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  1. 1. ®
  2. 2. FDA Advisory Panel Meeting May 29, 2003 Cardima ® , Inc. Linear Ablation REVELATION ® Tx Microcatheter RF Ablation System
  3. 3. Panel Presentation <ul><li>Corporate Profile Marianne Baldwin </li></ul><ul><li>Treatment Options for Atrial Fibrillation Neal Kay, M.D. </li></ul><ul><li>Pre-clinical Studies Hugh Calkins, M.D. </li></ul><ul><li>Protocol Development Hugh Calkins, M.D. </li></ul><ul><li>Clinical Study Results Abe Kocheril, M.D. </li></ul><ul><li>Conclusions Neal Kay, M.D. </li></ul>
  4. 4. Indications for Use <ul><li>Cardima ® , Inc., REVELATION ® Tx Microcatheter Ablation System is indicated for the treatment of atrial fibrillation in patients with drug refractory paroxysmal atrial fibrillation by mapping, pacing, and ablating with a set of continuous linear lesions in the right atrium. </li></ul>
  5. 5. <ul><li>Since 1993 Cardima has been developing, manufacturing and marketing catheter-based systems for the Electrophysiological field, exclusively. </li></ul><ul><li>The catheters include the PATHFINDER ™ family of mapping devices, the VENAPORT ® , VUEPORT ® and NAVIPORT ® guiding catheters and the REVELATION ® family of mapping and ablation systems. </li></ul>Cardima Background
  6. 6. <ul><li>Currently the company is marketing its diagnostic and guiding catheters in the USA, Canada, EU (CE Mark) and Japan. </li></ul><ul><li>The REVELATION ® mapping and ablation family of devices is marketed in Canada and EU (CE Mark). </li></ul>Cardima Background
  7. 7. <ul><li>Diagnostic Microcatheters </li></ul><ul><ul><li>PATHFINDER ™ (1997) </li></ul></ul><ul><ul><li>PATHFINDER ™ mini (1998) </li></ul></ul><ul><ul><li>REVELATION ® (1998) </li></ul></ul><ul><ul><li>TRACER ™ (1999) </li></ul></ul><ul><li>Guide Catheters </li></ul><ul><ul><li>VENAPORT ® ( 1995) </li></ul></ul><ul><ul><li>NAVIPORT ® (1998) </li></ul></ul><ul><ul><li>VUEPORT ® (1998) </li></ul></ul><ul><li>Surgical Ablation System (2002) </li></ul>Cardima Commercially Available Products (US)
  8. 8. PATHFINDER™ Mapping Catheter PATHFINDER™ mini PATHFINDER™
  9. 9. REVELATION ® Series REVELATION ® Tx
  10. 10. Guide Catheter 8Fr deflectable lumen catheter NAVIPORT ®
  11. 11. Technology Comparison One Eight Ablation Electrode Number 50-70 W Focal Sleeve Stiff, deflectable From the “inside-out” Plastic tube CONVENTIONAL RF 7-35 W Linear Fine-wire coiled Very flexible and torqueable From the “outside-in” Angioplasty guidewire technology REVELATION ® TX Manufacturing Electrode Type Power Req’d Lesion Type Flexibility Core Construction FEATURES
  12. 12. Lesion Shape Comparison Conventional Endocardial “ Hot Tip” Catheter Cardima Linear Coil Electrode Tip Ablation Electrode Coil Ablation Electrode
  13. 13. Linear Lesion Formation Coil Ablation Electrode Thermocouple
  14. 14. Treatment Options for Atrial Fibrillation G. Neal Kay, M.D. Professor of Medicine Director of Electrophysiology University of Alabama at Birmingham Birmingham, AL
  15. 15. US and AF Age Distribution Feinberg WM. Arch Intern Med 1995;155:469-473. U.S. population Population with atrial fibrillation Age, yr <5 5- 9 10- 14 15- 19 20- 24 25- 29 30- 34 35- 39 40- 44 45- 49 50- 54 55- 59 60- 64 65- 69 70- 74 75- 79 80- 84 85- 89 90- 94 >95 U.S. population x 1000 Population with AF x 1000 30,000 20,000 10,000 0 500 400 300 200 100 0
  16. 16. Classification of Atrial Fibrillation ACC/AHA/ESC Guidelines J Am Coll Cardiol. 2001;38:1231-1265 . Fuster V, Rydén LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation.) J Am Coll Cardiol. 2001;38:1231-1265 . Persistent (Not self-terminating) Paroxysmal (Self-terminating) Permanent First Detected
  17. 17. d,l-Sotalol vs Placebo for AF/AFl: Time to Symptomatic Recurrence of AF/AFl P values are vs placebo. Benditt Am J Cardiol 1999;84:270-277. Placebo (n=69) Sotalol 160 mg bid (n=62) Sotalol 120 mg bid (n=63) Sotalol 80 mg bid (n=59) Time (days) Recurrence-Free Survival 0.5 0.7 0.8 0.9 1.0 0.6 0.1 0.2 0.3 0.4 0.0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 P =.029 P =.325 P =.018
