The PARTNER (Placement of Aortic Transcatheter Valves)Trial represents a paradigm shift in clinical investigation and inter-

pretability. As the world’s first prospective, randomized, and controlled trial for transcatheter heart valves, The PARTNER Trial sets new standards in site selec-tion, case screening, study man-agement, multidisciplinary team-work, and patient follow-up.1

The PARTNER Trial consists of

two individually powered patient cohorts. In Cohort A, the safety and effectiveness of the Edwards SAPIEN Transcatheter Heart Valve (THV) was compared to surgical aortic valve replacement (sAVR) in high-risk patients with severe aortic stenosis. The results of Cohort A are forthcoming.1 In Cohort B, the safety and effectiveness of the Edwards SAPIEN THV was compared to best medical management (standard thera-py) in inoperable patients with severe aortic stenosis. Patient selec-tion required at least two cardiothoracic surgeons and an interven-tional cardiologist to agree that patients were not suitable candidates for surgery.1

THIS ISSUE

Guest Editors: AlEc VAHANIAN, MD, PhDDirector of carDiology, Hôpital BicHat, paris, france

FrIEDrIcH MoHr, MD, PhDHerzzentrum leipzig gmBH, universitätsklinik, leipzig, germany

Special Issue: The PArTNEr Trial, cohort B

TAVItalkJanuary 2011 / Europe The Edwards Transcatheter Heart Valve (THV) Newsletter

for use outsiDe tHe uniteD states only. not intenDeD for general DistriBution.

The PArTNEr Trial: The results are inJEAN-lUc lEMErcIEr vice president, tHv europe, edwards lifesciences

(See charts and addtional data at the top of pages 2–9)

While the results of the first randomised controlled trial of a transcatheter aortic heart valve–The PARTNER Trial–will

be discussed elsewhere in TAVItalk, it is worth remembering that before this trial, all previous transcatheter aortic valve implantation (TAVI) studies have been feasibility and safety studies interspersed with observational registries.

To best examine The PARTNER Trial in detail, this issue features a panel of recognised experts, under the stewardship of guest editors Pro-fessors Alec Vahanian and Friedrich Mohr. Among the topics covered in these pages are a surgeon’s perspective from Prof. Mohr, and comments from leading TAVI proponents and leaders of national societies. Prof. Vahanian discusses the implications of The PARTNER Trial on clinical practice and the trial results’ impact on new European TAVI guidelines, as developed by the dedicated Task Force. Dr. Martyn Thomas and Dr. Olaf Wendler reflect on the SOURCE Registry and, in conclusion,

“Engineers’ Corner” looks at the key differences of the European TAVI devices as compared to those used in The PARTNER Trial.WhAt next? Research and development is our lifeblood, providing us with the innovative new products needed to make a difference in patients’ lives. The results from The PARTNER Trial show that we are moving in the right direction.

Rarely does a week go by without the media highlighting how a new medical technology has contributed to a dramatic decline in mortality, a significant reduction in hospital days, and an increase in life expectancy. Through our major investment in R&D, Edwards is proud to have contributed to these improvements, while acknowledg-ing that more can be done to improve patient outcomes. It is for this reason that we will continue to invest significant funds in R&D in order to further enhance our existing product portfolio and develop our product pipeline. We look forward to our continued collaboration.

1 THE PArTNEr TrIAl: coHorT B1 THE PArTNEr TrIAl: THE rESUlTS ArE IN

Jean-luc lemercier, vp, tHv, eDwarDs lifesciences

2 THE SoUrcE rEGISTry IN THE coNTExT oF PArTNEr olaf wenDler, mD, phD anD martyn tHomas, mD

3 THE kEy rolE oF PATIENT ScrEENING alain criBier, mD

4 THE PArTNEr TrIAl: IMPAcT oN clINIcAl GUIDElINES? alec vaHanian, mD, phD

4 QUoTABlE: Digesting the data martin leon, mD

5 QUoTABlE: The stem or the flower gino gerosa, mD

6 A SUrGEoN’S PErSPEcTIVE frieDricH moHr, mD, phD

7 FroM A FEw INTErVENTIoNAlIST lEADErS: comments

8 VIEwPoINT FroM THE Uk mark De BelDer, mD

9 oN BEcoMING THE STANDArD oF cArE tHierry lefÈvre, mD

10 AN IDEA BEForE ITS TIME: Interview with Henning rud Andersen10 ENGINEErS’ corNEr: comparing SAPIEN and SAPIEN xT THVs

laksen sirimanne, vp, r&D, tHv, eDwarDs lifesciences

12 EDwArDS’ clINIcAl HISTory oF TAVI JoDi akin, vp, gloBal clinical affairs, eDwarDs lifesciences

In spite of many efforts during the training phase, I have realised while proctoring that patient screening often remains incomplete. Besides technical skill and experience, an optimal selection of patients is the key for a successful and safe TAVI

procedure. Declining to do a very high risk case is preferable to a procedural crash. Short-term, life-threatening comorbidities, low ejection fraction with no demonstrated contractility reserve, bulging septum with significant gradient, massively calcific bicuspid valves, bulky calcific leaflets, should be a matter of discussion with the Heart Team and may re-orientate some patients to an alternative treatment, including surgery. Under- or over-sizing the THV is frequently due to a suboptimal assessment of the annulus diameter by a single method (echo or CT). Porcelain aorta, hugely calcific valves, could interfere in the valve sizing decision. All borderline cases (diameter of 21 mm, for instance) should lead to “dynamic” sizing by aortography during balloon aortic valvuloplasty (BAV). The use of CT for assessing the valve, the aorta, the distance annulus to coronary ostia, and the ilio-femoral approach should be generalised. A careful assessment of the internal vessel diameters by cross-sectional CT (with or without contrast injection) must be obtained in all cases. Three-

dimensional (3D) reconstruction (when performed) is not enough, and the ra-diologist must understand our needs. Rashness is unacceptable when vascular complications are concerned. Finally, the geriatrician’s opinion should be more often required with the extension of TAVI to so-called “frail” patients.

TAVItalk

QUOTABLE

TAVItalk TAVItalkJANUAry 2011 EUroPE2 3

for use outside the united states only | not intended for general distribution.

TAVItalk TAVItalkJANUAry 2011 EUroPE2 3

similar or even lower risk compared to The SOURCE Registry patients, which is likely to result in improved 1-year survival. The comparison of these survival rates with the Cohort A surgi-cal arm in the randomised trial will have a huge influence on the speed of adoption for the TAVI procedure.

The next challenge for the technology will be to reduce the incidence of paravalvular leakage, stroke and vascular complica-tions; as well as acquiring quality of life information to allow

cost effectiveness to be assessed. In addition, the development of a dedicated TAVI “risk score” to predict 30-day and 1-year survival is urgently required. It will also be important to see what impact the next generation of transcatheter heart valves (Edwards SAPIEN XT) and delivery systems, released in Europe this past year, will have on outcomes. These major goals will be addressed with the next line in the SOURCE family of registries, with SOURCE XT Registry, commencing early in 2011. The outstanding results of Cohort B of The PARTNER Trial have

now been published. It is interesting to compare these randomised

trial results with those of the “real world” SOURCE European Registry and to speculate on any reasons for differences in outcomes.

The 30 day results of the >2,300 patients in The SOURCE Registry having both transfemoral (TF) and transapical (TA) procedures are displayed in Figure 1.

It is important to note that all patients receiving TAVI in the Cohort B of The PARTNER Trial were treated using the TF approach. Nonetheless, the 5% all-cause 30-day mortality reported is a remarkable achievement by the operators. Both these results and The SOURCE Registry data indicate that, with appropriate training and proctorship, balloon-expandable TAVI can be safely introduced into clinical practice. It can now reasonably be quoted to a patient that the 30-day TF mortality for TAVI using the Edwards SAPIEN device is in the region of 5-8%.

The 1-year results for The PARTNER Trial and The SOURCE Registry are shown in Figures 2 and 3. Figure 2 shows the 1-year mortality in The PARTNER Trial, Cohort B and Figure 3 shows the 1-year survival in Cohort 1 of The SOURCE Registry.

The remarkable treatment effect of TAVI in The PARTNER Trial is displayed in Figure 2 with only five patients requiring treatment to

avoid a single mortality at one year. However, it is interesting to see that the initial improved 30-day survival in The PARTNER Trial is

not resulting in improved one-year survival, which is 70% com-pared to >80% in the TF group in The SOURCE Registry.

This almost certainly is explained by the differences of the patient populations in both studies (Figure 4). In contrast to The PARTNER Trial, where only absolute surgical turn-downs were included in Cohort B, The SOURCE Registry patients were selected based on their high risk for conventional aortic valve surgery.

Although a direct comparison between studies with different selection criteria is always difficult to make, Figure 4 demonstrates that The PARTNER Trial, Cohort B randomised patients seem to have higher risk profiles than the TF SOURCE patients. This dif-ference in comorbidities is likely to explain the difference in 1-year outcomes between the two studies. Nonetheless, it is clear that balloon-expandable TAVI should become the “standard of care” in The PARTNER Trial, Cohort B inoperable types of patients, if deemed appropriate by a multidisciplinary team.

Results of Cohort A of the randomised trial (patients consid-ered appropriate, but high risk surgical candidates) will be available in 2011. The demographics of this Cohort are likely to be more

The SoUrcE registry in the context of PArTNEr

AlAIN crIBIEr, MD Hôpital charles nicolle, university of rouen rouen, france

Definitiveresults through rigorous design

The Edwards SAPIEN THV significantly improves survival

20% absolute reduction in mortality2

Despite expert care and frequent BAV (78.2%), standard therapy failed to alter the dismal natural course of disease1

The key role of patient screening

Major Complications (≤30 days)Total SOURCE Cohort

TFn=946

TA/Othern=1398

Totaln=2344

Death 71 (7.5%) 150 (10.7%) 221 (9.4%)Stroke 27 (2.9%) 35 (2.5%) 62 (2.7%)Renal Failure requiring dialysis 17 (1.8%) 89 (6.4%) 106 (4.5%)

Permanent Pacemaker 63 (6.7%) 99 (7.1%) 162 (6.9%)

Months

100%

80

60

40

20

00 6 12 18 24

P < .001∆ at 1 y = 20.0%NNT = 5.0 pts

Standard Rx

TAVI

30.7%

50.7%

The PARTNER Trial: All Cause Mortality

SOURCE: COHORT 11 Year Survival (All Approaches)

Are the patient populations of SOURCEand PARTNER different?

The PARTNER Trial The SOURCE Registry

1 Year Survival

100%

90%

80%

70%

60%

50%

ALL

76.1%

TA

72.1%

TF

81.1%

Log EuroSCORE 26.4 25.8

Age 83.1 yrs 81.7 yrs

Coronary Disease 67.6% 47.5%

Prior CABG 37.4% 17.5%

Peripheral Vascular Disease 30.3% 10.6%

Pulmonary Disease 41.3% 24.6%

Porcelaine Aorta 19% 4.5%

Major Complications (≤30 days)Total SOURCE Cohort

TFn=946

TA/Othern=1398

Totaln=2344

Death 71 (7.5%) 150 (10.7%) 221 (9.4%)Stroke 27 (2.9%) 35 (2.5%) 62 (2.7%)Renal Failure requiring dialysis 17 (1.8%) 89 (6.4%) 106 (4.5%)

Permanent Pacemaker 63 (6.7%) 99 (7.1%) 162 (6.9%)

Months

100%

80

60

40

20

00 6 12 18 24

P < .001∆ at 1 y = 20.0%NNT = 5.0 pts

Standard Rx

TAVI

30.7%

50.7%

The PARTNER Trial: All Cause Mortality

SOURCE: COHORT 11 Year Survival (All Approaches)

Are the patient populations of SOURCEand PARTNER different?

