1. Medtronic CoreValve® System Summary of Clinical Experience
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2. Agenda
Background on aortic stenosis (AS) and introduction to transcatheter aortic valve implantation (TAVI)
Overview of the CoreValve clinical portfolio
CoreValve clinical performance
All-cause Survival
Efficacy
Other Outcomes
This slide deck is meant to provide an overview of the CoreValve system, the Medtronic CoreValve clinical portfolio, and the clinical performance of CoreValve.
Clinical performance can be divided into several categories, including All-cause survival, efficacy, and other outcomes (including complications).
This slide deck focuses on the CoreValve® (Medtronic, Inc., Minneapolis, MN) System and provides a summary of the clinical experience regarding its benefits, risks, and potential use as an alternative to surgical aortic valve replacement.

3. Background
Aortic Stenosis (AS) is the most prevalent native valve disease1
More than 300,000 patients have severe AS worldwide
The mortality rate for untreated severe AS is up to 50%-60% within 2 years of the onset of severe symptoms
Key takeaway: % of AS patients die within 2 years of the time that severe symptoms begin to manifest. It is critical that these patients receive treatment.
1Carabello BA, et al. Lancet 2009; 373:956-66

4. Treatment of Severe Aortic Stenosis
Key Message:
SAVR is the gold standard for treatment of AS, but many patients are unable to undergo surgery or are at significant risk.
33% of elderly patients (75 years of age or older) with symptomatic severe AS are denied surgery.2
The reason for this is that the mortality rate associated with SAVR can be very high if the patient is in poor condition or has certain comorbidities, such as severe left ventricular dysfunction, previous cardiac operations, or COPD.
Surgical aortic valve replacement (SAVR) is the gold standard for treatment of severe AS
However, 33% of all patients ≥75 years of age with severe AS are declined for surgery1
The mortality rate associated with SAVR increases substantially if certain comorbidities are present
Left ventricular dysfunction
Previous cardiac operations
Chronic obstructive pulmonary disease
Liver or renal failure
Frailty
1lung B, et al. Eur Heart J. 2005; 26(24):
References:
Bagur R, et al. Eur Heart J. 2010;31:
Iung B, et al. Eur Heart J. 2005;26:

5. Treatment of Severe Aortic Stenosis
Transcatheter aortic valve implantation (TAVI) is a viable treatment strategy for AS patients at high or extreme surgical risk
TAVI has demonstrated significant survival improvements compared to medical management in inoperable patients in the PARTNER B trial1
High risk patients receiving TAVI had similar survival rates to SAVR in the PARTNER A trial2
The PARTNER trial was the first randomized study to demonstrate that TAVR provides a significant mortality benefit when compared to medical management in AS patients. PARTNER also showed that TAVR provides a similar survival benefit to SAVR in high risk AS patients.
This landmark study proved that TAVR is a viable treatment option for AS patients at high or extreme surgical risk.
PARTNER B
PARTNER A
1Kapadia , et al., presented at TCT Kodali S, et al., presented at ACC 2012

6. The Medtronic CoreValve System
The Medtronic CoreValve® System has been implanted in more than 45,000 patients in more than 60 countries worldwide.
Self-expanding nitinol frame
Tri-leaflet porcine pericardial tissue valve with supra-annular function
Four sizes (23, 26, 29, and 31 mm) to fit aortic annuli ranging from 18 to 29 mm
18-Fr delivery catheter for all valve sizes
Delivery from a transfemoral, subclavian, or direct aortic approach

7. CoreValve® System Clinical Experience
Medtronic CoreValve
Clinical Research Portfolio
Confirm Efficacy and Optimize Practice
Expand Access to New Populations and Markets
Key Message:
The CoreValve® System has significant global experience, and more than patients have been studied in independent registries.
Demonstrate Safety and Efficacy

8. CoreValve® System Clinical Experience
Medtronic CoreValve
Clinical Research Portfolio
Key Message:
The CoreValve® System has significant global experience, and more than patients have been studied in independent registries.
The Medtronic CoreValve clinical research portfolio can be divided into 3 categories: foundational studies which demonstrate safety and efficacy, expansion studies which expand access to new populations and markets, and confirmation studies which confirm efficacy and optimize practice.
References at end of presentation

9. CoreValve® System Clinical Experience
National CoreValve Registries
Key Message:
The CoreValve® System has significant global experience, and more than patients have been studied in independent registries.
In addition to Medtronic-sponsored research, data about CoreValve performance is being collected in a number of national registries. These registries represent a wealth of clinical experience in many different geographies.
References at end of presentation

10. All-cause Survival
This slide deck focuses on the CoreValve® (Medtronic, Inc., Minneapolis, MN) Percutaneous Aortic Valve Replacement System and provides a summary of the clinical experience regarding its benefits, risks, and potential use as an alternative to surgical aortic valve replacement.

11. All-cause Survival
When comparing all-cause survival across data sets, it is important to remember that many variables can influence a given rate.
Baseline characteristics, patient selection practices, operator experience, complication management techniques, and in the case of registries, reporting practices, all play a role.
Comparisons across data sets should be used to convey general trends, not to derive specific conclusions regarding TAVI devices.

