You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


J Am Heart Assoc. 2018;7:e007147 DOI: [10.1161/JAHA.117.007147](10.1161/JAHA.117.007147).29754127

Initially restricted to high‐risk and inoperable patients with symptomatic severe aortic stenosis (AS), transcatheter aortic valve replacement (TAVR) is increasingly being offered to younger and lower‐risk patients with fewer comorbidities who are otherwise good operative candidates and until now would have undergone surgical aortic valve replacement (SAVR). This evolution in clinical practice is underpinned by robust evidence, but do the data support the universal use of TAVR in all patients with AS, or is there still a role for surgery? In this review, we will review the data of TAVR in operable patients, examine potential limitations of TAVR in younger patients, and highlight the areas in which more research is required.

Concepts of Risk Assessment {#jah33207-sec-0002}
===========================

First, it is imperative to recognize that the widely used risk classification scheme for patients undergoing TAVR (extreme, high, intermediate, or low risk) is an artificial construct, important for the conduct of clinical trials, but not necessarily applicable to everyday clinical practice. The commonly used risk scores (Society of Thoracic Surgeons \[STS\], EuroSCORE, and EuroSCORE II) are designed to assess the risk of surgery and not TAVR. Although dedicated TAVR risk scores have been proposed, including the US STS/American College of Cardiology Transcatheter Valve Therapies,[1](#jah33207-bib-0001){ref-type="ref"} these are not widely used in clinical practice. Surgical risk scores typically overestimate the risk of TAVR. Arbitrarily selected STS thresholds to define risk categories for the pivotal TAVR trials were modified over time and varied between trials. Furthermore, the SAVR patient population in the STS database has changed in recent years, with most high‐risk patients now undergoing TAVR. As a result, individual patients\' STS scores have fallen, meaning there is overlap between clinical trial risk‐defined patient populations.[2](#jah33207-bib-0002){ref-type="ref"} Second, "low‐risk" does not necessarily mean "young." For example, it is theoretically possible for a 90‐year‐old man with severe AS and hypertension, but no other comorbidity, to have an STS score \<3%, even though most Heart Teams would probably consider his surgical risk to be substantial. Although this example is extreme, it highlights that score‐based risk assessment is just 1 factor to consider when weighing the relative advantages and disadvantages of TAVR or SAVR. In this review, we will focus on those patients who are deemed "operable" by the multidisciplinary Heart Team, analogous to the low‐ and intermediate‐risk cohorts from the pivotal trials.

Clinical Trials in Operable Patients {#jah33207-sec-0003}
====================================

Figure [1](#jah33207-fig-0001){ref-type="fig"} illustrates the regulatory timeline of TAVR in the United States. TAVR has been proven to be an effective treatment for patients with symptomatic severe AS and high or extreme surgical risk.[3](#jah33207-bib-0003){ref-type="ref"}, [4](#jah33207-bib-0004){ref-type="ref"}, [5](#jah33207-bib-0005){ref-type="ref"} Observational studies in Europe were the first to suggest that TAVR is safe in low‐ and intermediate‐risk patients, with low rates of procedural complications and short‐term mortality,[6](#jah33207-bib-0006){ref-type="ref"}, [7](#jah33207-bib-0007){ref-type="ref"}, [8](#jah33207-bib-0008){ref-type="ref"}, [9](#jah33207-bib-0009){ref-type="ref"} although a recent meta‐analysis suggested increased intermediate‐term mortality with TAVR compared with SAVR (relative risk 1.45, 95% confidence interval, 1.11--1.89, *P*=0.006) with median follow‐up of 2 years.[10](#jah33207-bib-0010){ref-type="ref"} More robust data were provided by the NOTION (Nordic Aortic Valve Intervention Trial), which randomized primarily low‐risk patients to SAVR versus TAVR with the self‐expanding CoreValve THV (Medtronic, Minneapolis, MN).[11](#jah33207-bib-0011){ref-type="ref"} There were no differences between groups in 2‐year mortality or composite outcome of all‐cause mortality, stroke, or myocardial infarction (Tables [1](#jah33207-tbl-0001){ref-type="table"} and [2](#jah33207-tbl-0002){ref-type="table"}). TAVR patients required a more permanent pacemaker (PPM), but had lower life‐threatening bleeding, acute kidney injury, and new‐onset atrial fibrillation.