  18. 18. Canadian Trial of Atrial Fibrillation (CTAF) * Excluded recurrence in first 21 days. Roy, et al NEJM 2000;342:913-920. Patients Without Recurrence, % 100 80 60 40 20 0 100 0 200 300 400 500 600 Amiodarone 10 mg/kg x 2 wk, 300 mg x 4 wk, 200 mg/d (n=201) Propafenone 300-450 mg/d (n=101) Sotalol 160 mg bid or 80 mg tid (n=101) Days of Follow-up
  19. 19. Antiarrhythmic Drugs CHF Amiodarone Dofetilide Non-Pharmacologic Options Coronary Artery Disease Sotalol Amiodarone Dofetilide HTN LVFW > 1.4 cm Yes No Amiodarone Type 1C Amiodarone Dofetilide Sotalol
  20. 20. Right Sided Approach to AF <ul><li>These results demonstrate that there is a place for right sided treatment of AF </li></ul><ul><li>Cardima has demonstrated this approach in a clinical study </li></ul>
  21. 21. Pre-clinical Studies Hugh Calkins, M.D. Professor of Medicine Director of Electrophysiology The Johns Hopkins Medical Center Baltimore, MD
  22. 22. Pre-Clinical Studies <ul><li>Biocompatible </li></ul><ul><ul><li>Compliant with applicable ISO 10993 requirements </li></ul></ul><ul><li>Reliable </li></ul><ul><ul><li>Compliant with mechanical and electrical performance requirements of Massi guidelines </li></ul></ul>
  23. 23. Animal Studies <ul><li>Studies submitted in support of PMA </li></ul><ul><li>David Keane, M.D. / Massachusetts General Hospital </li></ul><ul><ul><li>Performance of REVELATION ® Tx in Right Atrium of a Goat (n=7) </li></ul></ul><ul><li>Mauricio Arruda, M.D. / University of Oklahoma </li></ul><ul><ul><li>Performance of REVELATION ® Tx in the right atrium of a Canine (n=6) </li></ul></ul><ul><ul><li>RF Lesion Formation of REVELATION ® Tx in Canine Thigh Muscle (n=2) </li></ul></ul><ul><ul><li>RF Ablation Using the NavAblator™ in the Right Atrium (n=6) </li></ul></ul><ul><li>Additional independent studies performed……….. </li></ul>
  24. 24. Right Atrial Multipolar Catheter Ablation of Atrial Fibrillation in a Pace-Induced Goat Model Keane D, Guerrero L, Ettelson L, McGovern B, Ruskin J JACC 1997;32A. <ul><li>8 goats </li></ul><ul><li>AF (> 5 min) inducible at baseline </li></ul><ul><li>4 linear lesions with Cardima microcatheters </li></ul><ul><li>AF no longer inducible in 8 of 8 goats </li></ul><ul><li>Transmural linear lesions were achieved </li></ul>
  25. 25. Can Microcatheters Produce Linear Lesions without Sacrificing Transmurality in the Canine Atrium? Asirvatham S, Mayo Foundation Circulation 1999; 100(18):1-374 <ul><li>14 dogs </li></ul><ul><li>Linear right and left atrial lesions with Cardima microcatheters </li></ul><ul><li>30 linear lesions with 8 pole 3.7 Fr microcatheters </li></ul><ul><li>36 linear lesions with 10 pole 4mm ablation catheter </li></ul>Ablation Strategy Cardima vs Stnd multipolar abl catheter Width 4.2 + 1 vs 5.4 + 1.6 Depth 1.4 + 0.6 versus 1.3 + 0.7 Volume 29 + 15 versus 42 + 62 Lesion formation 98% vs 95% Transmural lesion 89% vs 85%
  26. 26. NavAblator Canine Study University of Oklahoma Mauricio Arruda <ul><li>6 dogs </li></ul><ul><li>NavAblator catheter for isthmus ablation </li></ul><ul><li>Lesion length: 20 – 30 mm </li></ul><ul><li>Lesion depth: 1.0 to 3.5 mm </li></ul><ul><li>Complete linear isthmus lesion in 5 of 6 dogs </li></ul>
  27. 27. Prospective Comparison of Lesions Created Using a Multipolar Microcatheter Ablation System with Those Created Using a Pullback Approach with Standard RF Ablation In the Canine Atrium Jumrussirikil P, Atiga W, Lardo A, Berger R, Halperin H, Hutchins G, Calkins H PACE 2000; 23:203-213. <ul><li>10 dogs </li></ul><ul><li>4 with standard pullback approach </li></ul><ul><li>6 with Cardima microcatheters </li></ul><ul><li>4 linear lesions: intercaval, septal, flutter, & anterior lines </li></ul><ul><li>One month to animal sacrifice </li></ul><ul><li>Compared lesion size and shape and complications </li></ul>
  28. 28. Linear Atrial Ablation Using the Drag and Burn Technique Jumrussirikil et al; PACE 2000; 23:203-213.
  29. 29. Linear Atrial Ablation Using the Cardima Multielectrode Ablation Catheter Jumrussirikil et al; PACE 2000; 23:203-213.