12. All-cause Survival │ 30-day National Registries and Medtronic Sponsored Studies (independent studies, not head-to-head comparisons) CoreValve
30-day all-cause mortality rates for patients receiving transcatheter valve replacements were acceptable.
Experience across clinical studies indicates that TAVR with the CoreValve® System is a safe and practical therapeutic option for patients with severe aortic stenosis.
1Chiam, et al., presented at EuroPCR 2013; 2Meredith, et al., presented at TCT 2012; 5Linke, et. al. presented at EuroPCR Rueck, et al., presented at London Valves 2012; 5Tamburino, et al., Circulation 2011; 123: ; 6Moat, et al. J Am Coll Cardiol 2011; 58(20): ; 7Godino, et al., J Am Coll Cardiol Intv 2010; 3: ; 8Avanzas, et al., Rev Esp Cardiol 2010; 63(2): ; 9Bosmans, et al., ICVTS 2011; 12: ; 10Gilard, et al. N Engl J Med 2012; 366:

13. All-cause Survival │ 1 Year National Registries and Medtronic Sponsored Studies (independent studies, not head-to-head comparisons) CoreValve
1-year survival rates for patients with severe aortic stenosis receiving transcatheter aortic valve replacements were comparable to those undergoing surgical aortic valve replacement
1Meredith, et al., presented at TCT 2012; 2Rueck, et al., presented at London Valves 2012; 3Tamburino, et al., Circulation 2011; 123: ; 4Avanzas, et al., Rev Esp Cardiol 2010; 63(2): ; 5Linke, et. al. presented at EuroPCR 2013; 6Bosmans, et al., ICVTS 2011; 12: ; 7Moat, et al. J Am Coll Cardiol 2011; 58(20): ; 8Gilard, et al. N Engl J Med 2012; 366:

14. All-cause Survival │ 1 Year Rigorous Industry-Sponsored TAVI Studies (independent studies, not head-to-head comparisons)
Comparison of All-cause survival outcomes from rigorous industry-sponsored studies shows that CoreValve was superior to Sapien and Sapien XT.
1Meredith, et. al. presented at TCT 2012; 2Linke, et. al. presented at EuroPCR 2013; 3Leon, et. al. presented at ACC 2013; 4Smith, et al. N Engl J Med 2011; 364: ; 5Leon, et al. N Engl J Med 2010; 363:
All routes

15. All-cause Survival │ 1 Year Select Contemporary Data Sets (independent studies, not head-to-head comparisons)
When looking across select contemporary data sets, CoreValve compares well against Sapien and Sapien XT in terms of all-cause survival at 1 year.
1Meredith, et. al. presented at TCT 2012; 2Linke, et. al. presented at EuroPCR 2013; 3Windecker, et. al. presented at EuroPCR 2013; 4Leon, et. al. presented at ACC 2013; 5Smith, et al. N Engl J Med 2011; 364: ; 6Leon, et al. N Engl J Med 2010; 363:
All routes

16. All-cause Survival │ 1 Year National Registries and Post-Market Approval Studies (independent studies, not head-to-head comparisons)
When looking across national registries and post-market approval studies, CoreValve compares well against Sapien and Sapien XT in terms of all-cause survival.
1Tamburino, et al., Circulation 2011; 123: ; 2Linke, et. al. presented at EuroPCR 2013; 3Windecker, et. al. presented at EuroPCR 2013; 4Moat, et al. J Am Coll Cardiol 2011; 58(20): ; 5Thomas, et al., presented at TCT 2012; 6Gilard, et al. N Engl J Med 2012; 366:
All routes

17. All-cause Survival │ Longer-Term (independent studies, not head-to-head comparisons)
The Italian registry1 and the Canadian registry2 have reported longer-term survival data on patient subsets
Limited information is available about longer-term survival outcomes following TAVR. The Italian registry has published on a subset of CoreValve patients out to 3 years, and all-cause survival remains strong at 65.2%. In comparison, there is a cohort of Sapien patients from the Canadian TAVR registry that have been followed out to 4 years. Survival dips to 43% at 4 years in this population.
1Ussia, et al., Eur Heart J 2012; 33: ; 2Rodes-Cabau, et al. J Am Coll Cardiol 2012; 60(19):

18. Efficacy
New York Heart Association (NYHA) Class status in the ADVANCE study
Health related quality of life (HRQoL) in the ADVANCE study
Hemodynamics
1-year CoreValve performance in the ADVANCE study
3-year CoreValve performance in the Italian Registry
This slide deck focuses on the CoreValve® (Medtronic, Inc., Minneapolis, MN) Percutaneous Aortic Valve Replacement System and provides a summary of the clinical experience regarding its benefits, risks, and potential use as an alternative to surgical aortic valve replacement.