![Regulatory timeline of TAVR in the US. ESRD indicates end‐stage renal disease; EU, European Union; FDA,US Food and Drug Administration; TAVR, transcatheter aortic valve replacement.](JAH3-7-e007147-g001){#jah33207-fig-0001}

###### 

Summary of Key Findings From TAVR Cohorts of Clinical Trials in Low‐ and Intermediate‐Risk Patients

  Type of Transcatheter Heart Valve      PARTNER 2[12](#jah33207-bib-0012){ref-type="ref"}   SURTAVI[14](#jah33207-bib-0014){ref-type="ref"}   NOTION[11](#jah33207-bib-0011){ref-type="ref"}   SAPIEN 3 IR[13](#jah33207-bib-0013){ref-type="ref"}
  -------------------------------------- --------------------------------------------------- ------------------------------------------------- ------------------------------------------------ -----------------------------------------------------
  Time to end point                      30 d                                                30 d                                              30 d                                             30 d
  All‐cause mortality                    3.9%                                                2.2%                                              2.1%                                             1.1%
  Disabling stroke                       3.2%                                                1.2%                                              1.4%                                             1.0%
  Paravalvular leak (≥ moderate)         3.7%                                                3.5%[a](#jah33207-note-0002){ref-type="fn"}       15.3%[b](#jah33207-note-0003){ref-type="fn"}     3.8%
  Major vascular complications           7.9%                                                6.0%                                              5.6%[a](#jah33207-note-0002){ref-type="fn"}      6.1%
  Major and life‐threatening bleeding    10.4%                                               12.2%                                             11.3%[a](#jah33207-note-0002){ref-type="fn"}     4.6%
  Acute kidney injury (stage 2 or 3)     1.3%                                                1.7%                                              0.7%[a](#jah33207-note-0002){ref-type="fn"}      0.5%
  New permanent pacemaker implantation   8.5%                                                25.9%                                             34.1%                                            10.2%
  Time to end point                      2 y                                                 2 y                                               2 y                                              1 y
  All‐cause mortality                    16.7%                                               11.4%                                             8.0%                                             7.4%
  Disabling stroke                       6.2%                                                2.6%                                              3.6%                                             2.3%
  Paravalvular leak (≥ moderate)         5.5%                                                5.7%                                              15.7%                                            1.5%
  New permanent pacemaker implantation   11.8%                                               25.6%                                             41.3%                                            12.4%

NOTION indicates Nordic Aortic Valve Intervention Trial; PARTNER 2, Placement of Aortic Transcatheter Valves; SURTAVI, Surgical Replacement and Transcatheter Aortic Valve Implantation; TAVR, transcatheter aortic valve replacement.

End point at hospital discharge.

End point at 3 months.

John Wiley & Sons, Ltd

###### 

Comparison of 30‐Day Outcomes With TAVR Versus SAVR in Clinical Trials of Low‐ and Intermediate‐Risk Patients

                                                        PPM Implantation                               Stroke                                        Moderate or Severe PVL                        New Atrial Fibrillation                                                                                                                                                                   
  ----------------------------------------------------- ---------------------------------------------- --------------------------------------------- --------------------------------------------- --------------------------------------------- ---------------------------------------------- --------------------------------------------- ---------------------------------------------- ----------------------------------------------
  PARTNER 2[12](#jah33207-bib-0012){ref-type="ref"}     8.5%                                           6.9%                                          3.2%                                          4.3%                                          3.7%[a](#jah33207-note-0005){ref-type="fn"}    0.6%[a](#jah33207-note-0005){ref-type="fn"}   9.1%[a](#jah33207-note-0005){ref-type="fn"}    26.4%[a](#jah33207-note-0005){ref-type="fn"}
  SURTAVI[14](#jah33207-bib-0014){ref-type="ref"}       25.9%[a](#jah33207-note-0005){ref-type="fn"}   6.6%[a](#jah33207-note-0005){ref-type="fn"}   1.2%                                          2.5%                                          3.5%[a](#jah33207-note-0005){ref-type="fn"}    0.7%[a](#jah33207-note-0005){ref-type="fn"}   12.9%[a](#jah33207-note-0005){ref-type="fn"}   43.4[a](#jah33207-note-0005){ref-type="fn"}
  NOTION[11](#jah33207-bib-0011){ref-type="ref"}        34.1%[a](#jah33207-note-0005){ref-type="fn"}   1.6%[a](#jah33207-note-0005){ref-type="fn"}   1.4%                                          3.0%                                          15.3%[a](#jah33207-note-0005){ref-type="fn"}   1.8%[a](#jah33207-note-0005){ref-type="fn"}   16.9%[a](#jah33207-note-0005){ref-type="fn"}   57.8%[a](#jah33207-note-0005){ref-type="fn"}
  SAPIEN 3 IR[13](#jah33207-bib-0013){ref-type="ref"}   10.2%                                          7.3%                                          1.0%[a](#jah33207-note-0005){ref-type="fn"}   4.4%[a](#jah33207-note-0005){ref-type="fn"}   3.8%[a](#jah33207-note-0005){ref-type="fn"}    0.6%[a](#jah33207-note-0005){ref-type="fn"}   3.2%[a](#jah33207-note-0005){ref-type="fn"}    28.5%[a](#jah33207-note-0005){ref-type="fn"}