The PARTNER Trial The SOURCE Registry

1 Year Survival

100%

90%

80%

70%

60%

50%

ALL

76.1%

TA

72.1%

TF

81.1%

Log EuroSCORE 26.4 25.8

Age 83.1 yrs 81.7 yrs

Coronary Disease 67.6% 47.5%

Prior CABG 37.4% 17.5%

Peripheral Vascular Disease 30.3% 10.6%

Pulmonary Disease 41.3% 24.6%

Porcelaine Aorta 19% 4.5%

Major Complications (≤30 days)Total SOURCE Cohort

TFn=946

TA/Othern=1398

Totaln=2344

Death 71 (7.5%) 150 (10.7%) 221 (9.4%)Stroke 27 (2.9%) 35 (2.5%) 62 (2.7%)Renal Failure requiring dialysis 17 (1.8%) 89 (6.4%) 106 (4.5%)

Permanent Pacemaker 63 (6.7%) 99 (7.1%) 162 (6.9%)

Months

100%

80

60

40

20

00 6 12 18 24

P < .001∆ at 1 y = 20.0%NNT = 5.0 pts

Standard Rx

TAVI

30.7%

50.7%

The PARTNER Trial: All Cause Mortality

SOURCE: COHORT 11 Year Survival (All Approaches)

Are the patient populations of SOURCEand PARTNER different?

The PARTNER Trial The SOURCE Registry

1 Year Survival

100%

90%

80%

70%

60%

50%

ALL

76.1%

TA

72.1%

TF

81.1%

Log EuroSCORE 26.4 25.8

Age 83.1 yrs 81.7 yrs

Coronary Disease 67.6% 47.5%

Prior CABG 37.4% 17.5%

Peripheral Vascular Disease 30.3% 10.6%

Pulmonary Disease 41.3% 24.6%

Porcelaine Aorta 19% 4.5%

Major Complications (≤30 days)Total SOURCE Cohort

TFn=946

TA/Othern=1398

Totaln=2344

Death 71 (7.5%) 150 (10.7%) 221 (9.4%)Stroke 27 (2.9%) 35 (2.5%) 62 (2.7%)Renal Failure requiring dialysis 17 (1.8%) 89 (6.4%) 106 (4.5%)

Permanent Pacemaker 63 (6.7%) 99 (7.1%) 162 (6.9%)

Months

100%

80

60

40

20

00 6 12 18 24

P < .001∆ at 1 y = 20.0%NNT = 5.0 pts

Standard Rx

TAVI

30.7%

50.7%

The PARTNER Trial: All Cause Mortality

SOURCE: COHORT 11 Year Survival (All Approaches)

Are the patient populations of SOURCEand PARTNER different?

The PARTNER Trial The SOURCE Registry

1 Year Survival

100%

90%

80%

70%

60%

50%

ALL

76.1%

TA

72.1%

TF

81.1%

Log EuroSCORE 26.4 25.8

Age 83.1 yrs 81.7 yrs

Coronary Disease 67.6% 47.5%

Prior CABG 37.4% 17.5%

Peripheral Vascular Disease 30.3% 10.6%

Pulmonary Disease 41.3% 24.6%

Porcelaine Aorta 19% 4.5%

Fig.1 Fig. 2 Fig. 3 Fig. 4

The PArTNEr TrialProtocol1

MArTyN THoMAS, MDclinical Director of cardiovascular services guy’s and st thomas’, london, uk co-pi for the source registry

olAF wENDlEr, MD, PhDclinical Director for cardiology and cardiothoracic surgery king’s college Hospital, london, uk co-pi for the source registry

(continued on page 4)

No

Yes

Yes ASSESSMENTTransfemoral Access

Not in Study

TransfemoralStandardTherapyVS

Cohort Bn = 358

Cohort An = 700

ASSESSMENTOperability

No

1:1 Randomization

Symptomatic Severe Aortic Stenosis

In spite of many efforts during the training phase, I have realised while proctoring that patient screening often remains incomplete. Besides technical skill and experience, an optimal selection of patients is the key for a successful and safe TAVI

procedure. Declining to do a very high risk case is preferable to a procedural crash. Short-term, life-threatening comorbidities, low ejection fraction with no demonstrated contractility reserve, bulging septum with significant gradient, massively calcific bicuspid valves, bulky calcific leaflets, should be a matter of discussion with the Heart Team and may re-orientate some patients to an alternative treatment, including surgery. Under- or over-sizing the THV is frequently due to a suboptimal assessment of the annulus diameter by a single method (echo or CT). Porcelain aorta, hugely calcific valves, could interfere in the valve sizing decision. All borderline cases (diameter of 21 mm, for instance) should lead to “dynamic” sizing by aortography during balloon aortic valvuloplasty (BAV). The use of CT for assessing the valve, the aorta, the distance annulus to coronary ostia, and the ilio-femoral approach should be generalised. A careful assessment of the internal vessel diameters by cross-sectional CT (with or without contrast injection) must be obtained in all cases. Three-

dimensional (3D) reconstruction (when performed) is not enough, and the ra-diologist must understand our needs. Rashness is unacceptable when vascular complications are concerned. Finally, the geriatrician’s opinion should be more often required with the extension of TAVI to so-called “frail” patients.

TAVItalk

QUOTABLE

TAVItalk TAVItalkJANUAry 2011 EUroPE2 3

for use outside the united states only | not intended for general distribution.

TAVItalk TAVItalkJANUAry 2011 EUroPE2 3

similar or even lower risk compared to The SOURCE Registry patients, which is likely to result in improved 1-year survival. The comparison of these survival rates with the Cohort A surgi-cal arm in the randomised trial will have a huge influence on the speed of adoption for the TAVI procedure.

The next challenge for the technology will be to reduce the incidence of paravalvular leakage, stroke and vascular complica-tions; as well as acquiring quality of life information to allow

cost effectiveness to be assessed. In addition, the development of a dedicated TAVI “risk score” to predict 30-day and 1-year survival is urgently required. It will also be important to see what impact the next generation of transcatheter heart valves (Edwards SAPIEN XT) and delivery systems, released in Europe this past year, will have on outcomes. These major goals will be addressed with the next line in the SOURCE family of registries, with SOURCE XT Registry, commencing early in 2011. The outstanding results of Cohort B of The PARTNER Trial have

now been published. It is interesting to compare these randomised

trial results with those of the “real world” SOURCE European Registry and to speculate on any reasons for differences in outcomes.

The 30 day results of the >2,300 patients in The SOURCE Registry having both transfemoral (TF) and transapical (TA) procedures are displayed in Figure 1.

It is important to note that all patients receiving TAVI in the Cohort B of The PARTNER Trial were treated using the TF approach. Nonetheless, the 5% all-cause 30-day mortality reported is a remarkable achievement by the operators. Both these results and The SOURCE Registry data indicate that, with appropriate training and proctorship, balloon-expandable TAVI can be safely introduced into clinical practice. It can now reasonably be quoted to a patient that the 30-day TF mortality for TAVI using the Edwards SAPIEN device is in the region of 5-8%.

The 1-year results for The PARTNER Trial and The SOURCE Registry are shown in Figures 2 and 3. Figure 2 shows the 1-year mortality in The PARTNER Trial, Cohort B and Figure 3 shows the 1-year survival in Cohort 1 of The SOURCE Registry.

The remarkable treatment effect of TAVI in The PARTNER Trial is displayed in Figure 2 with only five patients requiring treatment to

avoid a single mortality at one year. However, it is interesting to see that the initial improved 30-day survival in The PARTNER Trial is

not resulting in improved one-year survival, which is 70% com-pared to >80% in the TF group in The SOURCE Registry.

This almost certainly is explained by the differences of the patient populations in both studies (Figure 4). In contrast to The PARTNER Trial, where only absolute surgical turn-downs were included in Cohort B, The SOURCE Registry patients were selected based on their high risk for conventional aortic valve surgery.

Although a direct comparison between studies with different selection criteria is always difficult to make, Figure 4 demonstrates that The PARTNER Trial, Cohort B randomised patients seem to have higher risk profiles than the TF SOURCE patients. This dif-ference in comorbidities is likely to explain the difference in 1-year outcomes between the two studies. Nonetheless, it is clear that balloon-expandable TAVI should become the “standard of care” in The PARTNER Trial, Cohort B inoperable types of patients, if deemed appropriate by a multidisciplinary team.

Results of Cohort A of the randomised trial (patients consid-ered appropriate, but high risk surgical candidates) will be available in 2011. The demographics of this Cohort are likely to be more

The SoUrcE registry in the context of PArTNEr

AlAIN crIBIEr, MD Hôpital charles nicolle, university of rouen rouen, france

Definitiveresults through rigorous design

The Edwards SAPIEN THV significantly improves survival

20% absolute reduction in mortality2

Despite expert care and frequent BAV (78.2%), standard therapy failed to alter the dismal natural course of disease1

The key role of patient screening

Major Complications (≤30 days)Total SOURCE Cohort

TFn=946

TA/Othern=1398

Totaln=2344

Death 71 (7.5%) 150 (10.7%) 221 (9.4%)Stroke 27 (2.9%) 35 (2.5%) 62 (2.7%)Renal Failure requiring dialysis 17 (1.8%) 89 (6.4%) 106 (4.5%)

Permanent Pacemaker 63 (6.7%) 99 (7.1%) 162 (6.9%)

Months

100%

80

60

40

20

00 6 12 18 24

P < .001∆ at 1 y = 20.0%NNT = 5.0 pts

Standard Rx

TAVI

30.7%

50.7%

The PARTNER Trial: All Cause Mortality

SOURCE: COHORT 11 Year Survival (All Approaches)

Are the patient populations of SOURCEand PARTNER different?

The PARTNER Trial The SOURCE Registry

1 Year Survival

100%

90%

80%

70%

60%

50%

ALL

76.1%

TA

72.1%

TF

81.1%

Log EuroSCORE 26.4 25.8

Age 83.1 yrs 81.7 yrs

Coronary Disease 67.6% 47.5%

Prior CABG 37.4% 17.5%

Peripheral Vascular Disease 30.3% 10.6%

Pulmonary Disease 41.3% 24.6%

Porcelaine Aorta 19% 4.5%

Major Complications (≤30 days)Total SOURCE Cohort

TFn=946

TA/Othern=1398

Totaln=2344

Death 71 (7.5%) 150 (10.7%) 221 (9.4%)Stroke 27 (2.9%) 35 (2.5%) 62 (2.7%)Renal Failure requiring dialysis 17 (1.8%) 89 (6.4%) 106 (4.5%)

Permanent Pacemaker 63 (6.7%) 99 (7.1%) 162 (6.9%)

Months

100%

80

60

40

20

00 6 12 18 24

P < .001∆ at 1 y = 20.0%NNT = 5.0 pts

Standard Rx

TAVI

30.7%

50.7%

The PARTNER Trial: All Cause Mortality

SOURCE: COHORT 11 Year Survival (All Approaches)

Are the patient populations of SOURCEand PARTNER different?

