1. Optimizing Ventricular Pacing in Sinus Node Disease Michael O. Sweeney, MD Brigham and Women’s Hospital Assistant Professor of Medicine Harvard Medical School Boston, MA

2. Executive Summary Four major clinical trials have been unable to demonstrate a clear benefit of DDDR pacing over VVIR for the clinical endpoints of total mortality, cardiovascular mortality and stroke.Four major clinical trials have been unable to demonstrate a clear benefit of DDDR pacing over VVIR for the clinical endpoints of total mortality, cardiovascular mortality and stroke. It is possible that the higher level of ventricular pacing associated with conventional DDDR pacing systems has adverse long-term effects on ventricular performance that mitigate the benefit of AV synchrony.It is possible that the higher level of ventricular pacing associated with conventional DDDR pacing systems has adverse long-term effects on ventricular performance that mitigate the benefit of AV synchrony. Most patients with sinus node dysfunction (SND) have reliable AV conduction and normal ventricular activation. These patients would benefit from pacing systems that promote intrinsic AV conduction.Most patients with sinus node dysfunction (SND) have reliable AV conduction and normal ventricular activation. These patients would benefit from pacing systems that promote intrinsic AV conduction. The optimal pacing strategy to mitigate inappropriate ventricular pacing has not been identified.The optimal pacing strategy to mitigate inappropriate ventricular pacing has not been identified.

3. Presentation Overview BackgroundBackground Review of published clinical data on pacing mode in sinus node diseaseReview of published clinical data on pacing mode in sinus node disease –Danish –CTOPP –MOST –DAVID Why haven’t we been able to show a mortality and stroke benefit with DDDR pacing?Why haven’t we been able to show a mortality and stroke benefit with DDDR pacing? MOST Sub-Study: SND patients with QRS <120 msMOST Sub-Study: SND patients with QRS <120 ms Goals and strategies to reduce ventricular pacingGoals and strategies to reduce ventricular pacing Identifying SND patients for minimal ventricular pacing strategiesIdentifying SND patients for minimal ventricular pacing strategies ConclusionsConclusions

4. Background Dual chamber pacing has long been considered “physiologic” due to maintenance of AV synchrony.Dual chamber pacing has long been considered “physiologic” due to maintenance of AV synchrony. Atrial pacing and dual-chamber pacing are similar only in that both maintain AV synchrony.Atrial pacing and dual-chamber pacing are similar only in that both maintain AV synchrony. Since most sinus node disease patients have intact or intermittent conduction, the best pacing mode for these patients has often been debated.Since most sinus node disease patients have intact or intermittent conduction, the best pacing mode for these patients has often been debated. Several large-scale clinical studies have attempted to identify the optimal pacing mode in patients with sinus node disease.Several large-scale clinical studies have attempted to identify the optimal pacing mode in patients with sinus node disease.

5. Clinical Data: Pacing Mode and Sinus Node Disease Danish Study CTOPP MOST DAVID

6. Danish Study

7. Danish Study Overview Hypothesis:Hypothesis: –In patients with SND, atrial pacing (AAI) will result in less atrial fibrillation, thromboembolism, heart failure and overall mortality than ventricular pacing (VVI). Study Design:Study Design: –Single center, prospective, randomization of patients referred for first pacemaker implant

8. Primary:Primary: –Mortality –Cardiovascular death Secondary:Secondary: –Atrial fibrillation –Thromboembolic events –Heart failure –AV block Danish Study Endpoints

9. First pacemaker implantFirst pacemaker implant Symptomatic bradycardia ( 2 seconds)Symptomatic bradycardia ( 2 seconds) >50 years of age>50 years of age No history of:No history of: –Chronic AF or AF >50% of time or AF with QRS rate <40 bpm –Grade 1, 2, 3 AV block –Bundle branch block –Stroke within last 3 months –Hypertension (>250/120) Danish Study Inclusion Criteria

10. Danish Study Patient Characteristics AAl GroupVVI Group No. of Patients 110115 Age, y 76 + 8 75 + 8 Women7369 Men3746 Sinus bradycardia 1818 Sino atrial block 4946 Brady-Tachy Syndrome 4351

11. Danish Study Patient Characteristics AAl GroupVVI Group NYHA Class I7992 NYHA Class II2420 NYHA Class III73 NYHA Class IV00 Digoxin2211* Beta Blocker71 Calcium Blocker1311 Antiarrhythmic drugs126 Furosemide, mg/d32 + 5123 + 39 Aspirin4846 Warfarin61 * P = 0.04, atrial versus ventricular group

12. Danish Study Study Population (n=225) Randomised to AAI (n= 110) Randomised to VVI (n= 115) VVIAAIDDDAAIVVIDDD IPG removed Implantation6104115 Treatment at last FU or death 11945110932 Deaths3351561 Chronic AF 3621 AF at one or more abmulatory visits 9173721 Thromboembolism2112411

13. Danish Study Overall survival by pacing mode Andersen H, et al. Lancet 1997; 350: 1210-16. p = 0.045 Atrial pacing Ventricular pacing Time (years) 0246810 0 0-2 0-4 0-6 0-8 1-0 Number of patients at risk during follow-up Atrial Ventricular 110 115 102 103 97 96 92 91 82 80 59 56 38 29 86 85 13 12

14. Danish Study Cardiovascular death by pacing mode Andersen H, et al. Lancet 1997; 350: 1210-16. Time (years) p = 0.0065 Atrial pacing Ventricular pacing 0246810 0 0-2 0-4 0-6 0-8 1-0 Cumulative survival Number of patients at risk during follow-up Atrial Ventricular 110 115 102 103 97 96 92 91 82 80 59 56 38 29 86 85 13 12

