Results from the PROVIDE Trial Programming Implantable Cardioverter Defibrillators to Prolong Time to First Shock Results from the PROVIDE Trial Mohammad Saeed, MD Robert Styperek, MD Leo Polosajian, MD Ahmed Khan, MD Ibrahim Hanna, MD Joseph Alonso, MD Dionyssios Robotis, MD Curtis Neason, BS Linda Saberi, BS

Outline Key Conclusions Actual slides presented at HRS 2012

Key Conclusions By utilizing a combination of specific programming parameters, shock therapy can be significantly reduced without increasing syncope, in patients with ICD implanted for primary prevention. Majority of benefit was due to avoidance of inappropriate Shocks Appropriate shock rate was low and not different between groups There was no statistical difference between arrhythmic syncope among groups

Results from the PROVIDE Trial Programming Implantable Cardioverter Defibrillators to Prolong Time to First Shock Results from the PROVIDE Trial Mohammad Saeed, MD Robert Styperek, MD Leo Polosajian, MD Ahmed Khan, MD Ibrahim Hanna, MD Joseph Alonso, MD Dionyssios Robotis, MD Curtis Neason, BS Linda Saberi, BS

Financial Disclosures Mohammad Saeed, MD Clinical Investigator: Medtronic, Boston Scientific, St. Jude. Consultant/ Honoraria: Medtronic, Boston Scientific, St. Jude. The PROVIDE Trial was sponsored in full by St. Jude Medical.

Background SCD-HeFT1 and MADIT II2 have expanded the patient population eligible for ICDs to include primary prophylaxis of VT/VF. Nearly half of all shocks experienced by this patient population are inappropriate.3 Inappropriate shocks and other avoidable shocks can lead to ICD battery depletion, a decrease in the patient’s quality of life4,5,6 and may be detrimental to cardiac function. 1 Bardy GH et al. N Engl J Med, Jan 2005. 2 Moss AJ et al. N Engl J Med, 2002. 3 Wilkoff B et al. JACC, Aug 2008. 4 Schron EB et al. Circ, 2002. 5 Irvine JD et al. Am Heart J, Aug 2002. 6 Carroll DL et al. J Acute Crit Care, May 2005.

Background PainFREE Rx I1 & II2 showed that ATP is effective at terminating FVT in a broad ICD population. The PROVE trial3 demonstrated that ATP is highly effective at terminating VT safely in primary prevention population. EMPIRIC4 prescribed programming for all ICD recipients utilizing PF II programming and SVT discriminators. The PREPARE5 trial suggested that prolong detection interval (NID 30/40) in addition to ATP might reduce shocks in the primary prevention population. 1 Wathen MS et al. Circ, Aug 2001. 2 Wathen MS et al. Circ, Oct 2004. 3 Saeed M et al. JCE, Dec 2010. 4 Wilkoff BL et al. JACC, Jul 2006. 5 Wilkoff BL et al. JACC, Aug 2008.

Background However, PREPARE was non-randomized, used a historical control, and utilized programming changes limited only to the prolongation of detection intervals.1 Furthermore, programming an increased number of detection intervals in the VF detection zone may have contributed to the higher frequency of syncope in this study.1 Follow-up for PREPARE was 12 months. 1 1 Wilkoff BL, et al. JACC, Aug 2008.

Purpose To study the efficacy and safety of a strategic combination of programming parameters in order to reduce shocks: Higher detection rates Prolonged detection intervals Aggressive application of SVT discriminators Use of ATP therapy for FVT Patients receiving ICD for primary prevention of sudden cardiac death.

Methods Prospective, multi-center, randomized trial. Patients receiving a de novo ICD or CRT-D manufactured by St. Jude Medical for primary prevention indication. Visit schedule: Enrollment <30 days post implant and every 3 months until study conclusion. Patients with an inducible sustained VT <181 bpm during an electrophysiology test were excluded. All episodes were adjudicated by a panel of EPs to determine rhythm and success of therapy.

Methods Primary endpoint: Safety endpoint: Mean time to first shock Rate of arrhythmic syncope

Device Programming Control [MONITOR] 2x ATP Shocks (12 beats) Nominal SVTd Experiment 2x ATP Shocks (25 beats) 1x ATP (18 beats) (12 beats) Optimized SVTd 150 bpm 181 bpm 214 bpm 250 bpm

Device Programming Rationale for programming the Control Group Utilized zones and therapies from PROVE Trial One VT and VF zone along with monitor zone Very successful at terminating VT with ATP SVT discriminators were nominal settings except: All SVTd were turned ON SVTd Timeout was turned OFF [MONITOR] 2x ATP Shocks (12 beats) Nominal SVTd Control 150 bpm 181 bpm 214 bpm

Device Programming Rationale for programming the Experiment Group Zones and therapies based on PREPARE except: Detection intervals were tiered to minimize syncope Applied SVTd up to 214bpm (instead of 200 bpm) Attempted a second round of ATP between 182-214bpm SVT discriminators were based on literature Theuns et al.1 for DR and CRT-D settings Boriani et al.2 for SR settings 2x ATP Shocks (25 beats) 1x ATP (18 beats) (12 beats) Optimized SVTd Experiment 181 bpm 214 bpm 250 bpm 1 Theuns D et al. Heart Rhythm, Nov 2006. 2 Boriani G et al. PACE, Sep 2002.