NOTION indicates Nordic Aortic Valve Intervention Trial; PARTNER 2, Placement of Aortic Transcatheter Valves; PPM, permanent pacemaker; PVL, paravalvular leakage; SAVR, surgical aortic valve replacement; SURTAVI, Surgical Replacement and Transcatheter Aortic Valve Implantation; TAVR, transcatheter aortic valve replacement.

Statistically significant difference.

John Wiley & Sons, Ltd

Results from the first pivotal randomized clinical trial of TAVR in intermediate‐risk patients using the balloon‐expandable Sapien XT transcatheter heart valve (THV) (Edwards Lifesciences, Irvine, CA) were published in 2016.[12](#jah33207-bib-0012){ref-type="ref"} TAVR was noninferior to surgery with regard to death and disabling stroke, but there was a higher rate of moderate/severe paravalvular leakage (PVL) with TAVR versus SAVR. Similar to NOTION, TAVR was associated with lower rates of severe kidney injury, severe bleeding, and new‐onset atrial fibrillation. Use of the newer‐generation Sapien 3 THV in intermediate‐risk patients may be associated with even better results. Data from the registry arm of the PARTNER 2 (Placement of Aortic Transcatheter Valves) study comparing TAVR with the Sapien 3 THV with a propensity‐matched surgical cohort demonstrated both noninferiority and superiority of TAVR versus SAVR for the composite outcome of death, stroke, and moderate/severe aortic regurgitation, with overall low complication rates using this newer THV (Table [1](#jah33207-tbl-0001){ref-type="table"}).[13](#jah33207-bib-0013){ref-type="ref"} Comparable findings were revealed in the SURTAVI (Surgical Replacement and Transcatheter Aortic Valve Implantation) trial using the self‐expanding CoreValve or Evolut R THV in intermediate‐risk patients.[14](#jah33207-bib-0014){ref-type="ref"} At 2 years, there was no difference in the composite outcome of all‐cause death or disabling stroke. As with the balloon‐expandable valves, the PPM implantation rate was higher with TAVR, but new‐onset atrial fibrillation, significant bleeding, and acute kidney injury rates were lower (Table [1](#jah33207-tbl-0001){ref-type="table"}).

In addition, it is important to appreciate that most subjects were elderly in the clinical trials of intermediate‐risk patients, with mean age 79 to 82 years. Therefore, the results cannot necessarily be extrapolated to younger patients.

Potential Limitations of TAVR in Operable Patients {#jah33207-sec-0004}
==================================================