The PARTNER Trial The SOURCE Registry

1 Year Survival

100%

90%

80%

70%

60%

50%

ALL

76.1%

TA

72.1%

TF

81.1%

Log EuroSCORE 26.4 25.8

Age 83.1 yrs 81.7 yrs

Coronary Disease 67.6% 47.5%

Prior CABG 37.4% 17.5%

Peripheral Vascular Disease 30.3% 10.6%

Pulmonary Disease 41.3% 24.6%

Porcelaine Aorta 19% 4.5%

Major Complications (≤30 days)Total SOURCE Cohort

TFn=946

TA/Othern=1398

Totaln=2344

Death 71 (7.5%) 150 (10.7%) 221 (9.4%)Stroke 27 (2.9%) 35 (2.5%) 62 (2.7%)Renal Failure requiring dialysis 17 (1.8%) 89 (6.4%) 106 (4.5%)

Permanent Pacemaker 63 (6.7%) 99 (7.1%) 162 (6.9%)

Months

100%

80

60

40

20

00 6 12 18 24

P < .001∆ at 1 y = 20.0%NNT = 5.0 pts

Standard Rx

TAVI

30.7%

50.7%

The PARTNER Trial: All Cause Mortality

SOURCE: COHORT 11 Year Survival (All Approaches)

Are the patient populations of SOURCEand PARTNER different?

The PARTNER Trial The SOURCE Registry

1 Year Survival

100%

90%

80%

70%

60%

50%

ALL

76.1%

TA

72.1%

TF

81.1%

Log EuroSCORE 26.4 25.8

Age 83.1 yrs 81.7 yrs

Coronary Disease 67.6% 47.5%

Prior CABG 37.4% 17.5%

Peripheral Vascular Disease 30.3% 10.6%

Pulmonary Disease 41.3% 24.6%

Porcelaine Aorta 19% 4.5%

Major Complications (≤30 days)Total SOURCE Cohort

TFn=946

TA/Othern=1398

Totaln=2344

Death 71 (7.5%) 150 (10.7%) 221 (9.4%)Stroke 27 (2.9%) 35 (2.5%) 62 (2.7%)Renal Failure requiring dialysis 17 (1.8%) 89 (6.4%) 106 (4.5%)

Permanent Pacemaker 63 (6.7%) 99 (7.1%) 162 (6.9%)

Months

100%

80

60

40

20

00 6 12 18 24

P < .001∆ at 1 y = 20.0%NNT = 5.0 pts

Standard Rx

TAVI

30.7%

50.7%

The PARTNER Trial: All Cause Mortality

SOURCE: COHORT 11 Year Survival (All Approaches)

Are the patient populations of SOURCEand PARTNER different?

The PARTNER Trial The SOURCE Registry

1 Year Survival

100%

90%

80%

70%

60%

50%

ALL

76.1%

TA

72.1%

TF

81.1%

Log EuroSCORE 26.4 25.8

Age 83.1 yrs 81.7 yrs

Coronary Disease 67.6% 47.5%

Prior CABG 37.4% 17.5%

Peripheral Vascular Disease 30.3% 10.6%

Pulmonary Disease 41.3% 24.6%

Porcelaine Aorta 19% 4.5%

Fig.1 Fig. 2 Fig. 3 Fig. 4

The PArTNEr TrialProtocol1

MArTyN THoMAS, MDclinical Director of cardiovascular services guy’s and st thomas’, london, uk co-pi for the source registry

olAF wENDlEr, MD, PhDclinical Director for cardiology and cardiothoracic surgery king’s college Hospital, london, uk co-pi for the source registry

(continued on page 4)

No

Yes

Yes ASSESSMENTTransfemoral Access

Not in Study

TransfemoralStandardTherapyVS

Cohort Bn = 358

Cohort An = 700

ASSESSMENTOperability

No

1:1 Randomization

Symptomatic Severe Aortic Stenosis

for use outside the united states only | not intended for general distribution. *syntaX: synergy between percutaneous coronary intervention with taXus and cardiac surgery trial

TAVItalk TAVItalkJANUAry 2011 EUroPE4 5

The Edwards SAPIEN THV significantly improves haemodynamics and sustains valve performance.

Reduced mean gradient (P < .001)2

Increased and sustained

aortic valve area

(P < .001)2

44.6

43.2

33.0

10.8

39.5

11.3

44.4

12.1

Me

an

Gra

die

nt,

mm

Hg 70

60

50

40

30

20

10

0 Baseline 30 Days 6 Months 1 Year N = 163 N = 143 N = 100 N = 89

P < .001Error bars = ± 1 SD

Standard TherapyEdwards THV

Mean GRadIents OveR tIMe1aORtIc valve aReas (ava) OveR tIMe1

AV

A, c

m2

2.5

2.0

1.5

1.0

0.5

0

0.64

0.65

1.53

0.77

1.61

0.68

1.57

0.70

Baseline 30 Days 6 Months 1 Year N = 163 N = 143 N = 100 N = 89

P < .001Error bars = ± 1 SD

Standard TherapyEdwards THV

The ESC guidelines on valvular heart disease (VHD) were published early in 2007 at a time when TAVI was in its infancy

and the technique was only briefly mentioned. These guidelines will be updated by a joint group of experts from both the ESC and EACTS and are expected to be published in early 2012.

The PARTNER Trial provides important information which should be taken into account for several reasons. • Firstly, when writing guidelines, it is important to search for

evidence, and the data from randomised clinical trials have a special value. Unfortunately, in most domains of valve dis-ease there are no randomised clinical trials (RCTs), and the only conclusions are based on expert consensus— which

is useful, but still of lower value. Due to the efforts of the group that initiated and conducted The PARTNER Trial we have these data for TAVI from its very infancy.

• Secondly, The PARTNER Trial is one of the first important trials – besides SYNTAX*– in the field of coronary revascu-larisation where the decision to treat was based on a consen-sus between cardiologists and surgeons. This aspect should not only be stressed in the field of TAVI, but also emphasised in all decision-making in VHD interventions. A collabora-tive approach such as this one will increase the quality of the results and decrease the number of patients erroneously left untreated.

The PArTNEr Trial: Impact on clinical guidelines?AlEc VAHANIAN, MD, PhD, GUEST EDITorDirector of cardiology, Hôpital Bichat, paris, france

• Thirdly, the data from The PARTNER Trial, Cohort B, convincingly show that in inoperable patients with severe aortic stenosis, TAVI improves survival and quality of life when compared with medical therapy. The benefit was consistently shown in all specified subgroups. The price to be paid is an increase in stroke and vascular complications. These find-ings support and confirm what single centre series and large registries have already told us.

When analysing these important findings, one should not forget that not all-comers were included in the trial – i.e., not all inop-erable patients should be proposed for TAVI, and this requires a

careful reading of the exclusion criteria for randomisation, such as limited life expectancy. For inoperable patients not included in the trial, it is likely that medical treatment will remain the only reasonable option. However, more work has to be done in some patient categories; for example, such as those with low left ventric-ular ejection fraction or patients with concomitant coronary artery disease. The PARTNER Trial also confirmed the limited value of isolated balloon valvuloplasty in improving the midterm outcome of patients with severe aortic stenosis.

The process of producing the new guidelines is ongoing and there is no doubt that the results of The PARTNER Trial will be an important piece of information to be discussed by the committee. In addition, all of us are eagerly awaiting next spring to hear the results of The PARTNER Trial, Cohort A, in order to know if the tentative scheme, which was proposed jointly with Catherine Otto a few months ago, can be endorsed when treating patients with symptoms and severe aortic stenosis (AS): if surgery is high risk/contraindicated, if life expectancy is sufficient, if TAVI is feasible, it is the way to go. Thus, let us wait and see...

there is no doubt that the results of the PArtner trial will be an important piece of information to be discussed.

TAVItalk

QUOTABLE

Digesting the data from The PArTNEr Trial, and its profound impact on cardiovascular medicine and clinical practice

What do the results tell us? Aortic stenosis is life-threatening and may progress rapidly – therefore, treatment options and timing do matter. All healthcare providers managing patients with aortic stenosis symptoms need to ensure that these patients are appropriately referred and

receive a definitive diagnosis, and also are aware of their treatment options, whether surgical AVR or TAVI.

My co-PI of The PARTNER Trial, Craig R. Smith, MD, Chairman, Department of Surgery Columbia University College of Physicians and Surgeons and Chief, Division of Cardiothoracic Surgery, NewYork-Presbyterian Hospital/Columbia University Medical Center, believes that “this represents a significant advancement in treatment options for patients with severe AS. The number of patients treated in our hos-pital for AS has increased, including with surgical AVR—so, overall, more patients are being referred and treated than ever before.”

To best sum-up what the results of The PARTNER Trial mean, my co-authors and I wrote in the New England Journal of Medicine that: “on the basis of a rate of death from any cause at one year that was 20 percentage points lower with TAVI than with standard therapy, balloon-expandable TAVI should be the new standard of care for patients with aortic stenosis who are not suitable candidates for surgery.

Increase in ejection fraction at 1 year (P < .01)1

reduction in left ventricular mass index at 6 months and 1 year (P < .0001)1

reduction in mitral regurgitation at 1 year (P < .001)1

(continued on page 6)

What is more important, the stem or the flower?

Probably both, but undoubtedly a very elegant stem with a poor flower is not going to succeed. The same can apply to THV: For the interventional cardiologist the ideal stem seems to be the one that can be inserted in the tightest artery, and because of this, everyone is trying to make the stem thinner and thinner. However, we must keep in mind that our patient is being treated because of aortic valve disease, and what they need is a good and lasting bioprosthesis. Remembering this, we should look first for the best per-forming prosthesis. Only as a second endpoint, we should see if the prosthesis can be inserted through a thinner or larger introducer.

We have at our disposal today two very good ways to approach our patients (transfemoral or transapical), let us choose the one that allows us to insert the best performing valve. It would be a shame to jeopardise the transcatheter heart valve field by chasing after the stem while neglecting the flower.

TAVItalk

QUOTABLE

GINo GEroSA, MD associate professor of cardiac surgery university of padua medical school chief cardiac surgery unit, padua, italy

The stem or the flower

MArTIN lEoN, MD on behalf of the partner trial investigators

for use outside the united states only | not intended for general distribution. *syntaX: synergy between percutaneous coronary intervention with taXus and cardiac surgery trial

TAVItalk TAVItalkJANUAry 2011 EUroPE4 5

The Edwards SAPIEN THV significantly improves haemodynamics and sustains valve performance.

