Expanding indications for transcatheter aortic valve replacement Expert Review of Cardiovascular Therapy 2014.12:693-702. Downloaded from by Emory University on 04/21/15. For personal use only.

Expert Rev. Cardiovasc. Ther. 12(6), 693–702 (2014)

Gabriel Maluenda*1 and Danny Dvir2 1 Cardiovascular Center, Hospital San Borja Arriaran, School of Medicine, University of Chile, Santiago, Chile 2 Department of Cardiology, St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada *Author for correspondence: Tel.: +56 2574 9342 [email protected]

Transcatheter aortic valve replacement (TAVR) has emerged as an accepted indication for non-operable patients with severe symptomatic native aortic valve stenosis (AS) and as a reasonable alternative for high-risk surgical AS patients. Nonetheless, the safety and efficacy of performing TAVR in several other potential indications are yet unclear. In the present manuscript the authors review the current evidence supporting TAVR for other potential indications than the typical high-risk/non-operable AS patients, providing updated results of the main clinical trials and registries exploring these particular indications. Finally, the authors provide practical recommendations for TAVR in each of these conditions. KEYWORDS: aortic regurgitation • aortic stenosis • bicuspid aortic stenosis • moderate risk • transcatheter aortic valve replacement • valve-in-valve

The Medtronic CoreValve (Medtronic, Minneapolis, MN, USA) and Edwards SAPIEN (Edwards LifeSciences, Irvine, CA, USA) transcatheter heart valve (THV) prostheses obtained European mark approval in 2007, to treat high or prohibitive surgical risk patients with severe aortic stenosis (AS). Following the clinical results of the placement of aortic transcatheter valves (PARTNER) B trial [1], the US FDA commercially approved SAPIEN heart valve in November 2011 to treat inoperable patients with severe AS. Recently, according to the result of the CoreValve Extreme Risk study presented at TCT 2013 [2], the FDA has approved the CoreValve use for patients who are unable to undergo surgical aortic valve replacement (SAVR) [3]. Adding to this evidence, the recently published results presented at ACC 2014 of transcatheter AVR(TAVR) with CoreValve self-expandable THV in moderate- to high-risk AS patients compared with SAVR showed a significant reduction in mortality at 1-year follow-up [4]. Although similar to off-label indications use of coronary stent, patient selection criteria for TAVR are moving away from the premarket inclusion and exclusion criteria, a paradigm shift directed to treating lower risk patients [5]. Additionally, several other indications for TAVR have already gained room to treat high-risk/nonoperable


surgical candidates with THV including failed bioprosthesis valves, bicuspid AS and pure aortic regurgitation (AR). In the present article, we review in deep the current evidence supporting TAVR for different potential indications compared with the typical high-risk/ nonoperable AS patients, providing updated results on the main clinical trials and registries exploring these particular indications. TAVR for intermediate risk AS Rational to expand indication to moderate-risk patients

The introduction of novel technology into the cardiovascular field has been a breakthrough story. THV technology was challenged to prove safety and efficacy to treat high-risk AS population deemed to standard AVR, regardless of the outstanding clinical results previously published in octogenarians undergoing SAVR at large referring centers [6,7]. First, it was necessary to prove the concept, providing initial evidence from animal models [8], followed by first-in-man studies [9] to then demonstrate safety in order to move to treat patients in larger clinical series [10]. Second, large-scale randomized clinical trials (RCTs) were required. The PARTNER-B trial [1] was conducted to demonstrate superiority of TAVR over ‘standard therapy’, which included

 2014 Informa UK Ltd

ISSN 1477-9072



Maluenda & Dvir

August 2007–October 2011

Heart team decision 50

Consecutive TAVI patients n = 389

Expert Review of Cardiovascular Therapy 2014.12:693-702. Downloaded from by Emory University on 04/21/15. For personal use only.