Because TAVR was initially reserved for extreme‐ and high‐risk patients with advanced age and multiple comorbidities, very few patients lived long enough to test the lifespan of their bioprosthetic THV. So far, 5‐year THV hemodynamic data appear comparable to surgical bioprostheses with no evidence of increased early structural valve deterioration.[15](#jah33207-bib-0015){ref-type="ref"}, [16](#jah33207-bib-0016){ref-type="ref"}, [17](#jah33207-bib-0017){ref-type="ref"} Nonetheless, long‐term THV durability remains unknown, which tempers widespread adoption of TAVR in younger patients. Mechanisms to explain the recent observation that THV appear more susceptible to subclinical leaflet thrombosis compared with surgical bioprostheses are still unclear.[18](#jah33207-bib-0018){ref-type="ref"}, [19](#jah33207-bib-0019){ref-type="ref"} The first comprehensive data on durability will likely come from long‐term follow‐up of patients from the intermediate‐risk PARTNER 2 and SURTAVI trials. Additionally, the randomized US clinical trials in low‐risk patients will follow subjects for 10 years with yearly echocardiography to assess for structural valve deterioration, and all include a subgroup of patients undergoing 4‐dimensional contrast‐enhanced cardiac computed tomography to assess for leaflet thrombosis and restricted leaflet motion. In the meantime, as more patients undergo TAVR, THV failure will become more common. TAVR‐in‐TAVR has been shown to be safe, with comparable short‐ and midterm clinical and hemodynamic outcomes to valve‐in‐valve TAVR for failed surgical bioprostheses.[20](#jah33207-bib-0020){ref-type="ref"}, [21](#jah33207-bib-0021){ref-type="ref"}

Over the past decade, the morbidity associated with the first‐generation TAVR valves has dramatically improved. The increased risk of periprocedural stroke with TAVR compared with SAVR was a concern in high‐risk patients. However, with device and procedural improvements, the rate of disabling stroke was consistently lower with TAVR versus SAVR in intermediate‐risk patients (Table [2](#jah33207-tbl-0002){ref-type="table"}). Additionally, the rate of new‐onset atrial fibrillation was significantly lower with TAVR versus SAVR in all of the clinical trials (Table [2](#jah33207-tbl-0002){ref-type="table"}). In the TAVR cohort of the NOTION study using the first‐generation CoreValve self‐expanding THV, the rate of clinically relevant PVL at 30 days, defined as moderate or severe by echocardiography, was 15.3%. The PARTNER 2 and SAPIEN 3 IR studies using balloon‐expandable THV (Edwards Sapien XT or Sapien 3) demonstrated much lower rates of significant PVL under 4%, as did the SURTAVI trial using self‐expanding THV (CoreValve or Evolut R) (Table [1](#jah33207-tbl-0001){ref-type="table"}). The Sapien 3 valve features a sealing skirt, and the latest‐generation CoreValve Evolut PRO also incorporates a pericardial tissue wrap specifically designed to reduce PVL. However, the need for new PPM implantation remains the Achilles' heel of TAVR, with 30‐day PPM rates of ≈10% for balloon‐expandable THV[13](#jah33207-bib-0013){ref-type="ref"} and ≈25% for self‐expanding THV[14](#jah33207-bib-0014){ref-type="ref"} (Table [1](#jah33207-tbl-0001){ref-type="table"}). In the SURTAVI trial, there was no difference in PPM rate between the CoreValve and Evolut R THV (25.5% versus 26.7%, respectively), although only 16% of patients in the study received the newer Evolut R THV. This compares with PPM implantation rates after SAVR of 1.6% to 7.3% in these same studies. Strategies for high implantation, accurate computed tomography--based sizing, and newer TAVR devices may reduce the rates of PPM implantation in the future. The long‐term consequences of the need for a PPM following either TAVR or SAVR are unknown.

Do Clinical Trials of TAVR in Low‐Risk Patients Herald the End of Isolated SAVR? {#jah33207-sec-0005}
================================================================================

So long as TAVR was restricted for use only in high‐ and extreme‐risk patients, there remained a clear role for surgery for the many more patients with symptomatic severe AS who were operable. However, data from PARTNER 2 and SURTAVI have convincingly demonstrated that TAVR is noninferior to SAVR in intermediate‐risk patients and, if performed via transfemoral access, is associated with improved early health status improvements compared with SAVR.[22](#jah33207-bib-0022){ref-type="ref"} Thus, in 2018, it is reasonable to favor TAVR in all operable patients with symptomatic severe AS and increased surgical risk.