Reduced mean gradient (P < .001)2

Increased and sustained

aortic valve area

(P < .001)2

44.6

43.2

33.0

10.8

39.5

11.3

44.4

12.1

Me

an

Gra

die

nt,

mm

Hg 70

60

50

40

30

20

10

0 Baseline 30 Days 6 Months 1 Year N = 163 N = 143 N = 100 N = 89

P < .001Error bars = ± 1 SD

Standard TherapyEdwards THV

Mean GRadIents OveR tIMe1aORtIc valve aReas (ava) OveR tIMe1

AV

A, c

m2

2.5

2.0

1.5

1.0

0.5

0

0.64

0.65

1.53

0.77

1.61

0.68

1.57

0.70

Baseline 30 Days 6 Months 1 Year N = 163 N = 143 N = 100 N = 89

P < .001Error bars = ± 1 SD

Standard TherapyEdwards THV

The ESC guidelines on valvular heart disease (VHD) were published early in 2007 at a time when TAVI was in its infancy

and the technique was only briefly mentioned. These guidelines will be updated by a joint group of experts from both the ESC and EACTS and are expected to be published in early 2012.

The PARTNER Trial provides important information which should be taken into account for several reasons. • Firstly, when writing guidelines, it is important to search for

evidence, and the data from randomised clinical trials have a special value. Unfortunately, in most domains of valve dis-ease there are no randomised clinical trials (RCTs), and the only conclusions are based on expert consensus— which

is useful, but still of lower value. Due to the efforts of the group that initiated and conducted The PARTNER Trial we have these data for TAVI from its very infancy.

• Secondly, The PARTNER Trial is one of the first important trials – besides SYNTAX*– in the field of coronary revascu-larisation where the decision to treat was based on a consen-sus between cardiologists and surgeons. This aspect should not only be stressed in the field of TAVI, but also emphasised in all decision-making in VHD interventions. A collabora-tive approach such as this one will increase the quality of the results and decrease the number of patients erroneously left untreated.

The PArTNEr Trial: Impact on clinical guidelines?AlEc VAHANIAN, MD, PhD, GUEST EDITorDirector of cardiology, Hôpital Bichat, paris, france

• Thirdly, the data from The PARTNER Trial, Cohort B, convincingly show that in inoperable patients with severe aortic stenosis, TAVI improves survival and quality of life when compared with medical therapy. The benefit was consistently shown in all specified subgroups. The price to be paid is an increase in stroke and vascular complications. These find-ings support and confirm what single centre series and large registries have already told us.

When analysing these important findings, one should not forget that not all-comers were included in the trial – i.e., not all inop-erable patients should be proposed for TAVI, and this requires a

careful reading of the exclusion criteria for randomisation, such as limited life expectancy. For inoperable patients not included in the trial, it is likely that medical treatment will remain the only reasonable option. However, more work has to be done in some patient categories; for example, such as those with low left ventric-ular ejection fraction or patients with concomitant coronary artery disease. The PARTNER Trial also confirmed the limited value of isolated balloon valvuloplasty in improving the midterm outcome of patients with severe aortic stenosis.

The process of producing the new guidelines is ongoing and there is no doubt that the results of The PARTNER Trial will be an important piece of information to be discussed by the committee. In addition, all of us are eagerly awaiting next spring to hear the results of The PARTNER Trial, Cohort A, in order to know if the tentative scheme, which was proposed jointly with Catherine Otto a few months ago, can be endorsed when treating patients with symptoms and severe aortic stenosis (AS): if surgery is high risk/contraindicated, if life expectancy is sufficient, if TAVI is feasible, it is the way to go. Thus, let us wait and see...

there is no doubt that the results of the PArtner trial will be an important piece of information to be discussed.

TAVItalk

QUOTABLE

Digesting the data from The PArTNEr Trial, and its profound impact on cardiovascular medicine and clinical practice

What do the results tell us? Aortic stenosis is life-threatening and may progress rapidly – therefore, treatment options and timing do matter. All healthcare providers managing patients with aortic stenosis symptoms need to ensure that these patients are appropriately referred and

receive a definitive diagnosis, and also are aware of their treatment options, whether surgical AVR or TAVI.

My co-PI of The PARTNER Trial, Craig R. Smith, MD, Chairman, Department of Surgery Columbia University College of Physicians and Surgeons and Chief, Division of Cardiothoracic Surgery, NewYork-Presbyterian Hospital/Columbia University Medical Center, believes that “this represents a significant advancement in treatment options for patients with severe AS. The number of patients treated in our hos-pital for AS has increased, including with surgical AVR—so, overall, more patients are being referred and treated than ever before.”

To best sum-up what the results of The PARTNER Trial mean, my co-authors and I wrote in the New England Journal of Medicine that: “on the basis of a rate of death from any cause at one year that was 20 percentage points lower with TAVI than with standard therapy, balloon-expandable TAVI should be the new standard of care for patients with aortic stenosis who are not suitable candidates for surgery.

Increase in ejection fraction at 1 year (P < .01)1

reduction in left ventricular mass index at 6 months and 1 year (P < .0001)1

reduction in mitral regurgitation at 1 year (P < .001)1

(continued on page 6)

What is more important, the stem or the flower?

Probably both, but undoubtedly a very elegant stem with a poor flower is not going to succeed. The same can apply to THV: For the interventional cardiologist the ideal stem seems to be the one that can be inserted in the tightest artery, and because of this, everyone is trying to make the stem thinner and thinner. However, we must keep in mind that our patient is being treated because of aortic valve disease, and what they need is a good and lasting bioprosthesis. Remembering this, we should look first for the best per-forming prosthesis. Only as a second endpoint, we should see if the prosthesis can be inserted through a thinner or larger introducer.

We have at our disposal today two very good ways to approach our patients (transfemoral or transapical), let us choose the one that allows us to insert the best performing valve. It would be a shame to jeopardise the transcatheter heart valve field by chasing after the stem while neglecting the flower.

TAVItalk

QUOTABLE

GINo GEroSA, MD associate professor of cardiac surgery university of padua medical school chief cardiac surgery unit, padua, italy

The stem or the flower

MArTIN lEoN, MD on behalf of the partner trial investigators

for use outside the united states only | not intended for general distribution.

TAVItalk TAVItalkJANUAry 2011 EUroPE6 7

KC

CQ

Sc

ore

70

60

50

40

30

20

10

0

∆ = 13.9P < .001

∆ = 20.7P < .001

∆ = 24.5P < .001

MCID = 5 ptsEdwards THV

Control

Months

0 2 4 6 8 10 12

KccQ scORes OveR tIMe1

The Edwards SAPIEN THV significantly improves patient symptoms and quality of life

I

II

III

IVPa

tie

nts

, %

100

80

60

40

20

0 Edwards Standard Edwards Standard THV Therapy THV Therapy Baseline 1 Year

P = .68 P < .001

nYHa class OveR tIMe2

75% of the Edwards SAPIEN THV patients in NyHA class I or II at 1 year2

significant improvement observed as early as 30 days (P < .001)2

25-point treament effect in kccQ score

20-point improvement in kccQ score represents change of large clinical importance.3

kccQ, kansas city cardiomyopathy Questionnaire; mciD, minimum clinically important difference.

(continued on page 8)

The first published results of The PARTNER Trial are proof that TAVI yields superior short-term results as compared to medi-

cal therapy +/- valvuloplasty alone for patients who are not can-didates for conventional cardiac surgery. The shown benefit for survival and relief of symptoms is not surprising as it is consistent with what has been known about symptomatic aortic stenosis and aortic valve replacement from the past. However, the study and its results are very important, as they provide a rationale for the inva-sive and expensive treatment of very old patients at very high risk.

The high rates of stroke, vascular complications and major bleeding cast a cloud over the other-wise good results of transfemoral valve implantation. They are a reminder that the possible gain in life years and qual-ity of life have to be weighed carefully against a considerable risk, even with less invasive treatments.ADDItIonAL treAtMent oPtIonS In this context, a third treatment option for inoperable patients with aortic valve stenosis is missing: the transapical catheter-based aor-tic valve implantation. From our own experience and published larger series of high-risk patients, it is known that the results with the transapical approach are at least as good as with the transfemo-ral technique. In particular, low stroke rates of 1-2% and virtually no vascular complications have been reported. The surgical access through a left lateral mini-thoracotomy has other technical ben-efits such as more precise valve positioning, better coaxial valve alignment, the possible use of larger valve sizes as well as a shorter interval between balloon valvuloplasty and TAVI deployment. Fur-thermore, transapical valve implantation is also feasible in patients with severe peripheral vascular disease (excluded in The PART-NER Trial). The only true disadvantage of the transapical approach is the necessity for general anaesthesia, particularly in patients with

impaired lung function.The widespread strategy of offering high-risk patients a trans-

apical valve implantation only when the transfemoral access is not feasible is also followed in The PARTNER Trial. In the inoperable group of patients, this treatment option was not offered at all. This is a major drawback of the trial from the surgeons’ perspective.the FUtUre The treatment of aortic valve disease is changing. Transcatheter techniques have extended the indication for valve implantation to patients at a higher age and at higher risk. Future technical and procedural improvements will lower the complica-

tion rates for these interventions. This will certainly make TAVI at-tractive, even for patients with normal risk who receive conven-tional surgery today. Conven-tional aortic valve surgery, with its very good results and low compli-cation rates in “normal” patients,

will remain the gold standard for the foreseeable future. But the cardiac surgeon of tomorrow is well advised to get familiar with both transfemoral and transapical valve implantation techniques. With this armamentarium – and in collaboration with the cardi-ologist – the surgeon will then be able to objectively choose the best treatment for the individual patient.

Nevertheless, a close follow-up of mid- and long-term results of these valves is required in order to evaluate any possible negative impacts of high incidence of persistent aortic regurgitation and pacemaker implantations. In fact, there is a definite need for risk-adjusted, well-performed studies and registries to evaluate the true benefit of TAVI; as much as I share the enthusiasm for these new techniques.

We are eagerly awaiting the results of The PARTNER Trial, Cohort A.

The PArTNEr Trial, cohort B: A surgeon’s perspective

FrIEDrIcH MoHr, MD, PhD, GUEST EDITorHerzzentrum leipzig gmbHuniversitätsklinik, leipzig, germany

this will certainly make tAVI attractive, even for patients with normal risk who receive conventional surgery today.

NOTE

WORTHY

leaders in Interventional cardiology comment on The PArTNEr Trial

the “Italian” perspective: “There is no doubt that TAVI represents a breakthrough technology that is globally changing the land-scape of treatment for degenerative aortic stenosis. In Europe, the uptake of TAVI began long before the results of The PARTNER Trial, Cohort B became available. Italy, with more than 1,000 implants in 2009 and an estimate of around 2,000 procedures in 2010, is among the leading countries, despite serious issues with reimbursement. The PARTNER Trial shows that we were already heading in the right direc-tion, and the latest data on quality of life demonstrated that we are not only saving lives, but also significantly improving the health status of our patients as well. In addition, several Italian interventionalists have already had access to the newer SAPIEN XT THV device which makes the femoral access easier and safer. This strong evidence will fuel a further increase of TAVI procedures in our country, and hopefully encourage the health administration to develop new reimbursement strategies.” FrANcESco SAIA, MD, PhD institute of cardiology, university of Bologna, italy

on the impact of the PArtner trial: “The PARTNER Trial, Cohort B, is a landmark trial in the field of valvular heart disease. It is not only a major step in the evaluation of TAVI, but it is also the first study justifying – with a high level of evidence – the treat-ment of severe, symptomatic aortic stenosis in high-risk elderly patients.