15. Danish Study Cumulative risk of PAF by pacing mode Andersen H, et al. Lancet 1997; 350: 1210-16. 0 0-2 0-4 0-6 0-8 1-0 p = 0.012 Atrial pacing Ventricular pacing Time (years) 0246810 Proportion without AF Number of patients at risk during follow-up Atrial Ventricular 110 100 92 82 73 69 46 21 9 115 99 86 76 61 49 34 10 2

16. Danish Study Cumulative risk of chronic AF by pacing mode Andersen H, et al. Lancet 1997; 350: 1210-16. p = 0.004 Atrial pacing Ventricular pacing Time (years) 0 24 6 8 10 Proportion without chronic AF 0 0-2 0-4 0-6 0-8 1-0 Number of patients at risk during follow-up Atrial pacing Ventricular pacing 110 102 96 91 80 74 49 26 10 115 102 92 84 75 65 41 18 5

17. Danish Study Mortality as a result of CHF Andersen H, et al. Lancet 1997; 350: 1210-16. 1,00,80, 60 0 2 4 6 8 10 Atrial pacing Ventricular pacing p = 0.18 Time (years) Survival without death from CHF AAI: 110 102 97 92 86 82 59 38 13 VVI: 115 103 96 91 85 80 56 29 12

18. Danish Study CHF Analysis NYHA classification was higher in the ventricular group vs. the atrial group (p=0.010) at long term follow up.NYHA classification was higher in the ventricular group vs. the atrial group (p=0.010) at long term follow up. During follow up, NYHA class worsened in the ventricular group vs. the atrial group (p<0.005)During follow up, NYHA class worsened in the ventricular group vs. the atrial group (p<0.005) Mean dose of diuretics increased in the ventricular group vs. the atrial group (p=0.033)Mean dose of diuretics increased in the ventricular group vs. the atrial group (p=0.033)

19. Danish Study Conclusions In patients with SND, atrial pacing is associated with a significantly higher survival, less atrial fibrillation, fewer thromboembolic complications, and less heart failure compared to ventricular pacing.

20. Danish Study Limitations Physical exam, NYHA classification and M-mode echocardiography at follow-up were not done blinded with regard to randomization.Physical exam, NYHA classification and M-mode echocardiography at follow-up were not done blinded with regard to randomization. –Possible impact: Observer bias in these parameters. NYHA class was difficult to define precisely, but the higher use of diuretics in the ventricular group suggested a higher incidence of heart failure in this group.NYHA class was difficult to define precisely, but the higher use of diuretics in the ventricular group suggested a higher incidence of heart failure in this group. Pacemaker event counters were not checked regularly.Pacemaker event counters were not checked regularly. –Possible impact: it was not possible to correlate cumulative percent atrial or ventricular pacing to the changes in left atrial and left ventricular dimensions, LVFS, or occurrence of heart failure.

21. Danish Study References Andersen HR, Thuesen L, Bagger JP, et al. Prospective Trial of Atrial versus Ventricular Pacing in Sick Sinus Syndrome. Lancet 1994; 344: 1523-28.Andersen HR, Thuesen L, Bagger JP, et al. Prospective Trial of Atrial versus Ventricular Pacing in Sick Sinus Syndrome. Lancet 1994; 344: 1523-28. Andersen HR, Nielsen JC, Thomsen PE, et al. Long-Term Follow-Up of Patients from a Randomised Trial of Atrial Versus Ventricular Pacing for Sick Sinus Syndrome. Lancet 1997; 350: 1210-16.Andersen HR, Nielsen JC, Thomsen PE, et al. Long-Term Follow-Up of Patients from a Randomised Trial of Atrial Versus Ventricular Pacing for Sick Sinus Syndrome. Lancet 1997; 350: 1210-16. Nielsen JC, Andersen HR, Thomsen PE, et al. Heart Failure and Echocardiographic Changes During Long-term Follow-up of Patients with Sick Sinus Syndrome Randomized to Single- Chamber Atrial or Ventricular Pacing. Circulation. 1998; 97: 987-995.Nielsen JC, Andersen HR, Thomsen PE, et al. Heart Failure and Echocardiographic Changes During Long-term Follow-up of Patients with Sick Sinus Syndrome Randomized to Single- Chamber Atrial or Ventricular Pacing. Circulation. 1998; 97: 987-995.

22. Canadian Trial of Physiologic Pacing CTOPP

23. CTOPP Study Overview Hypothesis:Hypothesis: –Physiologic (dual-chamber or atrial) pacing is superior to single-chamber (ventricular) pacing because it is associated with lower risks of atrial fibrillation, stroke, and death. Study Design:Study Design: –32 Canadian centers –Prospective, randomized

24. CTOPP Study Endpoints Primary:Primary: –Stroke or death due to cardiovascular causes Secondary:Secondary: –Death from any cause –Atrial fibrillation –Hospitalization for heart failure

25. CTOPP Study Inclusion Criteria All-cause bradycardiaAll-cause bradycardia No chronic AFNo chronic AF >18 years old>18 years old

26. CTOPP Study Baseline Patient Characteristics Physiologic Pacing Group (n=1474) Ventricular Pacing Group (n=1094) Mean age (yr)73 + 10 Male sex (%)60.257.0 NYHA Class > II (%)37.241.5 Sinoatrial node disease33.933.4 AV nodal disease52.250.8 Both SA node and AV node disease8.18.5 Intermittent atrial fibrillation20.921.4 Anticoagulant drugs10.411.9 Antiplatelet drugs34.933.7 Antiarrhythmic drugs11.512.6

27. CTOPP Study Protocol Patients undergoing first IPG implant n=2,568 Ventricular-Based Pacing n = 1,474 Physiologic Pacing n = 1,094 Follow for an average of 3 years and compare: Stroke or death due to cardiovascular causes Death from any cause Atrial fibrillation Hospitalization for HF