19. Efficacy │ New York Heart Association Class (NYHA)
The ADVANCE study demonstrated significant improvement in functional status at 1 month post-TAVI, which was sustained to 1 year
The functional status of patients in the ADVANCE study dramatically improved due to TAVR. Prior to the procedure, approximately 80% of the patients were in NYHA class III or IV. At 1 year after TAVR, only 13% remained in NYHA class III or IV.
1Linke et al., presented at EuroPCR 2013

20. Efficacy │ Health Related Quality of Life 6-month Outcomes from the ADVANCE Study
The ADVANCE study demonstrated significant improvements in post-TAVI quality of life using multiple measurement tools
The functional improvement in the ADVANCE study translated into an improved quality of life. Several instruments were used to assess quality of life. All showed a statistically significant improvement between baseline and 1 month post TAVR, and this improvement was either sustained or improved at 6 months post TAVR.
1Bosmans, et al., presented at TCT 2012

21. Hemodynamics │ CoreValve ADVANCE Study
The ADVANCE study has demonstrated that the CoreValve EOA and mean gradient remain stable out to 1 year
The ADVANCE study demonstrated a significant reduction in mean gradient immediately post-TAVR, which was sustained out to 1 year. In addition, the effective orifice area increased from 0.7 to 1.7 cm2 immediately after the procedure, and this increase was sustained out to 1 year.
1Linke, et al., presented at EuroPCR 2013

22. Hemodynamics │ Italian CoreValve Registry
The Italian Registry has demonstrated that the CoreValve EOA and mean gradient remain stable out to 3 years
The Italian CoreValve registry reported on the 3-year hemodynamic performance of CoreValve in a subset of 181 patients. Notably the EOA and mean gradient remained stable from the time of discharge all the way to 3 years post implant.
1Ussia, et al., Eur Heart J 2012; 33:
Reference:
Buellesfeld L, et al. J Am Coll Cardiol. 2011;57:

23. Safety Acute outcomes in the ADVANCE study Long term safety measures
This slide deck focuses on the CoreValve® (Medtronic, Inc., Minneapolis, MN) Percutaneous Aortic Valve Replacement System and provides a summary of the clinical experience regarding its benefits, risks, and potential use as an alternative to surgical aortic valve replacement.

24. Safety │ Acute Outcomes The ADVANCE Study
The ADVANCE study shows that procedural complications are rare during CoreValve implants
Key Message:
The CoreValve® System has significant global experience, and more than patients have been studied in independent registries.
The ADVANCE study showed that procedural complications are rare during CoreValve procedures. No patients experienced an annular rupture.
1Linke, et al., presented at EuroPCR 2013

25. Safety │ Long-Term Outcomes Medtronic Foundational Studies
Key Message:
The CoreValve® System demonstrated long-term safety results.1,2
This conclusion was supported by the fact that there were no valve migrations, frame fractures, or structural valve deterioration at either 2 or 4 years1,2 in 2 foundational CoreValve studies.
Safety │ Long-Term Outcomes
Medtronic Foundational Studies
Two foundational CoreValve studies report no unexpected valve malfunctions or structural deterioration out to 4 years after implant
a Change in NYHA function resulting from intrinsic valve abnormality resulting in stenosis or regurgitation.
1Gerckens, et al., presented at EuroPCR 2011; 2Gerckens, et al., presented at ESC 2011
References:
Gerckens U. Stable durability and effectiveness at 2 years with CoreValve® transcatheter aortic valve. Presented at: EuroPCR; May 17-20, 2011; Paris, France.
Gerckens U. Four-year durability and patient survival with CoreValve® transcatheter aortic valve. Presented at: ESC; August 27-31, 2011; Paris, France.

26. Procedural Success
This slide deck focuses on the CoreValve® (Medtronic, Inc., Minneapolis, MN) Percutaneous Aortic Valve Replacement System and provides a summary of the clinical experience regarding its benefits, risks, and potential use as an alternative to surgical aortic valve replacement.

27. Procedural Success National Registries and Medtronic Sponsored Studies (independent studies, not head-to-head comparisons) CoreValve
1Chiam, et al., presented at EuroPCR 2013; 2Moat, et al. J Am Coll Cardiol 2011; 58(20): ; 3Meredith, et al., presented at TCT 2012; 4Avanzas, et al., Rev Esp Cardiol 2010; 63(2): ; 5Bosmans, et al., ICVTS 2011; 12: ; 6Gilard, et al. N Engl J Med 2012; 366: ; 7Linke, et. al. presented at EuroPCR 2013; 8Rueck, et al., presented at London Valves 2012; 9Tamburino, et al., Circulation 2011; 123: ;

28. Major Vascular Complications
Definition
Predictors
Incidence
This slide deck focuses on the CoreValve® (Medtronic, Inc., Minneapolis, MN) Percutaneous Aortic Valve Replacement System and provides a summary of the clinical experience regarding its benefits, risks, and potential use as an alternative to surgical aortic valve replacement.