Cardiovascular death (%)


45 40

Low vs high: RR (95% Cl) = 0.16 (0.04–0.70) Intermediate vs high: RR (95% Cl) = 0.35 (0.19–0.62) p < 0.001

35 High STS score

30 25 20 15

Intermediate STS score

10 5 Low STS score

0 n = 41

n = 254

n = 94


30 60 90 120 150 180 210 240 270 300 330 365 Days since TAVI

Figure 1. Cumulative incidence of all-cause mortality among patients with low (red line, STS score 8). STS: Society of Thoracic Surgeons; TAVI: Transcatheter aortic valve implantation.

medical treatment and balloon aortic valvuloplasty, the only available option at the moment for severe AS patients deemed to AVR due to aging or comorbidities. This study design will probably never be repeated again since TAVR proved to be superior to ‘standard therapy’. Consequently, the extreme risk CoreValve Cohort study [2], conducted in a registry fashion, demonstrated TAVR to be as effective as a predefined performance goal. In addition, the PARTNER-A [11] showed TAVR to be as effective as standard AVR. The exposed evidence has led the FDA to approve TAVR with Sapien THV for inoperable and high-risk surgical candidates and the CoreValve THV for extreme risk AS patients. Although TAVR has proven to be as safe as SAVR in reducing the rate of major bleeding and blood transfusions in high-risk patients [12], safety issues such as periprocedural stroke, paravalvular leak and prosthesis durability remain as the main concerns that will be clarified with larger and longer follow-up of the ongoing RCT and registries. However, moving to treat lower risk AS patients is not only the next natural step, but it is also greatly needed since the occurrence of periprocedural complications is expected to be lower than in high-risk patients, making TAVR use particularly attractive for this target population. Following this rationality, a natural shift to treat lower risk patient has occurred within the time in large TAVR European centers. Indeed, a retrospective cohort of 420 patients treated between 2007 and 2010 at the German Heart Center (Munich) pointed out a shift to treat lower risk patients during the timeline period analyzed into quartiles (Q1–Q4) [13]. Compared with Q4 patients, Q1 patients had higher logistic Euro-SCORES (25.4 ± 16.1% vs 17.8 ± 12.0%; p < 0.001), higher Society of Thoracic Surgeons (STS) scores (7.1 ± 5.5% vs 4.8 ± 2.6%; p < 0.001) and higher median N-terminal pro-B-type natriuretic peptide levels (3495 vs 1730 ng/dl; p < 0.046). From Q1 to Q4, the crude 30-day and 694

6-month mortality rate decreased significantly from 11.4 to 3.8% (unadjusted hazard ratio [HR] 0.33; 95% CI: 0.11–1.01; p = 0.053) and from 23.5 to 12.4% (unadjusted HR: 0.49; 95% CI: 0.25–0.95; p = 0.07), respectively. After adjustment for baseline characteristics, there were no significant differences between Q1 and Q4 in 30-day mortality rate (adjusted HR ratio: 0.29; 95% CI: 0.08–1.08; p = 0.07) and 6-month mortality rate (HR: 0.67; 95% CI: 0.25–1.77; p = 0.42). The results of this study demonstrate an important paradigm shift toward the selection of lower surgical risk patients for TAVR. This study demonstrated that significantly better clinical outcomes can be expected in lower than in higher surgical risk patients undergoing TAVR. Available results from registries

The clinical results of tree retrospective series are currently available and represent the main source of evidence to support TAVR in intermediate-risk AS population. The retrospective study of 389 consecutive patients undergoing TAVR at the Swiss Cardiovascular Center (Bern, Switzerland) to compare the clinical outcomes among patients with estimated low or intermediate surgical risk was performed between August 2007 and October 2011 [14]. Patients were categorized according to the STS score into low (STS, 3%; n = 41, 10.5%), intermediate (STS ‡3% and £8%; n = 254, 65.3%) and high-risk (STS >8%; n = 94, 24.2%) groups for the purpose of this study. Significant differences were found between the groups (low risk vs intermediate risk vs high risk) for age (78.2 + 6.7 vs 82.7 + 5.7 vs 83.7 + 4.9; p < 0.001), BMI (28.1 + 6.1 vs 26.5 + 4.9 vs 24.4 + 4.6; p < 0.001), chronic renal failure (34 vs 67 vs 90%; p < 0.001), all-cause mortality at 30 days (2.4 vs 3.9 vs 14.9%; p = 0.001) and all-cause mortality at 1 year (10.1 vs 16.1 vs 34.5%; p = 0.0003) (FIGURE 1). No differences were observed with regards to cerebrovascular accidents and myocardial infarction

