1. New Findings in the Management of AF in Pacemaker Patients Results from the MINERVA Trial a Medtronic sponsored trial February 2014

2. Steven Zweibel, MD, FACC, FHRS, CCDS Director of Electrophysiology Hartford Hospital Hartford, CT

3. 2013 Late-Breaking Clinical Trial Abstracts Circulation. 2013;128:2704-2722 World Wide Web at: http://circ.ahajournals.org/content/128/24/2704

4. Study Aim and Design Aim: to evaluate whether DDDRP + MVP or MVP reduces mortality, morbidity, or progression to permanent AF compared with standard dual chamber pacing. Multicenter (63 centers), international, randomized, single blind study with 3 arms enrolling 1,166 patients with: Class I or class II indications for dual chamber pacing Previous atrial tachyarrhythmias No history of permanent AF or third degree AV block

5. Primary Objective Compare the Control DDDR to DDDRP + MVP arms at 2 years using the composite clinical endpoint of: All-cause death CV hospitalizations Permanent AF

6. Patient Baseline Characteristics * p < 0.05 DDDRP + MVP vs. the other two groups

7. Primary Outcome (All-Cause Death, CV Hospitalizations, or Permanent AF) Intention-to-treat survival analysis using time to first event

8. All-Cause Death Intention-to-treat survival analysis using time to first event

9. CV Hospitalizations Intention-to-treat survival analysis using time to first event

10. Permanent AF Intention-to-treat survival analysis using time to first event

11. Cardioversion for atrial arrhythmias occurred less frequently in the DDDRP + MVP vs. Control DDDR (49% relative reduction, p = 0.001) AF-related hospitalizations and ER visits occurred less frequently in the DDDRP + MVP vs. Control DDDR (52% relative reduction, p < 0.0001)

12. Incidence of AF Intention-to-treat survival analysis using time to first event

13. Potential Contribution of Reactive ATP Risk of AF > 7 days and aATP efficacy Note:since ATP treated only episodes longer than 2 minutes, to compare the different groups in a correct and balanced way, this analysis considered only patients with at least 2 minutes of AF

14. Not conclusive results … Select Studies on Atrial Therapies

15. Evolution of Atrial ATP First Generation Treated atrial arrhythmias as if they were ventricular arrhythmias All therapies exhausted within 10 minutes AT/AF detected 8 hours Rhythm changed No ATP available to potentially terminate 100 ms350 ms 220 ms 320 ms All therapies delivered in 10 minutes ATP unsuccessful Atrial Therapy Zone

16. Evolution of Atrial ATP Second Generation Reactive ATP AT/AF detected 8 hours Rhythm changed ATP Therapy available for possible termination 100 ms350 ms 220 ms 320 ms All therapies delivered ATP Unsuccessful 150 ms200 ms250 ms300 ms Atrial Therapy Zone

17. Evolution of Atrial ATP Second Generation Regularity AT/AF detected 8 hours Rhythm changed Unorganized to organized with ATP Therapy available for possible termination 100 ms350 ms 220 ms 320 ms All therapies deilivered ATP unsuccessful 200 ms250 ms Atrial Therapy Zone

18. Example of Legacy ATP

19. Successful Ramp Following the Rhythm Transition (11 hour episode) Ramp ATP delivered Successful termination

20. Example of Reactive ATP in a MINERVA Patient

21. Discussion Recap The MINERVA study demonstrates the potential ability of atrial pacing interventions and reactive ATP to slow the progression to permanent AF Reactive ATP was a key therapy component affecting the reduction in time to permanent AF Reactive ATP opportunistically treats episodes of AF when they spontaneously organize or slow down

22. Potential Practice Implications No reduction in mortality at 2 years No change in CV hospitalizations at 2 years 52% relative reduction in atrial cardioversion, 49% relative reduction in AF hospitalization and ER visits AFIB begets AFIB and NSR begets NSR –Providing an extended opportunity for AF ablation Reasonable to consider Reactive ATP in any patient receiving a PM with history of AF or at risk Reasonable to consider Reactive ATP in ICD and/or CRT patients; however, they have not been studied