29. Major Vascular Complications │ Definition
According to VARC 1, Major Vascular Complications include all complications that can be caused by a wire and/or are related to vascular access, which lead to death, need for significant blood transfusions, unplanned intervention, or irreversible end-organ damage:
The VARC 2 definition2 downgraded unplanned intervention during the index procedure to a minor vascular complication, except if it was associated with qualifying consequences.
VARC 1 Definition1
Ventricular perforation
Aortic dissection or rupture
Iliofemoral dissection or rupture
Pseudoaneurysms
Closure failure
VARC 1 provides a definition of major vascular complications that has been applied in many studies. By using a clear definition, it is possible to compare this outcome across studies. VARC 2 was recently published which provides a slightly modified definition of major vascular complications.
1Leon, et al., J Am Coll Card 2011; 57 (3): ; 2Kappetein, et al., J Am Coll Cardiol 2012; 60:

30. Major Vascular Complications │ Predictors
Patient-Related Factors
Anatomical Factors
Procedural Factors (Device / Operator)
Femoral artery calcium score2, 4
Female gender1
Sheath to femoral artery ratio (SFAR)2
Vessel tortuosity4
Learning curve2
Complication management3
Percutaneous closure device failure5
Patient selection3
The literature was searched to determine the predictors of major vascular complications. These predictors can be divided into 3 categories: patient-related factors, anatomical factors, and procedure-related factors. The level of artery calcification, the size of the delivery catheter, and the experience level of the operator are strong predictors of major vascular complications.
1Genereux, et al. J Am Coll Cardiol 2012; 60(12): ; 2Hayashida, et al., J Am Coll Cardiol Cardiovasc Int 2011; 4(8): ; 3Webb, et al., presented at TCT 2012; 4Vavuranakis, et al. Cardiovasc Ther 2013; epub; 5Cockburn, et al., Cath and Cardiovasc Interv 2012; 79:

31. Major Vascular Complications │ Predictors
Effect of sheath size: the PRAGMATIC initiative showed patients treated with a 22F or 24F delivery sheath had significantly more vascular complications than patients treated with smaller caliber devices
(green bar represents Sapien, yellow is a mixture of Sapien XT and CoreValve)
The green bar represents Sapien, whereas the yellow bar represents a mixed population of CoreValve and Sapien XT
1Van Mieghem, et al., Am J Cardiol 2012; 110(9):

32. Major Vascular Complications │ Predictors (independent studies, not head-to-head comparisons)
Effect of learning curve: four studies confirm that increased operator experience decreases the incidence of major vascular complications
Four studies present data on major vascular complications which can be divided into 2 parts: the early operator experience and the late operator experience. All show that major vascular complications are higher in the early experience, as compared to the later experience.
1Fearon, et al., presented at ACC 2013; 2Hayashida, JACC Card Int 2011; 4(8): ; 3Nuis, Am J Cardiol 2011; 107: ; 4Toggweiler, JACC 2012; 59(2):

33. Major Vascular Complications │ Incidence
Major vascular complication rate can be impacted by variables unrelated to the TAVI device (e.g., patient selection practices, operator experience and technique, complication management strategy, percutaneous closure device function, reporting practices in the case of registries).
Examining outcomes over the wider clinical experience may lessen the impact of any one of these variables and provide a sense of TAVI device performance.
However, it is important to be mindful that all of these factors do contribute to the incidence of major vascular complications and should be considered when doing incidence comparisons across studies.

34. Major Vascular Complications │ Incidence Registry Data on CoreValve According to VARC 1 (independent studies, not head-to-head comparisons)
When considering major vascular complications across studies that use the VARC 1 definition, cohorts implanted with CoreValve often demonstrate an MVC rate of less than 5%.
1Linke, et al., presented at EuroPCR 2013; 2Gilard, et al. N Engl J Med 2012; 366: ; 3Meredith, et al., presented at TCT 2012; 4del Valle, et al., presented at London Valves 2012; 5Ussia, et al., presented at EuroPCR 2012

35. Major Vascular Complications │ Incidence Select Data Sets Reporting According to VARC 1* (independent studies, not head-to-head comparisons)
When considering major vascular complications across studies that use the VARC 1 definition, cohorts implanted with CoreValve often demonstrate an MVC rate of less than 5%.
1Leon, et al., presented at ACC 2013; 2Fearon, et al., presented at ACC 2013; 3Sack, et al., presented at TCT 2012; 4Linke, et al., presented at EuroPCR 2013; 5Treede, et al., presented at EuroPCR 2013; 6Gilard, et al. N Engl J Med 2012; 366: ; 7Meredith, et al., presented at TCT 2012; 8del Valle, et al., presented at London Valves 2012; 9Ussia, et al., presented at EuroPCR 2012

36. Aortic Regurgitation (AR)
Definition
Predictors
Incidence
Select Studies
CoreValve ADVANCE Study Outcomes
Clinical Impact
This slide deck focuses on the CoreValve® (Medtronic, Inc., Minneapolis, MN) Percutaneous Aortic Valve Replacement System and provides a summary of the clinical experience regarding its benefits, risks, and potential use as an alternative to surgical aortic valve replacement.

