randomizations Study Center Subjects Enrolled Subjects Randomized Europe 59 49 Academisch Ziekenhuis Maastricht, Maastricht, the Netherlands 3 2 Charite Universitatsmedizin Berlin - Campus Mitte, Berlin, Germany 1 0 Isala Klinieken, Zwolle, the Netherlands 5 4 Karolinska Universitetssjukhuset, Stockholm, Sweden 10 7 Marienhospital Herne, Herne, Germany 1 1 Na Homolce Hospital, Prague, Czech Republic 23 22 Policlinico Universitario Agostino Gemelli, Rome, Italy 3 3 Su/Ostra Sjukhuset - Multidisciplinary Pain Center, Goteborg, Sweden 4 2 Universitair Medisch Centrum Groningen, Groningen, the Netherlands 9 8 Canada 3 3 University of Calgary, Calgary, Alberta 0 0 Saint Paul's Hospital, Vancouver, British Columbia 1 1 Victoria Cardiac Arrhythmia Trials, Inc., Victoria, British Columbia 2 2 United States 17 12 Fletcher Allen Health Care, Burlington, Vermont 2 1 Heart Clinics Northwest, P.S., Spokane, Washington 5 4 Indiana University Krannert Institute, Indianapolis, Indiana 3 2 Lehigh Valley Hospital, Allentown, Pennsylvania 3 2 Mayo Clinic, Rochester, Minnesota 0 0 Minneapolis Heart Institute Foundation, Minneapolis, Minnesota 0 0 NYU - Langone Medical Center, New York, New York 1 0 Scripps Clinic, La Jolla, California 0 0 University of Miami Health System, Miami, Florida 2 2 University of Pennsylvania, Philadelphia, Pennsylvania 1 1 South Africa 2 2 Milpark Hospital, Johannesburg 2 2 Groote Schuur Hospital, Cape Town 0 0 Total 81 66 DEFEAT-HF AHA 2014

Key Eligibility Criteria • NYHA Class III heart failure •LVEF ≤ 35% • QRS duration < 120ms • LVEDD 55mm - 80mm • Stable optimal medical therapy for heart failure DEFEAT-HF AHA 2014

Device Information PrimeADVANCED™ Standard 1x8 lead Neurostimulator Model 3777 Model 37702 • Single percutaneous Treatment Parameters: epidural lead • Target: T2-T4 level of • Stimulation programmed for 12 hours a day spinal cord based upon individual sleep/wake cycle • Implant procedure in accordance with current • 50 Hz, 0.2ms and 90% maximum tolerated labeling voltage while sitting DEFEAT-HF AHA 2014

Trial Design Implant (SCS) Randomize 3:2 Treatment: Control: SCS ON SCS OFF Single- blind Follow-up Follow-up 1m, 3m, 6m 1m, 3m, 6m SCS ON at end of 6m visit Follow-up Follow-up 9m, 12m, Annual 7m, 9m, 12m, Annual DEFEAT-HF AHA 2014

CONSORT* Trials Flow Diagram Assessed for eligibility (n = 81) Excluded (n = 15) Not meeting inclusion criteria (n = 11) Declined to participate (n = 3) Death CV related (n = 1) Randomized 3:2 (n = 66) Allocated to SCS ON (n = 42) Allocated to SCS OFF (n = 24) Received intervention (n = 42) Received intervention (n = 24) Did not receive intervention (n = 0) Did not receive intervention (n = 0) No six month visit (n = 1) No six month visit (n = 3) Missed six month visit (n = 1) Missed six month visit (n = 1) Death CV related (n = 0) Death CV related (n = 2) Lost to follow-up (n = 0) Lost to follow-up (n = 0) Discontinued intervention (n = 0) Discontinued intervention (n = 0) Analyzed intention-to-treat (n = 40) Analyzed intention-to-treat (n = 20) (n = 1) (n = 1) Excluded due to unreadable echo Excluded due to unreadable echo DEFEAT-HF AHA 2014 * Consolidated Standards of Reporting

Demographics Therapy Control Total Subject Characteristics (N=42) (N=24) Subjects Male (N,%) 32 (76.2%) 20 (83.3%) 52 (78.8%) Age (years) (Mean ± SD) 58 ± 11 66 ± 11 61 ± 12 Systolic Blood Pressure (mmHg) (Mean ± SD) 114 ± 19 119 ± 16 116 ± 18 Diastolic Blood Pressure (mmHg) (Mean ± SD) 70 ± 10 70 ± 11 70 ± 10 BMI (kg/m 2 ) (Mean ± SD) 31 ± 6 29 ± 6 30 ± 6 6-minute walk test (m) (Mean ± SD) 309 ± 118 352 ± 118 324 ± 119 Baseline Medications (N,%) Beta-blocker 40 (95.2%) 23 (95.8%) 63 (95.5%) Diuretic 40 (95.2%) 22 (91.7%) 62 (93.9%) ACE-I or ARB 38 (90.5%) 22 (91.7%) 60 (90.9%) LVEF [Core Lab] (%) (Mean ± SD) 29 ± 5 29 ± 5 29 ± 5 LVEDD [Core Lab] (mm) (Mean ± SD) 60 ± 6 61 ± 8 61 ± 7 LVESVi [Core Lab] (mL/m 2 ) (Mean ± SD) 55 ± 17 61 ± 16 57 ± 17 Minnesota Living with Heart Failure Questionnaire (Mean ± SD) 51 ± 20 45 ± 18 49 ± 19 HF hospitalization 6 months prior to enrollment 1 8 (42.9%) 1 2 (50.0%) 3 0 (45.5%) DEFEAT-HF AHA 2014

