INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Transcatheter Aortic Valve Implantation Valve Hemodynamics: Aortic Regurgitation UC EE

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. TAVI Hemodynamics Reducing Aortic Regurgitation –Diagnostic Challenges –Clinical Experience –Role of Innovation

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Background | Definition Aortic Regurgitation (AR) can occur following TAVI implantation –The majority of AR is mild and paravalvular (PVL) in origin. Hemostasis between the prosthetic valve and the native aortic anatomy requires complete circumferential apposition of device and the host tissue. Primary contributors to PVL involve how well the transcatheter valve “fits” with the native annulus –Undersizing –Valve positioning including implant depth (too high or low), non-coaxial alignment, or incomplete expansion –Heavy and/or asymetical calcification

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Background | Definition Aortic regurgitation (AR) can be transvalvular (central), paravalvular (PVL) or both. AR = PVL + Transvalvular Leak What is clinically relevant is the total volume of flow through the valve Image courtesy of Dr. J. Sinning, University of Bonn

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Diagnostic Challenges | Standardization Intra-procedural measurement challenging –Valve may need up to 10 minutes to fully expand Lack of standardization in technique and application –Different imaging modality (angio, echo) utilized –Different guidelines and metrics –Variability among centers and operators, plus data most often self-reported Variations in patient populations served –Varying patient anatomical factors know to contribute to aortic regurgitation (e.g. annulus size, calcification)

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Criteria for Echocardiography Assessment of AR StudySeverity GradationReporting ADVANCENoneMildModerateSevereSite reported ANZNoneTraceMildModerateSevereSite reported AthensScale Not Defined, AR ≥ 2 Clinically SignificantSite reported France Site reported Ibero- American 01234Site reported SentinelNot DefinedSite reported Sweden0123Site reported ItalyScale Not Defined, Moderate and Severe was Clinically SignificantSite reported PARTNER A&B NoneTraceMildModerateSevere Echo Core Lab PARTNER II NoneTraceMildModerateSevere PRAGMATICNot DefinedSite reported Hayashida0: None1: Trivial2: Mild3: Moderate4: SevereSite reported Nombela- Franco 0: Absent to Trace 1: Mild 2: Mild to Moderate 3:Moderate to Severe 4: Severe Site reported Diagnostic Challenges | Standardization Standardized criteria can be applied in different ways If the study defined the type of AR that is clinically significant, it is indicated by a circle. References at the end of the presentation.

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Diagnostic Challenges | Standardization One dimensional imaging may be misleading Jet Seeping

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Clinical Experience │ PVL 30-Day and 1-Year data on Sapien and Sapien XT PVL in the PARTNER IIB study was presented at ACC 2013 by Dr. Leon. PARTNER IIB: Leon, et al. A Randomized Evaluation of the SAPIEN XT Transcatheter Valve System in Patients with Aortic Stenosis Who Are Not Candidates for Surgery: PARTNER II, Inoperable Cohort, ACC 2013

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Clinical Experience │ PVL at 30-Days Variation between studies even of the same device suggests inconsistency in measurement between site-reported data versus central echo core lab. ADVANCE: Linke, et al. Medtronic CoreValve ADVANCE Study, EuroPCR 2013; SOURCE XT: Treede, et al., One-Year Outcomes from the SOURCE XT Study—Propensity Score Matching for Transfemoral vs. Transapical Approach, EuroPCR 2013; PARTNER IIB: Leon, et al. A Randomized Evaluation of the SAPIEN XT Transcatheter Valve System in Patients with Aortic Stenosis Who Are Not Candidates for Surgery: PARTNER II, Inoperable Cohort, ACC 2013.; PARTNER B: Leon, et al., N Engl J Med 2010; 363: Supplement; PARTNER A: Smith, et al., N Engl J Med 2011; 364: , Supplement

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. The annulus is not round. Intra-annular valves may not be truly round after deployment. This may cause leaflet restriction or prolapse, leading to central AR 1. Images of non-circular valve shape have been published for both balloon-expandable 1 and self-expanding valves 2. Balloon-Expandable 1 Self-Expanding 2 Valve Design│ Intra-Annular Function 1. Zegdi, et al., J Thorac Cardiovasc Surg 2010; 140: e54-62; 2. Binder, et al., J Am Coll Cardiol Intv 2013; 6: 301-7