37. Aortic Regurgitation │ Definition
Aortic regurgitation (AR) can be transvalvular (central), paravalvular (PVL) or both.
Total 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

38. Aortic Regurgitation │ Predictors
Patient-Related Factors
Anatomical Factors
Procedural Factors (Device / Operator)
Calcified annulus (commissures, cusps, landing zone)3,4
Male gender2,3
Renal failure2
Peripheral vascular disease1
NYHA Class IV3
LVOT-AO angle1
Large annulus2
Elliptical annulus3
LVOT diameter5
Transfemoral approach9
Implant depth1,5,8
Learning curve6
Cover index (patient- prosthesis mismatch)4,5,6,7
The literature was searched to determine the predictors of aortic regurgitation. These predictors can be divided into 3 categories: patient-related factors, anatomical factors, and procedure-related factors. The level of annular calcification, how well the valve fits the annulus (cover index), the implant depth, and the approach used for implant strongly impact aortic regurgitation.
1 Sherif, et al., J Am Coll Cardiol 2010; 56: ; 2Abdel-Wahab, et al., Heart 2011; 97: ; 3Unbehaun, et al., J Am Coll Cardiol 2012; 59: ; 4Gripari, et al., Heart 2012; 98: ; 5Italy: Petronio, et al. The Italian CoreValve Registry. TCT 2012; 6Detaint, et al., J Am Colll Cardiol Intv 2009; 8: ; 7Santos, et al., Eur H J Cardiovasc Img 2012; 13: ; 8Chorianopoulos, et al., J Interven Cardiol 2012; 25: ; 9Van 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

39. Aortic Regurgitation │ Predictors
Effect of approach: FRANCE 21 and PARTNER2,3 demonstrate that the transfemoral approach (TF) results in approximately 50% more total AR than the transapical (TA) approach
1Van Belle, et. al., presented at TCT 2012; 2Kodali, et al., presented at TCT 2012;3Dewey, et. al., presented at TCT 2012;

40. Aortic Regurgitation │ Predictors
Effect of calcification: heavy calcification may prevent perfect apposition to the native annulus, increasing the risk of PVL
Mechanism of PVL in calcified valves2
Images of increasing levels of valve calcification1
1John, et al., J Am Coll Cardiol Intv 2010; 3: ; 2Sinning, et al, J Am Coll Cardiol 2012; 59:

41. Aortic Regurgitation │ Predictors
Effect of implant depth: appropriate implant depth minimizes potential flow around the valve skirt. With CoreValve, a depth of 4-6 mm is currently recommended to minimize paravalvular leak.
Mechanism of PVL in deep implant1
Mechanism of PVL in shallow implant1
1Sinning, et al, J Am Coll Cardiol ; 59: ; 2Tchetche, et al., EuroIntervention 2012; epub

42. CoreValve ADVANCE | Aortic Regurgitation

43. CoreValve ADVANCE | Paravalvular Leak

44. CoreValve ADVANCE | Transvalvular Regurgitation

45. Aortic Regurgitation │ Incidence
ASE / ESC guidelines, which are also recommended by VARC, are typically used to grade the severity of AR using echo.
NOTE: Until VARC 2, there was no consensus for measuring paravalvular leak in transcatheter valves.
Standardized criteria can be open to interpretation. It is important to verify that the severity grading criteria are the same when comparing AR across studies.
Is “mild” AR included in the study-specific definition of “significant” AR?
In addition to the semi-quantitative nature of AR grading, intraobserver variability and variable baseline and procedural characteristics make it very difficult to do a robust comparison of AR across studies.
Medtronic- and Edwards-sponsored TAVI studies apply similar echo criteria to grade the severity of AR, making it reasonable to compare the outcomes of these studies.
It is difficult to draw strong conclusions about a TAVI device by doing cross- study comparisons.

46. Aortic Regurgitation │ Incidence at 1 Year Select Contemporary Data Sets (independent studies, not head-to-head comparisons)
Aortic regurgitation is typically measured using echo, however the grading criteria used to assess the severity of the AR may not be applied consistently across studies. Note that the Sapien XT AR was 29.7% in PARTNER IIB, but only 6.7% in the SOURCE XT registry. PARTNER IIB used an echo core lab and is a rigorously controlled study, whereas Source XT uses site collected and reported data. Measurement and reporting technique may explain the dramatic difference in outcome for the same valve.
1Leon, et. al. presented at ACC 2013; 2Linke, et. al. presented at EuroPCR 2013; 3Leon, et al. N Engl J Med 2010; 363: ; 4Smith, et al. N Engl J Med 2011; 364: ; 5Windecker, et. al. presented at EuroPCR 2013

47. Paravalvular Leak (PVL) │ Incidence at 1 Year Select Contemporary Data Sets (independent studies, not head-to-head comparisons)
Aortic regurgitation is typically measured using echo, however the grading criteria used to assess the severity of the AR may not be applied consistently across studies. Note that the Sapien XT PVL was 29.2% in PARTNER IIB, but only 6.2% in the SOURCE XT registry. PARTNER IIB used an echo core lab and is a rigorously controlled study, whereas Source XT uses site collected and reported data.
1Leon, et. al. presented at ACC 2013; 2Linke, et. al. presented at EuroPCR 2013; 3Leon, et al. N Engl J Med 2010; 363: ; 4Smith, et al. N Engl J Med 2011; 364: ; 5Windecker, et. al. presented at EuroPCR 2013