  30. 30. Width of Lesion(mm)  2.6 4.9 Comparison of Lesion Width  p < 0.05 Jumrussirikil et al; PACE 2000; 23:203-213.
  31. 31. Comparison of Lesion Length p = 0.NS Jumrussirikil et al; PACE 2000; 23:203-213.
  32. 32. Depth of Lesion(mm) 2.4 Comparison of Lesion Depth 2.1 Jumrussirikil et al; PACE 2000; 23:203-213.
  33. 33. Multipolar Microcatheter Pullback Approach 25 in 25 lesions (100%) 6 in 16 lesions (37%) Comparison of Lesions Linearity  p < 0.05  Jumrussirikil et al; PACE 2000; 23:203-213.
  34. 34. Continuous 18/25 (72%) Continuous 6/16(37%) Comparison of Lesion Continuity Multipolar Microcatheter Pullback Approach   p < 0.05 Jumrussirikil et al; PACE 2000; 23:203-213.
  35. 35. Anchor 10/16 (62%) Multipolar Microcatheter Pullback Approach Comparison of Lesion Anchoring to an Anatomic Structure Anchor 23/25 (92%)  p < 0.05  Jumrussirikil et al; PACE 2000; 23:203-213.
  36. 36. Conclusions 1) Atrial lesions created using MICRO are narrower, more continuous, more linear, and more likely to be anchored to an anatomic structure than those created with STND. 2) These differences in lesions characteristics may facilitate cure of atrial fibrillation with a catheter based MAZE procedure. Jumrussirikil et al; PACE 2000; 23:203-213.
  37. 37. Rationale for a Right Atrial Procedure <ul><li>Very likely lower risk than left atrial ablation </li></ul><ul><li>May be more widely applicable </li></ul><ul><li>With lower risks, physicians are likely to offer a right atrial ablation procedure to highly symptomatic patients </li></ul>
  38. 38. Protocol Development and Study Design Hugh Calkins, M.D. Professor of Medicine Director of Electrophysiology The Johns Hopkins Medical Center Baltimore, MD
  39. 39. Indications for Use <ul><li>The Cardima ® Inc., REVELATION ® Tx Microcatheter Ablation System is indicated for the treatment of atrial fibrillation in patients with drug refractory paroxysmal atrial fibrillation by mapping, pacing, and ablating with a set of continuous linear lesions in the right atrium. </li></ul>
  40. 40. Protocol Development Chronology <ul><li>Initial Study Design Collaboration with MGH, FDA, CARDIMA ® </li></ul><ul><li>Phase Ia Mapping Study (PATHFINDER ™ AF) </li></ul><ul><li>Phase IIa Mapping and Ablation (REVELATION ® Tx) </li></ul><ul><li>Circulatory Systems Recommendations for Clinical Trial Design </li></ul><ul><li>Advisory Panel for AF Studies </li></ul><ul><li>Phase IIb Mapping and Ablation (REVELATION ® Tx) </li></ul><ul><li>Circulatory Systems Recommendations for Clinical Trial Design </li></ul><ul><li>Advisory Panel for AF Studies </li></ul><ul><li>2000 Phase III Mapping and Ablation </li></ul><ul><li>(REVELATION ® Tx and NAVABLATOR ™ ) </li></ul>
  41. 41. FDA Advisory Panel Recommendations * 3 episodes per month  * <ul><li>Two episodes over three </li></ul><ul><li>months </li></ul>Baseline AF  <ul><li>Failed 2 AADs or </li></ul><ul><li>amiodarone </li></ul>Patient Population  <ul><li>Patient as own control </li></ul>Control group  <ul><li>Single Arm </li></ul><ul><li>Non-Randomized </li></ul>Trial Design CARDIMA STUDY PANEL GUIDANCE STUDY PARAMETER
  42. 42. FDA Advisory Panel Recommendations (cont’d…)  “ Improved quality of life may be a very important outcome.” Quality of Life  Incidence of Major Complications Safety   <ul><li>50-75% reduction in frequency </li></ul><ul><li>of symptomatic AF episodes </li></ul><ul><li>Six months evaluation of </li></ul><ul><li>therapy effectiveness </li></ul>Long-Term Success CARDIMA STUDY PANEL GUIDANCE PARAMETER
  43. 43. <ul><li>Reduction in symptomatic AF episodes </li></ul><ul><li>Safety </li></ul><ul><li>Improvement in quality of life </li></ul>Study Objectives
  44. 44. Inclusion Criteria <ul><li>Three or more symptomatic AF episodes per 30 days (documented by cardiac event monitor) </li></ul><ul><li>Refractory to two or more (AADs) or to amiodarone alone </li></ul><ul><li>Absence of significant structural heart disease, LA size < 5 cm </li></ul><ul><li>Absence of echocardiographic evidence of intra-atrial thrombus, PFO, and/or ASD on TEE </li></ul>
  45. 45. <ul><li>Acute ablation failure within 2 months </li></ul><ul><li>MI within 6 weeks </li></ul><ul><li>CVA or TIA within 6 months </li></ul><ul><li>Pregnancy </li></ul><ul><li>Coagulopathy or bleeding diathesis </li></ul>Exclusion Criteria