28. CTOPP Cumulative Risk of Stroke or Cardiovascular Death CTOPP Cumulative Risk of Stroke or Cardiovascular Death Cumulative Risk Years after Randomization 0 1234 0 0.1 0.2 0.3 0.4 P = 0.33 Ventricular pacing Physiologic pacing Connolly S et al. N Engl J Med 2000; 342: 1385-91. No. at risk: Ventricular pacing 1474 1369 1259 847 366 Physiologic pacing 1094 1005 954 637 287

29. CTOPP Cumulative Risk of any AF Cumulative Risk 0 0.1 0.2 0.3 0.4 0134 Years after Randomization P = 0.05 Ventricular pacing Physiologic pacing Connolly S et al. N Engl J Med 2000; 342: 1385-91. No. at risk: Ventricular pacing 1474 1276 1127 731 303 Physiologic pacing 1094 936 857 559 250 2

30. CTOPP Cumulative Risk of Chronic AF CTOPP Cumulative Risk of Chronic AF Skanes A, et al. J Am Coll Cardiol 2001; 38: 167-72. Cumulative Risk Years Since Randomization 01234 0.0 0.1 0.2 0.3 0.4 Number V 1474 1317 1180 779331 At Risk P 1094 975 906 601269 P = 0.016 Ventricular pacing Physiologic pacing

31. CTOPP Subgroup Analyses Skanes A, et al. J Am Coll Cardiol 2001; 38: 167-72. Hazard Ratio 0.40.60.81.01.21.41.6 Physiologic Better Ventricular Better Age: <74 >=74 MICAD: No Yes LVF: Normal Abnormal SA Node: No Yes AFib: No Yes Hypten: No Yes Diabetes: No Yes P = 0.47 P = 0.09 P = 0.11 P = 0.65 P = 0.45 P = 0.80 P = 0.47

32. CTOPP Conclusions Physiologic pacing (dual-chamber or atrial) provides little benefit over ventricular pacing for the prevention of stroke or death due to cardiovascular causes.Physiologic pacing (dual-chamber or atrial) provides little benefit over ventricular pacing for the prevention of stroke or death due to cardiovascular causes. Physiologic pacing does provide a reduction in the relative risk of atrial fibrillation.Physiologic pacing does provide a reduction in the relative risk of atrial fibrillation.

33. CTOPP Limitations Dual-chamber pacemakers used did not have algorithms designed to minimize ventricular pacingDual-chamber pacemakers used did not have algorithms designed to minimize ventricular pacing –Possible result: High cumulative percentage of ventricular pacing offset benefits of atrial-based pacing. Relatively short follow-up period (3 years)Relatively short follow-up period (3 years) –There may not have been enough time to detect a true treatment effect if there is a delay before such an effect becomes evident.

34. CTOPP References Connolly SJ, Kerr CR, Gent M, et al. Effects of Physiologic Pacing Versus Ventricular Pacing on the Risk of Stroke and Death Due to Cardiovascular Causes. N Engl J Med 2000; 342: 1385-91.Connolly SJ, Kerr CR, Gent M, et al. Effects of Physiologic Pacing Versus Ventricular Pacing on the Risk of Stroke and Death Due to Cardiovascular Causes. N Engl J Med 2000; 342: 1385-91. Skanes AC, Krahn AD, Yee R, et al. Progression to Chronic Atrial Fibrillation After Pacing: The Canadian Trial of Physiologic Pacing. J Am Coll Cardiol 2001; 38: 167-72.Skanes AC, Krahn AD, Yee R, et al. Progression to Chronic Atrial Fibrillation After Pacing: The Canadian Trial of Physiologic Pacing. J Am Coll Cardiol 2001; 38: 167-72.

35. Mode Selection Trial in Sinus Node Dysfunction MOST

36. MOST Overview Hypothesis:Hypothesis: –Dual-chamber pacing improves survival and quality versus single-chamber ventricular pacing in patients with SND. Study Design:Study Design: –2,010 patients, randomized to DDDR vs. VVIR –91 clinical sites

37. MOST Endpoints Primary:Primary: –Death from any cause or nonfatal stroke Secondary:Secondary: –Composite of death from any cause, a first occurrence of stroke or a first occurrence of hospitalization for heart failure –Stroke –Death from any cause –Death from cardiovascular causes –Atrial fibrillation –The Minnesota Living with Heart Failure score –Pacemaker syndrome with a need for permanent reprogramming to dual-chamber –Health-related quality of life

38. MOST Inclusion Criteria Initial implant of a dual-chamber, rate modulated pacemaker for SNDInitial implant of a dual-chamber, rate modulated pacemaker for SND >21 years of age>21 years of age In sinus rhythm at implant randomizationIn sinus rhythm at implant randomization > 17 or higher on the Mini-Mental State Examination> 17 or higher on the Mini-Mental State Examination

39. MOST Baseline Patient Characteristics Characteristic VVIR (n=996) DDDR (n=1014)P-Value Median Age (yr) 74740.58 Female sex 477 (48) 478 (47) 0.74 Prior myocardial infarction 243 (24) 279 (28) 0.11 Prior heart failure 183 (18) 221 (22) 0.05 NYHA Class I or II 841 (84) 822 (81) 0.05 Any supraventricular tachycardia 514 (52) 545 (54) 0.34 Arial fibrillation 440 (44) 477 (47) 0.20 Any atrioventricular block 209 (21) 204 (20) 0.62 Complete heart block 52 (5) 39 (4) 0.16 Second-degree HB 62 (6) 72 (7) 0.48 Prolonged AV interval 102 (10) 101 (10) 0.83 Other heart block 23 (2) 25 (2) 0.88 VT or VF 24 (2) 42 (4) 0.03

40. MOST Protocol Patients Undergoing Initial IPG Implant for SND n=2010 Dual-Chamber Pacing n=1014 Ventricular Pacing n=996 Follow for a median of 33 months and compare: Death from any cause or non fatal stroke Composite of death, stroke, or hospitalization for HF Atrial fibrillation Heart Failure score Pacemaker syndrome Quality of Life