Table [3](#jah33207-tbl-0003){ref-type="table"} summarizes the study design of currently enrolling randomized clinical trials of TAVR in low‐risk patients.[23](#jah33207-bib-0023){ref-type="ref"}, [24](#jah33207-bib-0024){ref-type="ref"}, [25](#jah33207-bib-0025){ref-type="ref"}, [26](#jah33207-bib-0026){ref-type="ref"} The first results from these studies are expected in 2018. Assuming these results demonstrate noninferiority of TAVR versus SAVR, in the future it will likely be reasonable to consider TAVR in all patients with symptomatic severe AS, regardless of operative risk (Figure [2](#jah33207-fig-0002){ref-type="fig"}). If this is the case, then we wholeheartedly support continued Heart Team collaboration between interventional cardiologists and cardiothoracic surgeons, although the requirement for 2 surgeons to evaluate each patient for operative risk before TAVR would become obsolete. Availability of TAVR for all, regardless of operative risk, would also allow more opportunity for patient preference to direct decision‐making. Indeed, many low‐risk patients may prefer TAVR over SAVR for personal reasons that current guidelines and indications cannot encompass.

###### 

Ongoing Clinical Trials in Low‐Risk Patients

  ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  Name                                                                          Unique Identifier   Population            Study Design                                         Primary End Point                                                                THV in TAVR Arm                       Sample Size
  ----------------------------------------------------------------------------- ------------------- --------------------- ---------------------------------------------------- -------------------------------------------------------------------------------- ------------------------------------- --------------------------------
  LRT[23](#jah33207-bib-0023){ref-type="ref"}                                   NCT02628899         No age restriction\   Feasibility study\                                   All‐cause mortality at 30 d                                                      Transfemoral\                         200 TAVR in main arm\
                                                                                                    STS ≤3%               Prospective TAVR arm with historical SAVR controls                                                                                    SAPIEN 3 or Evolut R/PRO              Up to 100 TAVR in bicuspid arm

  PARTNER 3[24](#jah33207-bib-0024){ref-type="ref"}                             NCT02675114         Age ≥65 y\            Noninferiority\                                      All‐cause mortality, all stroke, and rehospitalization at 1 y                    Transfemoral\                         614 TAVR\
                                                                                                    STS \<4%              Randomized TAVR vs SAVR                                                                                                               SAPIEN 3                              614 SAVR

  Medtronic TAVR in low risk patients[25](#jah33207-bib-0025){ref-type="ref"}   NCT02701283         No age restriction\   Noninferiority\                                      All‐cause mortality or disabling stroke at 2 y                                   Transfemoral or subclavian Evolut R   625 TAVR\
                                                                                                    STS \<3%              Randomized TAVR vs SAVR                                                                                                                                                     625 SAVR

  NOTION 2[26](#jah33207-bib-0026){ref-type="ref"}                              NCT02825134         Age 18 to 75 y\       Noninferiority\                                      Composite rate of all‐cause mortality, myocardial infarction and stroke at 1 y   Transfemoral\                         496 TAVR\
                                                                                                    STS \<4%              Randomized TAVR vs SAVR                                                                                                               Any CE‐approved THV                   496 SAVR
  ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

CE indicates Conformité Européene; NOTION, Nordic Aortic Valve Intervention Trial; PARTNER 2, Placement of Aortic Transcatheter Valves; SAVR, surgical aortic valve replacement; STS, Society of Thoracic Surgeons; TAVR, transcatheter aortic valve replacement; THV, transcatheter heart valve.

John Wiley & Sons, Ltd

![Evolution of the treatment algorithm for patients with aortic stenosis in the United States. SAVR indicates surgical aortic valve replacement; TAVR, transcatheter aortic valve replacement.](JAH3-7-e007147-g002){#jah33207-fig-0002}

However, risk assessment is but 1 element of the decision‐making process. Special circumstances may still favor SAVR, namely, patient life expectancy, patients\' preference for a mechanical valve, aortic valve and root anatomy, available vascular access, and comorbidities (Table [4](#jah33207-tbl-0004){ref-type="table"}).

###### 

Indications for SAVR in Operable Patients

  Indications
  -------------------------------------------------------------------
  1\. Young patient requiring a mechanical valve
  2\. Bicuspid aortic stenosis with dilation of the ascending aorta
  3\. Very large aortic annulus
  4\. Patients ineligible for transfemoral access
  5\. Aortic stenosis with multivessel coronary artery disease

SAVR indicates surgical aortic valve replacement.

