TRIAL EVIDENCE OF TAVIDr.Praveen Nagula

Edwards SAPIEN valve April 16,2002 first case report. From 2003 -2004, single center registeries - for feasibility. I REVIVE – Initial Registry of Endovascular Implantation of Valves in Europe RECAST – Registry of Endovascular Critical Aortic Stenosis Treatment.

o 23 mm bioprosthesis o Equine pericardium mounted on a stainless steel balloon expandable stento Antegrade (trans septal ) approach.o Procedural success – 75%.o Aortic valve area increased consistently from 0.6 cm2 to 1.6 cm2.o Fall in mean trans valvular gradient (37 mm Hg to 9 mm Hg).o Increase in LVEF (45% +18% to 53% +14%) o 30 day mortality rate was 23%.o MACCEs – 26%.o Patient survival was 63% by 6 months.o Moderate to severe perivalvular AR (63%), valve embolization were limitations of the

procedure.

Overcoming the limitations

To reduce the degree of the perivalvular aortic insufficiency – valves were oversized in relation to the aortic annulus – 26 mm size prosthesis became available.

Appropriate valve sizing – transverse diameter of the aortic annulus at the level of the aortic leaflet insertion.

Retroflex catheter – atraumatic passage across the aortic arch, facilitated passage through retrograde approach.

Sheath length was increased to deliver the catheter-valve ensembly directly into the descending aorta.

Minimal arterial diameter, vessel tortuoisity and vessel calcification were still the major limiting factors.

The approval of valve (CE)

REVIVAL II REVIVE Canada (Canadian Special Access) Valve area < 0.8 cm2 High predictive operative mortality >20%. New valve modifications were included.

o Use of bovine pericardiumo Increase of the skirt to decrease the perivalvular insufficiency.o Addition of the anticalcification treatment

Webb et al – retrograde approach – 78% success – 96% after 25 cases. 30 day mortality was 12%(expected was 28%). Moderate perivalvular leaks in 3 patients at 1 month. Led to valve approval and commercialization in Europe in 2007

Trans apical approach Most recently developed form of transcatheter AVR. First reported by Lichtenstein 7 patients with severe AS. Valve implantation was successful in all of them. No Procedural deaths. Results were consistent with that of the retrograde approach. Observed 30 day mortality was 14%(expected 35%). Walther et al – 93.2% successful implantation. Conversion rate to conventional AVR -6.8%. Trace to mild AR - 23 patients. 30 day mortality was 13.6%(26.8%) Use of extracorporeal life support was frequent(47%)

U.S. feasibility study Rate of 90% successful valve placements. Persistent improvement in symptoms,valve area,mean

gradient,aortic insufficiency and quality of life(Qol). Survival

MACCEs were seen in 65%

1 month 81.8%3 months 71.7%6 months 58.7%

Stroke 5%

Emergent cardiac surgery 2.5%

Myocardial infarction 17.5%

Svensson LG,Kapadia S,et al. Ann Thorac Surg 86;46-55,2008.

No. of Patients 1123Centers in Europe 32 centersProcedural success 93.8%

30 day mortality was 6.3%Mean survival was 74%

NYHA class improvement was 86% at 30 days (p<0.001)Mean gradient decreased from 46.1 mm hg to 11.2 mm Hg

No valve deterioration structurally.

SOURCE Registry

Vascular complications 8.3% transfemoral approach ,hemodynamic support in 0.9%,

tamponade in 4%,PPI in 4.4%,

infection in 2.4%,stroke in 5.3%. AF 12%

The Trans apical paradox Trans apical approach is associated with high mortality not because of

procedure but because of increased comorbidities and age of the patient.

To date, transfemoral approach is the default one and transapical is offered only to those who donot qualify for transfemoral approach.

Comparison of SAVR and trans apical TAVR – similar operative mortality,similar 1 yr survival,shorter ICU stay and shorter duration of mechanical ventilation.

Trans apical is complementary to trans femoral approach.

Canadian Edwards SAPIEN Registry

2005-2009. 339 patients(high risk) 49.6% trans femoral ,50.4% - trans apical Procedural success was 93.3%. 30day mortality was 10.4%. Mortality increased to 22% at mean follow up of 8 months –

COPD,CKD, Periprocedural sepsis – independent predictors. Patients with porcelain aorta had better survival at 1 yr follow

up.

FRANCE RegistryFrench Aortic National Corevalve and Edwards Registry

19 sites in France. Valve area <0.6cm2.

Edwards SAPIEN Core ValveTrans femoral 39% 27%Trans apical 29%Sub clavian 5%

ResultsDeath at 30 days 13%

stroke 4%Vascular complications 7%Transfusions > 1 unit 21%

Need for PPI High in Core Valve groupMean survival was 76.5%

Mean valvular gradients were 10 mmHg

NYHA Ior II 86%

PARTNER European RegistryPrimary Safety end point Freedom from death from the index procedure to 30 days and 6

months.Primary efficacy end point Hemodynamic status of the valve,QoL,NYHA class improvement at

12 months after implantation. Inclusion criteria Logistic Euro SCORE >20%

STS score >10% if the earlier was less than 20%

Porcelain aorta or chest deformities

All patients had Senile degenerative aortic stenosis (<0.8cm2,PG >40mm Hg,AJV>4m/sec)

Mean patient age was 82 yrs

Clinical status 84% of transfemoral ,85% of trans apical – NYHA III,IV

Post procedure Mean gradient fell to 10 mm Hg,valve are increased to 1.6cm2.

NYHA class improvement 60% had improved to NYHA I/II at 6 months,1yr.