41. MOST Total Mortality or Stroke 06121824303642485460 0.00 0.10 0.20 0.30 0.40 0.50 Months Event Rate P = 0.48 Adjusted P = 0.32 Ventricular pacing Dual-chamber pacing Lamas G, et al. N Engl J Med 2002; 346: 1854-62. No. at risk: Ventricular pacing Dual-chamber pacing 996 934 897 813 678 557 431 320 218 125 39 1014 963 930 833 693 555 431 328 214 120 28

42. MOST CHF Hospitalization Lamas G, et al. N Engl J Med 2002; 346: 1854-62. No at risk: Ventricular pacing Dual-chamber pacing 996 890 885 766 637 516 402 300 200 116 36 1014 932 894 801 658 528 406 307 191 106 27 0612 18 243036 42 48 54 60 0.00 0.10 0.20 0.30 0.40 0.50 Months Event Rate P = 0.13 Adjusted P = 0.02 Ventricular pacing Dual-chamber pacing

43. MOST Heart Failure, Stroke, or Death Lamas G, et al. N Engl J Med 2002; 346: 1854-62. 0.50 No at risk: Ventricular pacing Dual-chamber pacing 996 880 839 752 624 504 388 287 193 110 35 1014 926 889 793 649 518 394 297 188 105 26 06 1218243036 42 48 54 60 0.00 0.10 0.20 0.30 0.40 Months Event Rate Ventricular pacing Dual-chamber pacing P= 0.23 Adjusted P = 0.05

44. MOST Atrial Fibrillation Lamas G, et al. N Engl J Med 2002; 346: 1854-62.

45. MOST Subgroup Analyses Lamas G, et al. N Engl J Med 2002; 346: 1854-62. 0.51.0 2.0 Better Results with Dual-Chamber Pacing Better Results With Ventricular Pacing CHARACTERISTIC No. of PATIENTS HAZARD RATIO (95% CI) All patients Sex Female Male Age ≥ 75 years ≤ 75 years Race White Nonwhite History of supra-ventricular tachycardia Yes No 2010 955 1055 987 1023 1704 306 1059 951 0.90 (0.77-1.06) 0.89 (0.71-1.13) 0.91 (0.73-1.15) 0.97 (0.79-1.21) 0.83 (0.65-1.07) 0.88 (0.73-1.05) 1.00 (0.68-1.46) 0.92 (0.74-1.14) 0.88 (0.69-1.13)

46. MOST Conclusions In patients with SND, dual-chamber pacing (versus single-chamber ventricular pacing) reduces newly diagnosed and chronic atrial fibrillation, reduces the signs and symptoms of heart failure, and slightly improves quality of life.In patients with SND, dual-chamber pacing (versus single-chamber ventricular pacing) reduces newly diagnosed and chronic atrial fibrillation, reduces the signs and symptoms of heart failure, and slightly improves quality of life. Dual-chamber pacing did not improve the rate of the primary endpoint of mortality or freedom from stroke.Dual-chamber pacing did not improve the rate of the primary endpoint of mortality or freedom from stroke.

47. MOST Limitations Randomly assigned pacing mode but not the type of pacemaker.Randomly assigned pacing mode but not the type of pacemaker. –Possible result: ease of cross-over may have reduced the number of clinical events in the ventricular arm Pacemakers used did not have algorithms designed to minimize ventricular pacing.Pacemakers used did not have algorithms designed to minimize ventricular pacing. –Possible result: High cumulative percent ventricular pacing offset benefits of atrial-based pacing. Impossible to determine whether atrial-based pacing prevents AF or whether ventricular pacing is arrhythmogenic, causing AF.Impossible to determine whether atrial-based pacing prevents AF or whether ventricular pacing is arrhythmogenic, causing AF.

48. Dual-Chamber and VVI Implantable Defibrillator Trial DAVID

49. DAVID Trial Overview Hypothesis:Hypothesis: –Aggressive management of LV dysfunction with optimized drug therapy and with dual chamber pacing could improve the combined endpoint of total mortality and hospitalization for heart failure, compared to similarly optimized drug therapy supported by ventricular backup pacing. Study design:Study design: –Single blind, multicenter, parallel group, randomized trial comparing DDDR (70 bpm lower rate) vs. VVI (40 bpm lower rate) pacing modes Wilkoff B, et al. JAMA. 2002; 288: 3115-3123.

50. DAVID Trial Endpoints Primary:Primary: –Freedom from death and heart failure hospitalization Wilkoff B, et al. JAMA. 2002; 288: 3115-3123.

51. DAVID Trial Inclusion Criteria ICD indicated patientsICD indicated patients No indication for antibradycardia pacingNo indication for antibradycardia pacing LVEF  40%LVEF  40% No persistent or frequent, uncontrolled AFNo persistent or frequent, uncontrolled AF Wilkoff B, et al. JAMA. 2002; 288: 3115-3123.

52. DAVID Trial Baseline Patient Characteristics VVI-40DDDR-70 p value Age, mean (SD), y 66(11)64(11)0.19 Male, % 81860.15 LVEF, mean (SD), % 28260.17 NYHA Class I, % 5047 NYHA Class II, % 39400.63 NYHA Class III/IV, % 1113 History of MI, % 67710.32 History of CHF, % 56580.66 History of CAD, % 84830.84 Wilkoff B, et al. JAMA. 2002; 288: 3115-3123.

53. DAVID Trial Baseline Patient Characteristics Indications for ICD, % VVI-40DDDR-70 P value VF1918 Syncopal VT 76 Symptomatic sustained VT 1623 Symptomatic NSVT + EPS positive 950.31 Asymptomatic NSVT + EPS positive 2523 Unexplained syncope + EPS positive 1518 Hemodynamically stable VT 108 Wilkoff B, et al. JAMA. 2002; 288: 3115-3123.