48. Paravalvular Leak (PVL) │ Incidence at 1 Year Select Contemporary Data Sets—Transarterial Cohorts (independent studies, not head-to-head comparisons)
When considering only transarterial cohorts (and therefore excluding transapical procedures), the incidence of PVL increases in Sapien and Sapien XT cohorts.
1Leon, et. al. presented at ACC 2013; 2Kodali, et al., presented at TCT 2012; 3Linke, et. al. presented at EuroPCR 2013; 4Leon, et al. N Engl J Med 2010; 363: ; 5Treede, et. al. presented at EuroPCR 2013

49. Aortic Regurgitation* │ Clinical Impact
Medtronic CoreValve ADVANCE Study
The ADVANCE study has shown that patients with mild aortic regurgitation after TAVR are not at increased mortality risk compared to patients with no aortic regurgitation after TAVR. Moderate and severe aortic regurgitation are impactful on mortality, however, which highlights the importance of minimizing AR as much as possible.
*At discharge
1Linke, et al. Presented at EuroPCR 2013

50. Stroke Predictors Timing Incidence
This slide deck focuses on the CoreValve® (Medtronic, Inc., Minneapolis, MN) Percutaneous Aortic Valve Replacement System and provides a summary of the clinical experience regarding its benefits, risks, and potential use as an alternative to surgical aortic valve replacement.

51. (30 days to 1 year after TAVI)
Stroke │ Predictors
Risk factors of early stroke tend to implicate embolization of annular debris, while risk factors of late stroke point to comorbid conditions.
Early Stroke
(within 30 days of TAVI)
Late Stroke
(30 days to 1 year after TAVI)
Female gender1
Surgical cutdown for access1
New onset atrial fibrillation2
Baseline aortic regurgitation 3+2
Smaller aortic valve area3
COPD4
BMI <25 kg/m4
Multiple implant attempts4
Valve dislodgement5
Balloon post-dilatation5
History of CABG1
History of stroke3,5
Coronary artery disease3
Peripheral vascular disease5
Baseline NYHA class3
Chronic atrial fibrillation5
The literature was searched to determine the predictors of stroke. Early stroke tends to be influenced by procedure-related factors, whereas late stroke is more strongly influenced by patient comorbidities, especially atherosclerotic burden.
1 Bosmans, et al., presented at EuroPCR 2013; 2Nuis, et al., Am J Cardiol 2012; 109: ; 3Miller, et al., J Thorac Cardiovasc Surg 2012;143( ): e13; 4Stortecky, et al., EuroIntervention 2012; 8: ; 5Nombela-Franco, et al., Circulation 2012; 126(25):

52. Stroke │ Type and Timing
The ADVANCE study showed that most strokes fall within 30 days of TAVI. However, due to their multi-morbid conditions, TAVI patients remain at risk for stroke long after their procedure.
30-day Stroke Rate in ADVANCE: 3.0%
1 Bosmans, et al., presented at EuroPCR 2013

53. Stroke │ Rate over Time
In the ADVANCE study, the overall stroke rate was low and remained relatively stable over time
This is a Kaplan Meier curve demonstrating the stroke rate in ADVANCE. Note that most of the strokes that occurred were within the first 30 days, and the rate remained relatively stable from 30 days to 1 year.
1 Bosmans, et al., presented at EuroPCR 2013

54. Stroke │ Learning Curve
Multicenter registry data on 4,563 patients indicate that CoreValve has a historically low stroke rate, staying below 4.5% for any given cohort. It appears there is minimal learning curve effect for this outcome.
OUS Registries for which the implant years and corresponding stroke rates are defined.
Arrows indicate implant period and the reported rate of total stroke for the CoreValve cohort

55. Stroke │ Incidence
Stroke rate is strongly impacted by patient comorbidities, and the timing of stroke events may indicate different mechanisms at play.
When doing a comparison of stroke rate across studies, it is important to remember that the baseline patient characteristics can vary greatly.
It is very difficult to draw conclusions about the performance of a particular TAVI device when comparing the incidence of stroke rate across studies.

56. Stroke │ Incidence at 30 Days Select Data Sets (independent studies, not head-to-head comparisons)
CoreValve has consistently shown low stroke rates.
1Leon, et al. N Engl J Med 2010; 363: ; 2Smith, et al. N Engl J Med 2011; 364: ; 3Thomas, et al., presented at TCT 2012; 4Leon, et al., presented at ACC 2013; 5Meredith, et al., presented at TCT 2012; 6Bosmans, et al., presented at EuroPCR 2013

57. Permanent Pacemaker Implantation (PPI)
Predictors
Incidence
Clinical Impact
Post-TAVI PPI
Post-TAVI Left Bundle Branch Block (LBBB)
This slide deck focuses on the CoreValve® (Medtronic, Inc., Minneapolis, MN) Percutaneous Aortic Valve Replacement System and provides a summary of the clinical experience regarding its benefits, risks, and potential use as an alternative to surgical aortic valve replacement.