SVT Discriminators DR/CRT-D Control Experiment SVT Discrimination Timeout OFF V<A, V=A If Any If All MD % Match 60% Stability Delta 80 ms 40 ms Onset Delta 100 ms 16% SR Control Experiment SVT Discrimination Timeout OFF VT Diagnosis If Any If 2 of 3 MD % Match 60% Interval Stability ON ON w/ SIH Stability Delta 80 ms 40 ms Onset Delta 100 ms 16%

Results All Patients (N=1670) Control (N=824) Experiment (N=846) P-value Follow-up Duration (days) , Mean, Range 548, 1-1019 531, 2-1005 565, 1-1019 0.002 Age (years), Mean ± SD 64 ± 13 64 ± 12 ns Gender, N 1219 (73%) 599 (73%) 620 (73%) NYHA Class I 79 (5%) 33 (4%) 46 (5%) II 520 (31%) 264 (32%) 256 (30%) III 782 (47%) 381 (46%) 401 (48%) IV 26 (2%) 8 (1%) 18 (2%) UNK 263 (16%) 138 (17%) 125 (15%) LVEF (%), Mean ± SD 27 ± 9 27 ± 10 QRS Dur (ms), Mean ± SD 124 ± 32 123 ± 31 124 ± 33 Cardiomyopathy Ischemic 1040 (62%) 510 (62%) 530 (63%) Non-Ischemic 630 (38%) 314 (38%) 316 (37%)

Results All Patients (N=1670) Control (N=824) Experiment (N=846) P-value Cardiac History Prior MI 817 (49%) 412 (50%) 412 (48%) ns Unstable Angina 180 (11%) 76 (9%) 104 (12%) 0.05 CABG 519 (31%) 258 (31%) 261 (31%) PTCA/Stents/Atherectomy 639 (38%) 313 (38%) 326 (39%) Other Medical Conditions Diabetes 600 (36%) 300 (36%) COPD 220 (13%) 115 (14%) 105 (12%) Hyperlipidemia 1005 (60%) 497 (60%) 508 (60%) Hypertension 1213 (73%) 607 (74%) 606 (72%) Peripheral Vascular Disease 150 (9%) 80 (10%) 70 (8%) Renal Disease 191 (11%) 105 (13%) 86 (10%) Valvular Disease 227 (14%) 112 (13%)

Results All Patients (N=1670) Control (N=824) Experiment (N=846) P-value Cardiac Medications, n (%) ACE Inhibitor 1015 (61%) 504 (61%) 511 (60%) ns Antiarrhythmic, Class I 19 (1%) 10 (1%) 9 (1%) Antiarrhythmic, Class III 155 (9%) 73 (9%) 82 (10%) ARB 305 (18%) 148 (18%) 157 (19%) Beta Blocker 1482 (89%) 734 (89%) 748 (88%) Calcium Channel Blocker 154 (9%) 76 (9%) 78 (9%) Diuretic 1092 (65%) 566 (69%) 526 (62%) 0.01 Nitrate 315 (19%) 159 (19%) 156 (18%) Aldosterone Inhibitor 295 (18%) 147 (17%) Anti-coagulant 491 (29%) 227 (28%) 264 (31%) Anti-platelet 1125 (67%) 564 (68%) 561 (66%) Arrhythmia History Atrial Fibrillation 443 (27%) 210 (25%) 233 (28%) Atrial Flutter 56 (3%) 27 (3%) 29 (3%) Sinus Tachycardia 54 (3%) 25 (3%) Atrial Tachycardia 13 (0.8%) 5 (0.6%) 8 (0.9%)

Device Type 22% 41% 37% p = ns 22% 40% 38%

Results: Primary Endpoint Time to First Shock : All-Cause 25 Control Experiment 18.7 % Patients 20 p = 0.0005 15 12.3 10 10.3 5 7.0 0.5 1.0 1.5 2.0 Years N at Risk Control 824 671 542 313 141 Experiment 846 729 599 392 190

Results: Primary Endpoint Time to First Shock - Appropriate Control Experiment 25 % Patients 20 15 p = 0.69 10 4.9 3.0 5 4.9 2.8 0.5 1.0 1.5 2.0 Years N at Risk Control 824 716 592 347 160 Experiment 846 749 625 406 196

Results: Primary Endpoint Time to First Shock - Inappropriate Control Experiment 25 % Patients 20 13.8 15 p < 0.0001 9.3 10 5 5.4 4.1 0.5 1.0 1.5 2.0 Years N at Risk Control 824 683 559 331 153 Experiment 846 743 616 411 199

Results: Safety Endpoint Time to First Arrhythmic Syncope 10 Control Experiment % Patients Number of Arrhythmic Syncopal Episodes Control 8 Experimental 14 5 p = 0.27 0.5 1.0 1.5 2.0 Years N at Risk Control 824 726 607 360 169 Experiment 846 759 635 415 201

Conclusions By utilizing a combination of specific programming parameters, shock therapy can be significantly reduced without increasing syncope, in patients with ICD implanted for primary prevention. Majority of benefit was due to avoidance of inappropriate Shocks Appropriate shock rate was low and not different between groups There was no statistical difference between arrhythmic syncope among groups

Recommendations The following programming parameters should be considered when implanting ICDs in primary prevention patients: Monitor zone OFF Lower rate cutoff for VT zone at 180 bpm Lower rate cutoff for VF zone at 250 bpm Prolonging the detection intervals SVTd ON with sustained rate timer OFF Empiric ATP for FVT up to 250bpm