John Wiley & Sons, Ltd

Young Patients Requiring a Mechanical Valve {#jah33207-sec-0006}
-------------------------------------------

The 2017 American College of Cardiology/American Heart Association focused guideline update on the management of patients with valvular heart disease lowered the age cutoff above which a bioprosthetic valve is reasonable to 50 years with a Class IIa recommendation.[27](#jah33207-bib-0027){ref-type="ref"} In patients under the age of 50 years, the guideline still recommends a mechanical valve unless the patient has a clear contraindication to anticoagulation. There is nonetheless a trend toward increased use of bioprosthetic surgical valves even in patients under the age of 50 years,[28](#jah33207-bib-0028){ref-type="ref"} often driven by patient preference and desire to avoid long‐term anticoagulation. Availability of newer mechanical valves that can safely be maintained with lower‐dose warfarin (target INR 1.5--2.0) and low‐dose aspirin[29](#jah33207-bib-0029){ref-type="ref"} may convince more patients to select a mechanical prosthesis. Conversely, patients and physicians may feel more comfortable selecting a bioprosthesis because valve‐in‐valve TAVR is now an option if a surgical bioprosthesis fails in the future.[21](#jah33207-bib-0021){ref-type="ref"} Irrespective of whether a mechanical valve or bioprosthesis is selected, aortic root enlargement surgery should be considered in patients with a small aortic annulus to prevent patient--prosthesis mismatch and facilitate TAVR valve‐in‐valve for the future.

Bicuspid Aortic Stenosis {#jah33207-sec-0007}
------------------------

The prevalence of a bicuspid aortic valve in the general population is 1% to 2%, with a 2:1 male‐to‐female ratio.[30](#jah33207-bib-0030){ref-type="ref"}, [31](#jah33207-bib-0031){ref-type="ref"} The specific genetic locus and protein abnormality in patients with a bicuspid aortic valve have not yet been identified; however, the tissue abnormality is not confined to the valve leaflets and these patients are at increased risk of aortic aneurysm and dissection. Although most cases of bicuspid aortic valve are sporadic, familial clusters have been identified. The high incidence of familial clustering is suggestive of autosomal‐dominant inheritance with reduced penetrance.[32](#jah33207-bib-0032){ref-type="ref"}

Nearly all patients with a bicuspid aortic valve will require valve surgery during their lifetime. A study of excised aortic valves revealed bicuspid morphology in 62% of patients aged 50 to 70 years undergoing isolated SAVR before the advent of TAVR.[33](#jah33207-bib-0033){ref-type="ref"} Bicuspid aortic valves are more prone to calcific degeneration leading to stenosis at a young age, and therefore, patients with bicuspid AS are likely to fall into low‐ and intermediate‐risk categories. Computed tomography analysis of aortic annulus and valve morphology demonstrates more eccentric annular calcification in bicuspid versus tricuspid valves (68% versus 32%).[34](#jah33207-bib-0034){ref-type="ref"} Consequently, TAVR could theoretically be associated with increased risk in patients with bicuspid versus tricuspid valves. First, the rate of moderate or severe PVL could be higher. Observational studies have reported PVL rates in bicuspid valves to range from 9.6% to 28.4%.[35](#jah33207-bib-0035){ref-type="ref"}, [36](#jah33207-bib-0036){ref-type="ref"} However, careful valve sizing using cardiac computed tomography angiography can reduce the incidence of PVL substantially.[36](#jah33207-bib-0036){ref-type="ref"} Use of newer‐generation valves that incorporate features to reduce PVL may be particularly advantageous in the setting of bicuspid AS. Second, the rate of valve embolization could be higher, although the same observational studies suggest that embolization with conversion to open chest surgery occurs rarely in bicuspid AS (2.2--4.0%).[36](#jah33207-bib-0036){ref-type="ref"}, [37](#jah33207-bib-0037){ref-type="ref"} Third, the rate of prosthesis--patient mismatch could be higher because the abnormal aortic valve morphology could prevent full expansion of the transcatheter valve.[38](#jah33207-bib-0038){ref-type="ref"} Fourth, the rate of PPM implantation could be higher, although a German TAVR registry analysis actually reported lower rates in patients with bicuspid versus tricuspid valves (17% versus 35%).[39](#jah33207-bib-0039){ref-type="ref"}