58. Permanent Pacemaker Implantation │ Predictors
More than 25 studies have been published on predictors of post-TAVI conduction disturbances (CDs) and permanent pacemaker implant (PPI)
Patient-Related Factors
Anatomical Factors
Procedural Factors (Device / Operator)
Right Bundle Branch Block (RBBB)2,3,4,5,7
Other pre-existing conduction disturbances3,4,8,9
Male gender3
Age > 75 years9
Previous MI3
Variations in location of LBBB exit point1
Septum thickness1,6
Thickness of the non- coronary cusp1
Implant Depth2,3,7
Application of PPI guidelines10
Learning Curve11
Balloon Aortic Valvuloplasty8
Radial force of the prosthesis3
The literature was searched to determine the predictors of pacemaker implant after TAVR. There are many studies on this topic. These predictors can be divided into 3 categories: patient-related factors, anatomical factors, and procedure-related factors. The presence of a conduction disturbance at baseline, the depth of implant, operator experience, and the way that pacemaker implantation guidelines are applied by individual centers are strong predictors of permanent pacemaker implantation.
1Jilaihawi, et al. Am Heart J 2009; 2Munoz-Garcıa, et. al. JACC CV 2012; 3Piazza et. al. EuroIntervention 2010; 4De Carlo , et. al. Am Heart J 2012; 5Calvi, et. al. JICE 2011; 6Saia, et. al. Cath Card Intv 2012; 7Fraccarao, et. al. Am J Card 2011; 8Khawaja, et. al. Circ 2011; 9Schroeter et. al. EuroPACE 2011; 10Wenaweser, et. al. presented at EuroPCR 2013; 11Meredith, et. al. presented at TCT 2012

59. Permanent Pacemaker Implantation │ Predictors
Effect of implant depth: data from independent studies plotted on the same graph show the strong relationship between PPI rate and implant depth
1Tchetche, et al. EuroIntervention 2012; 2Munoz-Garcıa, et. al. JACC CV 2012; 3Piazza et. al. EuroIntervention 2010; 4De Carlo , et. al. Am Heart J 2012; 5Calvi, et. al. JICE 2011; 6Saia, et. al. Cath Card Intv 2012; 7Fraccarao, et. al. Am J Card 2011; 8van der Boon, et. al. Int J Card 2013;

60. Permanent Pacemaker Implantation │ Predictors
Effect of learning curve: the rate of PPI in the CoreValve Australia-New Zealand Study decreased over time as operators gained experience
As operators gain more experience, the need for permanent pacemaker implantation after TAVR tends to decrease.
The initial increase in PPM rates may have been due to new centres being added to the study. Includes baseline PPM in the denominator.
Enrolling centers: 6 9 10
PPM rates in 6-mo blocks of pt enrollment, except most recent is 8-mo.
1Muller, et al. Presented at EuroPCR 2013

61. Permanent Pacemaker Implantation │ Predictors
Effect of PPI guideline use: varying 30-day pacemaker rates across geographies in the ADVANCE study may reflect differences in the application of PPI guidelines
Key Message:
Pacemaker implantation varied greatly among geographies in the ADVANCE study.
These differences may be explained by the fact that different policies were followed for the definitive pacemaker implantation criteria.
Colombia: 6 implants
Greece: 2 implants
Portugal: 12 implants
Countries with less than 15 implants not shown
1Wenaweser, et al. Presented at EuroPCR 2013

62. Permanent Pacemaker Implantation │ Incidence
The permanent pacemaker implantation rate can be impacted by variables unrelated to the TAVI device (e.g., baseline conduction disturbances, anatomical differences, clinician preference for prophylactic pacemaker use, and operator experience).
These factors should be kept in mind when comparing the incidence of permanent pacemaker implantation across studies.

63. Permanent Pacemaker Implantation │ Incidence CoreValve Outcomes in National Registries and Studies (independent studies, not head-to-head comparisons)
Pacemaker implantation varied greatly among studies.
1Chiam, et al., presented at EuroPCR 2013; 2Tamburino, et al., Circulation 2011; 123: ; 3Brito, et.al., presented at TCT 2011; 4Gilard, et al. N Engl J Med 2012; 366: ; 5Moat, et al., J Am Coll Cardiol 2011; 58(20): ; 6del Valle, et al., presented at London Valves 2012; 7Wenaweser, et al., presented at EuroPCR 2013; 8Muller, et al., presented at EuroPCR 2013

64. Permanent Pacemaker Implant │ Clinical Impact
Both the ADVANCE study1 and the Australia-New Zealand Study2 showed no impact of a new permanent pacemaker implant on mortality
A variety of studies have shown that patients receiving a permanent pacemaker after TAVR are not at increased mortality risk compared to patients that did not receive a permanent pacemaker implant.
1Wenaweser, et al. Presented at EuroPCR 2013; 2Muller, et al. Presented at EuroPCR 2013

