Ventricular Functional Response to Spinal Cord Stimulation for Advanced Heart Failure: Primary Results of the

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

Treatment Parameters:• Stimulation programmed for 12 hours a day

based upon individual sleep/wake cycle• 50 Hz, 0.2ms and 90% maximum tolerated

voltage while sitting

PrimeADVANCED™Neurostimulator

Model 37702

Standard 1x8 leadModel 3777

• Single percutaneous epidural lead

• Target: T2-T4 level of spinal cord

• Implant procedure in accordance with current labeling

DEFEAT-HF AHA 2014

Trial Design

DEFEAT-HF AHA 2014

Implant(SCS)

Randomize3:2

Treatment: SCS ON

Control:SCS OFF

Single-blind

Follow-up1m, 3m, 6m

Follow-up9m, 12m, Annual

Follow-up1m, 3m, 6m

SCS ON at end of 6m visit

Follow-up7m, 9m, 12m, Annual

Assessed for eligibility (n = 81)

Allocated to SCS ON (n = 42)

Received intervention (n = 42)

Did not receive intervention (n = 0)

Allocated to SCS OFF (n = 24)

Received intervention (n = 24)

Did not receive intervention (n = 0)

No six month visit (n = 1)

Missed six month visit (n = 1)

Death CV related (n = 0)

Lost to follow-up (n = 0)

Discontinued intervention (n = 0)

Analyzed intention-to-treat (n = 40)

Excluded due to unreadable echo (n = 1)

Excluded (n = 15)

Not meeting inclusion criteria (n = 11)

Declined to participate (n = 3)

Death CV related (n = 1)Randomized 3:2 (n = 66)

No six month visit (n = 3)

Missed six month visit (n = 1)

Death CV related (n = 2)

Lost to follow-up (n = 0)

Discontinued intervention (n = 0)

Analyzed intention-to-treat (n = 20)

Excluded due to unreadable echo (n = 1)

CONSORT* Trials Flow Diagram

DEFEAT-HF AHA 2014 * Consolidated Standards of Reporting

Demographics

DEFEAT-HF AHA 2014

Subject Characteristics Therapy(N=42)

Control(N=24)

Total 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/m2) (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/m2) (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 18 (42.9%) 12 (50.0%) 30 (45.5%)

General Cardiovascular History Demographics

DEFEAT-HF AHA 2014

Subject Characteristics Therapy(N=42)

Control(N=24)

Total 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%)

Primary Objective: Mean Change in LVESVi (ml/m2)

DEFEAT-HF AHA 2014

Treatment n Baseline(mean ± SD)

6 Month(mean ± SD)

Change(mean ± SD)

P-value1

Therapy 40 54.6±17.3 57.4±19.6 2.8±16.00.30

Control 20 61.9±16.3 58.3±18.6 -3.6±14.91ANCOVA (analysis of covariance)

Secondary Objective: Mean Change in Peak VO2 (ml/kg/min)

DEFEAT-HF AHA 2014

Treatment n Baseline(mean ± SD)

6 Month(mean ± SD)

Change(mean ± SD)

P-value1

Therapy 28 14.4±5.3 15.0±4.9 0.6±4.10.93

Control 13 16.7±3.0 16.5±3.1 -0.2±3.31ANCOVA

Secondary Objective: Mean Change in N-terminal pro β-type natriuretic peptide (NTproBNP; pg/ml)

DEFEAT-HF AHA 2014

Treatment n Baseline(mean ± SD)

6 Month(mean ± SD)

Change(mean ± SD)

P-value1

Therapy 34 1627±1711 1595±1743 -32±9940.79

Control 21 1830±2102 1904±3130 74±14681ANCOVA

Additional Objectives

Outcome Therapy(N=42)

Control(N=24) P-value

Free from hospitalization with HF or death at 6 months 76% 88% 0.28

Change in Minnesota Living with Heart Failure Score (Mean differences) -12 -9 0.90

Change in NYHA Class

Improved 58% 63%

0.70Unchanged 42% 37%

Worsened 0% 0%

Change in 6 minute hall walk (meters)(Mean differences) 16 -24 0.47

DEFEAT-HF AHA 2014

Adverse Events Resulting in Complications

DEFEAT-HF AHA 2014

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

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

BUT: HAVE THESE FACTS SLAIN THE HYPOTHESIS OR HAVE WE NOT TESTED THE HYPOTHESIS APPROPRIATELY?

“THE GREAT TRAGEDY OF SCIENCE – THE SLAYING OF A BEAUTIFUL HYPOTHESIS BY AN UGLY FACT”– THOMAS HENRY HUXLEY

Thank you for your attention

FINAL COMMENTS

Back-up slides

Primary Objective: Change in LVESVi Through 12 Months Data

DEFEAT-HF AHA 2014

Secondary Objective: Change in Peak VO2 Through 12 Months

DEFEAT-HF AHA 2014

Secondary Objective: Change in NT-proBNP Through 12 months

DEFEAT-HF AHA 2014

Change in 6 minute hallwalk

SURVIVAL

ADVERSE EVENTS

Change in mean LVEDVI and EF