  46. 46. Study Schema Yes Screen Failure Excluded From Study Informed Consent 30-Day Baseline Monitoring 3 or more Symptomatic episodes? Yes TEE Thrombus? No RF Ablation Pre-Discharge Evaluations Follow-Up Evaluations at 1, 3, 6, 12, and 24 months
  47. 47. Patient Follow-up Weekly and symptomatic transmissions @ baseline, months 1, 3, and month 6 Cardiac Event Monitor Baseline, Months 3 and 6 Quality of Life Questionnaires Baseline TEE Baseline and 3 months Echocardiogram and stress test 24 months Telephone interview Study Interval Assessment Baseline, and office visits at 1, 3, 6 and 12 months post ablation History, Physical Exam, 12-Lead EKG
  48. 48. Study Endpoints <ul><li>“ Primary clinical endpoints: </li></ul><ul><ul><li>Frequency of spontaneous symptomatic AF episodes </li></ul></ul><ul><ul><li>Incidence of adverse effects” </li></ul></ul><ul><li>“ Secondary clinical endpoint: </li></ul><ul><ul><li>Quality of life based on the SF-36 and the AFSS” </li></ul></ul>
  49. 49. Success Criteria <ul><li>Acute Procedural Success: </li></ul><ul><ul><li>Reduction in amplitude, fragmentation or widening of local electrograms </li></ul></ul><ul><ul><li>Appearance of split potentials </li></ul></ul><ul><ul><li>Increase in pacing threshold </li></ul></ul>
  50. 50. Success Criteria, cont’d <ul><li>Primary Endpoint: </li></ul><ul><ul><li> 50% reduction in AF episodes for patients with  5 AF episodes per month </li></ul></ul><ul><ul><li> 75% reduction in AF episodes for patients with  3-4 AF episodes per month </li></ul></ul><ul><li>Clinical Success </li></ul><ul><ul><li>Reduction in AF episodes as specified above </li></ul></ul><ul><ul><li>“ While maintained on the same anti-arrhythmic drug regimen or a reduced dosage” </li></ul></ul>
  51. 51. <ul><ul><li>N=80 evaluable subjects at 6 months follow up </li></ul></ul><ul><ul><li>Based on estimated patient success rate </li></ul></ul><ul><ul><li>Statistical considerations with a clinically acceptable margin of error (SE=0.056) </li></ul></ul><ul><ul><li>This sample size was specified in the FDA approved protocol </li></ul></ul>Sample Size
  52. 52. <ul><ul><li>Multiple animal studies have demonstrated safe creation of thin , transmural, linear ablation lesions </li></ul></ul><ul><ul><li>Clinical study was designed in collaboration with the FDA </li></ul></ul><ul><ul><li>Clinical study incorporates a large number of measures of safety and efficacy </li></ul></ul><ul><ul><li>As the first AF clinical trial this study is charting new waters </li></ul></ul>Summary
  53. 53. Patient Population and Study Results Abraham G. Kocheril, M.D. Head of Cardiac Electrophysiology, Carle Heart Center. Associate Professor of Medicine, University of Illinois COM at U-C, Urbana, IL
  54. 54. 20 Clinical Sites Regional Cardiology Associates, Sacramento, CA Arjun Sharma, M.D. Cornell University Medical Center, New York, NY Bruce Lerman, M.D. Access Clinical Trials, Beverly Hills, CA Eli Gang, M.D. Sequoia Hospital, Redwood City, CA Roger Winkle, MD Harper University Hospital, Detroit, MI Randy Lieberman, M.D. Cardiac Arrhythmia Consultants, Ltd., Chicago, IL Jose Nazari, M.D. Wisconsin Center for Clinical Research, Milwaukee, WI Imran Niazi, M.D. NYU Medical Center, New York, NY Larry Chinitz, M.D. Carle Heart Center, Urbana, IL Abraham Kocheril, M.D. Cardiac Medicine & Electrophysiology, Warren, NJ Sanjeev Saksena, M.D. Diagnostic Center, Chattanooga, TN Timothy Talbert, M.D. Lancaster Heart Foundation, Lancaster, PA Seth Worley, M.D. Catholic Medical Center, Manchester, NH Bruce Hook, M.D. University of Chicago, Chicago, IL David Wilber, M.D. Main Line Health Heart Center, Wynnewood, PA Roger Marinchak, M.D./ Inova Inst. of Research & Education, Falls Church, VA Ted Friehling, M.D. Mayo Clinic, Rochester, MN Douglas Packer, M.D. The Johns Hopkins Medical Center, Baltimore, MD Hugh Calkins, M.D. Massachusetts General Hospital, Boston, MA Jeremy Ruskin, M.D. Stanford University Medical Center, Stanford, CA Ruey Sung, M.D. CLINICAL INVESTIGATIONAL SITE INVESTIGATOR
  55. 55. Patient Accountability Ablated n=120 Withdrew <6 months, n=8  6 Months Post Ablation n=87 <6 Months Post Ablation n=18 Withdrew >6 months n=7