54. DAVID Trial Protocol 760 assessed for eligibility 250 excluded 149 Did not meet Rx criteria 55 refused 46 Other 510 eligible 4 Not randomized 2 Required pacing 1 Inadequate defibrillation threshold 1 Decided not to implant 506 randomized VVI-40 (n=256)DDDR-70 (n= 250) 1 had pacing mode set to DDD 1 LTF 10 Discontinued intervention 5 Bradycardia 1 CHF and AF 1 Brady induced Torsade 1 Heart Tx workup 1 AF w rapid V response 1 multiple shocks due to double counting 3 had pacing mode set to VVI 2 LTF 5 Discontinued intervention 1 Angina 1 CHF and Lead Failure 1 CHF Hospitalization 1 Exacerbation of VT 1 Lead Migration Wilkoff B, et al. JAMA. 2002; 288: 3115-3123.

55. DAVID Trial Drug Therapy 6 Months Post Randomization Drug Therapy, % VVI-40(n=156)DDDR-70(n=149) p value ACE inhibitor or ARB 84870.42 ß-Blocker 86850.74 ACE, ARB, ßB 97990.44 Digoxin41420.82 Diuretic64640.95 Nitrate25220.56 Spironelactone15220.13 Amiodarone23320.10 Sotolol720.04 Other ADD 120.29 Wilkoff B, et al. JAMA. 2002; 288: 3115-3123.

56. DAVID Death or First Hospitalization for New or Worsened CHF Hazard ratio (95% CI), 1.61 (1.06-2.44) 061218 Months Cumulative Probability 0.4 0.3 0.2 0.1 0 250 256 159 158 76 90 21 25 No. at Risk DDDR VVI Wilkoff B, et al. JAMA. 2002; 288: 3115-3123. DDDR VVI

57. DAVID Trial Results VVI-40DDDR-70HR (p-value, adj.) CHF Hospitalization or Death 16.1%26.7%1.61 (p = 0.03) CHF Hospitalization 13.3%22.6%1.54 (p=0.07) Death 6.5%10.1%1.61 (p=0.15) Wilkoff B, et al. JAMA. 2002; 288: 3115-3123.

58. DAVID First Hospitalization for New or Worsened CHF Hazard ratio (95% CI), 1.54 (0.97-2.46) 061218 Months Cumulative Probability 0.4 0.3 0.2 0.1 0 250 256 155 156 74 89 21 24 No. at Risk DDDR VVI Wilkoff B, et al. JAMA. 2002; 288: 3115-3123. DDDR VVI

59. DAVID Death From Any Cause Wilkoff B, et al. JAMA. 2002; 288: 3115-3123. Hazard ratio (95% CI), 1.61 (0.84-3.09) 061218 Months Cumulative Probability 0.4 0.3 0.2 0.1 0 250 256 173 172 95 96 30 25 No. at Risk DDDR VVI DDDR VVI

60. DAVID Wilkoff B, et al. JAMA. 2002; 288: 3115-3123. VVI-40DDDR-70P-value 6-month EKG: Sinus97.1%42.0%<0.001 V-paced2.9%55.7%<0.001 QRSd 117 + 29 ms 134 + 39 ms <0.001 Cum % VP: 3 months 1.5% + 8.0% 57.9% + 35.8% <0.001 6 months 0.6% + 1.7% 59.6% + 36.2% <0.001 12 months 3.5% + 14.9% 58.9% + 36.0% <0.001

61. DAVID Study results are consistent with the pacing literature.Study results are consistent with the pacing literature. –AAI was associated with slightly better survival and lower rate of severe CHF compared to VVI pacing mode in patients with SSS 1 –QOL was better in elderly patients with sinus node disease with VVI compared to DDD pacing. 2 –More than 40% ventricular pacing was associated with increased CHF hospitalizations. 3 –The benefit of DDDR pacing was most evident in patients who needed continuous pacing. 4 3.Sweeney et al. Pacing Clin Electro. 2002;25:690. 4.Kerr et al. Pacing Clin Electro. 2002;25:553. 1.Anderson et al. Lancet. 1997;350:1210-1216. 2.Lamas et al. N Engl J Med. 1997;337:1576-1583.

62. DAVID Conclusions Bradycardia pacing operation in dual-chamber ICDs should be optimized for individual patients.Bradycardia pacing operation in dual-chamber ICDs should be optimized for individual patients. –RV pacing in patients with LV dysfunction and no bradycardia indication for pacing can be harmful. –Programming of dual chamber devices to backup ventricular pacing is justified in this patient population. Wilkoff B, et al. JAMA. 2002; 288: 3115-3123.

63. DAVID Limitations The specific programming choices made by investigators and available pacemakers could have affected the results, e.g.The specific programming choices made by investigators and available pacemakers could have affected the results, e.g. –Choice of DDDR pacing rate of 70 –Choice of AV interval –DDDR devices did not have algorithms to promote intrinsic conduction (reduce ventricular pacing) Results may not apply to patients with a normal ejection fraction or with standard pacing indications.Results may not apply to patients with a normal ejection fraction or with standard pacing indications. Wilkoff B, et al. JAMA. 2002; 288: 3115-3123.

64. Summary of Clinical Trial Data: Atrial Based/Physiologic Pacing Benefits (vs. VVIR) Mortality Hospitalization for CHF AtrialFibrillationStroke Danish AAIR vs. VVIR; All SND pts But not until after 3 years FU Both acute and chronic NS CTOPP Physiologic vs. ventricular pacing; ~40% of pts had SND But not until 2 years FU MOST Dual-chamber vs. single chamber; All SND pts But still 10% at 36 months But still 24-25% at 36 months DAVID No indication for pacing (Composite endpoint) NSNS = No Difference Observed NS = Not a studied endpoint

65. Summary of Major Clinical Trials Despite maintenance of AV synchrony, DDDR did not improve survival or prevent stroke when compared with ventricular pacing.Despite maintenance of AV synchrony, DDDR did not improve survival or prevent stroke when compared with ventricular pacing. DDDR pacing does reduce the risk of developing atrial fibrillation and may reduce signs and symptoms of heart failure and hospitalizations for heart failure in some, but not all, patients.DDDR pacing does reduce the risk of developing atrial fibrillation and may reduce signs and symptoms of heart failure and hospitalizations for heart failure in some, but not all, patients.

