2. for internal use only Evidence Based Medicine The Need to Avoid Unnecessary Ventricular Stimulation

3. for internal use only ESC Guidelines Guidelines for cardiac pacing and CRT therapy Published by task force for cardiac pacing and CRT of the ESC in collaboration with European Heart Rhythm Association European Heart Journal (2007) 28, 2256-2295

4. for internal use only ESC Guidelines For patients with Sinus Node Disease and AV block a DDDR pacemaker with options to minimize ventricular pacing is indicated Class I, evidence level C indication Class I: evidence and/or general agreement that a given treatment or procedure is beneficial, useful and effective Level of evidence C: expert opinion and/or small studies, retrospective studies and registries EVITA: Evaluation of VIp feaTure in pacemaker pAtients

5. for internal use only MO de S election T rial (MOST) Adverse Effect of Ventricular Pacing On Heart Failure and Atrial Fibrillation Among Patients With Normal Baseline QRS Duration in a Clinical Trial of Pacemaker Therapy for Sinus Node Dysfunction Sweeney et al. Circulation, 2003; vol 107: 2932 - 2937

6. for internal use only Objectives MOST Objectives Study the effect of Cumulative % of Ventricular Pacing in DDDR and VVIR mode on Heart Failure Hospitalization and AF in Sinus Node Disease Pts with QRS duration < 120 ms

7. for internal use only Randomization, Characteristics MOST Randomization, Characteristics 1339 pts DDDR 707 pts VVIR 632 pts Pts with SND QRSd < 120 ms Median EF 55% Mild or no CHF > 50% history of A-tachycardia PR interval < 200 ms or mildly prolonged DDDR and VVIR: lower rate  60, upper rate  110 bpm DDDR: AV delay between 120 – 200 ms 90% Ventricular Pacing in DDDR: due to AV < PR 58% Ventricular Pacing in VVIR

8. for internal use only Results MOST Results

9. for internal use only DDDR Heart Failure Hospitalization MOST DDDR Heart Failure Hospitalization  40% VP > 40% VP months proportion event free

10. for internal use only DDDR 1 st incidence of AF MOST DDDR 1 st incidence of AF  40% VP 40-70% VP months proportion event free 70-90% VP

11. for internal use only DDDR Results MOST DDDR Results Risk of Heart Failure Hospitalization (HFH) for VP > 40% is 2.6 times risk compared with VP < 40% Early, sustained and increasing incidence of HFH for VP > 40% compared with VP < 40% The risk of AF increased by 1% for each % increase in percentage VP (up to 85%) Early, sustained and increasing incidence of AF with increasing percentage of VP

12. for internal use only Sponsor, Reference DAVID Trial Sponsor, Reference Study Sponsor St. Jude Medical. The sponsor had no role in protocol, data collection/management, statistical analysis, manuscript (except review) Reference Wilkoff BL et al. JAMA, Dec 2002; vol 288: 3115 - 3123

13. for internal use only Objectives, Hypothesis, End Points David Trial Objectives, Hypothesis, End Points Study Objectives Compare dual chamber with back-up single chamber pacing in pts with standard ICD indication (LVEF < 40%, no pacing indication) Hypothesis DDD(R) 70 bpm is superior to VVI 40 bpm End points 1. time to death 2. time to 1 st hospitalization for congestive heart failure

14. for internal use only Design, Randomization, Typical Result David Trial Design, Randomization, Typical Result design RV pacing 70% (no AV delay recommendation) Single blinded, parallel-group, randomized clinical trial randomization typical result RV pacing 4 % 506 pts VVI-40 256 pts DDDR-70 250 pts

15. for internal use only Relative Hazard (95% CI), 1.61 (1.06-2.44) VVI - 40bpm 250 256 159 158 76 90 21 25 No at Risk DDDR VVI 061218 Time, mo Cumulative Probability 0.4 0.3 0.2 0.1 0 DAVID Trial Endpoint: Death or 1st Hospitalization for New or Worsened CHF DDDR -70bpm 26.7% 16.1%

16. for internal use only Conclusion DAVID Trial Conclusion In patients with: standard ICD indication no pacing indication LVEF  40% DDDR-70 (no AV delay recommendation) versus VVI-40 offers: no clinical advantage may be detrimental by increasing the combined endpoint of death or hospitalization for heart failure