  56. 56. Effectiveness Cohorts Baseline data 6 months follow-up n= 87 Evaluable for 1 o effectiveness endpoint n=81 Indeterminate 6-month episode data n=1 Indeterminate baseline episode data n=5
  57. 57. Patients Withdrawn Prior to Six Months (n=8) * one patient included in effectiveness analysis 4* AVN ablation and/or PPM implantation 4 Unable/Unwilling to do follow-up # pts Reason for Withdrawal (n=8)
  58. 58. Demographic and Baseline Characteristics Freq. (%) Characteristic 84 (72) Cardiovascular Disease 89 (77) Male Gender 22 (19) Neurologic 30 (26) Endocrine 21 (18) Renal 30 (26) Respiratory Other Medical Conditions 56.9 ± 10.9 Age, mean ± SD, years
  59. 59. Prior Cardiac Interventions 9 (8) CABG 2 (2) Angioplasty 5 (4) PTCA/Stent 7 (6) Pacemaker 8 (7) DC Cardioversion 33 (28) RF Ablation Freq. (%) Type of Intervention
  60. 60. Breakdown of Ablations (for 87 subjects with 6 mo FU) <ul><ul><li>Types : </li></ul></ul>22 <ul><ul><li>Atrial Flutter </li></ul></ul>19 <ul><ul><li>SVT/ Atrial Tachycardia </li></ul></ul>22/87 (25) Subjects with Prior RFCA Freq. (%) Prior RF Ablation Procedures
  61. 61. Baseline Arrhythmia Symptoms 34 (31) Other 58 (50) Shortness of Breath 43 (37) Lightheadedness 68 (59) Fatigue 101 (87) Palpitations 22 (19) Chest Pain N (%) Symptoms
  62. 62. Baseline Symptomatic AF Episodes Per Month Mean, SD = 10.1 ± 8.9
  63. 63. SF-36 Mean Scores at Baseline Study Group vs. US Population* * Adjusted for the age and gender distribution of the study group
  64. 64. Study Results
  65. 65. Lesion Locations Post-Lateral A Isthmus C Septal B Anterior D A – 90.3% B – 93.0% C – 90.3% D – 8.7% ABC – 82.6%
  66. 66. Procedure Times 47 ± 46 Fluoroscopy Time 250 ± 123 Procedural Time Mean ± SD (minutes) Total Time
  67. 67. Acute Procedural Success <ul><li>Surrogate for clinical effectiveness </li></ul><ul><li>Initial plans to record specific measurements of acute procedural success became unwieldy </li></ul><ul><li>Investigator assessment of acute procedural success at the time of the procedure: </li></ul><ul><ul><li>110/118 (93%) </li></ul></ul>
  68. 68. Six Month Results <ul><li>Primary Endpoint </li></ul><ul><li> 50% reduction for pts with  5 sAF episodes per month </li></ul><ul><li> 75% reduction for pts with 3-4 sAF episodes per month </li></ul><ul><li>Results </li></ul><ul><li>69/81 (85%) met this endpoint </li></ul>
  69. 69. Per-Subject AF Episode Reduction (n=81)
  70. 70. No symptomatic AF episodes at 6 months: 44/81 (54%) AF Episode Reduction
  71. 71. Mean Episode Frequency Reduction (n=81)
  72. 72. Reduction in Common Arrhythmia Symptoms (Pre- vs. Six Months Post-RFA)
  73. 73. Secondary Endpoint <ul><li>Improvement in Quality of Life Scores </li></ul><ul><ul><li>Atrial Fibrillation Severity Score (AFSS) </li></ul></ul><ul><ul><li>SF-36 </li></ul></ul>
  74. 74. AFSS (Pre- vs. Six Months Post-RFA)
  75. 75. SF-36 Mean Scores Baseline vs. 6 Months
  76. 76. Major Complications* <ul><li>An adverse event that occurs within 7 days following investigational procedure and: </li></ul><ul><ul><li>Is life-threatening; </li></ul></ul><ul><ul><li>Results in permanent impairment or damage to a body structure; </li></ul></ul><ul><ul><li>Requires significant intervention to prevent permanent impairment </li></ul></ul><ul><ul><li>Requires hospitalization or an extended hospital stay; </li></ul></ul><ul><ul><li>Results in moderate transient impairment or damage to a body structure; </li></ul></ul><ul><ul><li>Requires intervention such as medication or cardioversion to prevent permanent impairment or damage to a body structure </li></ul></ul>*FDA definition of acute major complications for catheter ablation studies
  77. 77. Major Complications 4 /123 (3.3%) Not major complication: 1 pacemaker within 7d, but with documented preexisting sinus node dysfunction. Patients with pacemakers addressed later. <ul><li>Pericardial effusion requiring pericardial window one week post ablation </li></ul><ul><li>Sinus node injury requiring pacemaker implantation </li></ul><ul><li>Stroke 4 days post ablation </li></ul><ul><li>AV Fistula </li></ul>
  78. 78. Adverse Events during Follow-up 31/120 patients (27%) 41 Other 1 Stroke (>1yr FU) 53 Total 1 Sinus Node Dysfunction 2 Infection (URI, UTI) 2 Cardioversion 6 AVN Ablation/Permanent Pacemaker n Adverse Event