65. Left Bundle Branch Block │ Clinical Impact
Current Research is Inconclusive Regarding Mortality Impact of LBBB Post –TAVI
LBBB Post-TAVI
Mortality Impact
Patients not receiving permanent
pacemaker before discharge.
LBBB Post-TAVI
NO Mortality Impact
De Carlo, et. al. AHJ 2012, (N=275)
A new study on post-TAVR LBBB by Houthuizen, et al (Circulation) has gained recent attention. The study of 674 patients concludes that patients who develop LBBB post-TAVR have higher mortality than those who do not. 
We recognize that conduction disturbances is one important consideration in TAVR implantation.  Although this is an intriguing finding, there are important aspects of this study that need to be contemplated.
Importantly, patients in the study were implanted between 2005 and 2010 reflecting outdated CoreValve clinical practice and older generation product. The study does not reflect current outcomes. 
Recommended implant depth at that time was 8-12mm.
Aggressive balloon dilatation was common.
Optimal imaging for sizing not well defined and limited valve options were available, increasing the risk of over- or under-sizing.
The transient nature of conduction disturbances was not well understood and may have led to over implantation of pacemakers.
In addition, the study excludes new LBBB patients who received a pacemaker.  The rationale for pacemaker implantation in the study is not stated in the publication and, thus it is not clear if patients were appropriately treated (or not treated) with pacemaker therapy.
Interestingly, a similar analysis by De Carlos, et al (American Heart Journal) reports conflicting findings.  These authors find no difference in mortality for patients who developed LBBB and did not receive a pacemaker and those who did not develop LBBB.
Houthuizen, et. al. Circulation 2012, (N=679)
Urena, et. al. JACC 2012, (N=202)
Muller, et. al. EuroPCR 2013, (N=200)

66. Left Bundle Branch Block │ Clinical Impact
Both the ADVANCE study1 and PARTNER2 showed no impact of a new LBBB on mortality
Patients sometimes develop a left bundle branch block following TAVR. Both the CoreValve ADVANCE study and the Australia New Zealand study have shown that those patients with a new LBBB (and *no* permanent pacemaker implant) are not at increased mortality risk compared to patients that did not develop a new LBBB due to TAVR.
1Wenaweser, et al. Presented at EuroPCR 2013; 2Nazif, et al. Presented at ACC 2013

67. Left Bundle Branch Block │ Clinical Impact
Both the ADVANCE study1 and the Australia-New Zealand Study2 showed no significant adverse effect of a new LBBB at discharge on the mean LV ejection fraction
Patients sometimes develop a left bundle branch block following TAVR. Both the CoreValve ADVANCE study and the Australia New Zealand study have shown that a new LBBB due to TAVR does not adversely impact LVEF out to 1 year post TAVR.
1Wenaweser, et al. Presented at EuroPCR 2013; 2Muller, et al. Presented at EuroPCR 2013

68. References for slides 8, 9, and 54
1. ClinicalTrials.gov Identifier: NCT
2. Buellesfeld L, et al. J Am Coll Cardiol 2011; 57:
3. ClinicalTrials.gov Identifier: NCT
4. ClinicalTrials.gov Identifier: NCT
5. Meredith IT, et al. Presented at TCT 2012
6. Medtronic CoreValve Japan Trial, protocol MDT-2111
7. ClinicalTrials.gov Identifier: NCT
8. Linke A, et al. Presented at EuroPCR 2013.
9. ClinicalTrials.gov Identifier: NCT
10. ClinicalTrials.gov Identifier: NCT
11. France II Registry. Eltchaninoff H, Presented at TVT 2013
12. Italian Registry. Ussia GP, et al. Presented at EuroPCR 2012
13. Italian Registry. Petronio AS, et al., Presented at TCT 2012.
14. Israel Registry. Kornowski R, et al. Presented at EuroPCR 2012.
15. UK Registry. Moat NE, et al. J Am Coll Cardiol 2011; 58:
16. UK Registry. Moat NE, et al. Presented at TCT 2012.
17. Belgian Registry. Bosmans J, et al. Presented at EuroPCR 2012
18. Bosmans J, et al., Interact Cardiovasc Thorac Surg 2011; 12(5):
19. Brazilian Registry. Brito FS, et al. Presented at TCT 2011.
20. Spanish Registry. Avanzas P, et al., Rev Esp Cardiol. 2010;63:141-8.
21. Milan Registry. Buchanan GL, et al. Presented at EuroPCR 2012.
22. Asia Registry. Chiam P, Presented at EuroPCR 2013.
23. del Valle R, et al., Presented at PCR London Valves 2012
24. Ruck A, et al., Presented at PCR London Valves 2012
25. Figulla H, et al., Presented at TCT 2012
26. GARY, Mohr F, Presented at ACC 2013
27. German TAVI Registry: Sinning, et al., Am Heart J 2012; 164: e1
Key Message:
The CoreValve® System has significant global experience, and more than patients have been studied in independent registries.
CoreValve® is a registered trademark of Medtronic CV Luxembourg S.a.r.l.