66. Normal ventricular activation requires the synchronized participation of the distal components of the specialized conduction system (the main bundle branches and their ramifications). Majority of patients (~80%) with SND, including those with CHF, have intact AV conduction and narrow QRS duration (normal ventricular activation). 1 Conventional RV apical pacing results in “forced” ventricular desynchronization, which mimics LBBB and has adverse effects on ventricular structure and function. Why Haven’t We Been Able to Prove A Mortality or Stroke Benefit with DDDR? 1 Medtronic device registration (1997-present).

67. Conventional dual-chamber pacing systems* often result in a higher level of RV apical pacing due to: –AV delays that are programmed shorter than the patient’s intrinsic AV conduction –Lower rate settings higher than optimal/necessary –Rate-responsive algorithms which increase ventricular pacing in response to stress Why Haven’t We Been Able to Prove A Mortality or Stroke Benefit with DDDR? *without algorithms to minimize inappropriate V-pacing

68. Effect of Pacing Mode and Cumulative Percent Time Ventricular Paced on Heart Failure and Atrial Fibrillation in Patients with Sinus Node Dysfunction and Baseline QRS Duration <120 Milliseconds in MOST A MOST Sub-Study Michael O. Sweeney, Anne S. Hellkamp, Arnold J. Greenspon, Robert Mittleman, John McAnulty, Kenneth Ellenbogen, Roger Freedman, Kerry L. Lee, Gervasio A. Lamas, for the MOST Investigators Circulation 2003, in press

69. MOST Sub-Study Background: DDDR pacing preserves AV synchrony and reduces CHF compared to VVIR pacing in SND.DDDR pacing preserves AV synchrony and reduces CHF compared to VVIR pacing in SND. DDDR pacing results in prolonged QRS durations (QRSd) due to ventricular desynchronization.DDDR pacing results in prolonged QRS durations (QRSd) due to ventricular desynchronization.Hypothesis: DDDR pacing often results in prolonged QRS duration (QRSd) due to ventricular desynchronization in patients with normal baseline QRSd and may increase risk of heart failure and atrial fibrillation.DDDR pacing often results in prolonged QRS duration (QRSd) due to ventricular desynchronization in patients with normal baseline QRSd and may increase risk of heart failure and atrial fibrillation. Sweeney MO, et al. Circulation 2003, in press

70. Methods: Baseline QRSd obtained from 12-lead EKG prior to IPG implant in MOST (a 2,010 patient, 6-year randomized trial of DDDR vs. VVIR pacing in SND).Baseline QRSd obtained from 12-lead EKG prior to IPG implant in MOST (a 2,010 patient, 6-year randomized trial of DDDR vs. VVIR pacing in SND). Cumulative % time ventricular paced was determined from stored pacemaker diagnostic data.Cumulative % time ventricular paced was determined from stored pacemaker diagnostic data. Baseline QRSd <120 ms was observed in 1332 patients; 702 were randomized to DDDR; 640 to VVIR.Baseline QRSd <120 ms was observed in 1332 patients; 702 were randomized to DDDR; 640 to VVIR. MOST Sub-Study Sweeney MO, et al. Circulation 2003, in press

71. MOST Sub-Study: Results Cum%VP was greater in DDDR (90%) vs. VVIR (51%).Cum%VP was greater in DDDR (90%) vs. VVIR (51%). The rates of CHF hospitalization increased with Cum%VP:The rates of CHF hospitalization increased with Cum%VP: Sweeney MO, et al. Circulation 2003, in press

72. MOST Sub-study: Risk of HFH Relative to a DDDR Patient with Cum % VP = 0 Risk of HFH increased between 0% and 40% Cum VP, but was level at Cum%VP above 40%. Risk can be reduced to about 2% if ventricular pacing is minimized.

73. Sweeney MO, et al. Circulation 2003, in press MOST Sub-Study: Risk of HFH Relative to a VVIR Patient with Cum % VP = 0 Risk of CHF was constant between 0% and 80% Cum VP and increased by as much as 2.5-fold when Cum%VP exceeded 80%. Risk cannot be reduced regardless of minimization of ventricular pacing.

74. DDDR:DDDR: –Cum%VP >40% was associated with 3 times increased risk of CHF hospitalization (p=0.02). The risk of CHF hospitalization increased by 54% for each 10% increase in Cum%VP (Hazard ratio 1.54 [1.01, 2.36), p=0.05) between 0% and 40%. VVIR:VVIR: –Cum%VP > 80% was associated with 2.6 times increased risk of CHF hospitalization (p=0.007). The risk of CHF hospitalization increased by 96% for each 10% increase in Cum%VP (Hazard ratio 1.96 [1.39, 2.77], p=0.0001) above 80%. Sweeney MO, et al. Circulation 2003, in press MOST Sub-Study: CHF Risk

75. P=0.047 Sweeney MO, et al. Circulation 2003, in press MOST Sub-Study

76. P=0.0046 Sweeney MO, et al. Circulation 2003, in press MOST Sub-Study

77. Higher rates of CHF hospitalization were associated with higher Cum% VP:Higher rates of CHF hospitalization were associated with higher Cum% VP: –Cum % VP<10% was associated with the lowest rates of CHF hospitalization (DDDR 2%, VVIR 7%). –Cum % VP >90% was associated with the highest rates of CHF hospitalization (DDDR 12%, VVIR 16%). Ventricular pacing in the DDDR mode more than 40% confers a 3-fold increased risk of heart failure hospitalizationVentricular pacing in the DDDR mode more than 40% confers a 3-fold increased risk of heart failure hospitalization but can be reduced to about 2% if ventricular pacing is minimized. Sweeney MO, et al. Circulation 2003, in press MOST Sub-study Conclusions: CHF