  79. 79. Other Adverse Events Symptom Total Symptom Total Skin Burns/Irritation 6 Back Pain & Nausea 1 Sore Throat 4 Dehydration 1 Back Pain 2 Discomfort 1 Bleeding (at incision) 2 Groin Pain 1 Hematoma 2 Increased Palpitations 1 Hospitalization (INR/Ataxia) 2 Pauses Asystolic 1 Increased Weakness 2 Phlebitis 1 Pericarditis 2 Pulmonary Hypertension (post PPM) 1 Shortness Of Breath & Chronic Fatigue 2 Swelling (right hand) 1 Supraventricular Tachycardia 2 Asthma 1 Thigh Numbness 2 Upper Respiratory Infection 1 Atrial Flutter 1 Urinary Tract Infection 1
  80. 80. Adverse Events during Follow-up Summary <ul><li>No reports of: </li></ul><ul><ul><li>Mortality </li></ul></ul><ul><ul><li>Cardiac Perforation </li></ul></ul><ul><ul><li>AV Fistula or arterial injury </li></ul></ul><ul><ul><li>Thromboembolism </li></ul></ul><ul><li>73% reported no adverse events </li></ul>
  81. 81. Summary Results Quality of Life Statistically Significant QOL Improvements 1) SF-36 2) AFSS Secondary Endpoint 4/120 (3.3) Serious Adverse Events ≤ 7 Days Post Procedure Major Complications Safety 50/81 (62) Reduction in sAF episodes While Maintained on Same AAD Regimen or Reduced Dosage Clinical Success 69/81 (85) ≥ 50/75% Reduction in Frequency of sAF episodes at 6 Months Primary Endpoint Effectiveness # PTs (%) DEFINITION STUDY ENDPOINT
  82. 82. Issues for Clarification <ul><li>Catheters/Lesion Sets </li></ul><ul><li>Pacemakers </li></ul><ul><li>Clinical Success & Antiarrhythmic Drugs </li></ul><ul><li>TTM Compliance </li></ul>
  83. 83. Lesion Sets Post-Lateral A Isthmus C Septal B Anterior D A – 90.3% B – 93.0% C – 90.3% D – 8.7% ABC – 82.6%
  84. 84. Catheters/Lesion Sets <ul><li>REVELATION ® Tx used for all non-isthmus linear lesions </li></ul><ul><li>REVELATION ® Tx linear catheter could ablate some but not all flutter isthmus. </li></ul><ul><li>Thus, investigators used clinically available 4 mm tip ablation catheters to create the flutter line </li></ul><ul><li>NavAblator catheter developed for Phase III </li></ul><ul><li>Some investigators preferred use of their standard 4 mm catheters </li></ul>
  85. 85. <ul><li>Phase III FDA required that a conventional 4mm tip ablation catheter be specified. </li></ul><ul><li>Cardima manufactured the NAVABLATOR ™ to be specified as part of the “system”, solely for the creation of the “flutter line” at the isthmus when the anatomy was not compatible with the REVELATION ® Tx linear electrode array. </li></ul>Catheters/Lesion Sets
  86. 86. Pacemakers <ul><li>Per protocol: “Subjects electing to receive implantable ppms prior to 6 mo f/u will be considered failures.” </li></ul><ul><ul><li>Intent: subjects should not require adjunctive pacemaker therapy to address AF </li></ul></ul><ul><ul><li>Not all pts receiving ppm’s fall into this category </li></ul></ul><ul><li>Patients with pacemakers not excluded from study </li></ul>
  87. 87. Pacemakers 3 Treatment failures (n=3) 20 Total Post Procedure Device Implants 7 PPMs >6 months n Post Procedure Device Implants 1 Insurance coverage changed, new Dr. recommended AVN/PPM 1 DDDR for AV block & NSVT 1 Flutter ablation + AVN/PPM (no sAF reported prior to Tx 5 AVN/PPM <6 mo 1 ICD for Sinus Node injury at Tx (not WD) 6 PPM for pre-existing SSS or brady 13 PPMs < 6 months
  88. 88. Pacemakers <ul><li>3 Pacemakers shortly after procedure </li></ul><ul><li>All 3 had known preexisting sinus node dysfunction </li></ul><ul><ul><li>Pt.1: HR 49 when in SR – no AVN ablation </li></ul></ul><ul><ul><li>Pt.2: sinus pauses, 34 episodes to 1 at 6 mo – no AVN ablation </li></ul></ul><ul><ul><li>Pt.3: sinus brady, 3 sec pauses, 6 to 1 – no AVN ablation </li></ul></ul><ul><li>Not major complications </li></ul>
  89. 89. Percentage Of Patients Who Achieved Six Month Success Including “Failures&quot; 85.2 69/81 <ul><li>- 3 failures, - 5 patients with indeterminate baseline episodes </li></ul>82.0 73/89 <ul><li>+ 3 failures, + 5 with indeterminate baseline episodes </li></ul>% n Success (sAF  ) Subject Groups