In a paper from the Euro Heart Survey highlighting the insufficient referral of elderly patients with aortic stenosis, we concluded in 2005, ‘These findings underline particular difficulties regarding decision-making in the elderly, in whom current guidelines provide limited recom-mendations as a consequence of the low level of evidence from the literature. Randomised trials are unlikely to be conducted in this field…’

This was before TAVI gained wide application, and it illustrates how the evaluation of a new technique may contribute to addressing complex existing issues. There is no doubt that TAVI widens the field of effective therapies in high-risk patients with aortic stenosis. We now have proof of its usefulness in patients who were likely to be under-treated. Given new evidence from The PARTNER Trial, it can be expected that practitioners will become more interested in referring high-risk patients with aortic stenosis.”BErNArD IUNG, MD, PhD chairman, european society of cardiology, working group on valve Disease cardiology Department, Bichat Hospital and paris 7 university, paris, france

Viewpoint from Spain: “The results regarding mortality in this very sick cohort of patients, are of an unprecedented magnitude in interventional cardiology. A 20% absolute difference in mortality at one year is impressive, and speaks to both the efficacy of the treatment as well as the remarkably low (5%) periprocedural mortality.”JAVIEr GoIcolEA, MDpresident of the spanish working group of interventional cardiology, spanish society of cardiologyDirector of invasive cardiology, Hospital puerta de Hierro / majadahonda, madrid, spain

for use outside the united states only | not intended for general distribution.

TAVItalk TAVItalkJANUAry 2011 EUroPE6 7

KC

CQ

Sc

ore

70

60

50

40

30

20

10

0

∆ = 13.9P < .001

∆ = 20.7P < .001

∆ = 24.5P < .001

MCID = 5 ptsEdwards THV

Control

Months

0 2 4 6 8 10 12

KccQ scORes OveR tIMe1

The Edwards SAPIEN THV significantly improves patient symptoms and quality of life

I

II

III

IVPa

tie

nts

, %

100

80

60

40

20

0 Edwards Standard Edwards Standard THV Therapy THV Therapy Baseline 1 Year

P = .68 P < .001

nYHa class OveR tIMe2

75% of the Edwards SAPIEN THV patients in NyHA class I or II at 1 year2

significant improvement observed as early as 30 days (P < .001)2

25-point treament effect in kccQ score

20-point improvement in kccQ score represents change of large clinical importance.3

kccQ, kansas city cardiomyopathy Questionnaire; mciD, minimum clinically important difference.

(continued on page 8)

The first published results of The PARTNER Trial are proof that TAVI yields superior short-term results as compared to medi-

cal therapy +/- valvuloplasty alone for patients who are not can-didates for conventional cardiac surgery. The shown benefit for survival and relief of symptoms is not surprising as it is consistent with what has been known about symptomatic aortic stenosis and aortic valve replacement from the past. However, the study and its results are very important, as they provide a rationale for the inva-sive and expensive treatment of very old patients at very high risk.

The high rates of stroke, vascular complications and major bleeding cast a cloud over the other-wise good results of transfemoral valve implantation. They are a reminder that the possible gain in life years and qual-ity of life have to be weighed carefully against a considerable risk, even with less invasive treatments.ADDItIonAL treAtMent oPtIonS In this context, a third treatment option for inoperable patients with aortic valve stenosis is missing: the transapical catheter-based aor-tic valve implantation. From our own experience and published larger series of high-risk patients, it is known that the results with the transapical approach are at least as good as with the transfemo-ral technique. In particular, low stroke rates of 1-2% and virtually no vascular complications have been reported. The surgical access through a left lateral mini-thoracotomy has other technical ben-efits such as more precise valve positioning, better coaxial valve alignment, the possible use of larger valve sizes as well as a shorter interval between balloon valvuloplasty and TAVI deployment. Fur-thermore, transapical valve implantation is also feasible in patients with severe peripheral vascular disease (excluded in The PART-NER Trial). The only true disadvantage of the transapical approach is the necessity for general anaesthesia, particularly in patients with

impaired lung function.The widespread strategy of offering high-risk patients a trans-

apical valve implantation only when the transfemoral access is not feasible is also followed in The PARTNER Trial. In the inoperable group of patients, this treatment option was not offered at all. This is a major drawback of the trial from the surgeons’ perspective.the FUtUre The treatment of aortic valve disease is changing. Transcatheter techniques have extended the indication for valve implantation to patients at a higher age and at higher risk. Future technical and procedural improvements will lower the complica-

tion rates for these interventions. This will certainly make TAVI at-tractive, even for patients with normal risk who receive conven-tional surgery today. Conven-tional aortic valve surgery, with its very good results and low compli-cation rates in “normal” patients,

will remain the gold standard for the foreseeable future. But the cardiac surgeon of tomorrow is well advised to get familiar with both transfemoral and transapical valve implantation techniques. With this armamentarium – and in collaboration with the cardi-ologist – the surgeon will then be able to objectively choose the best treatment for the individual patient.

Nevertheless, a close follow-up of mid- and long-term results of these valves is required in order to evaluate any possible negative impacts of high incidence of persistent aortic regurgitation and pacemaker implantations. In fact, there is a definite need for risk-adjusted, well-performed studies and registries to evaluate the true benefit of TAVI; as much as I share the enthusiasm for these new techniques.

We are eagerly awaiting the results of The PARTNER Trial, Cohort A.

The PArTNEr Trial, cohort B: A surgeon’s perspective

FrIEDrIcH MoHr, MD, PhD, GUEST EDITorHerzzentrum leipzig gmbHuniversitätsklinik, leipzig, germany

this will certainly make tAVI attractive, even for patients with normal risk who receive conventional surgery today.

NOTE

WORTHY

leaders in Interventional cardiology comment on The PArTNEr Trial

the “Italian” perspective: “There is no doubt that TAVI represents a breakthrough technology that is globally changing the land-scape of treatment for degenerative aortic stenosis. In Europe, the uptake of TAVI began long before the results of The PARTNER Trial, Cohort B became available. Italy, with more than 1,000 implants in 2009 and an estimate of around 2,000 procedures in 2010, is among the leading countries, despite serious issues with reimbursement. The PARTNER Trial shows that we were already heading in the right direc-tion, and the latest data on quality of life demonstrated that we are not only saving lives, but also significantly improving the health status of our patients as well. In addition, several Italian interventionalists have already had access to the newer SAPIEN XT THV device which makes the femoral access easier and safer. This strong evidence will fuel a further increase of TAVI procedures in our country, and hopefully encourage the health administration to develop new reimbursement strategies.” FrANcESco SAIA, MD, PhD institute of cardiology, university of Bologna, italy

on the impact of the PArtner trial: “The PARTNER Trial, Cohort B, is a landmark trial in the field of valvular heart disease. It is not only a major step in the evaluation of TAVI, but it is also the first study justifying – with a high level of evidence – the treat-ment of severe, symptomatic aortic stenosis in high-risk elderly patients.

In a paper from the Euro Heart Survey highlighting the insufficient referral of elderly patients with aortic stenosis, we concluded in 2005, ‘These findings underline particular difficulties regarding decision-making in the elderly, in whom current guidelines provide limited recom-mendations as a consequence of the low level of evidence from the literature. Randomised trials are unlikely to be conducted in this field…’

This was before TAVI gained wide application, and it illustrates how the evaluation of a new technique may contribute to addressing complex existing issues. There is no doubt that TAVI widens the field of effective therapies in high-risk patients with aortic stenosis. We now have proof of its usefulness in patients who were likely to be under-treated. Given new evidence from The PARTNER Trial, it can be expected that practitioners will become more interested in referring high-risk patients with aortic stenosis.”BErNArD IUNG, MD, PhD chairman, european society of cardiology, working group on valve Disease cardiology Department, Bichat Hospital and paris 7 university, paris, france

Viewpoint from Spain: “The results regarding mortality in this very sick cohort of patients, are of an unprecedented magnitude in interventional cardiology. A 20% absolute difference in mortality at one year is impressive, and speaks to both the efficacy of the treatment as well as the remarkably low (5%) periprocedural mortality.”JAVIEr GoIcolEA, MDpresident of the spanish working group of interventional cardiology, spanish society of cardiologyDirector of invasive cardiology, Hospital puerta de Hierro / majadahonda, madrid, spain

for use outside the united states only | not intended for general distribution.

TAVItalk TAVItalkJANUAry 2011 EUroPE8 9

critical Insights

with standard therapy, predicted survival of inoperable patients with aortic stenosis is lower than with certain metastatic cancers

Not unreasonably, commissioners of healthcare are keen to sup-port treatments that are effective as well as cost-effective, and

have difficulty supporting treatments where the evidence base is in-secure or cost-effectiveness unproven.

Though we await formal cost-effectiveness analysis, the commis-sioners can be encouraged by the results of The PARTNER B trial as it assures them that they are almost certainly getting value for money. The dire outcome of symptomatic patients with severe aortic stenosis who are deemed too ill for aortic valve surgery has long been recognised. Moreover the natural history of these patients is often associated with multiple costly hospital admissions as their condition deteriorates. The 1-year 50% mortality rate in the standard-care arm of the study and the death or repeat hospitalisation rate of more than 70% attest to the severity of disease in these patients. It is of note that the event rates in both arms were higher than predicted in the original estimates used for the power calculation (standard-care arm 1-year mortality estimated at 37.5%).

A reALIStIC APPrAISAL We now have a trial that shows an extraor-dinary magnitude of benefit, both in terms of increased survival rates and a highly relevant improvement in quality of life. However, the clinical community remains realistic. First, although the results of this trial relate to those at the sickest end of the spectrum, we are learning that some patients are probably too sick for a TAVI proce-dure. We must recall that patients with significant coronary disease requiring revascularisation were excluded from The PARTNER Trial, as were those with an EF <20%, or with significant mitral or aortic regurgitation, severe renal dysfunction or recent myocardial infarc-tion or cerebrovascular event. It is of note that surgical risk scores do not measure all the factors that predict adverse outcomes and pa-tients were turned down for surgery because of factors such as por-celain aorta, oxygen-dependent respiratory disease and measures of frailty. The standard-care group had an unusually high use of balloon

aortic valvuloplasty (BAV) (63.7% within 30 days of randomisation and an additional 20.1% thereafter). BAV has not been used com-monly since earlier studies revealed a lack of sustained results, but it is highly unlikely that the standard-care patients had their outcomes adversely affected by the decision to utilise this treatment.

InCreMentAL rISK The 30-day all-cause mortality in the TAVI group (5% in the intention-to-treat population and 6.4% in those treated with TAVI), compares with the 2.8% mortality in the stan-dard-care group, so there was only a 3.6% incremental procedural risk compared with the natural history. The 1-year results were ob-tained in spite of an 11.8% rate of moderate or severe aortic regurgi-

tation following TAVI, but the one-year results and available registry data suggest durable results from the valve out to three years. We also note the higher risk of major vascular complications and a 5% risk of stroke in the TAVI cohort. Hopefully, the use of smaller femoral access sheaths, alternative vascular approaches and the judicious use of the transapical approach will reduce the rate of these problems. Patients must be informed of these complications as well as the un-deniable benefits in terms of survival and quality of life during the consent process. We also await further information on the longer-term durability of these results.