Expert Rev. Cardiovasc. Ther. 12(6), (2014)

Expanding indications for TAVR


Cumulative incidence (%)

Expert Review of Cardiovascular Therapy 2014.12:693-702. Downloaded from by Emory University on 04/21/15. For personal use only.

Cumulative incidence (%)

during 1-year follow-up. The authors conA 20 HR (95% Cl): 1.12 (0.58–2.15); p = 0.74 cluded that patients at intermediate/low risk selected by interdisciplinary ‘Heart Team’ appear to have favorable clinical outcomes 15 compared with patients at high-risk who underwent TAVR. With the aim to provide clinical data 10 on intermediate surgical risk undergoing TAVR or SAVR, a jointed experience of 5 three reference centers compared the 1-year mortality outcomes between TAVR and SAVR based on the propen0 sity score matching among intermediate0 5 10 15 20 25 30 risk surgical patients [15]. Propensity score Days after procedure matched pairs of TAVR and SAVR Number at risk patients with STS scores between 3 and TAVI 255 248 246 242 239 237 233 8% made up the study population. 250 248 244 243 241 237 SAVR 255 Between November 2006 and January 2010, 3666 consecutive patients underB 20 HR (95% Cl): 0.90 (0.57–1.42); p = 0.64 went either TAVR (n = 782) or SAVR (n = 2,884). Four hundred and five TAVR patients were matched to 405 SAVR 15 patients. Of matched TAVR patients, 99 (24%) patients had STS scores 8%. Among patients with STS scores between 3 and 8%, 20 (7.8%) versus 18 (7.1%) patients 5 had died up to 30 days (HR: 1.12, 95% CI: 0.58–2.15; p = 0.74) and 42 (16.5%) vs 43 (16.9%) patients had died up to 0 1 year (HR: 0.90, 95% CI: 0.57–1.42; 1 2 3 4 5 6 7 8 9 10 11 12 0 p = 0.64) after TAVR and SAVR, respecMonths after procedure tively (FIGURE 2). Effects of treatment on Number at risk 1-year mortality were similar across all TAVI 255 233 215 206 203 199 186 171 161 157 153 149 143 subgroups except for sex, with some eviSAVR 255 237 223 216 211 205 200 199 194 191 189 188 183 dence for a beneficial effect of TAVR in TAVI SAVR women but not in men (test for interaction p = 0.024). The authors concluded Figure 2. Cumulative all-cause mortality in patients potentially eligible for that cumulative all-cause mortality at SURTAVI/PATNER IIA. (A) Cumulative incidence of all-cause 30-day mortality in TAVR 30 days and 1 year was similar among pro(black line) and SAVR (Blue line). No mortality difference noted at 30-days between the pensity score matched TAVR and SAVR 2 groups. (B) Cumulative incidence of all-cause 1-year mortality in TAVR (black line) and patients at intermediate surgical risk. SAVR (Blue line). No mortality difference noted at 1-year between the 2 groups. Ultimately, a single-center propensity TAVI: Transcatheter aortic valve implantation; TAVR: Transcatheter aortic valve replacement; SAVR: Surgical aortic valve replacement. score matched case–control study of 182 consecutive intermediate-risk patients who underwent TAVR via transfemoral route and 111 historical case– 6.4% and 8.1%, respectively, at 1 year (p = 0.80). At 1 year, the controls who underwent SAVR were compared [16]. Baseline clini- rate of cerebrovascular events was similar in the two groups (4.6 vs cal characteristics, in particular logistic EuroSCORE (23.2 ± 9.1%; p = 0.19). These results suggest that intermediate surgical 15.1 vs 24.4 ± 13.4) and STS score (4.6 ± 2.3 vs 4.6 ± 2.6), were risk AS patients undergoing transfemoral TAVR and SAVR have well matched between groups. Transfemoral TAVR was associated similar mortality rates during follow-up but with a different specwith more vascular complications (33.3 vs 0.9%; p < 0.001). On trum of periprocedural complications. Of interest, there was a the other hand, acute kidney injury was more frequent after SAVR lower incidence of periprocedural cerebrovascular events and acute (8.1 vs 26.1%; p < 0.001). The rates of all-cause mortality in both kidney injury with TAVR but at the expense of more major TAVR and SAVR groups were 1.8% at 30 days (p = 1.00) and vascular complications.