  90. 90. Clinical Success & Antiarrhythmic Drugs <ul><li>Primary endpoint was reduction in AF frequency independent of AAD use (69/81, 85%) </li></ul><ul><ul><li>Study population was drug refractory (avg. 3) and had concomitant medical conditions </li></ul></ul><ul><li>“ Clinical Success” defined per protocol: Reduction in sAF episodes while maintained on the same anti-arrhythmic drug regimen or a reduced dosage </li></ul><ul><ul><li>As determined by clinical site, 19 of the 69 successful patients had an “increase” in AADs </li></ul></ul><ul><ul><li>Thus, the “clinical success rate” is 50/81 (62%) </li></ul></ul><ul><ul><li>Given current information on the efficacy of AADs, it is difficult to determine a true increase in an AAD regimen </li></ul></ul>
  91. 91. Clinical Success & Antiarrhythmic Drugs Evaluable for 1 o effectiveness endpoint n=81 < Req’d reduction in AF episodes n=12 (14.8%) ≥ 50/75% reduction in AF episodes n=69 (85.2%) Decrease or No Change in AAD n= 50 Increase in AAD n=19 AVN ablation n= 2 AVN ablation n= 2
  92. 92. Changes in AADs from BL to 6 Months (n=87) Amiodarone Membrane Active Drug Rate Control Drug 12 (10, 1, 1*) Baseline 6 Months 21 19 (17, 1, 1*) 52 47 (37, 10) 21 (19, 2) 14 5 *(Success/Failure) 1 patient with unknown # sAF at 6 months 4 7 39 3 11 (9, 2*) (31, 8) (3, 2) (7, 0) (3, 0) (4, 0) (6, 0) 6
  93. 93. Changes AADs from BL to 6 Months for 23 “Increases* Amiodarone Membrane Active Drug Rate Control Drug 4 Baseline 6 Months 4 6 15 15 2 4 2 12 3 1 1 * 2/23 had indeterminate baseline episode frequencies. ** 21/23 patients were considered successes.
  94. 94. Clinical Success & Antiarrhythmic Drugs Patients with Increased AADs (n=21) <ul><li>19 had reduction in AF episodes (success) </li></ul><ul><ul><li>10/19 show a 100% reduction in sAF episodes at 6 months with “increases” to an AAD regimen to which they were previously refractory </li></ul></ul><ul><ul><li>The remaining 9/19 had > 50% reduction in episodes </li></ul></ul>
  95. 95. Clinical Success & Antiarrhythmic Drugs Patient Success by AAD Use at Six Months
  96. 96. * Sotalol or beta-blockers are the initial drugs of choice for adrenergic AFIB. + Consider nonpharmacologic options to maintain sinus rhythm if drug failure occurs. HF= heart failure CAD= coronary artery disease LVH= left ventricular hypertrophy Treatment Algorithm for AF Heart disease? No (or minimal*) Flecainide Propafenone Sotalol Amiodarone, Dofetilide Disopyramide Procainamide Quinidine Consider nonpharmacologic options Yes + HF Amiodarone Dofetilide Sotalol Amiodarone Dofetilide Disopyramide Procainamide Quinidine CAD Hypertention LVH greater than or equal to 1.4 cm Yes No Amiodarone Flecainide Propafenone Amiodarone Dofetilide Sotalol Disopyramide, Procainamide, Quinidine
  97. 97. Patients with Decrease/No Change in AADs (n=60) <ul><li>36 patients had decrease in AADs at six months </li></ul><ul><li>6 patients were off AADs at 6 months </li></ul><ul><li>28 patients had no change in AADs </li></ul>
  98. 98. Transtelephonic Event Monitoring <ul><li>Three redundant mechanisms for symptomatic episode monitoring : </li></ul><ul><li>TTM (to capture both spontaneous and scheduled transmissions) </li></ul><ul><li>Arrhythmic events reports (CRFs) </li></ul><ul><ul><li>C linical history at baseline, 1, 3, 6, and 12 months to document reports of AF frequency and severity </li></ul></ul><ul><li>EKG at baseline, 1, 3, and 6 months </li></ul><ul><li>AFSS questionnaire </li></ul><ul><ul><li>Additional documentation of AF frequency and severity </li></ul></ul>
  99. 99. Transtelephonic Event Monitoring <ul><ul><li>Record and transmit each symptomatic episode </li></ul></ul><ul><ul><li>Transmit at least weekly ( with or without symptoms) </li></ul></ul><ul><ul><li>Perform as above at baseline & 1, 3 and 6 months post ablation </li></ul></ul>
  100. 100. Transtelephonic Event Monitoring <ul><li>Patients were blinded to number of AF episodes required for study eligibility </li></ul><ul><li>TTMs reviewed by independent cardiologist to verify sufficient AF episodes for study eligibility </li></ul>
  101. 101. Transtelephonic Event Monitoring <ul><li>22 subjects did not transmit recordings at six months. </li></ul><ul><li>All had EKG/Office Visit at 6 month FU </li></ul><ul><li>* One subject not included </li></ul>0-100 29.5 ± 35.6 0-100 57.4 ± 24.4 % Symptomatic AF Episodes per Transmission 0-11 1.3 ± 2.1 0-50 9.0 ± 8.9 # Symptomatic AF Episodes per Month 1-11 3.9 ± 2.4 5-53 15.5 ± 11.4 # Transmissions per Month Range Mean, SD Range Mean, SD Description 6 Months (n=65*) Baseline (n=86)
  102. 102. Transtelephonic Event Monitoring