All of the pivotal randomized clinical trials comparing TAVR and SAVR excluded patients with bicuspid aortic valves. However, observational studies suggest that TAVR may be safe and effective in this setting. A multicenter registry of 108 patients reported 30‐day and 1‐year mortality rates of 8.3% and 16.9%, respectively.[35](#jah33207-bib-0035){ref-type="ref"} An analysis of 139 low‐ and intermediate‐risk patients (mean STS score 4.9±3.4%) in 12 European centers corroborated these findings with 1‐year mortality of 17.5%.[36](#jah33207-bib-0036){ref-type="ref"} Another multicenter observational study comparing TAVR in patients with bicuspid versus tricuspid aortic valves did not demonstrate any difference in 30‐day mortality.[40](#jah33207-bib-0040){ref-type="ref"} A comparison of outcomes in high‐risk patients with bicuspid versus tricuspid aortic valves from the German national TAVR registry also demonstrated no difference in 1‐year mortality.[39](#jah33207-bib-0039){ref-type="ref"} A recent multicenter observational study of 51 patients in Canada and Europe with bicuspid aortic valve undergoing TAVR with the latest‐generation Edwards Sapien 3 valve reported promising results with low 30‐day mortality (3.9%) and no clinically significant PVL. These results suggest that the latest‐generation balloon‐expandable THV may achieve superior hemodynamic results compared with earlier‐generation devices. However, the rate of new PPM implantation was high at 23.5%.[41](#jah33207-bib-0041){ref-type="ref"} Further data on the safety and feasibility of TAVR in low‐risk patients with bicuspid AS will be provided by the LRT (Low Risk TAVR) study, which includes a separate bicuspid registry arm.[23](#jah33207-bib-0023){ref-type="ref"}

Regardless of these promising results, up to 80% of adult patients with bicuspid AS have concomitant dilation of the ascending aorta, and half of these patients meet criteria for surgical repair.[42](#jah33207-bib-0042){ref-type="ref"}, [43](#jah33207-bib-0043){ref-type="ref"} According to current guidelines, patients with ascending aorta diameter ≥4.5 cm should undergo surgical repair at the time of aortic valve replacement for bicuspid aortic valve pathology,[44](#jah33207-bib-0044){ref-type="ref"} and therefore TAVR is probably inappropriate. However, in patients with ascending aorta \<4.5 cm in diameter, the best strategy is to review historical imaging of the aorta to assess the rate of dilation. Rapid progression may push toward SAVR and ascending aortic repair, whereas slowing or absence of progression over preceding years may reassure that TAVR is a reasonable strategy.

Very Large Aortic Annulus {#jah33207-sec-0008}
-------------------------

Commercially available THV are indicated for aortic annuli measuring up to ≈30 mm in diameter (maximum area 683 mm^2^ for the 29‐mm Sapien 3; maximum perimeter 94.2 mm for the 34 mm Evolut R). Case reports and a small series support the safety and feasibility of overexpansion of the 29‐mm Sapien 3 THV up to a maximum annulus area of 800 mm^2^, which roughly corresponds to an annulus diameter of 32 mm.[45](#jah33207-bib-0045){ref-type="ref"}, [46](#jah33207-bib-0046){ref-type="ref"} However, the effect of overexpansion on THV leaflet function and long‐term durability is not known. The data for CoreValve THV in large annuli are less favorable with high rates of implantation of a second valve.[47](#jah33207-bib-0047){ref-type="ref"} Therefore, at present, SAVR should still be considered in patients with a very large annulus.

Patients Ineligible for Transfemoral Access {#jah33207-sec-0009}
-------------------------------------------