Survival at 18 months Transfemoral 71%,transapical 44% (not comparable )

PARTNER US RegistryPlacement of AoRTic traNscathetER

Severe symptomatic AS patients. Cohort A – powered for noninferiority analysis

o traditional AVR vs TAVI o 700 patients

Cohort B – powered for superiority analysiso 358 patientso Optimal medical treatment(including BAV ) vs TAVI

Cohort C – frail patientso Who die with aortic stenosis but not because of aortic stenosis.

Results of Cohort A AVR TAVI P valueAll cause mortality 50.7% 30.7% <0.001

CV mortality 41.9% 19.6% <0.001Repeat hospitalization 44.1% 22.3% <0.001

Death or repeat hospitalization

(composite end point)

72.6% 42.5% <0.001

Follow up No degenerationNo re stenosis

Less HF symptomsVascular complications 1.1% 16.2% <0.001

Major bleeding 11.2% 22.3% <0.001Major strokes 1.1% 5.5% 0.06

In patients with severe AS who are not suitable for AVR,

TAVI should be the new standard of care

Cohort B results

Five-Year Outcomes of Transcatheter Aortic Valve Replacement (TAVR) in “Inoperable” Patients With Severe Aortic Stenosis: The PARTNER Trial

PARTNER Study Design

N = 358Inoperable

StandardTherapyn = 179

ASSESSMENT: Transfemoral

Access

TF TAVRn = 179

Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority)

1:1 Randomization

VS

Symptomatic Severe Aortic Stenosis

• Primary endpoint evaluated when all patients reached one year follow-up.• After primary endpoint analysis reached, patients were allowed to cross-over to

TAVR.

Severe Symptomatic AS with AVA< 0.8 cm2 (EOA index < 0.5 cm2/m2), and mean gradient > 40 mmHg or jet velocity > 4.0 m/s

Inoperable defined as risk of death or serious irreversible morbidity of AVR as assessed by cardiologist and two surgeons exceeding 50%.

Key End-Points for 5 Year Analysis

• All-Cause Mortality

• Cardiac Mortality

• Re-hospitalization

• Stroke

• NYHA functional class

• Echo-derived valve areas, transvalvular gradients, and paravalvular leak.

• Mortality outcomes stratified by STS score, paravalvular leak and age.

N = 358Randomized Inoperable

N = 179TAVR

N = 179Standard Therapy

124 / 124 patients100% followed at 1 Yr

85 / 85 patients100% followed at 1 Yr

81 / 83 patients97.6% followed at 3 Yrs

19 / 19 patients100% followed at 3 Yrs

Study FlowInoperable Cohort

50 / 51 patients98.0% followed at 5 Yrs*

6 / 6 patients100% followed at 5 Yrs*

Cross Over 11 pts

Cross Over 9 pts

10 Patients Withdrew

* ± 2 months follow-up window

Patient CharacteristicsCharacteristic TAVR

N = 179Standard Rx

N = 179p-value

Age – yr 83.1 ± 8.6 83.2 ± 8.3 0.95Male sex (%) 45.8 46.9 0.92STS Score 11.2 ± 5.8 12.1 ± 6.1 0.14NYHA I or II (%) III or IV (%)

7.892.2

6.193.9

0.680.68

CAD (%) 67.6 74.3 0.20COPD Any (%) O2 dependent (%)

41.321.2

52.525.7

0.040.38

Creatinine > 2 mg/dL (%) 5.6 9.6 0.23Frailty (%) 18.1 28.0 0.09Porcelain aorta (%) 19.0 11.2 0.05Chest wall radiation (%) 8.9 8.4 1.00

Clinical Observations

• Mortality benefit was similar in elderly (>85 yr) patients compared to those ≤85 years.

• Cardiovascular mortality and all-cause mortality benefit was seen even in patients with high STS score.

• Patients with O2 dependent COPD may have less mortality benefit.

• Beyond early procedural risk of stroke there was no persistent risk over 5-year follow up.

• Moderate and severe paravalvular leak is associated with higher cardiovascular mortality particularly in patients with less comorbidities.

Main Conclusions

• At 5 years follow-up benefits of TAVR were sustained as measured by:– All-Cause Mortality – Cardiovascular Mortality– Repeat Hospitalization– Functional Status

• Valve durability was demonstrated with no increase in transvalvular gradient or attrition of valve area.

Core Valve Revalving System

USA Corevalve Pivotal Trial

Safety and efficacy of the CoreValve Revalving System in two cohorts of patients.

1 end point - 12 month all cause mortality or major stroke.

30 day risk of mortality

No. of patients

First Cohort Extreme risk for surgery (sAVR) or Inoperable for sAVR

>50% 487 pts

Subclavian –axillaryTrans aortic access

100 pts

Second cohort High risk for surgery (sAVR)

>15% 790 pts

SURTAVI Safety and Efficacy Study of the Medtronic CoreValve®

System in the Treatment of Severe, Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI).

intermediate risk [ STS score of 3-8% ]

SURTAVI Surgical Replacement and Transcatheter Aortic Valve

Implantation Multicenter randomized clinical study. Europe. Broader group of patients( intermediate risk for SAVR ) Safety and efficacy of TAVI vs SAVR Heart team approach is used.

ADVANCE Long term and real world impact of TAVI therapy. Prospective,observational international post market study to

evaluate clinical outcomes of patients with severe AS. 1000 patients 90 sites. Followed up for atleast 5 years after the implantation. 1 end point - MACCEs at 30 days after the procedure.

ADVANCE II Enrollment of 100 patients in 7 to10 experienced CoreValve

European sites Characterize implantation procedures at best european sites. Intermediate term outcomes in high risk patients. Best practice event rates. 30 day and 1 yr mortality Stroke Vascular complications AR Development of conduction disturbance requiring PPP.

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