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. A report on explanted Sapien valves from 20 patients shows the most common structural change was a less than round configuration that ranged from slightly oval to almost D-shaped. This finding was accompanied by mal- alignment or mal-apposition of valve cusps (cuspal tautness, laxity, and/or poor coaptation). Sapien Valve Design│ Intra-Annular Function Nietlispach, et al., J Am Coll Cardiol Intv 2012; 5:

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. A small series of autopsy cases after TAVI with CoreValve confirms that the valve remains circular. CoreValve Valve Design│ Supra-annular Function Noble, et al., EuroIntervention 2009; 5: 78-85

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. PARTNER A includes both TA and TF, PARTNER IIB has not yet been reported Clinical Evidence │ Central Leak ADVANCE: Linke, et al. Medtronic CoreValve ADVANCE Study,EuroPCR 2013; PARTNER B: Leon, et al., N Engl J Med 2010; 363: Supplement; PARTNER A: Smith, et al., N Engl J Med 2011; 364: , Supplement; PARTNER IIB: Leon, et al. A Randomized Evaluation of the SAPIEN XT Transcatheter Valve System in Patients with Aortic Stenosis Who Are Not Candidates for Surgery: PARTNER II, Inoperable Cohort; ACC Poor coaptation can lead to central regurgitation

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Clinical Experience │ Survival to 1-Year PARTNER A ADVANCE Variation across studies suggests inconsistency in measurement between studies or differences in valve performance. PARTNER A: Kodali, et al. Late (≥2 year) Clinical and Echocardiographic Outcomes after Transcatheter vs. Surgical Aortic Valve Replacement: Results from the High- Risk Cohort of the PARTNER Trial; ACC 2012; ADVANCE: Linke, et al. Medtronic CoreValve ADVANCE Study, TCT 2012.

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Clinical Experience│ All-Cause Survival CoreValve demonstrates superior 1 year survival ANZ: Meredith, et al. Australia-New Zealand CoreValve Transcatheter Aortic Valve Study, TCT 2012; ADVANCE: Linke, et al. Medtronic CoreValve ADVANCE Study, EuroPCR 2013; SOURCE XT: Windecker, et al., One-Year Outcomes from the SOURCE XT Post Approval Study, EuroPCR 2013; PARTNER IIB: Leon, et al. A Randomized Evaluation of the SAPIEN XT Transcatheter Valve System in Patients with Aortic Stenosis Who Are Not Candidates for Surgery: PARTNER II, Inoperable Cohort, ACC 2013.; PARTNER B: Leon, et al., N Engl J Med 2010; 363: Supplement; PARTNER A: Smith, et al., N Engl J Med 2011; 364: , Supplement

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Clinical Evidence │ Significant AR Over Time ADVANCE: Linke, et al. Medtronic CoreValve ADVANCE Study, EuroPCR 2013; SOURCE XT: Windecker, et al., One-Year Outcomes from the SOURCE XT Post Approval Study, EuroPCR 2013; PARTNER IIB: Leon, et al. A Randomized Evaluation of the SAPIEN XT Transcatheter Valve System in Patients with Aortic Stenosis Who Are Not Candidates for Surgery: PARTNER II, Inoperable Cohort, ACC 2013.; PARTNER B: Leon, et al., N Engl J Med 2010; 363: Supplement; PARTNER A: Smith, et al., N Engl J Med 2011; 364: , Supplement

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Clinical Experience │ Predictors of AR Anatomical and procedural factors are predictors of aortic regurgitation. Anatomical characteristics that make fit challenging: ―Oval-shaped annulus 1 ―LVOT diameter 2 ―Larger annular diameter 3 ―Male gender (likely relates to annular size) 1,2 Cover index (sizing) 2,4,5,6 Calcification (commissures, cusps, landing zone) 3,5 Fit-Related Anatomical characteristics that make positioning challenging: ―Angle between LVOT – AO 7 ―Larger annular diameter 15 Male gender (likely relates to annular size) 3,8 Procedural characteristics: ―Learning curve 4 ―Implant Depth 2,7,9 ―Access Approach 10 Positioning-Related References at end of presentation

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Clinical Experience │ Importance of Valve Fit Low cover index (i.e. undersizing) contributes to aortic regurgitation; use of 3D imaging reduces incidence of regurgitation Predicted AR ≥ 2 Based on Sizing Technique Retrospective analysis. Courtesy of Dr. Piazza and Prof. Lange, German Heart Center, Munich Germany % AR >2