17. for internal use only Clinical Implications DAVID Trial Clinical Implications DDDR-70 may be detrimental compared to VVI-40 Is this rate related (70  40 bpm): no DAVID II (late braking trial HRS 2007) no difference in endpoint comparing AAI 70 with VVI 40 Is % RV pacing important: yes DAVID Sub-Analysis Sharma et al. Heart Rhythm 2005; 2: 830-834

18. for internal use only Objectives, Hypothesis, Remarks David Sub-Analysis Objectives, Hypothesis, Remarks Study Objectives Evaluate the effect of % RV apical pacing on endpoint Endpoint: death or CHF hospitalization Study design Pts: DAVID pts, with 3 months follow-up, that did not reach endpoint % RV pacing at 3 month follow-up was examined Remarks There was a clear separation between DDDR pts with shipped settings of paced / sensed AV delay (180 – 150 ms) and an increased AV delay

19. for internal use only DAVID Sub-Analysis Endpoint: Death or 1st Hospitalization for New or Worsened CHF best separation for predicting endpoints was between DDDR > 40% and DDDR  40% pacing DDDR < 40% RV pacing patients were similar or better than VVI patients 126 195 59 70 118 35 26 47 16 354354 No at Risk DDDR > 40% VVI unpaced DDDR  40%

20. for internal use only Sponsor, Reference Intrinsic RV Trial Sponsor, Reference Study Sponsor Boston Scientific CRM Reference Olshansky B al. Circ, 2007; vol 115: 9-16

21. for internal use only Objectives, Hypothesis, End Points Intrinsic RV Trial Objectives, Hypothesis, End Points Study Objectives Compare DDDR with algorithm to avoid ventricular pacing with back- up single chamber pacing in pts with ICD indication Hypothesis DDD(R) + AV delay algorithm is not inferior to VVI-40 bpm End points 1. all-cause mortality 2. hospitalization for onset or worsening of CHF

22. for internal use only Results Intrinsic RV Trial Results P=0.072 DDDR with AVSH trends towards superiority compared to VVI

23. for internal use only Sub - Analysis Intrinsic RV Trial Sub - Analysis % of Patients with an Event (Death or HF Hospitalization) Cumulative % RV pacing 8% 3% 14%

24. for internal use only How Can We Avoid Unnecessary Ventricular Stimulation VIP Ventricular Intrinsic Preference

25. for internal use only Active Safety VIP Active Safety

26. for internal use only VIP Active Safety Monitors the heart’s intrinsic conduction Avoids unnecessary pacing Provides pacing when needed Activates and deactivates beat-by-beat AV extension dynamically self-adjusts

27. for internal use only Advanced Programmability VIP Advanced Programmability

28. for internal use only Advanced Programmability VIP Advanced Programmability VIP value  extension of paced / sensed AV-delay  Off - 200 ms, max paced / sensed AV delay 350 ms Search Interval  how often does the pm search for intrinsic rhythm  30 sec, 1, 3, 5, 10 or 30 min Search Cycles  the amount of cycles the AV-delay extension remains in effect while searching for intrinsic conduction  1, 2, 3

29. for internal use only To Activate VIP VIP To Activate VIP

30. for internal use only AV Extension VIP AV Extension

31. for internal use only Search Interval VIP Search Interval

32. for internal use only Search Cycles VIP Search Cycles

33. for internal use only Activation - Deactivation VIP Activation - Deactivation

34. for internal use only Activation Criteria VIP Activation Criteria One R-wave is sensed during the Search Interval 3 consecutive R-waves occur within programmed AV delay but outside the Search Interval 30 seconds after programming

35. for internal use only Deactivation Criteria VIP Deactivation Criteria VIP is deactivated when the consecutive number of VP events equals the number of programmed Search Cycles at the extended AV delay

36. for internal use only versus no VIP VIP versus no VIP

37. for internal use only Example: patient with intermittent complete AV block AV conduction AV block No VIPVIP long fixed AV delay (e.g. 320 ms) to prevent VPVIP induced AV delay extension to prevent VP too long (e.g. 320 ms) fixed AV delaychange to optimized AV delay (e.g. 195 ms)

