**3. Evolution of TAVR: indications and clinical trial evidence for TAVR**

After initial success with the Sheep model, first human implantation with the balloon expandable Edwards valve was done on 16th April 2002 after failed emergency BAV as a bailout procedure [4].

After encouraging initial results, Dr. Cribier and team were able to recapitulate TAVR in a few patients. Worldwide demonstrations of this innovative therapy led to its increased acceptance. TAVR was transforming from a crazy idea to a viable therapy option. The Cribier valve technology was acquired by Edwards Lifesciences (Irvine, CA) for further development, and the THV was further marketed as Edwards Sapien valve.

Simultaneously scientists from Europe were working on a self-expandable valve (CoreValve, Medtronic, Inc.; Minneapolis, MN) platform as an alternative to balloon expandable valve since 2004 and human implantations were being done successfully.

As the number of TAVR implantations increased, data from multiple small studies and registries like SOURCE, ADVANCE, FRANCE I and FRANCE II showed procedural success (30 days survival) ranging from 67–92%.

With the available data, the European CE mark authorization was granted in August 2007 for the Edwards Sapien balloon expandable THV with the transfemoral RetroFlex delivery system and in January 2008 for use with the transapical Ascendra delivery device.

PARTNER was the first randomized trial that compared TAVR with standard therapy. Cohort B of this landmark trial demonstrated superiority of TAVR over medical therapy in patients with severe symptomatic AS who were considered extreme (or prohibitive) risk for SAVR. At 1 year follow up, absolute risk reduction in all-cause mortality of 20% was observed, a finding which held true even at 5 years follow up [7].

Cohort A of PARTNER trial compared TAVR with SAVR and showed that TAVR was non-inferior to SAVR in patients with high surgical risk (society of thoracic surgeons (STS) score >8%). CoreValve extreme risk trial data showed benefit of TAVR with reduction in all-cause mortality.

In November 2011, United States Food and Drug Administration (US FDA) approved TAVR as a treatment option for patients with symptomatic severe AS who were considered inoperable for SAVR. Favourable clinical data using self-expanding THV CoreValve (Medtronic) led to its USFDA approval in 2014 on similar patient subset.

With the available evidence from randomised control trials (RCTs) and multiple registry data, TAVR was given Class I LOE B recommendation in patients with prohibitive (not suitable for SAVR) and increased surgical risk by ESC guidelines [8] and Class I LOE A by ACC/AHA guidelines [9].

Another important observation noted in PARTNER 1 trial was diminishing survival benefit of TAVR with higher STS score. This led to stress more importance on patient selection.

Intermediate surgical risk (STS score ≥4–8%) patients with symptomatic severe AS were enrolled in PARTNER 2 trial comparing TAVR using second generation Sapien valve (Sapien XT) with SAVR along with subgroup analysis of transfemoral and transthoracic cohorts. All-cause mortality in TAVR arm was non-inferior to SAVR at 2 years with comparable stroke and permanent pacemaker rates.

The SURTAVI (surgical replacement and transcatheter aortic valve implantation) trial used Self-expandable CoreValve and enrolled patients with symptomatic severe AS with intermediate surgical risk and showed all-cause mortality in TAVR group non-inferior to SAVR at 1 and 2 years.

PARTNER 2 and SURTAVI trials also showed a favourable decreasing trend in all-cause mortality and post-procedure stroke rates (refer to **Table 2**).

ACC/AHA has given Class II LOE (level of evidence) A recommendation for TAVR in intermediate-risk population [9].

With the availability of 5-year data on TAVR showing good valve durability, focus of attention shifted to extend the benefit of TAVR to low-risk population with severe AS.

NOTION trial [10] and low-risk TAVR trial [11] evaluated the role of TAVR in low-risk population (STS score <4%).

NOTION trial is one of the earliest randomized trials, started recruiting patients in 2009 in a single centre. NOTION trial enrolled patients with symptomatic severe AS with low surgical risk and randomized them to TAVR versus SAVR. All-cause mortality at 1 year seen in this study was lower in TAVR arm compared to SAVR, an effect that persisted at 5 years.

The post-procedure permanent pacemaker implantation (PPI) rates and PVL (paravalvular leak) were higher in the TAVR group. Despite higher PPI and PVL rates, the all-cause mortality was lower with TAVR than SAVR. Higher PPI rates were because of an overenthusiastic approach for pacemaker implantation in view of lack of experience during those days.

