Reactive ATP and MINERVA

Atrial Reactive ATP Overview Reactive ATP allows for multiple deliveries of programmed ATP therapies in response to two clinically relevant events: Change in the arrhythmia rhythm (cycle length or regularity) Elapsed period of time Atrial Reactive ATP looks to restore sinus rhythm by continuously searching for new opportunities to initiate ATP therapy in AT/AF episodes, particularly those of longer duration. Specifically it allows multiple deliveries of programmed ATP therapies in response to rhythm changes or a programmed/elapsed time interval. Reactive ATP allows the device to become more opportunistic in treating atrial arrhythmias.

Atrial Reactive ATP Programming Rhythm Change options: On/Off Time Interval options: Off, 2 hrs…48 hrs The Atrial Reactive ATP parameters of Rhythm Change and Time Interval can be programmed from the AT/AF Detection and Therapies window accessed from the Parameters icon. Details of operation on these two parameters are included in subsequent slides.

Reactive ATP – Rhythm Change If Rhythm Change is enabled: ATP Therapy “bins” are automatically created by the device based upon whether 1 or 2 zones for AT/AF detection are programmed The full set of programmed ATP therapies (Rx1, Rx2, Rx3) is available for each bin and for each zone Regular Irregular When Rhythm Change is programmed On, the device is automatically programmed to continuously look for the following changes in an atrial tachyarrhythmia episode: Changes in regularity (of intervals) or Changes in cycle length (rate) Depending upon the number of detection “Zones” programmed (1-zone or 2-zones), the device will automatically subdivide these zones into a series of narrower bins. One series of bins is used for regular atrial rhythms and the other for irregular atrial rhythms. Each bin is supplied with its own set of the atrial ATP therapies programmed (Rx1, Rx2 and/or Rx3). When single-zone (1-zone) detection is programmed, all sequences of Rx1, Rx2 and Rx3 are available within each sub-bin. If two-zone detection is used (Fast AT/AF, AT/AF), each of these two zones has its own unique set of ATP therapies assigned to it. The Fast AT/AF zone will get only one set of ATP therapies (there are no sub-bins). In the example on this slide, the Fast AT/AF Zone was programmed at 200 ms. All sequences of Rx1, Rx2 and Rx3 would be available only once for any tachyarrhythmias that have a cycle length of 100-200 ms. However, for any tachyarrhythmias that are slower than 200 ms, the Rx1, Rx2 and Rx3 sequences could be attempted multiple times depending whether the arrhythmia shifts in cycle length or regularity (i.e. shifts from bin-to-bin). Example of Rhythm Change ATP Delivery for One Zone Detection: AT/AF detected as “regular” with a cycle length of 200 ms. Device delivers all 8 sequences of programmed Rx1 (Ramp) – assuming this is the ATP therapy programmed for Rx1. Episode continues to be redetected as “regular” with a cycle length of 220 ms. Device delivers all 6 sequences of programmed Rx2 (Burst+) therapies – assuming this is the ATP therapy programmed for Rx2. There is no Rx3 programmed. Sinus rhythm is still not restored. All programmed therapies for 200-250 ms bin are now exhausted. Assume 4 hours later that the arrhythmia now slows to a cycle length of 340 ms. Rhythm Change recognizes this shift in cycle length (episode continues to be “regular”) and now initiates first sequence of Rx1 (Ramp sequence #1) in this new bin. This successfully terminates the episode and restores sinus rhythm. Regular Irregular

Treated AT/AF Programmer View

Evolution of Reactive ATP

Example of Changing Atrial Arrhythmias

Reactive ATP Example

Another Reactive ATP Example

MINERVA Study Why did the VP%>95 get excluded? Wanted to understand effects of MVP, that is why it is there. 95% or greater VP% in that first month were screened out. It was a secondary endpoint. Permanent RV pacing patients were put into a registry n=385 n=383 n=398

MINERVA MINimizE Right Ventricular pacing to prevent Atrial fibrillation and heart failure study Primary objective is to compare the Control DDDR to DDDRP+MVP arms at 2 years using the composite clinical endpoints of All Cause Death CV Hospitalizations Permanent AF

61% relative reduction between DDDRP + MVP arm and Control DDDR (p = 0

Risk of AF >7 Days and aATP Efficacy Implies that aATP is a driving force behind the results When aATP is successful, significantly fewer patients have AF >7 days. Patient with higher aATP success rates experienced markedly significant reductions in permanent AF. aATP is successfully disrupting the AT/AF episodes and stopping it from progressing.

MINERVA Key Results Primary End Point 2 year composite of death, CV hospitalizations, and permanent AF in DDDRP + MVP arm vs. Control DDDR (26% relative risk reduction, p = 0.04) End point driven by slowing progression of AF 61% relative reduction between DDDRP + MVP arm and Control DDDR (p = 0.004) Rates for HCU to AF (hospitalizations, ER visits, atrial CVs) lower in DDDRP + MVP arm compared to Control DDDR

Longevity Pacing thresholds rise as the coupling interval is reduced High outputs designed to maximize the ability to capture all coupling intervals during ATP 1000 aATP per month decreases longevity by less than 3%