1. Conduction Disturbances after Percutaneous Aortic Valve Replacement Reducing Post-TAVR Conduction Disturbances UC201303178a EE

2. Conduction Disturbances after TAVR Anatomical Considerations Conduction Disturbances and Pacemaker Implantation –Driving Factors –Patient Impact Conclusions

3. INTERNATIONAL. CAUTION: For distribution only in markets where CoreValve® is approved. Not for distribution in U.S., Canada or Japan. ©Medtronic, Inc. 2013. All Rights Reserved. Anatomical Considerations Conduction abnormalities are not atypical following TAVR due to the anatomical proximity of the aortic valve to the conduction system –Distance from the non-coronary cusp to the HIS bundle has been measured to be 6.3 ± 2.4 mm. Modified from Tawara. Igawa et. al, Jap Circ 2009

4. Conduction Disturbances after TAVR Anatomical Considerations Conduction Disturbances and Pacemaker Implantation –Driving Factors –Patient Impact Conclusions

5. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. Male gender 3 Age > 75 years 9 Previous MI 3 Right Bundle Branch Block (RBBB) 2,3,4,5,7 Other pre-existing conduction disturbances 3,4,8,9 Patient-Related Factors Variations in location of LBBB exit point 1 Septum thickness 1,6 Thickness of the non- coronary cusp 1 Radial force of the prosthesis 3 Implant Depth 2,3,7 Balloon Aortic Valvuloplasty 8 Application of PPI guidelines 10 Learning Curve 11 Anatomical Factors Procedural Factors (Device / Operator) Mechanisms Driving Post-TAVR Conduction Disturbances More than 25 studies have been published on predictors of post-TAVR conduction disturbances (CDs) and permanent pacemaker implant (PPI) 1 Jilaihawi, et al. Am Heart J 2009; 2 Munoz-Garcıa, et. al. JACC CV 2012; 3 Piazza et. al. EuroIntervention 2010; 4 De Carlo, et. al. Am Heart J 2012; 5 Calvi, et. al. JICE 2011; 6 Saia, et. al. Cath Card Intv 2012; 7 Fraccarao, et. al. Am J Card 2011; 8 Khawaja, et. al. Circ 2011; 9 Schroeter et. al. EuroPACE 2011; 10 Wenaweser, et. al. presented at EuroPCR 2013; 11 Meredith, et. al. presented at TCT 2012

6. Pre-existing Conduction Disturbances, including RBBB Patient-Related Drivers of Conduction Disturbances and Pacemaker Implantation

7. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. Pre-existing Conduction Disturbances Degenerative Aortic Stenosis (AS) is associated with electrical conduction abnormalities because calcification in and around the aortic valve can progress and extend to involve the electrical conduction system of the heart Rates of conduction disturbances at baseline are high in patients with AS Atrial Fibrillation 32% Hemiblock 23% LBBB 17% RBBB 17% Van Mieghem et. al., Ann Thorac Surg 2012

8. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. AV conduction at baseline: AV conduction after TAVI: AV conduction at follow-up: Black boxes = pts w/o follow-up, ▪ # in parentheses = pts with PPI Pre-existing Conduction Disturbances Pre-existing CDs may contribute to the development of post-TAVR arrhythmias which necessitate PPI This chart demonstrates how pre-existing RBBB can contribute to the formation of 3°AV block if the patient develops LBBB during TAVR Roten et. al., Am J Card 2010

9. Pre-implant BAV Procedural Drivers of Conduction Disturbances and Pacemaker Implantation

10. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. Contribution of TAVR Procedural Steps to Conduction Disturbances ECG recording during individual TAVR steps showed that BAV may contribute half of the CDs that develop during TAVR. Patients developing new CDs during BAV had a significantly higher balloon/annulus ratio (1.10 ± 0.10 vs. 1.03 ± 0.11, p=0.030) 1 2% 1 to 16% 2 of PPI in TAVR may be due to CDs caused during BAV 1 Nuis R. Eur Heart J. 2011;32(16):2067-2074. 2 Grube E. JACC Cardiovasc Interv 2011;4(7):751-757.

11. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. Procedural Drivers of Conduction Disturbances and Pacemaker Implantation Pre-implant BAV Implant Depth

12. INTERNATIONAL. CAUTION: For distribution only in markets where CoreValve® is approved. Not for distribution in U.S., Canada or Japan. ©Medtronic, Inc. 2013. All Rights Reserved. Gutierrez et al. Am Heart J 2009, (N=33) Implant Depth Impacts Conduction Disturbances A lower (ventricular) position of the valve relative to the hinge point of the anterior mitral leaflet was associated with a higher incidence of new LBBB (35% vs. 0%, P =.029). Implanted Below → 35% of patients developed LBBB Hinge Point of the Anterior Mitral Valve Implanted Above → 0% of patients developed LBBB

13. INTERNATIONAL. CAUTION: For distribution only in markets where CoreValve® is approved. Not for distribution in U.S., Canada or Japan. ©Medtronic, Inc. 2013. All Rights Reserved. Implant Depth and PPI Rate CoreValve Implant Depth (mm) Pacemaker Implants (% pts.) 1 Tchetche, et al. EuroIntervention 2012; 2 Munoz-Garcıa, et. al. JACC CV 2012; 3 Piazza et. al. EuroIntervention 2010; 4 De Carlo, et. al. Am Heart J 2012; 5 Calvi, et. al. JICE 2011; 6 Saia, et. al. Cath Card Intv 2012; 7 Fraccarao, et. al. Am J Card 2011; 8 van der Boon, et. al. Int J Card 2013; 1 2 3 5 4 Data from independent studies plotted on the same graph show the strong relationship between PPI rate and implant depth

14. INTERNATIONAL. CAUTION: For distribution only in markets where CoreValve® is approved. Not for distribution in U.S., Canada or Japan. ©Medtronic, Inc. 2013. All Rights Reserved. CoreValve Procedural Outcomes at Target Implant Depth N=134Patients (%) Procedural Success133 (99.2) BAV129 (98.5) Balloon-Annulus Ratio 0.95  0.09 Depth of Implant 4.9  2 PVL > 2/40 (0) Central leak0 (0) New LBBB18 (13.4) New Transient or Sustained AVB 17 (12.7) New Pacemaker Implantation 12* (10.6) 134 CoreValve patients treated at 2 experienced centers All implants performed using the AccuTrak delivery system and a 4-6 mm target implant depth Appropriately sized balloon used for pre-implant BAV *12 of 113 patients without baseline pacemaker. Tchetche, et al; EuroIntervention 2012; e-publication.

15. INTERNATIONAL. CAUTION: For distribution only in markets where CoreValve® is approved. Not for distribution in U.S., Canada or Japan. ©Medtronic, Inc. 2013. All Rights Reserved. Pre-implant BAV Implant Depth Variations in Application of Pacemaker Indications Procedural Drivers of Conduction Disturbances and Pacemaker Implantation

16. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. Application of PPI Guidelines Gillis et al HRS/ACCF Pacemaker Mode Selection PPI for relative indications by some centers and not others, driven by the desire to mobilize patients quickly after TAVR, may be a reason for the variability in reported pacemaker rates

17. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. CoreValve ADVANCE | Permanent Pacemaker Implant Rate by Geography Countries with less than 15 implants not shown Varying 30-day pacemaker rates across geographies in the ADVANCE study may reflect differences in the application of PPI guidelines 1 Wenaweser, et al. Presented at EuroPCR 2013

18. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. Absolute vs. Relative Pacemaker Indications Thygesen et al, London Valves 2012. 258 CoreValve patients from Nov 2007 to Feb 2012 (Copenhagen, Denmark) 9% with preexisting pacemaker 19.7% of patients had an absolute pacemaker indication (3°and 2°AVB) After periprocedural period only 9.8% of TAVR patients had an absolute pacemaker indication – –9.9% of conduction disturbances resolved

19. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. Pre-implant BAV Implant Depth Variations in Application of Pacemaker Indications Learning Curve Procedural Drivers of Conduction Disturbances and Pacemaker Implantation

20. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. Overall PPM =31.1% Recent experience = 17.2% PPM rates in 6-mo blocks of pt enrollment, except most recent is 8-mo. Enrolling centers: 6910 PPI Effect of Learning Curve on PPI Rate The overall rate of PPI in the CoreValve Australia-New Zealand Study decreased over time as operators gained experience. 1 Muller, et al. Presented at EuroPCR 2013

21. Conduction Disturbances after TAVR Anatomical Considerations Conduction Disturbances and Pacemaker Implantation –Driving Factors –Patient Impact Conclusions

22. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. Pacemaker Dependency Some TAVR-induced AV conduction disturbances may be transient 1-9 1 Piazza, et al. JACC CV 2008; 2 Gutierrez, et. al. Am Heart J 2009; 3 Piazza et. al. EuroIntervention 2010; 4 Guetta, et. al. Am J Cardiol 2011; 5 Fraccarao, et. al. Am J Card 2011; 6 van der Boon, et. al. Int J Card 2013; 7 Pereira, et. al. PACE 2013; 8 Simms, et. al. ICVTS 2013; 9 Franzoni, et al. Am J Card 2013 van der Boon, et. al, 2013 6 : More than half of patients who had received a new pacemaker after CoreValve were pacemaker independent at follow-up (median time: 12 months). Definition of pacemaker dependent: Presence of high degree AV block (HDAVB) a slow (<30 bpm) or absent escape rhythm

23. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. Tissue compression during BAV Hypotension during rapid pacing (BAV procedure) Other hypotensive episodes Ischemic Injury Pacemaker Dependency Conduction abnormalities may resolve due to the transient nature of some TAVR-induced tissue injury Mechanical Injury Wall tension due to radial force Procedural Inflammation Procedural Edema

24. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. Clinical Impact of LBBB Post-TAVR LBBB is typically associated with left ventricular dyssynchrony, ventricular remodeling, and impaired function 7. Several studies have looked at the impact of LBBB on cardiac function 1,2 and mortality post-TAVR 2-7. There is no consensus in the field on impact of post-TAVR LBBB on mortality or cardiac function. The frequency, degree, timing, and durability of CD recovery after TAVR is currently unknown. This variability may be driving inconsistent conclusions about the clinical impact of LBBB. 1 Hoffmann, et. al. JACC CV Int 2012; 2 Wenaweser, et al. Presented at EuroPCR 2013; 3 Franzoni et. al. Am J Card 2013; 4 De Carlo, et. al. Am Heart J 2012; 5 Testa, et. al. Circ 2013; 6 Urena, et. al. JACC 2012; 7 Houthuizen, et. al. Circ 2012;

25. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. CoreValve ADVANCE | Impact of LBBB The ADVANCE study showed no significant difference in survival between those patients with a new LBBB post-implant and those without. 1 Wenaweser, et al. Presented at EuroPCR 2013

26. INTERNATIONAL. CAUTION: For distribution only in markets where CoreValve® is approved. Not for distribution in U.S., Canada or Japan. ©Medtronic, Inc. 2013. All Rights Reserved. Current Research is Inconclusive Regarding Mortality Impact of LBBB Post –TAVR LBBB Post-TAVR NO Mortality Impact Houthuizen, et. al. Circulation 2012, (N=679) Urena, et. al. JACC 2012, (N=202) De Carlo, et. al. AHJ 2012, (N=275) LBBB Post-TAVR Mortality Impact Patients not receiving permanent pacemaker before discharge. Muller, et. al. EuroPCR 2013, (N=200)

27. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. 1 Year: p = 0.138 For this analysis, no patient in either group had a pacemaker Post-Implant LBBB N=145 N=115 N=119 N=102 No Post-Implant LBBB N=276 N=222 N=216 N=224 CoreValve ADVANCE | Impact of LBBB 1 Wenaweser, et al. Presented at EuroPCR 2013 The ADVANCE study showed no significant adverse effect of a new LBBB at discharge on the mean LV ejection fraction post-TAVR

28. INTERNATIONAL. CAUTION: For distribution only in markets where CoreValve® is approved. Not for distribution in U.S., Canada or Japan. ©Medtronic, Inc. 2013. All Rights Reserved. CoreValve ADVANCE | Survival by Pacemaker The ADVANCE study showed no significant difference in survival between those patients with a post-implant pacemaker and those without. 1 Wenaweser, et al. Presented at EuroPCR 2013

29. INTERNATIONAL. CAUTION: For distribution only in markets where CoreValve® is approved. Not for distribution in U.S., Canada or Japan. ©Medtronic, Inc. 2013. All Rights Reserved. Pacemaker Implantation Post-TAVR Not Associated With Increased Mortality Three additional large studies demonstrate no association between pacemaker implantation and mortality Buellesfeld, et. al. JACC 2012, (N=353) De Carlo, et. al. AHJ 2012, (N=275) CoreValve ANZ Study, Muller, et. al. EuroPCR 2013, (N=476)

30. INTERNATIONAL. CAUTION: For distribution only in markets where CoreValve® is approved. Not for distribution in U.S., Canada or Japan. ©Medtronic, Inc. 2013. All Rights Reserved. Conduction Disturbances after TAVR Anatomical Considerations Conduction Disturbances and Pacemaker Implantation –Driving Factors –Patient Impact Conclusions

31. INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA, Canada or Japan. Conclusions Conduction abnormalities are not atypical following AVR and TAVR due to the anatomical proximity of the aortic valve to the conduction system Rates of conduction abnormalities are high in patients with AS. These pre-existing conduction disturbances predict post-TAVR pacemaker implantation Post-TAVR pacemaker implantation is not associated with an increase in mortality – –The field has not reached consensus on the mortality effect of post- TAVI LBBB. Best practice in BAV sizing, depth of implant, and application of pacemaker implant guidelines can result in low rates of post-TAVR conduction disturbances CoreValve is a registered trademark of Medtronic CV Luxembourg S.a.r.l. For more information and a complete list of adverse events, warning and contraindications reference CoreValve IFU.