The above-mentioned trials showed a consistent reduction in 30 days all-cause mortality attributed to improved technical advances, procedural skills and better patient selection (refer to **Table 2**).


**Table 2.**

rupture.

**53**

*Clinical trials data.*

prosthetic aortic valve qualify for TAVR.

TAVR valve is still a concern.

patients with higher surgical risk profile.

label TAVR (6.1%) [12].

gradients and a higher risk of coronary obstruction.

Issues related to the use of TAVR in BiV are:

*Transcatheter Aortic Valve Replacement: Clinical Indications and Outcomes*

A valve in valve (ViV), by virtue of the procedure being a re-do sternotomy, with patients typically in their 70 and 80s age, they usually fall into an intermediate risk category for surgical treatment. Most of the patients with degenerated bio

The main issues with ViV are under expansion of the valve leading to higher

Bicuspid aortic valve (BiV), not approved, TAVR had been used off-label in BiV.

Large annulus with severe and asymmetric calcification or presence of raphe can hinder with positioning and expansion of the valve that can lead to PVL or annulus

Increased risk of aortic dissection or rupture in view of concomitant aortopathy. In view of relatively young patients with longer life expectancy, the durability of

A study by Ravi et al., which included 435 patients with BiV, showed higher 30 days all-cause mortality with off label TAVR (8.5%) when compared with on

Outcomes are not as favourable as tricuspid valve, still a valid alternative in

*DOI: http://dx.doi.org/10.5772/intechopen.84909*

*Transcatheter Aortic Valve Replacement: Clinical Indications and Outcomes DOI: http://dx.doi.org/10.5772/intechopen.84909*


#### **Table 2.**

*Aortic Stenosis - Current Perspectives*

severe AS.

TAVR in intermediate-risk population [9].

low-risk population (STS score <4%).

of lack of experience during those days.

patient selection (refer to **Table 2**).

effect that persisted at 5 years.

PARTNER 2 and SURTAVI trials also showed a favourable decreasing trend in

ACC/AHA has given Class II LOE (level of evidence) A recommendation for

With the availability of 5-year data on TAVR showing good valve durability, focus of attention shifted to extend the benefit of TAVR to low-risk population with

NOTION trial [10] and low-risk TAVR trial [11] evaluated the role of TAVR in

The post-procedure permanent pacemaker implantation (PPI) rates and PVL (paravalvular leak) were higher in the TAVR group. Despite higher PPI and PVL rates, the all-cause mortality was lower with TAVR than SAVR. Higher PPI rates were because of an overenthusiastic approach for pacemaker implantation in view

The above-mentioned trials showed a consistent reduction in 30 days all-cause mortality attributed to improved technical advances, procedural skills and better

NOTION trial is one of the earliest randomized trials, started recruiting patients in 2009 in a single centre. NOTION trial enrolled patients with symptomatic severe AS with low surgical risk and randomized them to TAVR versus SAVR. All-cause mortality at 1 year seen in this study was lower in TAVR arm compared to SAVR, an

all-cause mortality and post-procedure stroke rates (refer to **Table 2**).

**52**

*Clinical trials data.*

A valve in valve (ViV), by virtue of the procedure being a re-do sternotomy, with patients typically in their 70 and 80s age, they usually fall into an intermediate risk category for surgical treatment. Most of the patients with degenerated bio prosthetic aortic valve qualify for TAVR.

The main issues with ViV are under expansion of the valve leading to higher gradients and a higher risk of coronary obstruction.

Bicuspid aortic valve (BiV), not approved, TAVR had been used off-label in BiV. Issues related to the use of TAVR in BiV are:

Large annulus with severe and asymmetric calcification or presence of raphe can hinder with positioning and expansion of the valve that can lead to PVL or annulus rupture.

Increased risk of aortic dissection or rupture in view of concomitant aortopathy. In view of relatively young patients with longer life expectancy, the durability of

TAVR valve is still a concern.

A study by Ravi et al., which included 435 patients with BiV, showed higher 30 days all-cause mortality with off label TAVR (8.5%) when compared with on label TAVR (6.1%) [12].

Outcomes are not as favourable as tricuspid valve, still a valid alternative in patients with higher surgical risk profile.