78. In the VVIR mode, the risk of CHF hospitalization was level below Cum%VP  80% but cannot be reduced regardless of minimization of ventricular pacing. This risk is increased by as much as 2.5-fold when Cum%VP exceeds 80%. MOST Sub-study Conclusions: CHF

79. Sweeney MO, et al. Circulation 2003, in press Risk of AF increases linearly with Cum%VP up to  80- 85% in both DDDR and VVIR MOST Sub-study: AF Risk

80. Sweeney MO, et al. Circulation 2003, in press MOST Sub-study: AF Risk

81. Sweeney MO, et al. Circulation 2003, in press MOST Sub-study: AF Risk

82. Relationship between risk of AF and Cum%VP was similar between pacing modes:Relationship between risk of AF and Cum%VP was similar between pacing modes: –Risk of AF showed a linearly increasing relationship with increased Cum%VP from 0% pacing up to 80- 85% pacing in both pacing modes. –Within this range, the risk of AF increased by 1% for each 1% increase in Cum%VP (DDDR hazard ratio 1.01 [1.004, 1.022] p=0.012; VVIR 1.01 [1.001, 1.01], p=0.025). Sweeney MO, et al. Circulation 2003, in press MOST Sub-study Conclusions: AF

83. The adverse effects of forced ventricular desynchronization probably explain the difficulty in demonstrating a mortality and stroke benefit with physiologic (DDDR) compared to ventricular (VVIR) pacing in randomized trials.The adverse effects of forced ventricular desynchronization probably explain the difficulty in demonstrating a mortality and stroke benefit with physiologic (DDDR) compared to ventricular (VVIR) pacing in randomized trials. Further research is necessary to clarify the role of “electrical unloading” of the left ventricle using minimal ventricular pacing strategies in SND and normal QRSd.Further research is necessary to clarify the role of “electrical unloading” of the left ventricle using minimal ventricular pacing strategies in SND and normal QRSd. Sweeney MO, et al. Circulation 2003, in press MOST Sub-Study: Overall Conclusions

84. Goals and Strategies to Optimize Ventricular Pacing

85. The New Goals of Pacing Therapy Bradycardia-indicated patients (pacemaker and ICD patients)Bradycardia-indicated patients (pacemaker and ICD patients) –Prevent symptomatic bradycardia –Provide chronotropic competence when necessary –Maintain normal ventricular activation sequence whenever possible using minimal ventricular pacing modes Non-Bradycardia Patients (ICD patients with no brady indications)Non-Bradycardia Patients (ICD patients with no brady indications) –VT/VF detection –Maintain normal ventricular activation sequence whenever possible using minimal ventricular pacing modes

86. Strategies to Optimize RV Pacing Recognition of chronic adverse effects of RV pacing has stimulated interest in strategies to attenuate these effects.Recognition of chronic adverse effects of RV pacing has stimulated interest in strategies to attenuate these effects. Several approaches have been investigated:Several approaches have been investigated: –Optimal/novel RV pacing sites –Manipulation of DDDR timing cycles (AV delay) to minimize unnecessary RV pacing –Use of AAI or DDI/R pacing modes –Novel pacing algorithms

87. Optimal RV Pacing Sites RV apical pacing originated due to ease of placement, stability of the electrode, and good pacing thresholds in this location—not for hemodynamic reasons.RV apical pacing originated due to ease of placement, stability of the electrode, and good pacing thresholds in this location—not for hemodynamic reasons. With introduction of active fixation leads, alternative pacing sites have been shown to be feasible with respect to pacing thresholds, adequate sensing, and stability. 1With introduction of active fixation leads, alternative pacing sites have been shown to be feasible with respect to pacing thresholds, adequate sensing, and stability. 1 RVOT and Right ventricular septum (RVS) are the most frequently described alternate RV pacing sites. 2RVOT and Right ventricular septum (RVS) are the most frequently described alternate RV pacing sites. 2 Numerous acute and chronic studies have demonstrated mixed results—largely due to differences in study design. 3-17Numerous acute and chronic studies have demonstrated mixed results—largely due to differences in study design. 3-17

88. Future Directions: Large, long-term, randomized studies of alternative pacing sites vs. RV apex will be needed to change clinical practice.Large, long-term, randomized studies of alternative pacing sites vs. RV apex will be needed to change clinical practice. Specifically-designed leads, delivery systems, and pacing algorithms/modes to facilitate alternative site placement and/or multisite stimulation will also be needed for ease-of-use and broad acceptance.Specifically-designed leads, delivery systems, and pacing algorithms/modes to facilitate alternative site placement and/or multisite stimulation will also be needed for ease-of-use and broad acceptance. Optimal RV Pacing Sites

89. Long AV Delays During Dual Chamber Pacing: An Incomplete Solution Long AV delays may reduce unnecessary ventricular pacing and maintain normal ventricular activation sequence but require reliable AV nodal conduction.Long AV delays may reduce unnecessary ventricular pacing and maintain normal ventricular activation sequence but require reliable AV nodal conduction. Long AV delays may impose limitations on optimal DDDR operation:Long AV delays may impose limitations on optimal DDDR operation: –Reduced 2:1 block point due to increased TARP –Abandonment of mode-switching or significantly delayed AF recognition –Susceptibility to endless loop tachycardias