38. for internal use only Patient selection VIP Patient selection

39. for internal use only Patient Selection VIP Patient Selection VIP most beneficial Intermittent AV block Mild prolongation of AV conduction VIP not beneficial Complete permanent AV block Marked 1st degree AV block If CRT therapy is indicated

40. for internal use only versus AAI  DDD algorithms VIP versus AAI  DDD algorithms

41. for internal use only Patient Type: 1 st Degree AV block VIP Patient Type: 1 st Degree AV block VIP provides immediate ventricular support at the appropriate AV delay, avoiding inappropriately long AV delay AAI  DDD will continue in AAI mode with an inappropriately long AV delay until block occurs

42. for internal use only Patient Type: Intermittent 2 nd Degree AV block VIP Patient Type: Intermittent 2 nd Degree AV block VIP provides immediate ventricular support VIP allows switch to extended AV delay (avoid VP) after 30 seconds ______________________________________________________ AAI  DDD will continue in AAI mode with a (too) long AV delay until block occurs AAI  DDD allows for repeated ventricular pauses (can cause pause dependent VTs 1,2 ) 1.Grey C, et al. Inappropriate application of “Managed Ventricular Pacing” in a patient with Brugada syndrome leading to polymorphic VT and ICD shocks. Heart Rhythm 2006; 3(5): S137 2.Van Mechelen R, et al. Risk of Managed Ventricular Pacing in a patient with heart block. Heart Rhythm 2006; 3(11): 1384-1385

43. for internal use only Patient Type: High Grade 2 nd Degree, Intermittent 3 rd Degree AV Block VIP Patient Type: High Grade 2 nd Degree, Intermittent 3 rd Degree AV Block VIP provides immediate ventricular support at the first blocked ventricular event AAI  DDD occurs only after block, creates long ventricular intervals (can cause pause dependent VTs 2 ) AAI  DDD will not occur if ventricular escape rhythm during block is sufficiently fast: sustained AV dissociation 2.Van Mechelen R, et al. Risk of Managed Ventricular Pacing in a patient with heart block. Heart Rhythm 2006; 3(11): 1384-1385

44. for internal use only clinical benefits VIP clinical benefits

45. for internal use only Clinical Benefits VIP Clinical Benefits Less risk of heart failure progression 3,4 Less risk of developing AF 5 Better QoL trough improved hemodynamics 6 3.Wilkoff BL, et al. DAVID investigators. Dual chamber pacing or ventricular back-up pacing in patients with an implantable ICD. JAMA 2002; 288(24): 3115 – 3123. 4.Olshansky B, et al. Is dual chamber programming inferior to single chamber programming in an ICD? Results of the INTRINSIC RV Study. Circulation 2007; 115: 9 – 16. 5.Sweeny MO, et al. Minimizing ventricular pacing to reduce AF in sinus node disease. N Engl J Med 2007; 357: 1000 - 1008 6.Ovsyshcher E. Toward physiological pacing: optimization of cardiac hemodynamics by AV delay adjustment. PACE 1997; 20: 861 - 865

46. for internal use only additional information VIP additional information

47. for internal use only Additional Information VIP Additional Information PVCs have no effect on the timing of the VIP algorithm If paced AV delay = 350ms: VIP is off If rate responsive paced / sensed AV delay is enabled and active, the VIP AV delay extension will be added to the shortened paced / sensed AV delay

48. for internal use only Disabled When: VIP Disabled When: programmed base rate  110 bpm in DDD(R) or VDD(R) paced / sensed atrial rate  110 bpm Negative AV hysteresis / search is programmed On Advanced Hysteresis Response is initiated A magnet is applied

49. for internal use only And AutoCapture VIP And AutoCapture When AutoCapture is On the VIP parameter needs to be  100 ms (VIP + paced AV delay  350 ms) VIP is cancelled during AutoCapture Threshold Search and Loss of Capture recovery

50. for internal use only Summary VIP Summary There is a need to avoid unnecessary ventricular pacing VIP helps to avoid unnecessary ventricular pacing Advanced programmability: VIP, Search Intervals, Search Cycles Immediate ventricular support at the appropriate AV delay Provide necessary pacing with optimized AV delay To pace (with QuickOpt) or not to pace (with VIP)

51. for internal use only VIP to avoid unnecessary ventricular stimulation

52. for internal use only