  103. 103. Transtelephonic Event Monitoring Patient Compliance with 6-Month Assessments of Arrhythmic Events 80 (99%) EKG 74 (91%) AFSS Questionnaire 80 (99%) Arrhythmia Symptoms # Pts Completed (n=81) Assessment
  104. 104. AFSS Mean Scores at Six Months by Six-Month Transmission Compliance
  105. 105. Issues for Clarification <ul><li>Although this study design, while consistent with the recommendations of the FDA Advisory Panel, has some inherent limitations compared to a controlled, randomized study (CRT), Cardima believes it is unlikely that the patient improvements seen in these study results could be attributable individually or collectively to the effects of these limitations </li></ul>
  106. 106. Study Summary <ul><li>Effectiveness </li></ul><ul><li>Reduction in AF episodes at 6 mo 69/81 (85%) </li></ul><ul><li>No AF at 6 months 44/81 (54%) </li></ul><ul><li>Clinical success 50/81 (62%) </li></ul><ul><li>Off all AADs 6/81 (7 %) </li></ul><ul><li>Reduction in AADs 36/81 (44%) </li></ul><ul><li>Quality of Life Significant improvements </li></ul><ul><li>Safety </li></ul><ul><li>Mortality 0/120 (0%) </li></ul><ul><li>Major Complications 4/120 (3%) </li></ul>
  107. 107. Closing Remarks G. Neal Kay, M.D. Professor of Medicine Director of Electrophysiology University of Alabama at Birmingham Birmingham, AL
  108. 108. Conclusion <ul><li>The REVELATION Tx linear ablation system is safe and effective in treatment of patients with paroxysmal atrial fibrillation in the absence of significant structural heart disease. </li></ul>
  109. 109. Study Strengths <ul><li>Robust Study Design - Patients acted as their own control </li></ul><ul><li>Study consistent with FDA Advisory Panel recommendations </li></ul><ul><li>Use of TTM provided an objective measure of therapy success </li></ul><ul><li>Use of subjective measures of therapy effectiveness (i.e., QOL) captured important patient parameters </li></ul><ul><li>Study demonstrated excellent safety profile </li></ul><ul><li>Study demonstrated clinically meaningful improvement in patient outcomes </li></ul>
  110. 110. Summary of Study Results <ul><li>This is the first multicenter clinical trial of catheter ablation for atrial fibrillation to be completed </li></ul><ul><li>Right atrial linear ablation offers a level of success for control of paroxysmal atrial fibrillation </li></ul><ul><li>Most patients continued on AADs at the same or lower dose </li></ul><ul><li>AF did not appear to worsen in most PAF pts, as is the natural history of the disease </li></ul><ul><li>This level of success was accomplished with a very low risk of serious complications </li></ul>
  111. 111. The Atrial Fibrillation Challenge <ul><li>PV isolation is effective in about 2/3 of patients with paroxysmal AF </li></ul><ul><li>The risks are significant and include: </li></ul><ul><ul><li>PV stenosis - 1-8% and is related to experience </li></ul></ul><ul><ul><li>Stroke – 1-4% </li></ul></ul><ul><ul><li>Tamponade - 1-4% </li></ul></ul><ul><ul><li>Major bleeding - 2-3% </li></ul></ul><ul><li>Limited to physicians competent to perform transeptal catheterization </li></ul><ul><li>There have been no multicenter prospective trials of PVI </li></ul>
  112. 112. Risk : Benefit <ul><li>The lower risks of this relatively simple procedure are likely to allow it to be performed by a wider range of physicians than a complex left atrial ablation procedure </li></ul><ul><li>It is likely that a simple right atrial ablation procedure will be offered to patients with highly symptomatic paroxysmal atrial fibrillation before more risky techniques </li></ul>
  113. 113. Conclusions <ul><li>REVELATION ® Tx is a new RF catheter ablation technology specifically designed to create linear lesions in the right atrium </li></ul><ul><li>Provides an important treatment option for many patients with drug refractory paroxysmal AF </li></ul><ul><li>Addresses currently unmet public health need for safe and effective treatment of AF, a disease of great clinical significance to the medical community, both in terms of patient suffering and high medical costs of treating AF and its clinical sequelae </li></ul><ul><li>This technology has been demonstrated to eliminate > 50% of symptomatic AF episodes in treated patients </li></ul>
  114. 114. REVELATION ® Tx

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