We also recognise that these results relate to those patients for whom a transfemoral approach is possible. However, although the results cannot be directly extrapolated to those treated transapically

(who have more comorbidities), the available industry and national registry data suggest that the profound difference in outcomes in PARTNER Cohort B are not likely to be mitigated by the slightly higher procedural mortality associated with the transapical ap-proach.

ConSIDerInG PAtIentS CAreFULLY Current registry data suggest that TAVI is being used not just for surgical turn-downs but also for those where surgery could be contemplated, albeit at a high risk. The multidisciplinary teams selecting patients for different forms of treatment (which include surgeons) are weighing the surgical risks and prolonged recovery periods of such patients against a perceived lower risk and faster recovery rates with TAVI. However, additional information is required. The registry data cannot give us definitive

guidance and we need the results of the PARTNER Cohort A study before being confident that this is a correct approach. Although we need additional information, the multidisciplinary team approach not only has allowed appropriate patients to be treated by TAVI but also, as referrals have started to increase, more patients than ever before are being considered for conventional aortic valve surgery.

The PARTNER Trial, Cohort B results reflect one of the largest treatment effects ever seen. The cardiothoracic community must now engage with an educational process aimed at reversing the tra-ditional view that nothing can be done for these patients should sur-gery be declined. Patients, primary care physicians, and those with an interest in internal medicine and elderly care medicine must be informed of the new paradigm of care that is emerging.

There is no question that surgical replacement of the aortic valve is the standard treatment of aortic steno-

sis. This is a perfectly mature technique that is associ-ated with excellent outcomes in patients who are eligible for surgery.

However, many patients with severe and symptomatic aortic ste-nosis do not undergo surgical treatment due to the presence of con-traindications or major comorbidities, or because they are deemed too frail or too old by their physician or family.

The first compassionate TAVI case carried out in 2002 by Alain Cribier heralded a new era where high-risk patients were placed at the heart of medical team discussions, and provided with another treatment option that could potentially be far superior to balloon aortic valvuloplasty.

In the wake of various studies demonstrating the feasibility of transfemoral and transapical aortic valve implantation, The PARTNER Trial showed the benefit of a multidisciplinary approach in improving patient selection, allowing identification of the optimal procedural approach. It also confirmed the excellent outcomes of the transfemoral approach, with a 1-month all-cause mortality rate of 8%, and 21% at 1 year (1-month mortality predicted

by EuroSCORE was 26%).The eagerly awaited

results of The PARTNER Trial

(Cohort B) confirmed the benefit of TAVI in inoperable patients compared to medical treatment (including balloon dilatation). For the first time in medical history, a percutaneous technique was shown to decrease the one-year mortality by one death for every five treated patients. In addition, the quality of life of the study population was also dramatically improved. The results achieved in Cohort A, which are due to be presented in spring 2011, will shed some additional light on the benefit of TAVI in patients at high surgical risk.

The PARTNER Trial marked a turning point in the history of TAVI by irrefutably validating the benefits of this treatment strategy in inoperable patients, and by opening the way towards a gradual broadening of indications under the guidance of a multidisciplinary team.

There is still a long way to go before this technique reaches full maturity: reduction in the risk of vascular complications by decreas-ing introducer size and enhancing screening quality, reduction in the risk of periprosthetic regurgitation by achieving a more accurate measurement of the valve annulus size or more prosthetic conform-ability, reduction in the risk of periprocedural stroke (6% in The PARTNER Trial), optimisation of pre- and post-procedure anti-platelet treatment and, finally, validation of valve durability.

This technique is undoubtedly here to stay. Indeed, when we look at our national registry, we see that 1,500 cases were performed in France in 2010 as compared to only 300 in 2009.

on becoming a standard of care

*using constant hazard ratio.

*Using constant hazard ratio

23

Breast4 Lung4 Colorectal4 Prostate4 Ovarian4 Severe Inoperable AS*1

412

30

3

28

5-YeaR suRvIval Rate, %

Increased experience and next-generation technology may lower the incidence of acute major complications:

• Vascular complications (16.2%)2

• Bleeding episodes (16.8%)2

• Strokes (5.0%)2

The PArTNEr Trial, cohort B: Viewpoint from the United kingdom

MArk de BElDEr, MD consultant cardiologist the James cook university Hospital, middlesbrough, uk president, British cardiovascular intervention society.

Patients, primary care physicians, and those with an interest in internal medicine and elderly care medicine must be informed of the new paradigm of care that is emerging.

THIErry lEFèVrE, MD president of the french g.a.c.i. (groupe athérome coronaire et cardiologie interventionnelle) institut cardiovasculaire paris sud, massy, france

NOTE

WORTHY

rEFErENcES

1. Data on file, edwards lifesciences llc.

2. leon mB, smith cr, mack m, et al. transcath-eter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. n engl J med. 2010;363;1597-1607.

3. spertus J, peterson e, conrad mw, et al. monitor-ing clinical changes in patients with heart failure: a comparison of methods. am Heart J. 2005;150:707-715.

4. national institutes of Health. national cancer in-stitute. surveillance epidemiology and end results. cancer fact sheets. http://seer.cancer.gov/statfacts/. accessed november 16, 2010.

Based on 1-year results of cohort B patients treated with the edwards sapien tHv:

for use outside the united states only | not intended for general distribution.

TAVItalk TAVItalkJANUAry 2011 EUroPE8 9

critical Insights

with standard therapy, predicted survival of inoperable patients with aortic stenosis is lower than with certain metastatic cancers

Not unreasonably, commissioners of healthcare are keen to sup-port treatments that are effective as well as cost-effective, and

have difficulty supporting treatments where the evidence base is in-secure or cost-effectiveness unproven.

Though we await formal cost-effectiveness analysis, the commis-sioners can be encouraged by the results of The PARTNER B trial as it assures them that they are almost certainly getting value for money. The dire outcome of symptomatic patients with severe aortic stenosis who are deemed too ill for aortic valve surgery has long been recognised. Moreover the natural history of these patients is often associated with multiple costly hospital admissions as their condition deteriorates. The 1-year 50% mortality rate in the standard-care arm of the study and the death or repeat hospitalisation rate of more than 70% attest to the severity of disease in these patients. It is of note that the event rates in both arms were higher than predicted in the original estimates used for the power calculation (standard-care arm 1-year mortality estimated at 37.5%).

A reALIStIC APPrAISAL We now have a trial that shows an extraor-dinary magnitude of benefit, both in terms of increased survival rates and a highly relevant improvement in quality of life. However, the clinical community remains realistic. First, although the results of this trial relate to those at the sickest end of the spectrum, we are learning that some patients are probably too sick for a TAVI proce-dure. We must recall that patients with significant coronary disease requiring revascularisation were excluded from The PARTNER Trial, as were those with an EF <20%, or with significant mitral or aortic regurgitation, severe renal dysfunction or recent myocardial infarc-tion or cerebrovascular event. It is of note that surgical risk scores do not measure all the factors that predict adverse outcomes and pa-tients were turned down for surgery because of factors such as por-celain aorta, oxygen-dependent respiratory disease and measures of frailty. The standard-care group had an unusually high use of balloon

aortic valvuloplasty (BAV) (63.7% within 30 days of randomisation and an additional 20.1% thereafter). BAV has not been used com-monly since earlier studies revealed a lack of sustained results, but it is highly unlikely that the standard-care patients had their outcomes adversely affected by the decision to utilise this treatment.

InCreMentAL rISK The 30-day all-cause mortality in the TAVI group (5% in the intention-to-treat population and 6.4% in those treated with TAVI), compares with the 2.8% mortality in the stan-dard-care group, so there was only a 3.6% incremental procedural risk compared with the natural history. The 1-year results were ob-tained in spite of an 11.8% rate of moderate or severe aortic regurgi-

tation following TAVI, but the one-year results and available registry data suggest durable results from the valve out to three years. We also note the higher risk of major vascular complications and a 5% risk of stroke in the TAVI cohort. Hopefully, the use of smaller femoral access sheaths, alternative vascular approaches and the judicious use of the transapical approach will reduce the rate of these problems. Patients must be informed of these complications as well as the un-deniable benefits in terms of survival and quality of life during the consent process. We also await further information on the longer-term durability of these results.

We also recognise that these results relate to those patients for whom a transfemoral approach is possible. However, although the results cannot be directly extrapolated to those treated transapically

(who have more comorbidities), the available industry and national registry data suggest that the profound difference in outcomes in PARTNER Cohort B are not likely to be mitigated by the slightly higher procedural mortality associated with the transapical ap-proach.

ConSIDerInG PAtIentS CAreFULLY Current registry data suggest that TAVI is being used not just for surgical turn-downs but also for those where surgery could be contemplated, albeit at a high risk. The multidisciplinary teams selecting patients for different forms of treatment (which include surgeons) are weighing the surgical risks and prolonged recovery periods of such patients against a perceived lower risk and faster recovery rates with TAVI. However, additional information is required. The registry data cannot give us definitive

guidance and we need the results of the PARTNER Cohort A study before being confident that this is a correct approach. Although we need additional information, the multidisciplinary team approach not only has allowed appropriate patients to be treated by TAVI but also, as referrals have started to increase, more patients than ever before are being considered for conventional aortic valve surgery.

The PARTNER Trial, Cohort B results reflect one of the largest treatment effects ever seen. The cardiothoracic community must now engage with an educational process aimed at reversing the tra-ditional view that nothing can be done for these patients should sur-gery be declined. Patients, primary care physicians, and those with an interest in internal medicine and elderly care medicine must be informed of the new paradigm of care that is emerging.

There is no question that surgical replacement of the aortic valve is the standard treatment of aortic steno-

sis. This is a perfectly mature technique that is associ-ated with excellent outcomes in patients who are eligible for surgery.

However, many patients with severe and symptomatic aortic ste-nosis do not undergo surgical treatment due to the presence of con-traindications or major comorbidities, or because they are deemed too frail or too old by their physician or family.

The first compassionate TAVI case carried out in 2002 by Alain Cribier heralded a new era where high-risk patients were placed at the heart of medical team discussions, and provided with another treatment option that could potentially be far superior to balloon aortic valvuloplasty.

In the wake of various studies demonstrating the feasibility of transfemoral and transapical aortic valve implantation, The PARTNER Trial showed the benefit of a multidisciplinary approach in improving patient selection, allowing identification of the optimal procedural approach. It also confirmed the excellent outcomes of the transfemoral approach, with a 1-month all-cause mortality rate of 8%, and 21% at 1 year (1-month mortality predicted

by EuroSCORE was 26%).The eagerly awaited

results of The PARTNER Trial

(Cohort B) confirmed the benefit of TAVI in inoperable patients compared to medical treatment (including balloon dilatation). For the first time in medical history, a percutaneous technique was shown to decrease the one-year mortality by one death for every five treated patients. In addition, the quality of life of the study population was also dramatically improved. The results achieved in Cohort A, which are due to be presented in spring 2011, will shed some additional light on the benefit of TAVI in patients at high surgical risk.