In the PARTNER 1 study in high‐risk patients, transthoracic access was an independent predictor of 2‐year all‐cause mortality with hazard ratio 1.52 (95% confidence interval, 1.12--2.07), *P*=0.008.[48](#jah33207-bib-0048){ref-type="ref"} Similar findings were observed in the PARTNER 2 study in intermediate‐risk patients, with hazard ratio 1.55 (95% confidence interval, 1.23--1.96), *P*\<0.001.[12](#jah33207-bib-0012){ref-type="ref"} A much smaller prospective randomized trial of transapical TAVR versus SAVR in operable patients (the STACCATO trial) was stopped early because of a higher complication rate in the transapical TAVR arm, specifically death and stroke.[49](#jah33207-bib-0049){ref-type="ref"} Furthermore, health status improvements using the Kansas City Cardiomyopathy Questionnaire at 30 days in the PARTNER 2 study were greater with TAVR compared with SAVR, but only in patients who underwent transfemoral TAVR.[22](#jah33207-bib-0022){ref-type="ref"} Those who underwent transthoracic TAVR (transapical or transaortic) did not show any early health status improvement benefit over surgery. Transfemoral TAVR has been shown to be more cost effective than transthoracic TAVR in high‐risk patients[50](#jah33207-bib-0050){ref-type="ref"} and was recently demonstrated to be more cost effective than SAVR in intermediate‐risk patients (Cohen DJ, Meeting Presentation, Transcatheter Cardiovascular Therapeutics, 2017). Combined, these data suggest that there is likely to be little benefit of TAVR over SAVR in operable patients who are ineligible for transfemoral access because of small or diseased iliofemoral arteries. However, newer options for percutaneous or surgical minimally invasive alternate access, such as transcaval,[51](#jah33207-bib-0051){ref-type="ref"} subclavian,[52](#jah33207-bib-0052){ref-type="ref"} transaxillary,[53](#jah33207-bib-0053){ref-type="ref"} or carotid,[54](#jah33207-bib-0054){ref-type="ref"} have been shown to be safe and appear to avoid the morbidity of transthoracic access, although none have been compared with transthoracic access in a randomized trial. Some can be performed with patients under conscious sedation, allowing rapid ambulation after TAVR and shorter hospital length of stay. Further studies are needed to determine whether TAVR via these newer alternate access approaches confers benefit over SAVR in operable patients. Indeed, all of the ongoing clinical trials in low‐risk patients (Table [3](#jah33207-tbl-0003){ref-type="table"}) mandate transfemoral access exclusively and therefore will not provide any new information on alternate access in low‐risk patients.

Multivessel Coronary Artery Disease {#jah33207-sec-0010}
-----------------------------------

Patients with unrevascularized multivessel coronary artery disease were excluded from all of the pivotal TAVR trials, including from ongoing trials in low‐risk patients. The Interventional Section Leadership Council of the American College of Cardiology recommends that patients undergo limited percutaneous coronary intervention (PCI) to proximal coronary stenoses before TAVR[55](#jah33207-bib-0055){ref-type="ref"} even though this indication is not consistent with current PCI guidelines. It is important to recognize that this recommendation is based on expert consensus in the absence of randomized clinical trial data. However, a number of studies are under way to address this paucity of data. The ACTIVATION (percutaneous coronary intervention prior to transcatheter aortic valve implantation) study is a randomized trial of PCI versus no PCI before TAVR.[56](#jah33207-bib-0056){ref-type="ref"} The FAITAVI (Functional assessment in TAVI) study, a randomized trial of fractional flow reserve versus angiography‐guided PCI before TAVR, aims to explore the role of invasive physiological assessment of coronary stenoses to guide revascularization in patients with AS.[57](#jah33207-bib-0057){ref-type="ref"}

Conclusions {#jah33207-sec-0011}
===========

In summary, the use of TAVR in intermediate‐risk patients with both balloon‐expandable and self‐expanding THV is supported by robust data from multiple randomized clinical trials. Comparable data in low‐risk patients are not yet available because the pivotal trials are ongoing. Nonetheless, the balance of evidence in operable patients is certainly leaning toward the use of TAVR as the preferred strategy for most patients with symptomatic severe AS. Choice of strategy should continue to be personalized based on individual patient demographics, aortic valve and root anatomy, available vascular access, and relevant comorbidities.

Disclosures {#jah33207-sec-0012}
===========

Rogers reports consulting for Medtronic. Thourani reports consulting for Abbott Vascular, Boston Scientific, Claret Medical, Edwards Lifesciences, JenaValve, and Gore Medical. Waksman reports consulting for Abbott Vascular, Biosensors International, Biotronik, Boston Scientific, Medtronic Vascular, Symetis, Lifetech; Speakers Bureau: AstraZeneca, Boston Scientific, Biotronik, Abbott Vascular; grant support from Biosensors International, Biotronik, Boston Scientific, Edwards Lifesciences, and Abbott Vascular.