Maluenda & Dvir

Aortic protrusion

Aortic height

Internal diameter Outer diameter

Expert Review of Cardiovascular Therapy 2014.12:693-702. Downloaded from by Emory University on 04/21/15. For personal use only.

External diameter

Figure 3. Dimensions of stented bioprosthetic valves. The labeled valve size corresponds to the outer diameter. For valve-in-valve procedures, the internal diameter is more relevant.

In summary, the results of the three described retrospective series of intermediate-risk patients suggest that mortality at 1-year follow-up is apparently similar in comparable patients undergoing TAVR or SAVR, but with some differences in periprocedural outcomes. As expected, using VARC definitions, more vascular complications might occur in patients undergoing transfemoral TAVR. However, the rate of stroke at 30-day and 1-year follow-up did not appear to be higher in TAVR patients as one of the propensity score matched analysis suggest lower rate of cerebrovascular events in TAVR patients compared with SAVR patients [17]. Update on the ongoing RCT: SURTAVI & PARTNER II

Although the previously described registries provide meaningful evidence to support TAVR indication in moderate-risk AS population, only RCT enough powered to demonstrate noninferiority to SAVR will determine the true clinical role of TAVR in such population. Currently, two large ongoing RCT, SURTAVI and PARTNER IIA, attempted to provide this data. The multicenter SUrgical Replacement and Transcatheter Aortic Valve Implantation (SURTAVI) is a 1:1 randomized, noninferiority designed study that compares CoreValve against AVR across 75 centers in Europe, Canada and the USA [17]. Approximately 2500 patients will be enrolled based on STS mortality risk score of 4–10%. Inclusion echo criteria are similar to those used in the PARTNER trial. Randomization is stratified by the need for coronary revascularization, and key inclusion criteria include CAD and Syntax score £22, where concomitant PCI + TAVR or CABG + SAVR will be performed. The primary endpoint is all-cause mortality and major stroke at 24 months. The 23, 26, 29 and 31 mm CoreValve (Medtronic) sizes will be deployed via transfemoral, transaxillary and transaortic approaches. Thirty European centers and several Canadians and US centers have been already selected and are actively enrolling candidates. The PARTNER IIA trial is a randomized clinical trial intended to test noninferiority of TAVR with Sapien XT percutaneous prosthesis against standard AVR in intermediate-risk AS population randomized in a 1:1 fashion [18]. Inclusion 696