23. Thank You

24. Brief Statement Indications Implantable Pulse Generators (IPGs) are indicated for rate adaptive pacing in patients who may benefit from increased pacing rates concurrent with increases in activity and increases in activity and/or minute ventilation. Pacemakers are also indicated for dual chamber and atrial tracking modes in patients who may benefit from maintenance of AV synchrony. Dual chamber modes are specifically indicated for treatment of conduction disorders that require restoration of both rate and AV synchrony, which include various degrees of AV block to maintain the atrial contribution to cardiac output and VVI intolerance (e.g. pacemaker syndrome) in the presence of persistent sinus rhythm. For the MR Conditional IPG, a complete pacing system consisting of either an Advisa DR MRI™ SureScan ® Model A2DR01 IPG or Revo MRI SureScan ® Model RVDR01 IPG and 2 CapSure Fix MRI ® SureScan 5086MRI leads is required for use in the MR environment. Contraindications IPGs are contraindicated for dual chamber atrial pacing in patients with chronic refractory atrial tachyarrhythmias; asynchronous pacing in the presence (or likelihood) of competitive paced and intrinsic rhythms; unipolar pacing for patients with an implanted cardioverter defibrillator because it may cause unwanted delivery or inhibition of ICD therapy; and certain IPGs are contraindicated for use with epicardial leads and with abdominal implantation. Warnings/Precautions Changes in a patient’s disease and/or medications may alter the efficacy of the device’s programmed parameters. Patients should avoid sources of magnetic and electromagnetic radiation to avoid possible underdetection, inappropriate sensing and/or therapy delivery, tissue damage, induction of an arrhythmia, device electrical reset or device damage. Do not place transthoracic defibrillation paddles directly over the device. Potential complications Potential complications include, but are not limited to, rejection phenomena, erosion through the skin, muscle or nerve stimulation, oversensing, failure to detect and/or terminate arrhythmia episodes, and surgical complications such as hematoma, infection, inflammation, and thrombosis. See the device manual for detailed information regarding the implant procedure, indications, contraindications, warnings, precautions, and potential complications/adverse events. For further information, please call Medtronic at 1 (800) 328-2518 and/or consult Medtronic’s website at www.medtronic.com. Caution: Federal law (USA) restricts these devices to sale by or on the order of a physician. www.medtronic.com World Headquarters Medtronic, Inc. 710 Medtronic Parkway Minneapolis, MN 55432-5604 USA Tel: (763) 514-4000 Fax: (763) 514-4879 Medtronic USA, Inc. Toll-free: 1 (800) 328-2518 (24-hour technical support for physicians and medical professionals) UC201405311 EN February 2014

25. Back Up

26. Intervention algorithms Atrial rate stabilization (ARS) Atrial pacing preference (APP) Post mode switch overdrive pacing (PMOP) 26

27. Atrial Rate Stabilization (ARS) Intrinsic premature beats not followed by a long pause (“short-long”) Each atrial interval is measured. The next pacing escape is this interval + a percentage (12.5, 25 or 50%) The fastest pace allowed is set by the Minimum Interval (shared by APP) Marker Channel paces are marked “PP” if generated by ARS 27

28. ARS - Atrial Rate Stabilization 28

29. Atrial Pacing Preference (APP) Designed to maintain a high percentage of atrial pacing On every non-refractory atrial sense, pacing escape interval is shortened. Amount of decrease is programmable, nominally 50ms After consecutive atrial paces (nominally 10), the escape interval is lengthened by 20 ms APP cannot go faster than the Minimum Interval. Marker Channel paces are marked “PP” if generated by APP 29

30. APP - Atrial Pacing Preference 30

31. Post Mode Switch Overdrive 31 paced beats Atrial tachyarrhythmia pacing rate (DDDR) time Atrial rate Sinus Rhythm Overdrive Rate (DDIR) pacing rate (not slower than 70) (DDIR) Overdrive Period Confirm sinus (about 15 beats)