The PARTNER Trial marked a turning point in the history of TAVI by irrefutably validating the benefits of this treatment strategy in inoperable patients, and by opening the way towards a gradual broadening of indications under the guidance of a multidisciplinary team.

There is still a long way to go before this technique reaches full maturity: reduction in the risk of vascular complications by decreas-ing introducer size and enhancing screening quality, reduction in the risk of periprosthetic regurgitation by achieving a more accurate measurement of the valve annulus size or more prosthetic conform-ability, reduction in the risk of periprocedural stroke (6% in The PARTNER Trial), optimisation of pre- and post-procedure anti-platelet treatment and, finally, validation of valve durability.

This technique is undoubtedly here to stay. Indeed, when we look at our national registry, we see that 1,500 cases were performed in France in 2010 as compared to only 300 in 2009.

on becoming a standard of care

*using constant hazard ratio.

*Using constant hazard ratio

23

Breast4 Lung4 Colorectal4 Prostate4 Ovarian4 Severe Inoperable AS*1

412

30

3

28

5-YeaR suRvIval Rate, %

Increased experience and next-generation technology may lower the incidence of acute major complications:

• Vascular complications (16.2%)2

• Bleeding episodes (16.8%)2

• Strokes (5.0%)2

The PArTNEr Trial, cohort B: Viewpoint from the United kingdom

MArk de BElDEr, MD consultant cardiologist the James cook university Hospital, middlesbrough, uk president, British cardiovascular intervention society.

Patients, primary care physicians, and those with an interest in internal medicine and elderly care medicine must be informed of the new paradigm of care that is emerging.

THIErry lEFèVrE, MD president of the french g.a.c.i. (groupe athérome coronaire et cardiologie interventionnelle) institut cardiovasculaire paris sud, massy, france

NOTE

WORTHY

rEFErENcES

1. Data on file, edwards lifesciences llc.

2. leon mB, smith cr, mack m, et al. transcath-eter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. n engl J med. 2010;363;1597-1607.

3. spertus J, peterson e, conrad mw, et al. monitor-ing clinical changes in patients with heart failure: a comparison of methods. am Heart J. 2005;150:707-715.

4. national institutes of Health. national cancer in-stitute. surveillance epidemiology and end results. cancer fact sheets. http://seer.cancer.gov/statfacts/. accessed november 16, 2010.

Based on 1-year results of cohort B patients treated with the edwards sapien tHv:

TAVItalk TAVItalkJANUAry 2011 EUroPE10 11

for use outside the united states only | not intended for general distribution.

The world, however, was not ready to entertain this concept, and his early attempts to publish his work were rejected by both JACC and Circulation. Three years went by before his idea was published in the European Heart Journal1. Henning’s submissions for oral presenta-tions were also turned down, preventing him from showing his films on just how well this concept worked—even with low budget and suboptimal equipment.

At that time, companies found the idea inconceivable as well, and he had to wait another three years until the concept was embraced by a few champions, and TAVI started to gain interest and momentum. This was further sparked by the success of a first-in-man (FIM) percutaneous pul-monic valve implant (Bonhoeffer, 2000) and the FIM aortic valve implant (Cribier, 2002). Professor Cribier’s early TAVI patients had to be extremely sick, with a required life expectancy of < 7 days, and therefore had very high mortality rates. Still, successful implants were pivotal in showing that this could not only be done in humans, but that they

could also be done leaving the native valve in place (the original intention of early believers was that the native valve material would need to be removed in humans.) Fortunately, Bonhoeffer’s FIM

pulmonic implantation helped people accept the initial and understandably high mortality rates in the early aortic patients, helped deal with the initial scepticism about the procedure in these sicker patients.

Dr. Andersen has several philosophical insights for future inventors and pioneers. “It is usually young people, without exces-sive indoctrination into the established stan-dards, that are open-minded enough to cre-ate these revolutionary ideas—as they are able to look at a situation from a fresh angle and without untoward bias. Always believe in yourself, don’t let doubt get in your way. Be

a dreamer, not a naysayer, and don’t listen to peo-ple who say that some-thing cannot be done. They may just be wrong.”

From ‘foolish idea’ to ‘genius’

1989: Henning Andersen, FIA–aortic2000: Philipp Bonhoeffer, FIM–pulmonic

2002: Alain Cribier, FIM–aortic

Below: The original handmade Andersen THV

hIGh rADIAL StrenGth

The Edwards transcatheter heart valves established a new paradigm in valve delivery, one key feature of this was

the fact they possess a strong supportive frame with high radial strength. The Edwards SAPIEN frame strength has shown throughout its large volume of implants to result in a large effective orifice area, even in heavily calcified an-nuli. It was designed for reliable deployment with nominal diameter which is necessary for proper leaflet coaptation. This high radial strength results in proper haemodynamics and valve durability.

The Edwards SAPIEN XT frame offers comparable radial strength to the original Edwards SAPIEN frame. This was one of the the key design inputs. The new feature of this frame is that it also allows for low profile crimping. In order to com-bine radial strength with low profile crimping the frame geometry and material had to be changed. The new geometry features fewer rows and cobalt chromium to facilitate these two criteria.

ProVen LeAFLet DeSIGn

The Edwards line of transcatheter heart valves share many features that are core to Edwards’ long

history of tissue valve design. The leaflets are made of bovine peri-cardial tissue, which has clinically proven long-term durability. The leaflets undergo the Carpentier-Ed-wards ThermaFix treatment process which is intended to minimise the risk of calcification. The leaflets are all matched for thickness and elas-ticity to promote consistent leaflet function and coaptation.

One new feature of the Edwards SAPIEN XT THV is the new leaflet design. This valve features a proprietary surgical leaflet shape based upon Edwards surgical leaflet shape design; the design has been updated for stress distribution, to support valve durability.

oPtIMAL FrAMe heIGht

A significant design input for the Edwards transcatheter heart valves was to have a frame

height that is designed for proper placement and non-interference with the surround-ing anatomy. The Edwards SAPIEN frame is 14 mm (23 mm valve) and 16 mm (26 mm valve) tall. It is designed to fit within the native annulus, minimising the risk of atrioven-tricular (AV) block and disrup-tion of mitral leaflet function. It is also designed for placement below coronary arteries, allowing clear access for future percutaneous coro-nary interventions (PCIs).

The Edwards SAPIEN XT frame had the same design require-ment. The Edwards SAPIEN XT frame is 14 mm (23 mm valve) and 17 mm (26 mm valve) high.

PreDICtABLe VALVe DePLoYMent

The Edwards SAPIEN THV was delivered transapi-cally with the Ascendra delivery system and trans-

femorally with the RetroFlex 3 delivery system. The de-livery systems were designed for their means of access and featured balloon-expandable delivery engineered for predictably accurate valve placement.

The Edwards SAPIEN XT THV is delivered trans-apically with the Ascendra2 delivery system and transfemorally with the NovaFlex delivery system. Both systems were designed to take advantage of the low profile crimping frame design to decrease their sheath sizes while maintaining the predictable valve placement.

ENGINEERS’ CORNER

Edwards SAPIEN THV Edwards SAPIEN XT THV

comparing Edwards SAPIEN and Edwards SAPIEN xT THVs

The results of The PARTNER Trial validate the balloon-expandable design concept that Edwards released to Europe in late 2007 with the Edwards SAPIEN transcatheter heart valve. Since its release, our team of engineers has worked hard to continue to advance the design of

Edwards’ line of balloon-expandable valves. Utilising clinical feedback and R&D advancements, Edwards released the Edwards SAPIEN XT valve early 2010, and this is the latest generation THV available in Europe.

The Edwards SAPIEN valve product line is based upon four key design elements: proven leaflet design, optimal frame height, high radial strength, and predictable valve deployment. These elements went into the original design of the Edwards SAPIEN valve, and were also the core design criteria for the advanced design of the Edwards SAPIEN XT valve.

Valve size Edwards SAPIEN valve height Edwards SAPIEN XT valve height

23mm

26mm

14mm

16mm

14mm

17mm

When a paradigm shift takes place, a person proves that something can be done that no one ever conceived possible.

nIneteenth CentUrY PArADIGM:

“Don’t touch the heart.” (Stephen Paget,1896 textbook, Surgery of the Chest); “If you touch the heart, you will lose the respect of colleagues.” (Theodor Billroth, 1883).

WWII PArADIGM ShIFt:

When urgent care was needed to treat bullet/grenade wounds in the heart, it became “OK” to open the heart, and it was proven that open heart surgery was possible as an open chest procedure.

hennInG AnDerSen’S PArADIGM ShIFt:

He claimed that implantation of heart valves does not require open

heart surgery, but can be performed as a closed chest procedure. He proved this paradigm shift by performing the first in animal (FIA) closed chest implantation.

Henning Andersen first envisioned the idea of replacing a diseased aortic valve with a stented biological valve without opening the

chest during a 1989 interventional meeting he attended in Scottsdale, Arizona, USA. He arrived back home in Denmark and took on his first challenge for proof of concept. On May 1st, a mere 2 ½ months later, he performed the FIA implantation using a home-made valve-stent made from metal wire and native porcine valves obtained from the local butcher shop. During the following two years, he further improved the technique and performed more than 40 implantations in animals to provide evidence for the new paradigm.

An idea before its time: How shifting paradigms have led to today’s TAVIAN INTErVIEw wITH

HENNING rUD ANDErSEN

lAkSEN SIrIMANNE vice-president, research & Development, tHv, edwards lifesciences

rEFErENcES:

1. andersen, Hr et al, transluminal implantation of artificial heart valves. Description of a new expandable aortic valve and initial results with implantation by catheter technique in closed chest pigs, eur Heart J (1992) 13 (5): 704-708.

SAPIen xt thV with novaFlex delivery system

 

TAVItalk TAVItalkJANUAry 2011 EUroPE10 11

for use outside the united states only | not intended for general distribution.

The world, however, was not ready to entertain this concept, and his early attempts to publish his work were rejected by both JACC and Circulation. Three years went by before his idea was published in the European Heart Journal1. Henning’s submissions for oral presenta-tions were also turned down, preventing him from showing his films on just how well this concept worked—even with low budget and suboptimal equipment.

At that time, companies found the idea inconceivable as well, and he had to wait another three years until the concept was embraced by a few champions, and TAVI started to gain interest and momentum. This was further sparked by the success of a first-in-man (FIM) percutaneous pul-monic valve implant (Bonhoeffer, 2000) and the FIM aortic valve implant (Cribier, 2002). Professor Cribier’s early TAVI patients had to be extremely sick, with a required life expectancy of < 7 days, and therefore had very high mortality rates. Still, successful implants were pivotal in showing that this could not only be done in humans, but that they

could also be done leaving the native valve in place (the original intention of early believers was that the native valve material would need to be removed in humans.) Fortunately, Bonhoeffer’s FIM

pulmonic implantation helped people accept the initial and understandably high mortality rates in the early aortic patients, helped deal with the initial scepticism about the procedure in these sicker patients.

Dr. Andersen has several philosophical insights for future inventors and pioneers. “It is usually young people, without exces-sive indoctrination into the established stan-dards, that are open-minded enough to cre-ate these revolutionary ideas—as they are able to look at a situation from a fresh angle and without untoward bias. Always believe in yourself, don’t let doubt get in your way. Be

a dreamer, not a naysayer, and don’t listen to peo-ple who say that some-thing cannot be done. They may just be wrong.”