criteria contains the same echo criteria used in PARTNER I, severe, symptomatic calcific AS in intermediate-risk population, per-protocol definition STS score ‡4% or specific qualifying intermediate-risk criteria requiring formal petition to the ‘Heart Team’ (‘generally’ STS score ‡4% and £8%). Patients requiring myocardial revascularization will be substratified as follows to compare different revascularization strategies: TAVR + PCI vs SAVR + CABG, and less aggressive complete revascularization acceptable (both for TAVR and AVR). Transfemoral TAVR includes patients with vascular anatomy appropriate for lower profile Sapien XT + Novaflex system (Edwards Lifescience); and alternative access includes transapical and transaortic TAVR for nonsuitable patients for transfemoral access. Primary endpoint was defined as a nonhierarchical composite of all-cause mortality and disabling stroke. Based on PARTNER IA (high-risk) study results in SAVR control arm of death and stroke at 1-year rate of 28%, it estimated a sample size of 1744 patients (872 patients per arm). Finally, a study sample size of 2000 patients to account for lost to follow-up, withdrawals and other study contingencies was defined. The study has recently finished enrolment; therefore, 1-year followup results are expected by the end of 2014. In conclusion, evidence provided by large nonrandomized series coming from experienced centers currently suggest that the use of TAVR in intermediate-risk AS population might be similar to SAVR results in terms of efficacy. Nonetheless, some safety TAVR issues such as periprocedural stroke, paravalvular leak and prosthesis durability remain to be defined, in addition to the compelling amount of literature showing great surgical results of SAVR in octogenarians. Therefore, conclusive evidence is required to confirm this indication, which will be soon available from the results of the ongoing described RCTs. TAVR for failed bioprosthesis Rationality & basis for valve-in-valve for failed aortic bioprosthesis

The use of bioprosthetic valves to treat native valve failure is increasing due to the lower risk of thromboembolic events and the lack of need for long-term anticoagulation compared with mechanical prosthesis [19,20]. However, bioprosthetic valves have limited durability and most degenerate in 10–20 years, resulting in stenosis or regurgitation. Nevertheless, morbidity and mortality related to reoperative valve replacement are significantly higher than the first cardiac operation, not only because of the complexity of reoperation but also due to comorbidities and aging [21]. As a result, the use of THV to treat failed aortic bioprosthesis, a procedure named ‘Valve-in-Valve’ (VinV) appears to be an attractive alternative to reoperative cardiac surgery, particularly in high-risk patients [22,23]. Currently, two types of bioprostheses are available for SAVR stented and stentless bioprostheses [24]. Stented Bioprostheses are the most commonly used. They are usually constructed from bovine pericardium or whole porcine aortic valves attached to a frame comprising alloy or polymer materials. The frame is responsible for its unique fluoroscopic appearance, which is Expert Rev. Cardiovasc. Ther. 12(6), (2014)

THV experience from the Global VIV registry

A Post procedural gradients (mmHg)

attached to a basal ring. The manufacturer’s label size corresponds to the external diameter of the inflow portion that matches the annular measurements of the surgical sizing tools [25]. However, the inner diameter of the valve is the relevant measure for VinV procedures (FIGURE 3) [26]. On the other hand, stentless bioprostheses are also available, most commonly made from porcine or human aortic root tissue. Although stentless valves have more laminar flow and lower transvalvular gradients than stented valves, improved durability has not been demonstrated [27]. Sizing of stentless grafts is even less standardized, with the labeled size offering only a general guide for the surgeon at the time of implantation.

23-mm device in stented 23-mm device in stentless 26-mm device in stented 26-mm device in stentless


Edwards SAPIEN




0 14 B Post procedural gradients (mmHg)

Expert Review of Cardiovascular Therapy 2014.12:693-702. Downloaded from by Emory University on 04/21/15. For personal use only.

Expanding indications for TAVR











26-mm device in stented 26-mm device in stentless 29-mm device in stented 29-mm device in stentless


The results of the Global VinV registry, with a smaller series from the same registry 0 published in 2012 [23] have been recently 22 24 26 28 14 16 18 20 updated at the 2013 Transcatheter Valve Surgical valve internal diameter (mm) Therapies conference by Dvir et al. [28]. The overall reported series involved Figure 4. Postprocedural valves gradients. Analysis of high post-procedural gradients 459 procedures of which mechanisms of (mean gradients 20 mmHg) after valve-in-valve procedures, according to surgical biobioprosthetic failure consisted of stenosis prosthesis size: large (internal diameter ‡23 mm); intermediate (‡20 and

Expanding indications for transcatheter aortic valve replacement.

Transcatheter aortic valve replacement (TAVR) has emerged as an accepted indication for non-operable patients with severe symptomatic native aortic va...
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