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Clinical Experience │ Calcification Heavy calcification may prevent perfect apposition to native annulus 3 increasing the risk of PVL Images of increasing levels of valve calcification 2 Mechanism of PVL in calcified valves 1 1.Sinning, et al, J Am Coll Cardiol 2012; 59: John, et al., J Am Coll Cardiol Intv 2010; 3: Gripari, et al., Heart 2012; 98:

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Clinical Experience │ Importance of Positioning Appropriate implant depth minimizes potential flow around the valve skirt. When positioned at 4-6 mm depth CoreValve shows minimal AR. Mechanism of PVL in deep implant 1 Mechanism of PVL in shallow implant 1 N=134 (Ref. 2)Patients (%) 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) Transient or Sustained AVB17 (12.7) New Pacemaker Implantation 12* (10.6) 1.Sinning, et al, J Am Coll Cardiol 2012; 59: Tchetche, et al., EuroIntervention 2012; e-publication

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Clinical Experience │ Importance of Positioning Direct implant approaches are associated with reduced AR possibly due to more optimal positioning PARTNER Aortic Regurgitation FRANCE 2: Van Belle, et. al. Peri-valvular Aortic Regurgitation in Balloon-expendable and Self-expendable TAVI procedures: Predictors and Impact on clinical outcome - Insights from the FRANCE2 Registry; TCT 2012; PARTNER TA: Dewey, et. al. New Data from PARTNER Continued Access (Non-randomized): Transapical Outcomes after TAVR; TCT 2012; PARTNER TF: Kodali, et al. New Data from PARTNER Continued Access (Non-randomized): Transfemoral Outcomes after TAVR; TCT 2012

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. Conclusions Aortic regurgitation can be a challenge following TAVI. –However, AR and PVL are difficult to access consistently and results are not comparable: Standardized criteria for grading the severity of AR are often applied differently. Patient and procedural characteristics are risk factors for the development of aortic regurgitation after TAVI. –AR following TAVI has been associated with less favorable patient outcomes. However, overall survival rates suggest that additional considerations should be explored.

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. References for Slide 6 PARTNER IIB: Leon, et al. A Randomized Evaluation of the SAPIEN XT Transcatheter Valve System in Patients with Aortic Stenosis Who Are Not Candidates for Surgery: PARTNER II, Inoperable Cohort; ACC PRAGMATIC: Chieffo, et al., J Am Coll Cardiol 2013; epub Hayashida, et al., J Am Coll Cardiol Intv 2012; 5: Nombela-Franco, L. Am J Cardiol 2013; epub ahead of print ADVANCE: Brecker, et al. Medtronic CoreValve ADVANCE Study; EuroPCR 2013 ANZ: Meredith, et al. Australia-New Zealand CoreValve Transcatheter Aortic Valve Study; TCT 2012 ATHENS: Spargias, et al., Hellenic J Cardiol 2013; 54: FRANCE 2: Gilard, et al., N Engl J Med 2012; 366: Ibero-American: del Valle, et al. The Ibero-American Transcatheter Aortic Valve Implantation Registry: acute and long-term results. PCR London Valves 2012 Sentinel: Di Mario, et al., EuroIntervention 2012; 8: epub Sweden: Ruck, et al. The Swedish TAVI Registry PCR London Valves 2012 Italy: Petronio, et al. The Italian CoreValve Registry. TCT 2012 PARTNER B: Leon, et al., N Engl J Med 2010; 363: Supplement PARTNER A: Smith, et al., N Engl J Med 2011; 364: Supplement

INTERNATIONAL. CAUTION—For distribution only in markets where CoreValve has been approved. Not approved in the USA or Japan. ©Medtronic, Inc All Rights Reserved. References for Slide 17 1.Di Mario, et al., EuroIntervention 2012; 8: epub 2.Tchetche, et al., EuroIntervention 2012; e-publication 3.Gripari, et al., Heart 2012; 98: John, et al., J Am Coll Cardiol Intv 2010; 3: Hayashida, et al., J Am Coll Cardiol Intv 2012; 5: Genereux,et al., J Am Coll Cardiol 2013; 61(11): Chorianopoulos, et al., J Interven Cardiol 2012; 25: Sherif, et al., J Am Coll Cardiol 2010; 56: Moat, et al. J Am Coll Cardiol 2011; 58: epub 10.Nombela-Franco, L. Am J Cardiol 2013; epub ahead of print CoreValve® is a registered trademark of Medtronic CV Luxembourg S.a.r.l. Edwards SAPIEN and SAPIEN XT are registered trademarks of Edwards Lifesciences Corporation.