From ‘foolish idea’ to ‘genius’

1989: Henning Andersen, FIA–aortic2000: Philipp Bonhoeffer, FIM–pulmonic

2002: Alain Cribier, FIM–aortic

Below: The original handmade Andersen THV

hIGh rADIAL StrenGth

The Edwards transcatheter heart valves established a new paradigm in valve delivery, one key feature of this was

the fact they possess a strong supportive frame with high radial strength. The Edwards SAPIEN frame strength has shown throughout its large volume of implants to result in a large effective orifice area, even in heavily calcified an-nuli. It was designed for reliable deployment with nominal diameter which is necessary for proper leaflet coaptation. This high radial strength results in proper haemodynamics and valve durability.

The Edwards SAPIEN XT frame offers comparable radial strength to the original Edwards SAPIEN frame. This was one of the the key design inputs. The new feature of this frame is that it also allows for low profile crimping. In order to com-bine radial strength with low profile crimping the frame geometry and material had to be changed. The new geometry features fewer rows and cobalt chromium to facilitate these two criteria.

ProVen LeAFLet DeSIGn

The Edwards line of transcatheter heart valves share many features that are core to Edwards’ long

history of tissue valve design. The leaflets are made of bovine peri-cardial tissue, which has clinically proven long-term durability. The leaflets undergo the Carpentier-Ed-wards ThermaFix treatment process which is intended to minimise the risk of calcification. The leaflets are all matched for thickness and elas-ticity to promote consistent leaflet function and coaptation.

One new feature of the Edwards SAPIEN XT THV is the new leaflet design. This valve features a proprietary surgical leaflet shape based upon Edwards surgical leaflet shape design; the design has been updated for stress distribution, to support valve durability.

oPtIMAL FrAMe heIGht

A significant design input for the Edwards transcatheter heart valves was to have a frame

height that is designed for proper placement and non-interference with the surround-ing anatomy. The Edwards SAPIEN frame is 14 mm (23 mm valve) and 16 mm (26 mm valve) tall. It is designed to fit within the native annulus, minimising the risk of atrioven-tricular (AV) block and disrup-tion of mitral leaflet function. It is also designed for placement below coronary arteries, allowing clear access for future percutaneous coro-nary interventions (PCIs).

The Edwards SAPIEN XT frame had the same design require-ment. The Edwards SAPIEN XT frame is 14 mm (23 mm valve) and 17 mm (26 mm valve) high.

PreDICtABLe VALVe DePLoYMent

The Edwards SAPIEN THV was delivered transapi-cally with the Ascendra delivery system and trans-

femorally with the RetroFlex 3 delivery system. The de-livery systems were designed for their means of access and featured balloon-expandable delivery engineered for predictably accurate valve placement.

The Edwards SAPIEN XT THV is delivered trans-apically with the Ascendra2 delivery system and transfemorally with the NovaFlex delivery system. Both systems were designed to take advantage of the low profile crimping frame design to decrease their sheath sizes while maintaining the predictable valve placement.

ENGINEERS’ CORNER

Edwards SAPIEN THV Edwards SAPIEN XT THV

comparing Edwards SAPIEN and Edwards SAPIEN xT THVs

The results of The PARTNER Trial validate the balloon-expandable design concept that Edwards released to Europe in late 2007 with the Edwards SAPIEN transcatheter heart valve. Since its release, our team of engineers has worked hard to continue to advance the design of

Edwards’ line of balloon-expandable valves. Utilising clinical feedback and R&D advancements, Edwards released the Edwards SAPIEN XT valve early 2010, and this is the latest generation THV available in Europe.

The Edwards SAPIEN valve product line is based upon four key design elements: proven leaflet design, optimal frame height, high radial strength, and predictable valve deployment. These elements went into the original design of the Edwards SAPIEN valve, and were also the core design criteria for the advanced design of the Edwards SAPIEN XT valve.

Valve size Edwards SAPIEN valve height Edwards SAPIEN XT valve height

23mm

26mm

14mm

16mm

14mm

17mm

When a paradigm shift takes place, a person proves that something can be done that no one ever conceived possible.

nIneteenth CentUrY PArADIGM:

“Don’t touch the heart.” (Stephen Paget,1896 textbook, Surgery of the Chest); “If you touch the heart, you will lose the respect of colleagues.” (Theodor Billroth, 1883).

WWII PArADIGM ShIFt:

When urgent care was needed to treat bullet/grenade wounds in the heart, it became “OK” to open the heart, and it was proven that open heart surgery was possible as an open chest procedure.

hennInG AnDerSen’S PArADIGM ShIFt:

He claimed that implantation of heart valves does not require open

heart surgery, but can be performed as a closed chest procedure. He proved this paradigm shift by performing the first in animal (FIA) closed chest implantation.

Henning Andersen first envisioned the idea of replacing a diseased aortic valve with a stented biological valve without opening the

chest during a 1989 interventional meeting he attended in Scottsdale, Arizona, USA. He arrived back home in Denmark and took on his first challenge for proof of concept. On May 1st, a mere 2 ½ months later, he performed the FIA implantation using a home-made valve-stent made from metal wire and native porcine valves obtained from the local butcher shop. During the following two years, he further improved the technique and performed more than 40 implantations in animals to provide evidence for the new paradigm.

An idea before its time: How shifting paradigms have led to today’s TAVIAN INTErVIEw wITH

HENNING rUD ANDErSEN

lAkSEN SIrIMANNE vice-president, research & Development, tHv, edwards lifesciences

rEFErENcES:

1. andersen, Hr et al, transluminal implantation of artificial heart valves. Description of a new expandable aortic valve and initial results with implantation by catheter technique in closed chest pigs, eur Heart J (1992) 13 (5): 704-708.

SAPIen xt thV with novaFlex delivery system

 

Edwards lifesciences irvine, usa i nyon, switzerland i tokyo, Japan i singapore, singapore i são paulo, Brazil edwards.com

TAVItalk EUroPE | JANUAry 201112

The ‘Nautilus” depicts the evolution and momentum of the Edwards Lifesciences global clinical research program for TAVI.

The year 2010 saw the results of TRAVERCE, PARTNER EU, The SOURCE Registry and The PARTNER Trial all published in peer reviewed journals. Each study and manuscript reflect upon unique aspects of the TAVI experience, from feasibility through randomised controlled pivotal trials and extensive post-market surveillance of real world practice.

the trAVerCe StUDY was the first study to assess transapical delivery of the SAPIEN valve. Reporting more than three year follow-up, the TRAVERCE study demonstrates durable haemodynamic outcomes of the Edwards SAPIEN valve. The PARTNER EU study holds particular importance in that it is the first “Heart Team”-based trial in TAVI, and created the paradigm leading to the piv-otal PARTNER Trial itself. The SOURCE Registry, reporting on a second full year of consecutive enrolment, continues to bench-mark the TAVI experience in the real world. The significance of the SOURCE Registry is that it provides reliable and interpretable data sets for the examination of learning curves, trends in outcomes over time and across regions and inspires hypotheses for new in-vestigations. The success of this registry in-spired a more in-depth look at post-market TAVI experience leading to the development of The SOURCE XT Registry. This study, recently initiated, includes more instruments such as the “Frailty Index” and “EuroQOL survey”. It will also include adjudication of major adverse events in accordance with VARC endpoint definitions. Other new features of The SOURCE XT Registry include a rich website dedicated for investigators (www.thesourceregistry.com), an expanded Executive Committee, and a Safety Committee comprised of independent physician adjudica-tors, as well as expanded monitoring.UneqUIVoCAL ProoF. Finally, as has been broadly communicated in the clinical and scientific arenas, the investigators of The PARTNER Trial reported the world’s first randomised controlled data in TAVI comparing TAVI to medical management (including BAV) control. The PARTNER Trial proved unequivocally that TAVI saves and im-proves the quality of life in patients with critical aortic stenosis who

cannot otherwise undergo surgical aortic valve surgery. We anticipate many more publications to come in 2011, including results from the Cohort A (high risk surgery versus AVR) arm as well as numerous sub-group analyses.

Probably the most important aspect of the Edwards TAVI clinical programs is the oft-cited and important theme of dedicated scientific and clinical leadership demonstrated by the study investigators them-

selves. Each study has a dedicated Execu-tive Committee as well as Co-Principal In-vestigators representing the cardiac surgery and interventional cardiology disciplines. Also of note, the tireless commitment of investigators across all of our trials which has led to the initiative for the harmonisa-tion of TAVI endpoints. This effort resulted in the publication of the VARC guidelines which now serve as a foundational refer-ence for new trials such as The SOURCE XT Registry and The PARTNER II Trial, both recently initiated. In 2011, we aim to provide more forums for our investigators around the globe to come together and dis-cuss ways to coordinate research efforts.

5,000 PAtIentS enroLLeD. In total, more than 5,000 patients have been enrolled in Edwards TAVI clinical studies to date. Each of these studies has a unique methodology and purpose, and each is designed to pro-

vide evidence to inform and guide TAVI practice for the future. Be-cause of the rigour, completeness of data and independent oversight of the trial processes, Edwards TAVI studies impact regulatory approvals worldwide, as well as inform decisions for reimbursement and econom-ic analyses and technology assessments.

Our commitment to continued leadership in clinical research is un-wavering. In 2011 we will see enrolment in four new trials (SOURCE XT, PREMIER [pulmonic] Registry, The PARTNER II Trial and a Valve-in-Valve study), as well as continued follow-up and publication of results from all of the trials previously reported.

We wish to thank all of our investigators and scientific collaborators such as statisticians, clinical event adjudicators, core laboratories and thought leaders for their collective expertise and contributions to these important programs.

The Edwards SAPIEN transcatheter heart valve and delivery systems bearing the CE conformity marking comply with the requirements of the European Medical Device Directive 93/42/EEC.

Caution: Not intended for US distribution.

Edwards is a trademark of Edwards Lifesciences Corporation. Edwards Lifesciences, the stylized E logo, The stylized Edwards logo, Edwards SAPIEN, Edwards SAPIEN XT, TRAVERCE, PARTNER, PARTNER II, PREMIER, Ascendra2, NovaFlex and RetroFlex 3 are trademarks of Edwards Lifesciences Corporation and registered in the United States Patent and Trademark Office.

Edwards Lifesciences, S.A. Route de l’Etraz 70, 1260 Nyon, Switzerland Tel: +41 22 787 4362.

Additional company information can be found at http://www.edwards.com

TAVItalk

PUBLISHER: Edwards Lifesciences, S.A., Europe EDITORIAL AND DESIGN SERVICES: SAVIpartners, Paris and New York CONTACT INfORmATION: For general information on the Edwards TAVI Programme, please contact TAVItalk@edwards.com

E1803/01-11/THV

For professional use. For additional information, indications, contraindications, warnings, precau-tions and adverse events, please refer to the Instructions For Use provided with the products.

The ‘Nautilus’: Edwards’ clinical history of TAVI

COmPANy AND PRODUCT INfORmATION

JoDI AkINvice president, global clinical affairs, edwards lifesciences