General Cardiovascular History Demographics Therapy Control Total Subject Characteristics (N=42) (N=24) Subjects Implanted ICD at Baseline (N, %) 32 (76.2%) 17 (70.8%) 49 (74.2%) QRS Width (msec) (Mean ± SD) 104 ± 14 105 ± 13 105 ± 14 Ischemic Cardiomyopathy 25 (59.5%) 12 (50.0%) 37 (56.1%) Atrial Arrhythmias 18 (42.9%) 9 (37.5%) 27 (40.9%) Atrial fibrillation 10 (23.8%) 6 (25.0%) 16 (24.2%) Sinus node dysfunction 3 (7.1%) 0 (0.0%) 3 (4.5%) Ventricular Arrhythmias 16 (38.1%) 16 (66.7%) 32 (48.5%) Ventricular tachycardia 11 (26.2%) 8 (33.3%) 19 (28.8%) DEFEAT-HF AHA 2014

Primary Objective: Mean Change in LVESVi (ml/ m 2 ) P-value 1 Treatment n Baseline 6 Month Change (mean ± SD) (mean ± SD) (mean ± SD) Therapy 40 54.6 ± 17.3 57.4 ± 19.6 2.8 ± 16.0 0.30 Control 20 61.9 ± 16.3 58.3 ± 18.6 -3.6 ± 14.9 1 ANCOVA (analysis of covariance) DEFEAT-HF AHA 2014

Secondary Objective: Mean Change in Peak VO 2 (ml/kg/min) P-value 1 Treatment n Baseline 6 Month Change (mean ± SD) (mean ± SD) (mean ± SD) Therapy 28 14.4 ± 5.3 15.0 ± 4.9 0.6 ± 4.1 0.93 Control 13 16.7 ± 3.0 16.5 ± 3.1 -0.2 ± 3.3 DEFEAT-HF AHA 2014 1 ANCOVA

Secondary Objective: Mean Change in N-terminal pro β -type natriuretic peptide (NTproBNP; pg/ml) P-value 1 Treatment n Baseline 6 Month Change (mean ± SD) (mean ± SD) (mean ± SD) Therapy 34 1627 ± 1711 1595 ± 1743 -32 ± 994 0.79 Control 21 1830 ± 2102 1904 ± 3130 74 ± 1468 1 ANCOVA DEFEAT-HF AHA 2014

Additional Objectives Therapy Control Outcome P-value (N=42) (N=24) Free from hospitalization with HF or 76% 88% 0.28 death at 6 months Change in Minnesota Living with Heart -12 -9 0.90 Failure Score (Mean differences) Change in NYHA Class Improved 58% 63% Unchanged 42% 37% 0.70 Worsened 0% 0% Change in 6 minute hall walk (meters) 16 -24 0.47 (Mean differences) DEFEAT-HF AHA 2014

Adverse Events Resulting in Complications Complications included lead dislodgement, lead fracture, implant site hematoma, decompensated HF post procedure. No complication type occurred in more than 5% of patients. The Data Monitoring Committee observed no safety concerns during the trial, and there were no significant differences between randomized arms DEFEAT-HF AHA 2014

Conclusions •SCS programmed to 90% maximum tolerated threshold voltage in the population studied does not appear to offer any clinical benefit or improvement in clinical outcomes as a treatment for HF • This does not necessarily invalidate the hypothesis of SCS benefits because: – Low power: enough to establish neutral effects but not for analyzing subgroups to understand why. – Possible incorrect SCS dosing: 24 hours? Higher output? Two leads? – Patients not followed long enough? – Impact of single center ? – Impact of excluding QRS>120ms? (Could include CRT nonresponders) – LVEDD not large enough? DEFEAT-HF AHA 2014

FINAL COMMENTS “THE GREAT TRAGEDY OF SCIENCE – THE SLAYING OF A BEAUTIFUL HYPOTHESIS BY AN UGLY FACT” – THOMAS HENRY HUXLEY BUT: HAVE THESE FACTS SLAIN THE HYPOTHESIS OR HAVE WE NOT TESTED THE HYPOTHESIS APPROPRIATELY? Thank you for your attention

Back-up slides

Primary Objective: Change in LVESVi Through 12 Months Data DEFEAT-HF AHA 2014

Secondary Objective: Change in Peak VO 2 Through 12 Months DEFEAT-HF AHA 2014