90. Long AV delays do not sufficiently reduce ventricular pacing Two approaches to programming long AV delays to permit native ventricular activation:Two approaches to programming long AV delays to permit native ventricular activation: 1.AV delays > resting PR intervals 1 AV delays > resting PR intervals (222  24 ms vs. 184  23 ms) Mean time Vp for all patients was 80%; > 50% for 88% 2.Long fixed AV delay (300 ms) 2-3 Mean time Vp 17.7% overall but 39% in nearly 50% of patients Resting PQ interval (177  28 vs. 204  38), atrial stimulus-Q interval at 100 bpm (213  40 vs. 220  49) or AV delay (299  3.2 vs. 288  21) did not predict Vp High incidence of endless loop tachycardia –Can be reduced if rate-adaptive AV delays are used 1 Sgarbossa E et al PACE 1993; ;16:872A. 2 Nielsen JC et al PACE 1997:20:1574A. 3 Nielsen JC et al Europace 1999;1:113-120

91. AAI Pacing: Too Risky? AAI pacing preserves a normal ventricular activation sequence but requires stable long-term AV conduction and sinus rhythmAAI pacing preserves a normal ventricular activation sequence but requires stable long-term AV conduction and sinus rhythm SND is a spectrum of electrical disorders that includes AF and AV blockSND is a spectrum of electrical disorders that includes AF and AV block AAI pacing is ineffectual for ventricular bradycardia duringAAI pacing is ineffectual for ventricular bradycardia during –Paroxysmal and permanent AF –AV block

92. Development of Persistent (Complete) AV Block in Studies of Pacemaker Therapy for SND StudyMean Follow-Up Time Incidence of CHB Annualized Incidence Rosenqvist 1989 (literature review) 3 years Median 2.1% Range: 0-11.9% Median: 0.6% Range: 0-4.5% Andersen 1997 8 years 3.6%0.6% Brandt 1992 5 years 8.5%1.8% Sutton 1986 3 years 8.4%2.8% Rosenqvist 1986 2 years 4.0%2.0% Rosenqvist 1985 5 years 3.3%0.7% Hayes 1984 3 years 3.4%1.1%

93. Development of Chronic AF in Studies of Pacemaker Therapy for SND and CHB Study Pacing Mode Mean Follow-Up Time Incidence of AF Annualized Incidence Andersen 1997 AAI 5 years 8.8%1.8% Sutton 1986 AAI 3 years 4.5%1.5% Brandt 1992 AAI 5 years 7.0%1.4% PASE 1998 DDDR only 18 months 19.0%12.7% CTOPP 2000 DDDR/VVIR 3 years 16.6% 5.5% (DDDR)

94. DDIR Mode: A Limited Solution Permits long AV delays without the possibility of upper rate limit tracking during AF (unlike DDDR).Permits long AV delays without the possibility of upper rate limit tracking during AF (unlike DDDR). –However, limitations of long AV delays in reducing ventricular pacing still persist. Unique limitations imposed by DDIR modeUnique limitations imposed by DDIR mode –Operationally VVIR during AV block if sinus rate exceeds lower rate limit. –Competitive atrial pacing during sensor-modulation may precipitate AF. Can be mitigated with a non-competitive atrial pacing algorithm May be more applicable to the ICD populationMay be more applicable to the ICD population –Lower prevalence of AV block compared to conventional brady pacing population. 1-5

95. Novel Pacing Algorithms to Optimize Ventricular Pacing Current-generation devices have features that work to minimize ventricular pacing in appropriate patient populations:Current-generation devices have features that work to minimize ventricular pacing in appropriate patient populations: –Using Medtronic’s Search AV algorithm, 27% and 47.2% reductions in ventricular pacing have been observed by Silverman and Ellenbogen, respectively, in patients with 1:1 conduction. 1,2

96. Silverman et al, NASPE 2000 Novel Pacing Algorithms to Optimize Ventricular Pacing

97. Minimal ventricular pacing modes can be used in all patients, but are most effective in SND patients with reliable AV conduction and normal ventricular activation.Minimal ventricular pacing modes can be used in all patients, but are most effective in SND patients with reliable AV conduction and normal ventricular activation. Development will continue on new pacing algorithms which have been identified as an important means of minimizing ventricular pacing.Development will continue on new pacing algorithms which have been identified as an important means of minimizing ventricular pacing. Novel Pacing Algorithms to Optimize Ventricular Pacing

98. Identifying SND Patients for Optimize Ventricular Pacing Suitable for all SND patients with reliable AV conduction and normal ventricular activation.Suitable for all SND patients with reliable AV conduction and normal ventricular activation. Factors that might constrain minimal ventricular pacing modes in SND:Factors that might constrain minimal ventricular pacing modes in SND: –incidence of AV block at time of pacemaker implantation, –incidence of abnormal ventricular activation at time of pacemaker implantation –long-term stability of AV conduction –optimization of AV delay –development of chronic atrial fibrillation –rate-responsive atrial pacing with long AV delays

99. Overall Conclusions Intact or intermittent 1:1 conduction is found in ~80+% of patients with sinus node dysfunction.Intact or intermittent 1:1 conduction is found in ~80+% of patients with sinus node dysfunction. In patients with SND and DDDR pacing systems, preserving 1:1 conduction:In patients with SND and DDDR pacing systems, preserving 1:1 conduction: –Reduces unnecessary ventricular pacing –Reduces the risk of CHF hospitalizations –Is associated with less AF –May increases device longevity

100. Overall Conclusions The long-term risks associated with chronic RV apical pacing are now apparent.The long-term risks associated with chronic RV apical pacing are now apparent. Clinical attempts to preserve normal ventricular activation sequence should be top priority.Clinical attempts to preserve normal ventricular activation sequence should be top priority. AAI/DDI mode selections and long AV delays are limited solutions.AAI/DDI mode selections and long AV delays are limited solutions. Selective site pacing appears promising, but more studies are needed.Selective site pacing appears promising, but more studies are needed. Novel pacing algorithms have shown promise to date, and work will continue to improve these algorithms to optimize the level of ventricular pacing.Novel pacing algorithms have shown promise to date, and work will continue to improve these algorithms to optimize the level of ventricular pacing.